Primary Outcomes

Description: Weight will be obtained using the same scale over the study period that is accessible to people with and without a mobility device (e.g. walker; wheelchair)

Measure: Change in weight

Time: Baseline, 3 months, 6, months, 12 months, and 18 months

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Secondary Outcomes

Description: The Garmin Vivofit will be worn for the study duration to measure physical activity data.

Measure: Step Count

Time: 3 months, 6 months, 12 months, and 18 months

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Description: Waist circumference will be measured at the umbilicus and mild-upper arm circumference following American College of Sports Medicine guidelines.

Measure: Waist and Arm Circumference

Time: Baseline, 3 months, 6 months, 12 months, and 18 months

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Description: Using an automatic cuff (average of three readings, patient seated) diastolic and systolic scores will be recorded.

Measure: Blood Pressure

Time: Baseline, 3 months, 6 months, 12 months, and 18 months

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Description: Fasting venous sample will be obtained for blood glucose, HDL/LDL, cholesterol, and triglyceride level.

Measure: HbA1c and Lipid Panel

Time: Baseline, 3 months, 6 months, 12 months, and 18 months

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Description: The Framingham Heart Study diabetes risk score will be calculated using predictors including age, gender, fasting glucose, body mass index, HDL cholesterol and triglyceride levels, blood pressure, and parental history. Risk score calculator and regression model are free and used in GLB weight-loss trials. Each risk predictor is assigned points ranging from. Risk factors are combined and a total score is calculated, with higher scores designating greater 8-year risk.. The age range for this score is 45 years or older, and therefore only individuals over this age will have calculated scores. Furthermore, the minimum cut-off score is 3.

Measure: Risk of Diabetes

Time: Baseline, 3 months, 6 months, 12 months, and 18 months

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Description: Satisfaction with life will be measured using the Satisfaction with Life Scale (SWLS). The SWLS is a 5-item scale designed to measure global cognitive judgements of one's life satisfaction. Participants indicate how much they agree or disagree with each of the 5 items using a 7-point scale that ranges from 7-strongly agree to 1-strongly disagree. Scores are added together and a total score is calculated, with higher scores signifying higher satisfaction with life and lower scores signifying lower satisfaction with life.

Measure: Satisfaction with Life

Time: Baseline, 3 months, 6 months, 12 months, and 18 months

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Description: TSH, Cortisol, IL-6, THNF, BDNF, IGF, and VEGF will be collected.

Measure: Biomarkers

Time: Baseline, 3 months, 6 months, 12 months, and 18 months

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Description: Assesses walking speed in (m/s) which is correlated to mobility in the community, capacity to perform ADLs, risk of falls, re-hospitalization, and risk of cognitive decline.

Measure: 10 Meter Walk Test (10MWT)

Time: Baseline, 3 months, 6 months, and 12 months

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Description: Assesses distance walked (rolled for wheelchair users) over 6 minutes as a sub-maximal test of aerobic capacity.

Measure: 6 Minute Walk Test (6MWT)

Time: Baseline, 3 months, 6 months, and 12 months

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Description: Social Support for Diet and Exercise Behaviors Scale is a 23-item survey including four subscales: support for healthy eating (5 items); support for physical activity (11 items); social undermining for healthy eating (5 items) and physical activity (2 items). Each item is rated on a scale of 1 to 5 (1 none; 5 very often), with respondents asked to rate support from family, friends, and coworkers. Higher scores represent greater support and internal consistency ranged from Cronbach's α 0.72-0.76.

Measure: Social Support assessed by the Social Support for Diet and Exercise Behaviors Scale

Time: Baseline, 3 months, 6 months, 12 months, and 18 months

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Description: The Feasibility and Usability survey includes 14 items that assesses the participant's subjective experience with the App, level of difficulty, prompting sequence, length, and understanding. Scores above 3 on the scale (1 [totally disagree] - 5 [totally agree]) indicate that the App was easy to use.

Measure: App Feasibility and Usability using the Feasibility and Usability Survey

Time: 6 months, 12 months, and 18 months

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Description: NEWS assesses residents' perception of neighborhood design features, categorized into subscales related to physical activity, including residential density, land use mix (including both indices of proximity and accessibility), street connectivity, infrastructure for walking/cycling, neighborhood aesthetics, traffic and crime safety, and neighborhood satisfaction. Subscales are scored as a mean of items. Higher scores denote higher walkability.

Measure: Neighborhood Walkability assessed by the Neighborhood Environment Walkability Scale (NEWS)

Time: Baseline and 12 months

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Description: Measure includes 28 items that assess health practices among people with disabilities and yields a total Health Practices score plus 4 subscales scores regarding Exercise, Nutrition, Health Practices, and Psychological Well Being. Items are rated on a 5-point scale from 0 'not at all' to 4 'completely.' Scores range from 0-28 with higher scores indicating higher exercise self-efficacy.

Measure: Self-Reported Activities of Health using the Self-Reported Activities of Health for Health Promotion Scale

Time: Baseline, 12 months, and 18 months

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Description: This inventory consists of 40 life events and asks the participant to recall if any of the events happened within the previous year (e.g., death of spouse; personal illness; change in sleep). Endorsement of these events are totaled and higher scores indicate a greater amount of stressful life events. Point values for the Holmes and Rahe Stress Inventory were weighted and summed for each individual based on scoring instructions. Individuals who scored 150 points or less were categorized as low susceptibility to a health breakdown in the next two years, 151-300 points were 50% chance of health breakdown, and 301 points or more were 80% chance of health breakdown.

Measure: Stressful Life Events assessed by the Holmes and Rahe Stress Inventory

Time: Baseline, 3 months, 6 months, 12 months, and 18 months

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Description: The GLB TBI/Attention Control groups will both use this app. Usage and engagement will be collected.

Measure: App Data

Time: 6 months, 12 months, and 18 months

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Description: The MOCA is a brief, 8-section assessment of various cognitive domains including executive function, memory, language, attention, concentration, orientation, and working memory in neurologic populations. Each item on the MOCA is allocated a set of points adding up to 30.

Measure: Executive Function assessed by the Montreal Cognitive Assessment

Time: Baseline, 3 months, and 12 months

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Description: Self-Report Habit Index measures self-reported perceptions of habit strength for an identified behavior. The measure has high internal reliability across four studies. The measure consists of 12 items using a 7-point Likert scale ranging from "completely disagree" to "completely agree", with higher scores representing greater perception of habit strength.

Measure: Self-reported perceptions of habit strength assessed by the Self-Report Habit Index (SRHI)

Time: Baseline, 3 months, and 12 months

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Description: The PHQ-8 is a brief self-report measure of major depressive disorder, derived from the PHQ-9 by removing the last question regarding suicide assessment.It is considered to be a valid measure of depression for population-based studies and clinical populations, and has been used in studies of patients with physical injury. Frequency of symptoms during the last 2 weeks is assessed on a 0 (not at all) to 3 (nearly every day) scale. A cut-off score of 10 or greater is considered diagnostic for current depression

Measure: Depression assessed using the Patient Health Questionnaire-8 item

Time: Baseline, 12 months, and 18 months

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Description: Walk Score is publically available and measures walkability of any address using a patented system. Fore each address, Walk Score analyzes hundreds of walking routes to nearby amenities and awards points based on distance to each amenities. Scores are given on a scale of 0 to 100.

Measure: Walk Score

Time: Baseline and 12 months

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Description: The BAST is a 47 item, theoretically grounded, validated survey of behavioral and emotional symptoms for community-based adults with TBI. This assessment is a shortened version of the validated 77-item survey, with questions related to environmental stressors and mood removed due to repetitiveness to other questions in survey packet. Responses are asked over the past two weeks using an ordinal scale from 0 "rarely" to 5 "very often." There are 6 subscales: Negative Affect, Substance Use, Executive Function, Fatigue, Impulsivity, and Maladaptive Coping. Higher scores indicate more symptoms in those domains. This measure will be used to characterize behavioral/emotional symptoms and to explore whether these are factors that influence

Measure: Behavioral Assessment

Time: Baseline and 6 months

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Description: The ten items from the General Self-Efficacy Scale (GSE) are deigned to examine goal-setting, effort investment, persistence in face of barriers and recovery from setbacks as constructs of perceived self-efficacy. The total score is the sum ranging from 10-40 and the instrument has been normed against the U.S. Adult population with a mean score of 29.48.

Measure: General Self Efficacy

Time: Baseline, 12 months, and 18 months

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Description: The BRFSS is a state-based system of health surveys that collects information on health risk behaviors, preventative health practices, and health care access primarily related to chronic disease and injury. The GLB-TBI uses the two subscales of Healthy Eating and Physical Activity from the 2017 version of the BRFSS. It consists of 14 items.

Measure: Behavioral Risk Factor Surveillance

Time: Baseline, 3, 6, 12, and 18 months.

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Description: This is an FDA cleared and validated indirect calorimetry device. It is handheld and measures oxygen consumption (V02) to determine resting metabolic rate (RMR)

Measure: MedGem

Time: Baseline

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Description: The metabolic score calculator will be used at all time points to determine the risk for metabolic syndrome. The following variables will be used to determine metabolic risk using the free metabolic risk calculator: gender, race and ethnicity, systolic blood pressure, fasting glucose, triglycerides, high-density lipoprotein (HDL), weight, height, and waist circumference. Scores are calculated are standardized to the general population.

Measure: Metabolic Score Calculator (MetS)

Time: Baseline, 3, 6, 12, and 18 months

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Description: Information on substance use will be collected using the AUDIT-C (for alcohol use) and three questions regarding tobacco and non-prescriptive drug use.

Measure: Substance Use

Time: Baseline, 12 months

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Description: This self-report survey was developed by the National Institute of Mental Health. The full survey consists of 64 questions with an open-ended section at the end to elicit concerns and feedback related to the effects of COVID-19. For this current study, however, only sections on Exposure Status (10 items), Life Changes (15 items), and Emotions/Worries (7 items), and the open-ended question will be asked. Questions are asked "over the past two weeks."

Measure: CRISIS (CoRonavIruS Health Impact Survey) V0.3 Adult Baseline Form

Time: Up to 12 months

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Description: The Social Isolation Short-Form 4a is taken from the Patient-Reported Outcomes Measurement Information System (PROMIS). This form assesses the perceptions of being "avoided, excluded, detached, disconnected from, or unknown by, others. There is no timeframe for the form. The measure is normed to the US population.

Measure: PROMIS Social Isolation Short Form 4a

Time: Up to 12 months

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Description: To assess media exposure and fear of media exposure during COVID-19 we have added 6 questions. These are asked "over the past two weeks." These questions address time spent watching the television, listening to radio, reading the newspaper, and searching the internet and social media. In addition, a 6th question related to fear is asked using a 5-point Likert scale.

Measure: Media Questionnaire

Time: Up to 12 months

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Primary Outcomes

Description: Tcore will be continuously monitored throughout baseline and thermal challenge periods (with heated & non-heated vests) by a TX-2 Rectal probe and Iso-Thermex Multichannel Thermometer (Columbus Instruments, Columbus, OH). The probe will be placed 10 cm beyond the anal sphincter.

Measure: Change in Core Body Temperature (Tcore)

Time: Visits 2 & 3 (subjects with tetraplegia only): Continuously throughout baseline & Thermal Challenge (2 hrs) periods. The change in Tcore from baseline to the end of Thermal Challenge will be determined.

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Description: The cognitive battery will be administered once at BL and once after Thermal Challenge in persons with tetraplegia only (Visits 2 & 3). Testing conditions will be identical, quiet, and distraction-free. Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV): Subjects will be asked to repeat 2-9 numbers forward, backward and in ascending order to assess attention, processing speed, and working memory. Each assessment requires 10 min.

Measure: Change in Cognitive Performance: WAIS-IV

Time: Visits 2 & 3 (subjects with tetraplegia only): At the end baseline (at 15 min) & end of Thermal Challenge (at 120 min) periods. The change in cognitive performance from baseline to the end of Thermal Challenge will be determined.

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Description: Delayed Recall section of the Montreal Cognitive Assessment (MoCA): Subjects will be asked to repeat 5 simple words immediately and then recall them after a 5-minute delay to assess working memory. Each assessment requires 6 min.

Measure: Change in Cognitive Performance: Delayed Recall

Time: Visits 2 & 3 (subjects with tetraplegia only): At the end baseline (at 15 min) & end of Thermal Challenge (at 120 min) periods. The change in cognitive performance from baseline to the end of Thermal Challenge will be determined.

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Description: Stroop Color and Word: Subjects will be asked to read words of colors, colors of fonts to assess attention and processing speed; color of fonts of words which describe conflicting colors to assess response inhibition (executive functioning). Subjects will practice each of the assessments for approximately 10 seconds prior to the actual test to ensure understanding of the instructions. Each assessment requires 4 min.

Measure: Change in Cognitive Performance: Stroop

Time: Visits 2 & 3 (subjects with tetraplegia only): At the end baseline (at 15 min) & end of Thermal Challenge (at 120 min) periods. The change in cognitive performance from baseline to the end of Thermal Challenge will be determined.

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Secondary Outcomes

Description: Thermal Comfort will be measured every 10 minutes throughout BL and thermal challenge periods by the Zhang 6-point thermal comfort scale: +3 (very comfortable), +2 (comfortable), +1 (just comfortable), -1 (just uncomfortable), -2 (uncomfortable), and -3 (very uncomfortable). A greater frequency of +1, +2, and +3 scores are considered more desirable than -1, -2, and -3 scores during the Thermal Challenge. Each assessment requires only the time needed for the subject to respond (typically less than 10 seconds).

Measure: Change in Thermal Comfort (TC)

Time: Visits 1, 2, & 3 (all subjects): During baseline & every 10 minutes throughout Thermal Challenge (2 hrs). The change in TC from baseline to the end of Thermal Challenge will be determined.

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Other Outcomes

Description: Skin thermocouples (TX-4 Skin Surface probes, Columbus Instruments, Columbus, OH) will be taped to 12 sites on the anterior trunk. Tsk data will be collected continuously throughout the baseline (BL) and Thermal Challenge periods. All areas under the vest will have skin temperatures less than or equal to 39 degrees C.

Measure: Change in Skin Temperature (Tsk) under the heated vest

Time: Visits 2 & 3 (all subjects): Continuously throughout baseline (15 min) & Thermal Challenge (2 hrs) periods. The change in Tsk from baseline to the end of Thermal Challenge will be determined.

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Description: Thermal sensation will be measured on the Zhang 9-point Thermal Sensation scale: +4 (very hot), +3 (hot), +2 (warm), +1 (slightly warm), 0 (neutral), -1 (slightly cool), -2 (cool), -3 (cold), and -4 (very cold). TS should be no greater than "warm" this would include identification of "hot spots". Each assessment requires only the time needed for the subject to respond (typically less than 10 seconds).

Measure: Change in Thermal Sensation (TS)

Time: Visit 1 (able-bodied subjects only): During baseline & every 10 minutes throughout Thermal Challenge (2 hrs). The change in TS from baseline to the end of Thermal Challenge will be determined.

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Primary Outcomes

Description: The SCS is a 26-item self-report questionnaire in which respondents describe how they relate to themselves during times of distress. The SCS includes the 5 item Self-Kindness subscale (ranging from 5-25; higher scores reflect more self-kindness), the 5-item Self-Judgment subscale (ranging from 5-25; higher scores reflect more self-judgment), the 4-item Common Humanity subscale (ranging from 4-20; higher scores reflect higher levels of common humanity), the 4-item Isolation subscale (ranging from 4-20; higher scores indicate higher levels of isolation), the 4-item Mindfulness subscale (ranging from 4-20; higher scores reflect higher levels of mindfulness) and the 4-item Over-Identification subscale (ranging from 4-20). Responses are given on a 5-point scale from "1-Almost Never" to "5-Almost Always." Mean scores on the six subscales are then averaged to create an overall self-compassion score ranging from 26 to 130. Higher scores correspond to higher levels of self-compassion.

Measure: Self-Compassion Scale (SCS); Change from baseline in Self-Compassion at post-treatment (2 mo) and follow up (3mo)

Time: Baseline, 8-10 weeks, 12-14 weeks

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Description: The TRGI is a 32-item validated self-report measure assessing traumatic guilt. The TRGI has three scales - Guilt Severity, Distress, and Guilt Cognitions. In all 32 items the answers are recorded on 5-point scale (ranging from 0 - not at all true to 4 - extremely true). Eight items are reverse-scored. We will use the TRGI as one of our eligibility criteria and to monitor changes in guilt and related cognitions over time.

Measure: Trauma-Related Guilt Inventory (TRGI); Change from baseline in trauma-related guilt at post-treatment (2 mo) and follow up (3mo)

Time: Baseline, 8-10 weeks, 12-14 weeks

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Description: The ISS is a 30-item self-report measure assessing shame proneness scored on a 5-point Likert scale ranging from 0 = "never" to 4 = "almost always". The ISS yields sum scores for two subscales, self-esteem (6 items; range = 0-24 with higher scores reflecting higher levels of self-esteem) and internalized shame (24 items; range = 0-96 with higher scores reflecting higher levels of shame) and has been well-validated with research and clinical populations. The self-esteem items are interspersed to counteract a negative response set.

Measure: Internalized Shame Scale (ISS); Change from baseline in shame at post-treatment (2 mo) and follow up (3mo)

Time: Baseline, 8-10 weeks, 12-14 weeks

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Secondary Outcomes

Description: The CAPS is a semi-structured interview used to assess PTSD diagnostic criteria and severity. Respondents select up to three of the most traumatic events they have experienced, and those events are used as the basis for assessing PTSD symptoms. The CAPS assesses each of the 20 items from the DSM-5 criteria B, C, D, and E. The assessor combines information about frequency and intensity of an item into a single severity rating (0=Absent; 1=Mild/subthreshold; 2=Moderate/threshold; 3=Severe/markedly elevated; 4=Extreme/incapacitating). CAPS-5 total symptom severity score is calculated by summing severity scores for the 20 DSM-5 PTSD symptoms (range = 0-40). Similarly, CAPS-5 symptom cluster severity scores are calculated by summing the individual item severity scores for symptoms corresponding to a given DSM-5 cluster: Criterion B (items 1-5); Criterion C (items 6-7); Criterion D (items 8-14); and, Criterion E (items 15-20).

Measure: Clinician Administered PTSD Scale for DSM-5; Change from baseline in PTSD symptoms at post-treatment (2 mo) and follow up (3mo)

Time: Baseline, 8-10 weeks, 12-14 weeks

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Description: The WHO-QOL BREF is a 26-item validated self-report measure that that assesses quality of life across four domains: physical (7 items, range 1-5), psychological (6 items, range 1-5), social relationships (3 items, range 1-5), and environment (8 items, range 1-5). The four domain scores denote an individual's perception of quality of life in each particular domain. The mean score of items within each domain is used to calculate the domain score. Domain scores are scaled in a positive direction (i.e. higher scores denote higher quality of life). There are also two items that are examined separately: question 1 asks about an individual's overall perception of quality of life on a scale of 1 - "very poor" to 5 - "very good". Question 2 asks about an individual's overall perception of their health on a scale of 1 - "very dissatisfied" to 5 - "very satisfied". The WHO-QOL-BREF has excellent internal validity and test-retest reliability.

Measure: Quality Of Life Enjoyment & Satisfaction Questionnaire (WHO-QOL-BREF); Change from baseline in quality of life at post-treatment (2 mo) and follow up (3mo)

Time: Baseline, 8-10 weeks, 12-14 weeks

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Description: The Alcohol TLFB is a drinking assessment method that obtains estimates of daily drinking. The TLFB will be employed at all three assessment points to evaluate alcohol and other substance use during the 90 days preceding each interview. Using a calendar, people provide retrospective estimates of their daily drinking over a specified time period. The TLFB will be used at each follow-up to establish: percentage days heavy drinking, percent days abstinent, length of initial abstinence, length of use episodes, severity of relapse and current alcohol/drug use pattern. The Alcohol TLFB has been shown to have good psychometric characteristics with a variety of groups, and can generate variables that provide a wide range of information about an individual's use (e.g., pattern, variability, and magnitude of use).

Measure: Timeline Follow-back; Change from baseline in frequency of substance use at post-treatment (2 mo) and follow up (3mo)

Time: Baseline, 8-10 weeks, 12-14 weeks

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Other Outcomes

Description: Beck Scale for Suicidal Ideation (BSSI): This scale is a 19-items instrument that evaluates the presence and intensity of suicidal thoughts in a week before evaluation (19). Each item is scored based on an ordinal scale from 0 to 2 and the total score is 0 to 38 with higher score indicating more risk for suicide.

Measure: Beck Scale for Suicidal Ideation; Change from baseline in suicidal risk at post-treatment (2 mo) and follow up (3mo)

Time: Baseline, 8-10 weeks, 12-14 weeks

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Primary Outcomes

Description: The cardiorespiratory fitness is measured using a heart rate recovery test

Measure: Change from baseline cardiorespiratory fitness at 3 months

Time: Baseline and post 12-week intervention

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Description: Muscle strength is measured with grip strength using a hand-held dynamometer.

Measure: Change from baseline muscle strength at 3 months

Time: Baseline and post 12-week intervention

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Secondary Outcomes

Description: Lower extremity function is assessed using the Short Physical Performance Battery (SPPB)

Measure: Change from baseline lower extremity function at 3 months

Time: Baseline and post 12-week intervention

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Description: Lower extremity function will be assessed using the Timed Up and Go (TUG) test.

Measure: Change from baseline lower extremity function at 3 months

Time: Baseline and post 12-week intervention

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Description: Health-related quality of life is measured using the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) Global-10 Health Items. The instrument is a 10-item measure with the response scores ranging from 1 (very severe) to 5 (none). Two summary scores, a global physical health score and a global mental health score, can be calculated from this scale, with each score ranging from 4 to 20. Higher scores indicate better health. The total raw score is translated into a T-score for each participant for analysis.

Measure: Change from baseline health-related quality of life at 3 months

Time: Baseline and post 12-week intervention

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Description: Social participation is measured using the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) Ability to Participate in Social Roles and Activities. The instrument is a 8-item measure with the response scores ranging from 1 (always) to 5 (never). The lowest possible total raw score is 8 and the highest possible score is 40. Higher scores indicate better ability to participate in social roles and activities. The total raw score is translated into a T-score for each participant for analysis.

Measure: Change from baseline social participation at 3 months

Time: Baseline and post 12-week intervention

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Description: Physical activity is measured using the Godin Leisure Time Exercise Questionnaire. The questionnaire contains two questions. The first question asks participants to report weekly frequencies of activities they perform at different intensities. A total weekly leisure activity is a sum of activity scores calculated by multiplying the weekly frequencies of strenuous, moderate, and light activities by 9, 5, and 3, respectively. The second question asks participants the frequency of weekly leisure-time activities performed that are long enough to work up a sweat.

Measure: Change from baseline physical activity at 3 months

Time: Baseline and post 12-week intervention

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Other Outcomes

Description: Barriers in physical activity will be assessed using the Barriers in Physical Activity Questionnaire. The instrument contains 43 items. Each item is responded with either no (1) or yes (2). If response is yes, a follow-up response that ranges from 1 (very small) to 5 (very large) is selected. There are 8 domains, which include personal health, attitudes/beliefs towards physical activity, friends, family, fitness center built environment, policy/programs/staff, community built environment, and safety. Each domain score is calculated by summing the item responses with its respective item weight. Higher domain scores indicate greater perceived barriers to physical activity.

Measure: Change from baseline barriers in physical activity at 3 months

Time: Baseline and post 12-week intervention

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Description: Exercise self-efficacy will be assessed using the Exercise Self-Efficacy Scale. The scale contains 8 items, with response options of each item ranging from 0% (not at all confident) to 100% (highly confident). All items are summed and a mean score is calculated. Higher scores indicate higher levels of self-efficacy.

Measure: Change from baseline exercise self-efficacy at 3 months

Time: Baseline and post 12-week intervention

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Description: Exercise goal-setting will be measured using the Exercise Goal-Setting Scale. The instrument contains 10 items with response options ranging from 1 (does not describe) to 5 (describes completely). A mean score is calculated. A higher mean score indicate better goal-setting and self-monitoring for exercise.

Measure: Change from baseline exercise goal-setting at 3 months

Time: Baseline and post 12-week intervention

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Description: Outcome expectations for exercise will be assessed using the Multidimensional Outcome Expectations for Exercise Scale. The instrument contains 15 items, with the response options ranging from 1 (strongly disagree) to 5 (strongly agree). Three domains of outcome expectations for exercise are assessed, which include physical outcome expectations (6 items), social outcome expectations (4 items), and self-evaluative outcome expectations (5 items). Each dimension is scored by summing the item responses. Higher scores indicate higher levels of outcome expectations for exercise.

Measure: Change from baseline outcome expectations for exercise at 3 months

Time: Baseline and post 12-week intervention

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Description: Social support will be assessed using the Social Provision Scale. The instrument contains 24 items, with the response options ranging from 1 (strongly disagree) to 4 (strongly agree). A total score is calculated by summing scores from all items. A higher score indicates a greater degree of perceived support.

Measure: Change from baseline social support at 3 months

Time: Baseline and post 12-week intervention

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Primary Outcomes

Description: Covid-19 infection rates in cannabis users will be compared to rates in the general population. Our online questionnaire responses will compare infection rates of cannabis users in this study against the Johns Hopkins University Coronavirus Research Center data (https://coronavirus.jhu.edu).

Measure: Prevention of COVID-19

Time: Five years

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Description: Severity of persistent symptoms in cannabis users testing positive for active infection and/or antibodies will also be compared to the general population. Patients will answer the widely used FLU-PRO questionnaire, which asks about flu symptoms and severity, to capture diagnoses, symptoms, and medical interventions related to COVID-19. The data from cannabis user patients will be compared with national and international data surveys, such as the Covid Symptom Study (https://covid.joinzoe.com/us-2).

Measure: Treatment of COVID-19

Time: Five years

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Description: The primary objective is to assess the efficacy and safety of medical cannabis as medicine for treatment of chronic pain and other chronic debilitating diseases. Pain will be measured by Brief Pain Inventory (BPI) numeric scale. Change from baseline in BPI will be assessed at 3-month intervals. For prospective associations between cannabis use and outcomes, use of a lagged mixed-effects models will examine temporal associations between cannabis use and pain severity, opioid sparing, and patient satisfaction. Data will be analyzed from baseline and the annual follow-up waves.

Measure: Treatment of Symptoms

Time: Five years

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Secondary Outcomes

Description: Secondary objectives include evaluating increases or decreases in quality of life, and increases or decreases in concomitant opioid use. Satisfaction with treatment will be measured by a Visual Analog Score (VAS). Change From baseline in Satisfaction with treatment measured by (VAS) be assessed at 3-month intervals.

Measure: Cannabis Impact on Quality of Life

Time: Five years

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Description: Tertiary objectives will examine preferences for routes of administration, and preferences for THC / CBD ratios. Categorical factors will be summarized using frequencies and percentages, while continuous measure distributions will be described using means, standard deviations, and quartiles of interest.

Measure: Cannabis Route and Dosing

Time: Five years

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Description: Incidence of Treatment-Related Adverse Events will be measured by Physician Global Assessment (PGA) numeric scale. Number of participants with Treatment-Related Adverse Events will be assessed by CTCAE v4.0.

Measure: Monitoring Adverse Events

Time: Five years

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Primary Outcomes

Description: The therapists will monitor discrepancies between intervention delivery and the CICI-manual by using extensive checklists relating to each of the intervention sessions. The number of non-delivered treatment components will be counted, and the percentage of deviation will be calculated compared to the total number of treatment components. High feasibility: 15 % deviation or less, Moderate feasibility: 15-25 % deviation, Low feasibility: > 25 % deviation

Measure: Protocol adherence assessed by study-specific checklists

Time: Will be evaluated after the intervention period, i.e. 4-5 months after inclusion.

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Description: The acceptability Scale is rated on a scale from 0 ("Completely disagree") to 4 ("Completely agree"). The total mean score on the Responsiveness subscale (6 items) on the Acceptability Scale, rated by the child, will determine child responsiveness. The responsiveness subscale consists of the following items (the wording adapted to the child's age): I would recommend participating in the study to others, the therapist was warm and understanding, I trusted the therapist, I had the opportunity to state my opinions about the therapist's suggestions, my opinions were taken seriously, I was given sufficient information during the study about the work we were doing. High feasibility: Mean score ≥ 3 ("Agree"), Moderate feasibility: Mean score ≥ 2 and < 3, Low feasibility: < 2.

Measure: Child Responsiveness to the intervention assessed by ratings on the study specific Acceptability Scale.

Time: Will be evaluated after the intervention period, i.e. 4-5 months after inclusion.

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Description: The acceptability Scale is rated on a scale from 0 ("Completely disagree") to 4 ("Completely agree"). The total mean score on the Responsiveness subscale (6 items) on the Acceptability Scale, rated by the caregiver, will determine caregiver responsiveness. The responsiveness subscale consists if the following items: I would recommend participating in the study to others, the therapist was warm and understanding, I trusted the therapist, I had the opportunity to state my opinions about the therapist's suggestions, my opinions were taken seriously, I was given sufficient information during the study about the work we were doing. High feasibility: Mean score ≥ 3 ("Agree"), Moderate feasibility: Mean score ≥ 2 and < 3, Low feasibility: < 2.

Measure: Caregiver Responsiveness to the intervention assessed by ratings on the study specific Acceptability Scale.

Time: Will be evaluated after the intervention period, i.e. 4-5 months after inclusion.

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Description: The acceptability Scale is rated on a scale from 0 ("Completely disagree") to 4 ("Completely agree"). The total mean score on the Usefulness subscale (6 items) in the Acceptability Scale will determine perceived usefulness of the intervention. The child version of the usefulness subscale consists of the following items: The program has helped me, the program has helped my family, I would recommend participating in the program to others, I have learned something new that helps me, I have learned more about what I struggle with after the injury, I have learned what I can say to others about what I struggle with due to the injury. High feasibility: Mean score ≥ 3 ("Agree"), Moderate feasibility: Mean score ≥ 2 and < 3, Low feasibility: < 2.

Measure: a. Usefulness of the intervention assessed by child ratings on the study-specific Acceptability Scale for this study

Time: Will be evaluated after the intervention period, i.e. 4-5 months after inclusion.

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Description: The acceptability Scale is rated on a scale from 0 ("Completely disagree") to 4 ("Completely agree"). The total mean score on the Usefulness subscale (9 items) in the Acceptability Scale will determine perceived usefulness of the intervention. The caregiver version of the usefulness subscale consists of the following items: The program has helped my child, the program has helped my family, the program has helped me, I would recommend participating in the program to others, I have gained more insight into my child´s challenges, I will use my new knowledge in the future, I have used my new knowledge in other settings, I found it useful to meet other families who are in a similar situation as we are, the school meetings were useful. High feasibility: Mean score ≥ 3 ("Agree"), Moderate feasibility: Mean score ≥ 2 and < 3, Low feasibility: < 2.

Measure: b. Usefulness of the intervention assessed by caregiver ratings on the study-specific Acceptability Scale for this study.

Time: Will be evaluated after the intervention period, i.e. 4-5 months after inclusion.

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Secondary Outcomes

Description: The therapist will log consent rate of families and schools. High feasibility: ≥ 30%, Moderate feasibility: 15-29%, Low feasibility: <15%

Measure: Recruitment procedures assessed by a) consent rate

Time: Will be evaluated after the intervention period, i.e. 4-5 months after inclusion.

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Description: Therapist will record duration of recruitment procedures, hereunder the telephone screening interview and other telephone calls. High feasibility: 3 hours or less, Moderate feasibility: ˃3 and ≤5 hours, Low feasibility: >5 hours

Measure: Recruitment procedures assessed by b) duration of phone calls and screening interview per family

Time: Will be evaluated after the intervention period, i.e. 4-5 months after inclusion.

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Description: High feasibility: One family excluded at or after baseline, Moderate feasibility: Two families excluded at or after baseline, Low feasibility: More than two families excluded at or after baseline

Measure: Recruitment procedures assessed by c) the number of participants excluded at or after baseline

Time: Will be evaluated after the intervention period, i.e. 4-5 months after inclusion.

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Description: Description: Number of families out of six that participate in the first intervention meeting (after baseline) and complete the entire intervention. High feasibility: Six families completed the intervention, Moderate feasibility: Five families completed the intervention, Low feasibility: Four or fewer families completed the intervention

Measure: Recruitment procedures assessed by d) the number of families that completed the whole intervention

Time: Will be evaluated after the intervention period, i.e. 4-5 months after inclusion.

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Description: The acceptability Scale is rated on a scale from 0 ("Completely disagree") to 4 ("Completely agree"). The total mean score on the following four items in the Acceptability Scale will determine the child burden of the assessment protocol: If the child was comfortable being tested and if the child was comfortable expressing his/her symptoms and opinions through the questionnaires, if the child understood the questionnaires and if the assessment made the child tired. High feasibility: Mean score ≥ 3 ("Agree"), Moderate feasibility: Mean score ≥ 2 and < 3, Low feasibility: < 2.

Measure: The burden of the assessment protocol for the child, reported by the child on the study-specific Acceptability Scale.

Time: Will be evaluated after the intervention period, i.e. 4-5 months after inclusion.

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Description: The acceptability Scale is rated on a scale from 0 ("Completely disagree") to 4 ("Completely agree"). The total mean score on the following four items in the Acceptability Scale will determine the child burden of the assessment protocol perceived by the caregiver: If the child was comfortable being tested, if the child was comfortable expressing his/her symptoms and opinions through the questionnaires, if the child understood the questionnaires and if the assessment made the child tired. High feasibility: Mean score ≥ 3 ("Agree"), Moderate feasibility: Mean score ≥ 2 and < 3, Low feasibility: < 2.

Measure: The burden of the assessment protocol for the child, reported by caregivers on the study-specific Acceptability Scale.

Time: Will be evaluated after the intervention period, i.e. 4-5 months after inclusion.

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Description: Description: The acceptability Scale is rated on a scale from 0 ("Completely disagree") to 4 ("Completely agree"). The following item in the Acceptability Scale will determine the caregiver burden of the assessment protocol: There were too many questionnaires. High feasibility: Mean score ≥ 3 ("Agree"), Moderate feasibility: Mean score ≥ 2 and < 3, Low feasibility: < 2.

Measure: The burden of the assessment protocol for the caregivers, reported by caregivers on the study-specific Acceptability Scale.

Time: Will be evaluated after the intervention period, i.e. 4-5 months after inclusion.

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Description: The acceptability Scale is rated on a scale from 0 ("Completely disagree") to 4 ("Completely agree"). The caregivers' perceived relevance of the topics in caregiver-questionnaires will be measured with two items on the Acceptability Scale: I was able to give important information through the questionnaires, the questionnaires were not relevant for me. Mean score will be calculated. High feasibility: Mean score ≥ 3 ("Agree"), Moderate feasibility: Mean score ≥ 2 and < 3, Low feasibility: < 2.

Measure: Caregiver reported relevance of topics in questionnaires

Time: Will be evaluated after the intervention period, i.e. 4-5 months after inclusion.

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Description: The therapist will record the duration of the baseline assessment through logs. High feasibility: ≤ 3hours, Moderate feasibility: ˃3 hours and ˂4 hours, Low feasibility: ≥4 hours

Measure: Therapist reported burden of the baseline assessment measured by the duration of the assessment.

Time: Will be evaluated after the intervention period, i.e. 4-5 months after inclusion.

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Description: The acceptability Scale is rated on a scale from 0 ("Completely disagree") to 4 ("Completely agree"). The perceived relevance of working with SMART-goals for the caregivers will be measured with three items on the Acceptability Scale ("The goals we set were important", "The strategies we used for working towards the goals have helped my family", "The strategies we used for working towards the goals have helped my child"). Mean score will be calculated. High feasibility: Mean score ≥ 3 ("Agree"), Moderate feasibility: Mean score ≥ 2 and < 3, Low feasibility: < 2.

Measure: The perceived relevance of working with SMART-goals as rated by caregivers on the study-specific Acceptability Scale.

Time: Will be evaluated after the intervention period, i.e. 4-5 months after inclusion.

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Description: The acceptability Scale is rated on a scale from 0 ("Completely disagree") to 4 ("Completely agree"). The perceived relevance of working with SMART-goals for the child will be measured with one item on the Acceptability Scale ("The goals we set were important"). High feasibility: Mean score ≥ 3 ("Agree"), Moderate feasibility: Mean score ≥ 2 and < 3, Low feasibility: < 2.

Measure: The perceived relevance of working with SMART-goals rated by the child on the study-specific Acceptability Scale.

Time: Will be evaluated after the intervention period, i.e. 4-5 months after inclusion.

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Description: The therapist records the number of sessions interrupted due to technical failure, per family. High feasibility: Restart of equipment in 0-1 sessions per family, Moderate feasibility: Restart of equipment in 2-3 sessions per family, Low feasibility: Restart of equipment in 4-5 sessions per family.

Measure: Therapist-recorded technical failures in using videoconference in treatment delivery assessed by a study-specific log.

Time: Will be evaluated after the intervention period, i.e. 4-5 months after inclusion.

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Description: The therapist will record the time spent on installing the technical equipment for video conference use, including software, per family. High feasibility: Installment completed in ≤ 20 minutes in one go, Moderate feasibility: Installment completed in > 20 minutes in one go, Low feasibility: Additional visit required to complete installment.

Measure: Therapist-recorded time spent on installment of the equipment for using videoconference in treatment delivery

Time: Will be evaluated after the intervention period, i.e. 4-5 months after inclusion.

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Description: The study-specific acceptability Scale is rated on a scale from 0 ("Completely disagree") to 4 ("Completely agree") and includes one question concerning the quality of communication through videoconference. The wording is adapted to the children's age, and the children, their parents, and the therapists will rate the question. The mean score will be calculated. High feasibility: Mean score ≥ 3 ("Agree"), Moderate feasibility: Mean score ≥ 2 and < 3, Low feasibility: < 2 on the item assessing quality of communication through videoconference.

Measure: Experienced quality of communication in using videoconference in treatment delivery, assessed by the Acceptability scale.

Time: Will be evaluated after the intervention period, i.e. 4-5 months after inclusion.

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Description: Explored topics: responsiveness to the intervention, usefulness of the intervention, the perceived relevance of working with SMART-goals, and experienced quality of communication in using videoconference in treatment delivery.

Measure: Semi-structured qualitative interviews with all participating children, caregivers and teachers will be conducted to elaborate aspects of feasibility as described above.

Time: Will be performed after the intervention period, i.e. 4-5 months after inclusion.

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Primary Outcomes

Description: Post-procedure surgical site infection using CDC criteria will be documented at each follow-up appointment up to six months

Measure: Post procedure surgical site infection

Time: six months

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Description: All unplanned reoperations will be documented

Measure: Unplanned fracture-related reoperation

Time: six months

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Primary Outcomes

Description: the incidence of Acute Kidney Injury

Measure: Rate of Acute Kidney Injury

Time: From date of admission until the date of discharge or death from any cause, up to 60 days

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Secondary Outcomes

Description: death from any cause in the hospital

Measure: Rate of Death

Time: From date of admission until the date of death from any cause, up to 60 days

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Description: days from admission to discharge or death

Measure: the length of hospital stay

Time: From date of admission until the date of discharge or death from any cause, up to 60 days

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Primary Outcomes

Description: Will correlate FAST+ pulmonary findings and published CT findings noted in active COVID infection to determine if FAST+ is a suitable diagnostic tool in detecting active COVID infection. Plan to use FAST+ imaging findings to stratify patients into low or high-risk COVID-19 infection groups.

Measure: Correlation of FAST+ pulmonary findings with active COVID infection

Time: 12 months

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Secondary Outcomes

Description: Exploratory outcomes will focus on description of additional ancillary findings of the FAST+ examination in those patients who later are determined to be COVID-19 positive compared to those determined to be COVID-19 negative (e.g., patterns of pleural space disease).

Measure: Description of additional ancillary findings of the FAST+ examination among infected and non-infected patients

Time: 12 months

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Primary Outcomes

Description: Assess the days until clinical stability is achieved after initiating randomization in hospitalized patients with elevated inflammatory parameters and severe COVID-19 lung injury. Clinical stability is defined if all the following criteria are met for 48 consecutive hours: Body temperature ≤ 37.0ºC; PaO2 / FiO2> 400 and / or SatO2 / FiO2> 300; Respiratory rate ≤ 24 rpm

Measure: Time to reach clinical stability

Time: 28 days

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Secondary Outcomes

Description: days

Measure: Time to reach an afebrile state for 48 hours.

Time: 56 days

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Description: days

Measure: Time to reach PaO2 / FiO2> 400 and / or SatO2 / FiO2> 300

Time: 56 days

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Description: days

Measure: Time to reach FR ≤ 24 rpm for 48 hours

Time: 56 days

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Description: days

Measure: Time to normalization of D-dimer (<250 ug / L)

Time: 56 days

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Description: days

Measure: Time until PCR normalization (<5mg / L).

Time: 56 days

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Description: days

Measure: Time until normalization of ferritin (<400ug / L)

Time: 56 days

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Description: viral load

Measure: Study the impact of immunosuppressive treatment on viral load using quantitative PCR

Time: 56 days

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Description: days

Measure: Time until hospital discharge

Time: 56 days

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Description: days

Measure: Need for ventilatory support devices

Time: 56 days

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Description: days

Measure: Duration that it is necessary to maintain ventilatory support.

Time: 56 days

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Description: days

Measure: COVID-19 mortality

Time: 56 days

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Description: days

Measure: all-cause mortality

Time: 56 days

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Description: cytokines quantification technique by Luminex

Measure: Analyze the expanded cytokine profile before the start of treatment and their evolution every 7 days after admission

Time: 56 days

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Description: IDIBELL Clinical Research and Clinical Trials Unit will oversee the monitoring and pharmacovigilance

Measure: Describe the side effects and their severity attributed to tacrolimus and / or methylprednisolone.

Time: 56 days

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Primary Outcomes

Description: COVID disease status will be measured by the 9-point (from 0 to 8) World Health Organization (WHO) ordinal scale for disease improvement at 28 days.

Measure: Change in COVID disease status

Time: Baseline to 28, 60 and 90 days

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Secondary Outcomes

Description: Change in serum oxalate levels

Measure: Renal safety biomarkers - serum oxalate

Time: On days 5,7 and 14

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Description: Microscopic analysis of urine for presence of oxalate stones

Measure: Renal safety biomarkers - urine oxalate stones

Time: On days 5,7 and 14

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Description: 24-hour urine oxalate levels

Measure: Renal safety biomarkers - 24-hour urine oxalate levels

Time: On days 5,7 and 14

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Description: Renal-failure free days, with AKI defined by the KDIGO criteria

Measure: Acute Kidney Injury-free days

Time: On day 28, 90

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Description: Mortality by all causes

Measure: Number of deaths

Time: On day 28, 60 and 90 days

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Description: Difference in plasma ferritin levels in ng/mL, compared to baseline levels

Measure: Change in plasma ferritin levels

Time: Days 1-7 compared with baseline

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Description: Difference in D-dimer levels in mcg/mL, compared to baseline levels

Measure: Change in plasma D-dimer levels

Time: Days 1-7 compared with baseline

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Description: Difference in lactate dehydrogenase (LDH) levels in units/L, compared to baseline levels

Measure: Change in serum lactate dehydrogenase (LDH) levels

Time: Days 1-7 compared with baseline

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Description: Difference in syndecan-1 levels in ng/mL, to with baseline levels

Measure: Change in plasma syndecan-1 levels

Time: Days 1-7 compared with baseline

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Description: Difference in cell-free DNA levels in ng/μL, compared to baseline levels

Measure: Change in plasma cell-free DNA levels

Time: Days 1-7 compared with baseline

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Description: Difference in plasma IL-6 levels in pg/mL, compared to baseline levels

Measure: Change in plasma IL-6 levels

Time: Days 1-7 compared with baseline

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Description: Respiratory failure defined as resource utilization requiring at least 1 of the following: Endotracheal intubation and mechanical ventilation, Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20L/min with fraction of delivered oxygen ≥0.5), noninvasive positive pressure ventilation, extracorporeal membrane oxygenation

Measure: Proportion of patients alive and free of respiratory failure

Time: At 28-days

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Description: Percentage of patients alive and not requiring invasive mechanical ventilation

Measure: Proportion of patients alive and free of invasive mechanical ventilation

Time: At 28-days

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Primary Outcomes

Description: Hospitalized patients with COVD-19 who developed liver injury

Measure: Liver injury in patients with COVID-19

Time: through study completion, an average of 6 months

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Secondary Outcomes

Description: Factors associated with worse outcome

Measure: Prognostic factors associated with death

Time: through study completion, an average of 6 months

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Description: Description of patients hospitalized with COVID-19

Measure: Clinical characteristics of patients who developed liver injury

Time: through study completion, an average of 6 months

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Primary Outcomes

Description: estimated glomerular filtration rate (eGFR), ml/min, in groups with mild, moderate and severe COVID-19

Measure: The effect of COVID-19 severity on the severity of renal failure

Time: 2 months

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Secondary Outcomes

Description: viral RNA concentration in urine, ME/ml

Measure: The expression of viral RNA in the urine with the severity of renal failure

Time: 2 months

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Description: albumine excretion with urine, g/ml

Measure: The severity of microalbuminuria in patients with COVID-19 of different conditions and renal failure

Time: 2 months

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Description: estimated glomerular filtration rate (eGFR), ml/min

Measure: Assessment of the severity of renal impairment in patients who died from COVID-19

Time: 2 months

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Description: Duration of viral RNA detection in urine by PCR, weeks

Measure: Estimation of the duration of urinary viral RNA isolation in patients undergoing COVID-19

Time: 2 months

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Description: expression of ACE-2 by imminohistochemistry at autopsy specimen

Measure: Expression of ACE-2 receptors in the kidneys of patients with renal failure who died from COVID-19

Time: 2 months

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Primary Outcomes

Description: Number of intrusive memories of traumatic events recorded by participants in a daily pen and and paper diary.

Measure: Frequency of intrusive memories

Time: Baseline weeks 1-3, throughout the duration of the intervention phase (approximately 5 weeks), post-intervention weeks 1-2 and for 1 week 2 months post-intervention. Change is assessed from baseline to post-intervention.

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Secondary Outcomes

Description: A brief bespoke measure of concentration adapted from that used previously with refugees (Holmes et al., 2017). It has three questions about disruption to concentration from intrusive memories. A higher score on each question means a worse outcome.

Measure: Concentration

Time: Baseline, 2-weeks post-intervention and 2-months post-intervention

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Description: Developed by Woodfield Trauma Service. The measure asks how many hours the person has spent doing various activities in the past two weeks (for example, domestic chores, exercise, cultural activities). A higher score means a better outcome.

Measure: Social and Occupational Activity Tally (SOAT)

Time: Baseline, 2-weeks post-intervention and 2-months post-intervention

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Description: Four items from the Dissociative Experiences Scale II - items two, three, 14 and 20 (DES II; Carlson, & Putnam, 1993). Each item asks how often (from 0% to 100% of the time) the dissociative experience described happens to the individual. A higher score on each question means a worse outcome.

Measure: Dissociation

Time: Baseline, 2-weeks post-intervention and 2-months post-intervention

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Description: The PCL-5 (Weathers, Litz, Keane, Palmieri, Marx, & Schnurr, 2013) is a 20-item self-report measure that assesses the 20 DSM-5 symptoms of PTSD. Total scores can range from 0 to 80, with higher scores meaning a worse outcome.

Measure: Post-Traumatic Stress Disorder (PTSD) Checklist for Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) (PCL-5)

Time: Baseline and 2-weeks post-intervention

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Description: The PHQ-9 (Kroenke, Spitzer & Williams, 2001) is a nine-item self-report measure that assesses the nine DSM-IV symptoms of depression. Total scores can range from 0 to 27, with higher scores meaning a worse outcome.

Measure: Patient Health Questionnaire (PHQ-9)

Time: Baseline and 2-weeks post-intervention

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Description: The WHO DAS 2.0 (World Health Organisation, 2010) is a measure of health and disability. Total scores can range from 0 to 48, with higher scores meaning a worse outcome.

Measure: World Health Organisation Disability Assessment Schedule 2.0 (WHO DAS 2.0) 12 item version

Time: Baseline and 2-weeks post-intervention

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Other Outcomes

Description: A bespoke measure to assess adherence to self-guided practice of the intervention. It includes four questions to assess how often, and for how long, the person played Tetris after experiencing intrusive memories during the previous week.

Measure: Self-Guided Intervention Adherence Questionnaire

Time: Time Frame: Intervention sessions 2-5, 1 week post-intervention, 2 weeks post-intervention and 2 months post-intervention.

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Description: A bespoke questionnaire to gain feedback on the intervention. It includes 16 questions to assess acceptability and usefulness of the intervention with a variety of response options including yes/no, visual analogue scales and open responses.

Measure: Feedback Questionnaire

Time: 1-week post-intervention.

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Primary Outcomes

Measure: Mean daily PaO2 to FiO2 ratio

Time: 10 days

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Secondary Outcomes

Measure: Duration of mechanical ventilation

Time: 30 days

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Measure: ICU length of stay

Time: 30 days

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Measure: Mortality Rate

Time: 30 days

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Measure: Incidence of adverse drug events

Time: 10 days

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Primary Outcomes

Description: Number of death during hospitalization

Measure: Number of In-Hospital Death

Time: During hospitalization, average 2-3 weeks

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Secondary Outcomes

Description: Length of stay in the hospital

Measure: Length of Stay

Time: During hospitalization, average 2-3 weeks

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Description: Successful treatment will be defined by two consecutive negative tests for COVID-19

Measure: Number of Successful Treatment

Time: During hospitalization, average 2-3 weeks

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Primary Outcomes

Description: To evaluate the efficacy of intravenous LSALT peptide plus standard of care to prevent the progression of COVID-19 to mild, moderate or severe ARDS, acute kidney injury, cardiomyopathy, acute liver injury, coagulopathy, or death in patients infected with SARS-CoV-2 compared with placebo plus standard of care.

Measure: Development of Acute Respiratory Distress Syndrome (ARDS) and Other Organ Injuries

Time: 28 days

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Secondary Outcomes

Description: High-frequency oscillatory ventilation, with its rapid delivery of low tidal volumes and a respiratory rate in the range of 60 to 900 breaths/minute, has also been utilized in ARDS patients.

Measure: Ventilation-free days

Time: 28 days

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Description: Oxygen therapy provided as non-invasive therapy for ARDS patients.

Measure: Time on nasal cannula or oxygen masks

Time: 28 days

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Description: 28 day mortality - all cause and attributable

Measure: 28 day mortality - all cause and attributable

Time: 28 days

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Description: ICU and hospitalization length of stay (days)

Measure: ICU and hospitalization length of stay (days)

Time: 28 days

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Description: Swab (nasopharyngeal, nasal, throat, sputum, or lower respiratory tract) at baseline (Day 1) and every 3 days thereafter until eradication → virologic clearance rate

Measure: SARS-CoV2 testing

Time: 28 days

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Description: Extracorporeal membrane oxygenation (ECMO) is often used for severe ARDS to allow lung healing/repair and reverse respiratory failure.

Measure: Need and duration for extracorporeal membrane oxygenation (ECMO)

Time: 28 days

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Description: Vasopressor free days

Measure: Vasopressor free days

Time: 28 days

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Description: Chest X-rays performed at Baseline, Day 3, at clinical improvement, and end-of-treatment (EOT) and study (EOS) to determine presence of bilateral opacities.

Measure: Radiographic pulmonary assessments

Time: 28 days

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Description: Change in daily mMRC dyspnea and SOFA scores (0 to 4) with 4 being the most severe outcome

Measure: Change in modified Medical Research Council (mMRC) dyspnea and Sequential Organ Failure Assessment (SOFA) scores

Time: 28 days

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Description: Incidence of other organ (non-lung) disorders

Measure: Incidence of non-lung disorders

Time: 28 days

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Description: Change in liver function tests (ALT, AST, and total bilirubin levels) from baseline

Measure: Measures of liver dysfunction

Time: 28 days

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Description: Change in SCr and eGFR from baseline

Measure: Measures of kidney dysfunction

Time: 28 days

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Description: Change in highly-sensitive troponin (hs-troponin) from baseline

Measure: Measures of cardiac dysfunction

Time: 28 days

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Description: Change from baseline ACT, aPTT, and/or PT/INR levels

Measure: Measures of coagulopathies

Time: 28 days

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Description: Change in baseline antiviral immunoglobulins (IgG, IgM) at EOS.

Measure: Changes in immunogenic responses

Time: 28 days

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Description: Changes in total healthcare costs from admission to discharge between treatment groups.

Measure: Healthcare outcomes

Time: 28 days

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Description: Change in serum cytokines including IL-1α, IL-1ß, IL-1ra, IL-5, IL-6, IL-8, IL-12, TNFα, CXCL10/IP10, MCP-3, and ferritin drawn at the same time as LSALT peptide levels

Measure: Molecular changes in pro-inflammatory pathways

Time: 28 days

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Description: Pharmacokinetics of LSALT peptide over the study period.

Measure: Pharmacokinetics of LSALT peptide

Time: 28 days

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Primary Outcomes

Description: Occurence of moderate or severe AKI

Measure: Occurence of acute kidney injury (AKI)

Time: within 7 days after beginning of moderate or severe ARDS

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Secondary Outcomes

Measure: Occurence of transient and persistent AKI

Time: within 7 days after beginning of moderate or severe ARDS

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Measure: Occurence of Renal replacement therapy during hospital stay

Time: up to 4 weeks after beginning of moderate or severe ARDS

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Measure: Duration of renal replacement therapy

Time: up to 4 weeks after beginning of moderate or severe ARDS

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Measure: Mortality

Time: up to 4 weeks after beginning of moderate or severe ARDS

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Measure: Duration of mechanical ventilation

Time: up to 4 weeks after beginning of moderate or severe ARDS

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Measure: Duration of vasopressor administration

Time: up to 4 weeks after beginning of moderate or severe ARDS

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Measure: ICU length of stay

Time: up to 4 weeks after beginning of moderate or severe ARDS

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Measure: Hospital length of stay

Time: up to 4 weeks after beginning of moderate or severe ARDS

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Other Outcomes

Description: e.g., Analysis of interleukin (IL) 6, IL8

Measure: Add-on analysis: pro- and antiinflammatory mediators

Time: within 7 days after beginning of moderate or severe ARDS

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Primary Outcomes

Description: Respiratory failure defined based on resource utilization requiring at least one of the following: Endotracheal intubation and mechanical ventilation Oxygen delivered by high-flow nasal cannula (heated, humidified oxygen delivered via reinforced nasal cannula at flow rates >20L/min with fraction of delivered oxygen ≥0.5) Noninvasive positive pressure ventilation, Extracorporeal membrane oxygenation

Measure: Proportion of patient alive and free of respiratory failure

Time: Baseline to Day 28

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Secondary Outcomes

Description: 1-month mortality

Measure: Proportion of subjects who are alive

Time: Baseline to Day 28

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Primary Outcomes

Description: Instrumental Support refers to the perception that people in one's social network are available to provide material or functional aid in completing daily tasks (such as making meals or providing transportation) if needed. This self-report measure for adults (ages 18 and above) is an 8-item calibrated scale.This study will use the measure to determine if people's instrumental support changes during a pandemic.

Measure: NIH Toolbox Instrumental Support Survey - change in instrumental support

Time: Baseline, 3 month and 6 month

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Secondary Outcomes

Description: A scale designed to measure one's subjective feelings of loneliness as well as feelings of social isolation. Participants rate each of the 3 items as hardly ever (score of "1"), some of the time (score of "2"), or often (score of "3"). The scores for each individual question can be added together to give you a possible range of scores from 3 to 9. The higher the score the more lonely the person will be. This study will use the measure to determine if people feel socially isolated during a pandemic.

Measure: UCLA (University of California - Los Angeles) 3-item Loneliness Scale - change in social isolation

Time: Baseline, 3 month and 6 month

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Primary Outcomes

Description: Fear of COVID-19 Questionnaire

Measure: Change in Fear of COVID-19

Time: baseline, 3 months, 6 months

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Secondary Outcomes

Description: NeuroQol SF v1.0 - Ability to Part. in SRA

Measure: Change in ability to participate in social roles and activities

Time: baseline, 3 months, 6 months

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Description: NeuroQol SF v1.0 - Depression

Measure: Change in depressive symptoms

Time: baseline, 3 months, 6 months

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Description: NeuroQol SF v1.0 - Pos. Affect & Well-Being

Measure: Change in positive affect and well-being

Time: baseline, 3 months, 6 months

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Description: NeuroQol SF v1.0 - Anxiety

Measure: Change in anxiety

Time: baseline, 3 months, 6 months

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Description: NeuroQol SF v1.0 - Fatigue

Measure: Change in fatigue

Time: baseline, 3 months, 6 months

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Description: NeuroQol SF v1.0 - Emotional & Beh. Dyscontrol

Measure: Change in emotional and behavioural dyscontrol

Time: baseline, 3 months, 6 months

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Description: NeuroQol SF v1.0 - Satisfaction w SRA

Measure: Change in satisfaction with social roles and activities

Time: baseline, 3 months, 6 months

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Description: NeuroQol SF v1.0 - Sleep Disturbance

Measure: Change in sleep disturbance

Time: baseline, 3 months, 6 months

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Description: NeuroQol SF v1.0 - Stigma

Measure: Change in stigma

Time: baseline, 3 months, 6 months

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Description: NeuroQol SF v1.0 - Cognitive Function

Measure: Change in cognitive function

Time: baseline, 3 months, 6 months

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Description: 23 questions about strategies to social distance

Measure: Change in social distancing strategies used

Time: baseline, 3 months, 6 months

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Description: 22 questions about social distancing

Measure: Change in thoughts and feelings about social distancing

Time: baseline, 3 months, 6 months

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Primary Outcomes

Measure: Safety and tolerability as measured by incidence of IP-related serious adverse events

Time: Outcomes and Serious Adverse Events through Day 180

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Primary Outcomes

Description: As defined by Kidney Diseases: Improving Global Outcomes (KDIGO) criteria

Measure: Incidence of any stage of acute kidney injury

Time: 14 days

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Secondary Outcomes

Description: Mortality

Measure: Mortality

Time: 14-day, hospital, and intensive care unit (ICU) mortality

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Description: Defined by return of creatinine to < 1.5 times of baseline

Measure: Renal recovery

Time: 14 days

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Description: Percentage

Measure: Percentage of patients who receive renal replacement therapy

Time: 14 days

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Description: Percentage of participants who are dialysis dependent

Measure: Percentage of participants who are dialysis dependent

Time: Through study completion, an average of 90 days

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Description: Days without vasoactive medications and mechanical ventilation

Measure: Free-days of vasoactive medications and mechanical ventilation

Time: Day 30

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Description: Length of intensive care unit and hospital stay

Measure: Length of intensive care unit and hospital stay

Time: Through study completion, an average of 90 days

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Description: Congestive heart failure, Arrhythmia, Acute respiratory distress syndrome, Septic shock, Acute cardiac injury, pneumonia

Measure: Number of participants with consequences following AKI

Time: Through study completion, an average of 90 days

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Description: Time from illness onset to need for mechanical ventilator support

Measure: Time from illness onset to need for mechanical ventilator support

Time: Through study completion, an average of 30 days

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Primary Outcomes

Description: AKI will be defined according with KDIGO guidelines: increase in creatinine of more than 1,5 fold compared to baseline Severe CVOID-19 infection is defined as 1/ confirm COVID-19 infection (by TDM and/or qRT-PCR) 2/ Requirement of ICU support during more than 72h

Measure: Primary endpoint is the incidence, the severity and the mortality associated with AKI during COVID-19 severe infection

Time: 7 months

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Primary Outcomes

Description: Kidney Disease Improving Global Outcomes (KDIGO) Staged AKI by serum creatinine or urine output

Measure: Acute Kidney Injury (AKI)

Time: 14 days

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Secondary Outcomes

Description: Survival to ICU discharge or Day 14

Measure: Survival

Time: 14 days

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Description: The use of extracorporeal membrane oxygenation (ECMO) and/or renal replacement therapy

Measure: Rate of Extracorporeal Therapy Requirement

Time: 14 days

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Description: >20% fluid overload as defined as the net fluid balance since ICU admission (in liters) divided by ICU admission weight

Measure: Fluid overload

Time: Day of Enrollment

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Description: The exposure of enrolled patients to known nephrotoxic medications, including diuretics

Measure: Rate of nephrotoxic medication exposure

Time: Day of Enrollment

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Primary Outcomes

Description: within the study period, trauma patients who admitted to any of the seven study centers will be recorded.

Measure: trauma admissions

Time: 3 months

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Primary Outcomes

Measure: In-hospital Mortality

Time: At hospital discharge, approximately 1 month

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Measure: 30-day mortality

Time: 30 days post-hospital discharge

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Secondary Outcomes

Description: Care treatment such as ventilator use, intubation, and/or tracheostomy

Measure: Limitations of patient care- Frequency of care not being provided

Time: During In-hospital course, up to 1 month

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Measure: Limitations of patient care- Conversion of DNR/DNI/CMO status

Time: During In-hospital course, up to 1 month

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Primary Outcomes

Description: Composite of all-cause mortality

Measure: All Cause Mortality

Time: 90 days

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Description: Need for Mechanical Ventilation

Measure: Mechanical Ventilation

Time: 90 days

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Description: Need for Mechanical Circulatory Support

Measure: Mechanical Circulatory Support

Time: 90 days

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Secondary Outcomes

Description: Time to Primary Endpoint

Measure: Time to Deterioration

Time: 90 days

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Description: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0".

Measure: Adverse Events

Time: 90 days

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Description: Peak Troponin Levels

Measure: Troponin

Time: 90 days

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Description: Troponin Levels Change from Baseline

Measure: Delta

Time: 90 days

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Description: Change from Baseline on BNP levels

Measure: BNP

Time: 90 days

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Description: Changes from Baseline on C Reactive Protein

Measure: Changes in C Reactive Protein

Time: 90 days

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Description: Hospital Length of Stay

Measure: LOS

Time: 90 days

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Description: Re-Hospitalization Rates

Measure: Re-Hospitalization

Time: 90 days

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Description: Changes in D Dimer from Baseline

Measure: Changes in D Dimer

Time: 90 days

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Primary Outcomes

Description: Effect of nebulised heparin on d-dimer profile, assessed via d-dimer AUC and via a mixed effects model, with data collected on days 1, 3, 5 and 10.

Measure: D-dimer profile

Time: Up to day 10.

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Description: Safety of nebulised heparin delivered by aerogen solo nebuliser in patients with COVID-19 induced severe respiratory failure, as measured by the incidence of severe adverse events.

Measure: Frequenccy of Severe Adverse Outcomes

Time: Up to day 60

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Secondary Outcomes

Description: Determine the impact of nebulised heparin on oxygenation index

Measure: Oxygenation Index

Time: Up to day 10

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Description: Effect of nebulised heparin on indices of inflammation (Interleukin (IL)-1β, IL-6, IL-8, IL-10 and soluble TNF receptor 1 (sTNFR1), C-reactive protein, procalcitonin, Ferritin,) will be assessed (AUC on days 1, 3, 5 and 10)

Measure: Indices of Inflammation

Time: Up to day 10

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Description: Effect of nebulised heparin on the ratios of IL-1β/IL-10 and IL-6/IL-10 will also be assessed.

Measure: Ratios of Indices of Inflammation

Time: Up to day 10

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Description: Effect of nebulised heparin on other indices of coagulation (Fibrinogen; lactate dehydrogenase) will be assessed (AUC on days 1, 3, 5 and 10).

Measure: Indices of Coagulation

Time: Up to day 10

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Description: Determine the effect of nebulised heparin on Quasi-Static Lung Compliance (i.e. tidal volume/(Plateau pressure-PEEP) measured on days 1,3,5,10.

Measure: Quasi-Static Lung Compliance

Time: Up to day 10

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Description: Time to separation from invasive ventilation, where non survivors are treated as though not separated from invasive ventilation.

Measure: Time to separation from invasive ventilation

Time: Up to day 28

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Description: Number treated with neuromuscular blockers instituted after enrolment

Measure: Number treated with neuromuscular blockers

Time: Up to day 10

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Description: Number treated with prone positioning instituted after enrolment

Measure: Number treated with Prone positioning

Time: Up to day 10

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Description: Number treated with extra-corporeal membrane oxygenation instituted after enrolment

Measure: Number treated with extra-corporeal membrane oxygenation

Time: Up to day 10

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Description: Number tracheotomised

Measure: Number requiring Tracheostomy

Time: Up to day 28

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Description: Time to separation from invasive ventilation among survivors

Measure: Time to separation from invasive ventilation among survivors

Time: Up to day 28

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Description: Time to separation from the ICU to day 28, where non-survivors to day 28 are treated as though not separated from invasive care

Measure: Discharge to ward

Time: Up to day 28

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Description: Time to discharge from the ICU to day 28, among survivors

Measure: Discharge to ward in survivors

Time: Up to day 28

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Description: Survival to day 28; Survival to day 60; and Survival to hospital discharge, censored at day 60

Measure: Patient Survival

Time: Up to day 60

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Description: Number residing at home or in a community setting at day 60

Measure: Number of patients residing at home or in a community setting at day 60

Time: Up to day 60

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Description: Number residing at home or in a community setting at day 60, among survivors

Measure: Number of surviving patients residing at home or in a community

Time: Up to day 60

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Primary Outcomes

Description: Critical illness is defined by respiratory failure (requiring any of the following: endotracheal intubation, oxygen delivered by high flow nasal cannula, non-invasive positive pressure ventilation, extracorporeal membrane oxygenation or clinical diagnosis of respiratory failure) or shock (systolic blood pressure < 90 mm Hg, or diastolic blood pressure < 60 mm Hg, or requiring vasopressors)

Measure: The proportion of patients who achieve treatment success through Day 28, defined as avoidance of death and critical illness

Time: Day 1 (Baseline) through Day 28

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Secondary Outcomes

Description: Defined as measure of safety

Measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent fatal and life-threatening SAEs, Treatment-emergent Serious Adverse Events

Time: Day 1 (Baseline) through Day 70

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Description: Safety evaluation via review of labs (white blood cell (WBC) with differential counts, hemoglobin, platelet count, liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and total bilirubin levels), serum chemistry, cardiac troponin coagulation markers (prothrombin time [PT], partial thromboplastin time [PTT], D dimer, fibrinogen), and urinalysis)

Measure: Change in safety laboratory parameters

Time: Day 1 (Baseline) through Day 70

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Primary Outcomes

Description: Primary feasibility outcome will be the proportion of patients treated who achieve >50% of urine measurements pH ≥= 7.2 over the duration of treatment.

Measure: pH

Time: 10 days

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Description: Primary efficacy outcome will be the number of days alive and free of stage 2-3 AKI (up to 28) in each group.

Measure: Number of Days Alive Free of Stage 2-3 AKI

Time: 28 days post-treatment

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Secondary Outcomes

Description: proportion of patients developing stage 2-3 AKI (or stage 3 if already at stage 2 at enrollment).

Measure: Stage 2-3 AKI

Time: 28 days

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Description: Ventilator-free days to 28 days

Measure: Vent-Free

Time: 28 days

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Description: Hospital-free days to 60 days

Measure: Hospital-Free

Time: 60 days post-index hospitalization

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Primary Outcomes

Measure: Frequency and severity of Adverse Events, including Serious Adverse Events, by treatment group and dose level, including the frequency of premature discontinuation of study intervention due to Adverse Events.

Time: Through study completion at Day 28 following last dose.

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Secondary Outcomes

Measure: Incidence of clinically significant changes from baseline in clinical laboratory values, ADA, autoantibody panel, vital signs, physical examination, ECG, radiography, and concomitant medications.

Time: Through study completion at Day 28 following last dose; (if positive ADA/antibodies, Day 90 and Day 180 following last dose).

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Measure: Number of patients with positive ADA titers after receiving a single dose (Part A) or multiple doses (Part B) of RLS-0071.

Time: Through study completion at Day 28 following last dose; (if positive ADA/antibodies, Day 90 and Day 180 following last dose).

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Measure: Estimates of single-dose maximum plasma concentration (Cmax) for RLS-0071.

Time: Pre-Dose (within 30 minutes before start of dosing), 5 and 30 minutes after start of dosing, and 1, 2, 3, 4, 5, 6, 7, 8,12, 18, 24, 36, and 48 hours after the start of dosing, up to 28 days following last dose.

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Measure: Estimates of single-dose time to maximum plasma concentration (Tmax) for RLS-0071.

Time: Pre-Dose (within 30 minutes before start of dosing), 5 and 30 minutes after start of dosing, and 1, 2, 3, 4, 5, 6, 7, 8,12, 18, 24, 36, and 48 hours after the start of dosing, up to 28 days following last dose.

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Measure: Estimates of single-dose minimum plasma concentration (Cmin) for RLS-0071.

Time: Pre-Dose (within 30 minutes before start of dosing), 5 and 30 minutes after start of dosing, and 1, 2, 3, 4, 5, 6, 7, 8,12, 18, 24, 36, and 48 hours after the start of dosing, up to 28 days following last dose.

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Measure: Estimates of single-dose area under the plasma concentration-time curve (AUC) for RLS-0071.

Time: Pre-Dose (within 30 minutes before start of dosing), 5 and 30 minutes after start of dosing, and 1, 2, 3, 4, 5, 6, 7, 8,12, 18, 24, 36, and 48 hours after the start of dosing, up to 28 days following last dose.

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Measure: Estimates of single-dose apparent total volume of distribution for RLS-0071.

Time: Pre-Dose (within 30 minutes before start of dosing), 5 and 30 minutes after start of dosing, and 1, 2, 3, 4, 5, 6, 7, 8,12, 18, 24, 36, and 48 hours after the start of dosing, up to 28 days following last dose.

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Measure: Estimates of single-dose apparent total body clearance for RLS-0071.

Time: Pre-Dose (within 30 minutes before start of dosing), 5 and 30 minutes after start of dosing, and 1, 2, 3, 4, 5, 6, 7, 8,12, 18, 24, 36, and 48 hours after the start of dosing, up to 28 days following last dose.

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Measure: Estimates of single-dose apparent first-order terminal elimination half-life for RLS-0071.

Time: Pre-Dose (within 30 minutes before start of dosing), 5 and 30 minutes after start of dosing, and 1, 2, 3, 4, 5, 6, 7, 8,12, 18, 24, 36, and 48 hours after the start of dosing, up to 28 days following last dose.

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Measure: Estimates of multiple-dose maximum plasma concentration (Cmax) for RLS-0071.

Time: Pre-Dose (within 30 minutes before start of dosing); 30 minutes after the start of dosing; and 1, 2, 4, 6, 12, 18, 24, 36, and 48 hours after the start of dosing. The last PK sample will be taken 48 hours following the last dosing (the 9th infusion).

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Measure: Estimates of multiple-dose peak time to maximum plasma concentration (Tmax) for RLS-0071.

Time: Pre-Dose (within 30 minutes before start of dosing); 30 minutes after the start of dosing; and 1, 2, 4, 6, 12, 18, 24, 36, and 48 hours after the start of dosing. The last PK sample will be taken 48 hours following the last dosing (the 9th infusion).

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Measure: Estimates of multiple-dose area under the plasma concentration-time curve (AUC) for RLS-0071.

Time: Pre-Dose (within 30 minutes before start of dosing); 30 minutes after the start of dosing; and 1, 2, 4, 6, 12, 18, 24, 36, and 48 hours after the start of dosing. The last PK sample will be taken 48 hours following the last dosing (the 9th infusion).

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Measure: Estimates of multiple-dose average plasma drug concentration observed (Cavg) for RLS-0071.

Time: Pre-Dose (within 30 minutes before start of dosing); 30 minutes after the start of dosing; and 1, 2, 4, 6, 12, 18, 24, 36, and 48 hours after the start of dosing. The last PK sample will be taken 48 hours following the last dosing (the 9th infusion).

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Measure: Estimates of multiple-dose trough concentration prior to dose administration (Ctrough).

Time: Pre-Dose (within 30 minutes before start of dosing); 30 minutes after the start of dosing; and 1, 2, 4, 6, 12, 18, 24, 36, and 48 hours after the start of dosing. The last PK sample will be taken 48 hours following the last dosing (the 9th infusion).

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Measure: Estimates of multiple-dose apparent total volume of distribution for RLS-0071.

Time: Pre-Dose (within 30 minutes before start of dosing); 30 minutes after the start of dosing; and 1, 2, 4, 6, 12, 18, 24, 36, and 48 hours after the start of dosing. The last PK sample will be taken 48 hours following the last dosing (the 9th infusion).

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Measure: Estimates of multiple-dose apparent total body clearance for RLS-0071.

Time: Pre-Dose (within 30 minutes before start of dosing); 30 minutes after the start of dosing; and 1, 2, 4, 6, 12, 18, 24, 36, and 48 hours after the start of dosing. The last PK sample will be taken 48 hours following the last dosing (the 9th infusion).

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Measure: Estimates of multiple-dose apparent first-order terminal elimination half-life for RLS-0071.

Time: Pre-Dose (within 30 minutes before start of dosing); 30 minutes after the start of dosing; and 1, 2, 4, 6, 12, 18, 24, 36, and 48 hours after the start of dosing. The last PK sample will be taken 48 hours following the last dosing (the 9th infusion).

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Measure: Assessment of dose response relationship of single and multiple doses of RLS-0071 on C1q levels and the complement activity assay.

Time: Through study completion at Day 28 following last dose.

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Measure: Overall survival.

Time: Through Day 15 and through study completion at Day 28 following last dose.

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Measure: Incidence of progression to respiratory failure requiring mechanical ventilation.

Time: Days on ventilation while in the hospital through study completion at Day 28.

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Measure: Incidence of transfer to the ICU.

Time: Through Day 15 following last dose; through study completion at Day 28 following last dose; and duration of ICU stay days in the hospital post-dose through study completion at Day 28.

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Measure: Duration of hospitalization after treatment (days).

Time: Through study completion at Day 28 following last dose.

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Measure: Incidence, severity, and duration after treatment (days) of fever (≥ 39.0°C).

Time: Through study completion at Day 28 following last dose.

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Measure: Incidence, severity, and duration after treatment (days) of cough per investigator assessment of CTCAE's latest version.

Time: Through study completion at Day 28 following last dose.

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Measure: Duration of requirement for supplemental oxygen after treatment (days).

Time: Through study completion at Day 28 following last dose.

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Measure: PaO2/FiO2

Time: Through study completion at Day 28 following last dose.

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Measure: Incidence, severity, and duration after treatment (days) of new cardiovascular events as assessed by the investigator (e.g. myocardial infarction, stroke, TIA, ischemic limb) with CTCAE's latest version.

Time: Through Day 15 and through study completion at Day 28 following last dose.

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Measure: Incidence, severity, and duration after treatment (days) of respiratory acidosis as assessed by the investigator with CTCAE's latest version.

Time: Through Day 15 and through study completion at Day 28 following last dose.

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Description: Dialysis will be assessed by the investigator with CTCAE's latest version.

Measure: Incidence and duration after treatment (days) of dialysis.

Time: Through Day 15 and through study completion at Day 28 following last dose.

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Measure: Levels of complement activity (eg, CH50).

Time: Through study completion at Day 28 following last dose.

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Measure: Levels of C1q (free and bound to RLS-0071).

Time: Through study completion at Day 28 following last dose.

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Primary Outcomes

Description: Kidney disease progression will be defined as a decline in estimated glomerular filtration rate (eGFR; ml/min/1.73m2) of ≥30%

Measure: Incidence of kidney disease progression at 12 months.

Time: 12 months after hospital discharge.

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Secondary Outcomes

Description: Albuminuria will be defined as a urine albumin to creatinine ratio (UACR) of >30mg/mmol.

Measure: Incidence of albuminuria at 6-9 months.

Time: 6-9 months after hospital discharge.

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Description: Albuminuria will be defined as a urine albumin to creatinine ratio (UACR) of >30mg/mmol.

Measure: Incidence of albuminuria at 12-15 months.

Time: 12-15 months after hospital discharge.

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Description: Combined kidney disease progression outcome of ≥30% decline in eGFR (ml/min.1.73m2) and/or albuminuria (UACR>30mg/mmol).

Measure: Incidence of combined kidney disease progression and albuminuria at 6-9 months.

Time: 6-9 months after hospital discharge.

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Description: Combined kidney disease progression outcome of ≥30% decline in eGFR (ml/min.1.73m2) and/or albuminuria (UACR>30mg/mmol).

Measure: Incidence of combined kidney disease progression and albuminuria at 12-15 months.

Time: 12-15 months after hospital discharge.

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Description: Multi-variable Cox proportional hazards models will be used to assess the factors associated with all-cause mortality

Measure: Factors associated with all-cause mortality at 6-9 months.

Time: 6-9 months after hospital discharge.

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Description: Multi-variable Cox proportional hazards models will be used to assess the factors associated with all-cause mortality

Measure: Factors associated with all-cause mortality at 12-15 months.

Time: 12-15 months after hospital discharge.

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Description: Number of hospital readmissions

Measure: Incidence of hospital readmissions at 6-9 months

Time: 6-9 months after hospital discharge.

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Description: Number of hospital readmissions

Measure: Incidence of hospital readmissions at 12-15 months

Time: 12-15 months after hospital discharge.

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Primary Outcomes

Description: Global organ structure will be assessed through structural T1- and T2-weighted MRI scans which will provide information about automated segmentation and volume assessment of whole kidney (and both cortex and medulla) as well as other abdominal organs (including liver and spleen). Global organ structure will also be assessed through longitudinal (T1) and transverse (T2) relaxation time mapping. T1 and T2 increase with tissue inflammation, oedema and fibrosis. A respiratory-triggered inversion recovery (IR) spin-echo echo-planar scheme will be used for abdominal T1 mapping and a Gradient and spin echo (T2-GraSE) scheme for abdominal T2 mapping.

Measure: MRI assessment of global organ structure at 12 months.

Time: 12 months

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Description: R2* data will be acquired using a multi-echo fast field echo (mFFE) scheme to assess thrombi. Conventionally R2* mapping is used as a measure of oxygenation, but R2*is likely to be altered by other factors in COVID-19, including oedema and small vessel thrombotic processes.

Measure: MRI assessment of thrombi (R2*) at 12 months.

Time: 12 months

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Description: Mean transit time and perfusion depicting changes in microvascular blood flow and large vessel flow/thrombosis will be determined using a FAIR labelling scheme with a multi-slice spin-echo echo-planar imaging readout and multiple labelling delay times.

Measure: MRI assessment of organ perfusion (Arterial spin labelling [ASL]) at 12 months.

Time: 12 months

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Secondary Outcomes

Description: Global organ structure will be assessed through structural T1- and T2-weighted MRI scans which will provide information about automated segmentation and volume assessment of whole kidney (and both cortex and medulla) as well as other abdominal organs (including liver and spleen). Global organ structure will also be assessed through longitudinal (T1) and transverse (T2) relaxation time mapping. T1 and T2 increase with tissue inflammation, oedema and fibrosis. A respiratory-triggered inversion recovery (IR) spin-echo echo-planar scheme will be used for abdominal T1 mapping and a Gradient and spin echo (T2-GraSE) scheme for abdominal T2 mapping.

Measure: MRI assessment of global organ structure.

Time: 3-6 and 24 months

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Description: R2* data will be acquired using a multi-echo fast field echo (mFFE) scheme to assess thrombi. Conventionally R2* mapping is used as a measure of oxygenation, but R2*is likely to be altered by other factors in COVID-19, including oedema and small vessel thrombotic processes.

Measure: MRI assessment of thrombi (R2*).

Time: 3-6 and 24 months

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Description: Mean transit time and perfusion depicting changes in microvascular blood flow and large vessel flow/thrombosis will be determined using a FAIR labelling scheme with a multi-slice spin-echo echo-planar imaging readout and multiple labelling delay times.

Measure: MRI assessment of organ perfusion (ASL)

Time: 3-6 and 24 months

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Description: Correlations between MRI measures (Cortical T1, ASL-perfusion, T2, R2*) with estimated glomerular filtration rate (ml/min/1.73m2).

Measure: Correlations between MRI measures with estimated glomerular filtration rate.

Time: 3-6, 12 and 24 months

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Description: Correlations between MRI measures (Cortical T1, ASL-perfusion, T2, R2*) with urine albumin creatinine ratio (mg/mmol) and urine protein creatinine ratio (mg/mmol).

Measure: Correlations between MRI measures with urine albumin and protein creatinine ratios.

Time: 3-6, 12 and 24 months

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Description: Correlations between MRI measures (Cortical T1, ASL-perfusion, T2, R2*) with the mental component score. A score between 0 and 100 is calculated from the 36-Item Short-Form Health Survey; the higher the score, the better the quality of life mental domain.

Measure: Correlations between MRI measures with mental component score.

Time: 3-6, 12 and 24 months

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Description: Correlations between MRI measures (Cortical T1, ASL-perfusion, T2, R2*) with the physical component score. A score between 0 and 100 is calculated from the 36-Item Short-Form Health Survey; the higher the score, the better the quality of life physical domain.

Measure: Correlations between MRI measures with physical component score.

Time: 3-6, 12 and 24 months

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Description: Correlations between MRI measures (Cortical T1, ASL-perfusion, T2, R2*) with the health state score calculated from the European Quality of Life 5-Dimensions questionnaire. The health state score ranges from -0.285 (for the worst health state) to 1 (for the best health state).

Measure: Correlations between MRI measures with health state score.

Time: 3-6, 12 and 24 months

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Description: Correlations between MRI measures (Cortical T1, ASL-perfusion, T2, R2*) with the visual analogue score from the European Quality of Life 5-Dimensions questionnaire. The visual analogue score uses a thermometer-like scale numbered from 0 to 100; the higher the score, the better the health state.

Measure: Correlations between MRI measures with visual analogue score.

Time: 3-6, 12 and 24 months

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Description: Correlations between MRI measures (Cortical T1, ASL-perfusion, T2, R2*) with the fatigue score from the Fatigue Severity Scale, a 9-item questionnaire scored on a 7-point scale (minimum score=9; maximum score=63); the higher the score, the greater the fatigue severity.

Measure: Correlations between MRI measures with fatigue severity.

Time: 3-6, 12 and 24 months

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Description: Correlations between MRI measures (Cortical T1, ASL-perfusion, T2, R2*) with the fatigue score from the Visual Analogue Fatigue Scale, which uses an horizontal line scale numbered from 0 to 10; the higher the score, the higher the fatigue.

Measure: Correlations between MRI measures with fatigue score.

Time: 3-6, 12 and 24 months

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Description: Correlations between MRI measures (Cortical T1, ASL-perfusion, T2, R2*) with skin autofluorescence levels (arbitrary units) measured with the validated Autofluorescence Reader Standard Unit (SU) version 2.4.3 (AGE Reader SU, DiagnOptics Technologies BV, Aarhusweg 4-9, Groningen, The Netherlands).

Measure: Correlations with MRI measures with skin autofluorescence levels.

Time: 3-6, 12 and 24 months

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Description: Mean change in mental component score. A score between 0 and 100 is calculated from the 36-Item Short-Form Health Survey; the higher the score, the better the quality of life mental domain.

Measure: Mean change in mental component score.

Time: 3-6, 12 and 24 months

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Description: Mean change in physical component score. A score between 0 and 100 is calculated from the 36-Item Short-Form Health Survey; the higher the score, the better the quality of life physical domain.

Measure: Mean change in physical component score.

Time: 3-6, 12 and 24 months

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Description: Mean change in health state score calculated from the European Quality of Life 5-Dimensions questionnaire. The health state score ranges from -0.285 (for the worst health state) to 1 (for the best health state).

Measure: Mean change in health state score.

Time: 3-6, 12 and 24 months

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Description: Mean change in visual analogue score from the European Quality of Life 5-Dimensions questionnaire. The visual analogue score uses a thermometer-like scale numbered from 0 to 100; the higher the score, the better the health state.

Measure: Mean change in visual analogue score.

Time: 3-6, 12 and 24 months

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Description: Mean change in fatigue score as assessed by the Fatigue Severity Scale, a 9-item questionnaire scored on a 7-point scale (minimum score=9; maximum score=63); the higher the score, the greater the fatigue severity.

Measure: Mean change in fatigue severity scale.

Time: 3-6, 12 and 24 months

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Description: Mean change in fatigue score as assessed by the Visual Analogue Fatigue Scale, which uses an horizontal line scale numbered from 0 to 10; the higher the score, the higher the fatigue.

Measure: Mean change in fatigue score.

Time: 3-6, 12 and 24 months

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Description: Mean change in skin autofluorescence levels (arbitrary units) measured with the AGE Reader.

Measure: Mean change in skin autofluorescence levels.

Time: 3-6, 12 and 24 months

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Description: Assessment of kidney disease progression defined as decrease in estimated glomerular filtration rate (eGFR) of ≥25% associated with a decline in eGFR stage.

Measure: Incidence of kidney disease progression.

Time: 3-6, 12 and 24 months

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Description: Recording of the number of participants who developed any cardiovascular events.

Measure: Incidence of cardiovascular events.

Time: 3-6, 12 and 24 months

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Description: Correlations between MRI measures (Cortical T1, ASL-perfusion, T2, R2*) with all-cause mortality using multi-variable Cox proportional hazards models.

Measure: Correlations between MRI measures with all-cause mortality.

Time: 12 and 24 months

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Primary Outcomes

Description: All cause death or invasive or non-invasive mechanical ventilation

Measure: Composite of death or mechanical ventilation

Time: 28 days after randomization

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Secondary Outcomes

Description: (1) an elevation to >99th percentile URL upper reference limit (URL) in those with a baseline cardiac troponin level ≤99th percentile URL; or 3x elevation from baseline in those with a baseline cardiac troponin >99th percentile URL; measured at 1 week (7-days) post randomization.

Measure: cardiac troponin level

Time: 7±2 days after randomization

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Description: (1) an elevation to >99th percentile URL upper reference limit (URL) in those with a baseline cardiac troponin level ≤99th percentile URL; or 3x elevation from baseline in those with a baseline cardiac troponin >99th percentile URL; measured at 1 week (7-days) post randomization.

Measure: cardiac troponin level

Time: 14±2 days after randomization

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Description: The ECG will be evaluated for deviation from normal or from baseline (QRS, ST-T wave changes

Measure: ECG

Time: Day 7±2 and Day 14±2

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Description: The number of days that a patient is alive and free of organ support through 28 days after trial entry. Organ support is defined by receipt for non-invasive mechanical ventilation, high flow nasal cannula oxygen, mechanical ventilation, or vasopressor therapy. Non-invasive mechanical ventilation is defined as bilevel positive airway pressure (BIPAP) or continuous positive airway pressure (CPAP) when used for acute respiratory support (Use of BIPAP or CPAP at night or when sleeping for sleep apnea is not considered organ support) High Flow Nasal Cannula Oxygen: defined as receiving ≥30 l/min flow at FiO2 ≥40% Invasive mechanical ventilation is defined as positive pressure ventilation through endotracheal tube or tracheostomy Vasopressor support includes infusion of any vasoactive or inotropic medication

Measure: 28-day organ support-free days

Time: 28 days

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Description: Intensification of medical therapy includes the need for ECLS, mechanical ventilation (invasive or non-invasive [BIPAP]) and/or vasopressor/inotropic therapy on Day 180 post randomization.

Measure: A composite of death or intensification of medical therapy

Time: 180 days

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