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Report for Clinical Trial NCT03117530

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

Targeting Microglial Activation for Treatment of Autism Spectrum Disorder (ASD): A Proof-of-Concept, Target-Engagement Study

Autism spectrum disorders (ASD) are highly disabling, persistent neurodevelopmental disorders. There are no available treatments for core symptoms of ASD or biologically-based clinical biomarkers. Emerging evidence indicates that levels of brain inflammation are increased in ASD. In particular, recent work implicates hyperactivity of microglial cells, the resident immune cells of the brain. However, the functional consequences of microglial activation remain unknown. This study will measure microglial activation in ASD using positron emission tomography (PET) brain imaging. Adult males with ASD (n=15) and healthy controls (n=15) will be recruited for this study and undergo comprehensive clinical and behavioral baseline assessment. All subjects will then undergo baseline PET imaging using a radiotracer that labels activated microglia. Subjects with ASD will then undergo 12-week open label treatment with minocycline, an FDA-approved antibiotic thought to block microglial activation. PET imaging will be repeated at 12 weeks to confirm target engagement. A subset of control subjects will also undergo repeat PET imaging to determine test-retest reliability. During minocycline treatment, ASD subjects will be evaluated every 2 weeks for safety, clinical impression, behavioral functioning, and measures of cognition. Results will provide important information regarding the relationship between levels of brain inflammation, cognitive and behavioral function in ASD.

NCT03117530 Autism Spectrum Disorder
MeSH:Autistic Disorder Autism Spectrum Disorder
HPO:Autism Autistic behavior

1 Interventions

Name: Minocycline

Description: Following initial baseline PET-CT imaging and clinical evaluation, adults with ASD will undergo a 12- week open-label treatment trial of minocycline to be conducted at UCLA under supervision of the UCLA IRB. During weeks 1-6, ASD subjects will be treated with 50 mg minocycline twice daily (low dose). From weeks 7-12, dosing will be increased to 100mg twice daily (typical clinical dosage). Every two weeks during this phase, a treating clinician will measure vital signs, assess safety, record adverse effects, and monitor compliance. Compliance will be obtained as an index of tolerability and will assessed through weekly medication diaries and pill counts.
Type: Drug
Group Labels: 1

Minocycline


Primary Outcomes

Measure: Evaluate differences in CNS microglial activation in adults with ASD versus healthy volunteers via in vivo CNS binding of [11C]-DAA1106

Time: Data will be collected at PET scan #1, which will take place during screening (Days -28 to 0) for the study

Measure: Evaluate the effect of 12-weeks of minocycline exposure on CNS microglial activation in adults with ASD by measuring change in [11C]-DAA1106 binding pre- and post- treatment

Time: Data will be collected at PET scan #1 (between days -28 and 0 before intervention) and at PET scan #2 during Week 12 of intervention

Secondary Outcomes

Measure: Effect of minocycline exposure on cognition across seven cognitive domains before and after low dose intervention and regular dose intervention as measured by MCCB (MATRICS Consensus Cognitive Battery) subdomain scores

Time: Data will be collected at baseline and during Weeks 6 and 12 of intervention

Measure: Effect of minocycline exposure on self-rated anxiety and emotion regulation as measured by ADAMS (Anxiety and Depression Mood Scale)

Time: Data will be collected at baseline and during Weeks 6 and 12 of intervention

Measure: Effect of minocycline exposure on peripheral inflammatory cytokine profiles as measured by DNA and RNA expression in blood samples

Time: Data will be collected PET #1 (week 0) and at PET scan #2 (Week 12)

Other Outcomes

Measure: Change in clinician-rated global improvement as measured by CGI

Time: Data will be collected at Screening Visit #1 (between days -28 and 0 before intervention) and at visits during Weeks 6 and 12 of intervention

Measure: Change in self-reported symptoms of ASD with minocycline treatment as measured by SRS-2

Time: Data will be collected at Screening Visit #1 (between days -28 and 0 before intervention) and at visits during Weeks 6 and 12 of intervention

Measure: Change in informant-reported symptoms of ASD with minocycline treatment as measured by ABC-CV

Time: Data will be collected at Screening Visit #1 (between days -28 and 0 before intervention) and at visits during Weeks 6 and 12 of intervention

Purpose: Treatment

Allocation: N/A

Single Group Assignment


There is one SNP

SNPs


1 rs6971

hepatic, neurologic, renal disease) to increase risk to the subject 3. Presence of severe behavioral disturbance likely to require initiation of treatment during the course of the protocol 4. Clinical judgment of the study physician of inability to perform the requirements of the study 5. Current or recent (past 30 days) treatment with minocycline or related compounds, immunosuppressives, or benzodiazepines 6. Homozygous genotype for minor allele of rs6971 7. History of recent febrile illness in past 30 days 8. History of allergic reactions to tetracycline antibiotics 9. Concomitant medication treatment not stable for the 4 weeks prior to study entry or anticipated to change 10.

hepatic, neurologic, renal disease) to increase risk to the subject 4. Presence of current or lifetime severe psychopathology potentially confounding assessment of TSPO binding (psychosis, severe depression, bipolar disorder, Obsessive-Compulsive Disorder) 5. Current prescribed medication likely to confound assessment of TSPO binding 6. Clinical judgment of the study physician of inability to perform the requirements of the study 7. Current or recent (past 30 days) treatment with minocycline or related compounds, immunosuppressives, benzodiazepines, or psychotropic medications likely to confound assessment of TSPO binding 8. Homozygous genotype for minor allele of rs6971 9. SRS-2 T-score score of >59 10.



HPO Nodes


HPO:
HP:0000729: Autistic behavior
Genes 559
MID2 PTCHD1 SARS1 AP1S2 SYNJ1 FMN2 UBE3A CXORF56 ST3GAL5 NAA10 OTUD6B FGF12 STXBP1 KCNB1 ASH1L NDUFAF3 PAH MAPK10 SDHD CNTNAP2 PIGC HNF1B GABRD PWRN1 TRNL1 ZC3H14 SETD5 PSMD12 PRODH TUBB3 FMR1 HCFC1 PPP2CA VPS13C PDE4D CTNNB1 KCNA2 USP9X STS B3GALNT2 MAPT NDST1 VCP ANK3 HDAC8 PDE4D NAGA DCPS TCF4 C9ORF72 POLA1 NLGN3 TSPAN7 TBX1 NR2F1 SCN1B ND1 DEAF1 MED13L MAPK8IP3 SCN1A KMT2A NEUROD2 PIGG NDUFS1 COX2 GABRD CLCN4 MEF2C SIM1 GNAO1 MED12 UFD1 RARS1 RNF135 PODXL IL1RAPL1 SATB2 SMG9 CACNA1A C12ORF4 CHD8 SH2B1 SNRPN TBC1D23 IQSEC2 PGAP3 ACOX1 RSPRY1 TRNQ NDP JMJD1C MEIS2 CC2D1A DNM1 RSPRY1 IFNG TRIM8 DPYD CC2D2A ND3 SNORD116-1 AP3B2 CTCF RPL10 TBR1 IPW GABRA5 FTSJ1 FRMPD4 TMEM216 ACSL4 PARK7 NDUFS2 KDM6B WASHC4 NUS1 TRNS1 ALMS1 FGFR1 TSC1 NTRK2 CHD2 PIGL SEC24C PIGQ SDHC ALG13 SMC1A FBXO31 HERC1 SLC9A6 TRRAP THOC2 ANKRD11 HCN1 GAMT ADNP IQSEC2 CUX2 SDHB METTL23 MECP2 UPF3B TCF4 PAK3 GRIA3 WARS2 SNORD115-1 SPATA5 NDUFAF4 TBCK EP300 HIVEP2 UBTF SYP EXT2 COMT POMT1 CRADD BCKDK SZT2 NAA10 CDKL5 SCN9A ZNF41 PIGY AP2M1 CARS2 RERE STS MAN1B1 DNM1 STXBP1 CLP1 OPHN1 COX1 HCN1 DEAF1 AGTR2 MEF2C SLC6A1 YWHAG PTEN ND5 ND4 PTEN IREB2 PIGP ZNF423 MED25 DNAJC6 NSUN2 UBA5 CNKSR2 MAGEL2 DMD ELN NONO NUS1 CAMTA1 CASK USF3 EXT2 ARV1 RREB1 NDUFA11 SRY MTOR SPECC1L NDUFAF2 HCN1 KLLN MBOAT7 NDUFB9 STXBP1 DDX3X RAI1 FOXRED1 NDUFS7 TECR LMAN2L HERC2 GP1BB PSEN1 CYFIP2 AARS1 SETD2 RFC2 NDUFAF1 PCDH19 COG5 FRMPD4 PUF60 TWNK AUTS2 PLXND1 ND6 SYT1 EZR WFS1 EP300 NFIB GRN SLC25A22 ZNF81 NLGN4X RSRC1 CUX2 GABRA2 CXORF56 KCNA1 TRNF MKRN3-AS1 ACTL6B GJA8 MICOS13 NDUFA6 NAGA TRAK1 CDH15 NDUFAF4 USP7 CLTC PRDM16 ND2 SMC3 ALDH5A1 TBX1 ZFPM2 CNTNAP2 SLC35A3 ARHGEF6 TMEM106B PCDH19 FOXG1 SKI PDE4D MECP2 KCNAB2 PRKN SIN3A CHD7 IL1RAPL1 ST3GAL3 CTCF PPM1D LIMK1 SNCA ATRX LHX1 TBL2 SHANK3 SLC1A2 UCHL1 CEP290 ZBTB20 GABRB3 DYRK1A RPS23 TM4SF20 CHD2 TAF1 SCN2A MEIS2 TBR1 YY1 RERE NDUFS4 ALG11 SLC9A7 NDUFS3 SOX2 ALG13 HERC2 NEUROD2 SLC6A8 WFS1 PIGW HNRNPH2 ARNT2 HIRA DEPDC5 REV3L IQSEC2 SNX14 SH2B1 NDUFS6 SHANK3 RAD21 GABRB2 GDI1 ACADL SLC35C1 NDUFAF3 TREM2 STAG1 ATP1A3 SIM1 SCN2A CLIP2 NDUFV1 MED12 HTRA2 TRAPPC9 SEC23B GABRA1 ALDH18A1 PIGO SETD5 RAB11B NIPBL SIK1 GRIK2 ST3GAL3 PCGF2 NRXN1 TMEM126B MECP2 GFM1 AHDC1 MED23 SCN1B ASXL3 DHCR7 GJA5 CNKSR2 AUTS2 GRIA3 EHMT1 TMEM138 TMLHE TIMMDC1 TAF1 HECW2 NDUFAF5 TBC1D24 PROKR2 DHCR7 SYNGAP1 MED13L MECP2 ST3GAL5 SQSTM1 ADGRV1 SLC35A3 CLCN4 KMT5B ADSL KCNA2 ALG13 NHS EHMT1 KDM5B NDUFS8 ND1 ADNP MSTO1 AGTPBP1 SYN1 EEF1A2 TBX2 EDC3 PGAP1 TMEM237 SLC6A8 MKRN3 SON ATP6V1A CACNA1B DLG3 SCN1B PIGP AIMP1 GRIN2D LINS1 PIK3CA CHRNA7 NDN NDUFB10 DPYD UBA5 SMAD4 SLC45A1 HESX1 MCTP2 TCF20 C12ORF4 NEXMIF SNX14 EGF NALCN PRSS12 TSC2 CDKL5 AKT1 TLK2 DOCK7 CLCN4 PIGV TSC2 PPP3CA BCORL1 NLGN4X FOXP2 NDUFS4 CHD1 NDUFB11 AFF2 OTUD6B ARVCF GTF2I KCNT1 FTSJ1 RORA TRNW COX3 PIGL GABRG2 NAA15 CDKL5 PRKAR1A ARFGEF2 SYNGAP1 ARID1B BCOR PACS2 GPHN TRNH NDUFA13 KMT2C NLGN3 GNAQ TCF12 LRRK2 PPP2R5D CRBN MBOAT7 CLIP1 TBX1 PUF60 AP3B2 DHDDS PTCHD1 SLC25A12 TRNS2 USP27X HDAC4 PGAP2 WDR26 NUBPL SNRPN TRIO PWAR1 GATM STAG2 POGZ ARX PACS1 FLCN MAN1B1 MAOA NPAP1 FRRS1L GABRG2 BAZ1B HNMT WWOX POLA1 NDUFV2 GATAD2B SCN8A GABRG2 PINK1 KDM5C TUSC3 SLC13A5 SCN9A EXTL3 KPTN CACNA1C DYM ZNF711 PARS2 IQSEC1 OTX2 NEXMIF NTRK2 SOX3 SCN2A GRIN1 ARX TNIK SCN1A PNKP SLC25A1 NDUFB3 RAB39B CHD2 FOXP1 TMEM231 SCN3A RPS6KA3 STX1B FMR1 MECP2 CACNA2D2 SCN8A SEMA3E SCN1A NDUFA1 RERE CNNM2 NECAP1 GTF2IRD1 CHMP2B CREBBP TSC1 SH2B1
Protein Mutations 1
S1009A
SNP 1
rs6971