Measuring Brain Inflammation in Autism

NCT03117530 | Suspended Phase 1 DMC FDA Drug

• 1 other identifier: 16-001784
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Autism Spectrum Disorder

Keywords

minocycline; brain inflammation; microglia; cognition

Outcome Measures

Primary Outcomes (2)

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

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

• 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

  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 (3)

• 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

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

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

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

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

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

Other Outcomes (3)

• Change in clinician-rated global improvement as measured by CGI

  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

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

  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

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

  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

Study Arms (1)

Minocycline

EXPERIMENTAL

Drug: Minocycline

Interventions

Minocycline DRUG

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.

Also known as: minocin

Minocycline

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Male with a diagnosis of ASD as defined by DSM-5, confirmed by clinical evaluation and ADOS-2.
• Age 18-35 years inclusive
• IQ estimate of \>70 on VIQ or PIQ
• Capacity to consent to research
• Ability to comply with all protocol procedures and assessments
• Availability of an informant willing to provide information regarding subject behavior and health status (Note: Informant role requires a responsible adult with close, ongoing contact and knowledge of the subject; parent/caregiver acceptable, but not necessary for role)

You may not qualify if:

• Evidence of current nicotine, drug, or alcohol abuse or dependence
• Presence of a chronic medical condition which would potentially influence the assessment of TSPO binding, or interact with study medication (eg. hepatic, neurologic, renal disease) to increase risk to the subject
• Presence of severe behavioral disturbance likely to require initiation of treatment during the course of the protocol
• Clinical judgment of the study physician of inability to perform the requirements of the study
• Current or recent (past 30 days) treatment with minocycline or related compounds, immunosuppressives, or benzodiazepines
• Homozygous genotype for minor allele of rs6971
• History of recent febrile illness in past 30 days
• History of allergic reactions to tetracycline antibiotics
• Concomitant medication treatment not stable for the 4 weeks prior to study entry or anticipated to change
• Current prescribed medication likely to confound assessment of TSPO binding
• Male in good general health, confirmed by clinical evaluation
• Age 18-35 years inclusive
• IQ estimate of \>70 on VIQ or PIQ
• Ability to comply with all protocol procedures and assessments
• Diagnosis of an autism spectrum disorder (ASD)

Sponsors & Collaborators

• University of California, Los Angeles: lead

Study Sites (1)

UCLA

Los Angeles, California, 90095, United States

Location

MeSH Terms

Conditions

Autism Spectrum Disorder; cyclopia sequence; Encephalitis

Interventions

Minocycline

Condition Hierarchy (Ancestors)

Child Development Disorders, Pervasive; Neurodevelopmental Disorders; Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuroinflammatory Diseases

Intervention Hierarchy (Ancestors)

Tetracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Study Officials

• Michael Gandal, MD PhD

  University of California, Los Angeles

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 30, 2016
• First Posted: April 18, 2017
• Study Start: April 11, 2017
• Primary Completion: December 1, 2022
• Study Completion: December 1, 2022
• Last Updated: August 10, 2020

Record last verified: 2020-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)