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Measuring Brain Inflammation in Autism

Primary Purpose

Autism Spectrum Disorder

Status

Suspended

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Minocycline

About this trial

This is an interventional treatment trial for Autism Spectrum Disorder focused on measuring minocycline, brain inflammation, microglia, cognition

Eligibility Criteria

18 Years - 35 Years (Adult)MaleAccepts Healthy Volunteers

Inclusion criteria for participants with ASD

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)

Exclusion criteria for participants with ASD

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

Inclusion criteria for healthy volunteer participants

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

Exclusion criteria for healthy volunteer participants

Diagnosis of an autism spectrum disorder (ASD)
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 current or lifetime severe psychopathology potentially confounding assessment of TSPO binding (psychosis, severe depression, bipolar disorder, Obsessive-Compulsive Disorder)
Current prescribed medication likely to confound assessment of TSPO binding
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, benzodiazepines, or psychotropic medications likely to confound assessment of TSPO binding
Homozygous genotype for minor allele of rs6971
SRS-2 T-score score of >59
History of recent febrile illness in past 30 days

Sites / Locations

UCLA

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Minocycline

Arm Description

Outcomes

Primary Outcome Measures

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

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

Secondary Outcome Measures

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

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

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

Full Information

NCT ID

NCT03117530

First Posted

November 30, 2016

Last Updated

August 6, 2020

Sponsor

University of California, Los Angeles

1. Study Identification

Unique Protocol Identification Number

NCT03117530

Brief Title

Measuring Brain Inflammation in Autism

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2020

Overall Recruitment Status

Suspended

Why Stopped

COVID

Study Start Date

April 11, 2017 (Actual)

Primary Completion Date

December 2022 (Anticipated)

Study Completion Date

December 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of California, Los Angeles

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Autism Spectrum Disorder

Keywords

minocycline, brain inflammation, microglia, cognition

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Minocycline

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

Minocycline

Other Intervention Name(s)

minocin

Intervention 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.

Primary Outcome Measure Information:

Title

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

Time Frame

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

Title

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 Frame

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 Outcome Measure Information:

Title

Time Frame

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

Title

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

Time Frame

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

Title

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

Time Frame

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

Other Pre-specified Outcome Measures:

Title

Change in clinician-rated global improvement as measured by CGI

Time Frame

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

Title

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

Time Frame

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

Title

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

Time Frame

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

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

35 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria for participants with ASD 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) Exclusion criteria for participants with ASD 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 Inclusion criteria for healthy volunteer participants 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 Exclusion criteria for healthy volunteer participants Diagnosis of an autism spectrum disorder (ASD) 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 current or lifetime severe psychopathology potentially confounding assessment of TSPO binding (psychosis, severe depression, bipolar disorder, Obsessive-Compulsive Disorder) Current prescribed medication likely to confound assessment of TSPO binding 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, benzodiazepines, or psychotropic medications likely to confound assessment of TSPO binding Homozygous genotype for minor allele of rs6971 SRS-2 T-score score of >59 History of recent febrile illness in past 30 days

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Michael Gandal, MD PhD

Organizational Affiliation

University of California, Los Angeles

Official's Role

Principal Investigator

Facility Information:

Facility Name

UCLA

City

Los Angeles

State/Province

California

ZIP/Postal Code

90095

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

IPD will not be shared

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Measuring Brain Inflammation in Autism

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