Clinical trial NCT03304717: Reverse Transcriptase Inhibitors in Aicardi Goutières Syndrome
Official title: Reverse Transcriptase Inhibitors in Aicardi Goutières Syndrome
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
PHASE2
Conditions: Aicardi Goutières Syndrome
Keywords: Leukodystrophy
Antiretroviral Drugs
Lead sponsor: Children's Hospital of Philadelphia
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: National Human Genome Research Institute (NHGRI)
name: Gilead Sciences
name: Emerson Resources
name: National Institutes of Health (NIH)
First posted: 2017-10-09
Enrollment: 0
Sex: ALL
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The overall objectives are to explore the safety and efficacy of Reverse Transcriptase Inhibitors Tenofovir (TDF)/ Emtricitabine (FTC) administered in AGS affected children 2 to 18 years of age.

Detailed description: The investigators propose that a trial to assess the proof of principle that antiretroviral therapy through a drug combination of Tenofovir (TDF) and Emtricitabine (FTC) can decrease endogenous retroelement accumulation, and alter interferon signaling in Aicardi Goutières Syndrome (AGS) patients is reasonable and warranted at this time, based on existing in vitro and animal data. Additionally, this trial will further the investigators understanding of this disorder, measuring for the first time retroelements in human participants, exploring the retroviral burden in cerebrospinal fluid (CSF), the Interferon (IFN) signaling response, as well as evaluating antigen targets of autoimmunity and cytokines. If successful, this approach will clearly demonstrate the need for a larger trial of antiretrovirals in AGS with more clinically relevant outcomes.

Eligibility criteria: Inclusion Criteria:

* Molecular, neuroimaging, and clinical findings consistent with a diagnosis of AGS, with the exception of Double-stranded RNA-specific adenosine deaminase (ADAR1) and IFIH1, which are not postulated to result in nucleic acid accumulation
* Evidence of interferon activation such as elevation of CSF neopterin/tetrahydrobiopterin measured on the first evaluation.
* Ages 2-18 years (the age of 2 years is used because the drugs are FDA approved in children greater than 2 years)
* Weight of at least 10 kg
* Willingness to undergo serial lumbar punctures and blow draws for evaluation of laboratory based outcome measures
* Willingness to abstain from initiating the use of immune modulating therapies including corticosteroids
* Able to receive medications orally, by nasogastric (NG) tube or by Gastric (G)-tube
* No concomitant illness which would preclude safe participation as judged by the investigator
* Signed informed consent by the subject's legally acceptable representative
* Negative testing for HIV
* Negative testing for Hepatitis B
* Concurrent enrollment in the Myelin Disorders Biorepository Project (MDBP, ClinicalTrials.gov NCT03047369) and willingness to undergo associated procedures

Exclusion Criteria:

* Age \< 2 years or \>18 years
* Hepatic insufficiency with liver function tests greater than 3-times the upper limit of normal
* Renal insufficiency with creatinine clearance \<60
* Significant malabsorption
* Any clinical or laboratory abnormality or medical condition that, at the discretion of the investigator, may put the subject at an additional risk by participating in this study
* HIV infection
* Hepatitis B infection
* Mutations in ADAR1 or IFIH1

Primary outcomes:
measure: Change in interferon activation as measured by interferon response genes
timeFrame: From Baseline to 13 months
Secondary outcomes:
measure: Determination of immune cell composition in CSF
timeFrame: From Baseline to 13 months
measure: Determination of immune cell composition in blood
timeFrame: From Baseline to 13 months
measure: Accumulation of endogenous retroelements as measured in circulating immune cells
timeFrame: From Baseline to 13 months
measure: Accumulation of endogenous retroelements as measured in circulating CSF
timeFrame: From Baseline to 13 months
measure: Change in presence of non-specific and specific autoantibodies in blood
timeFrame: From Baseline to 13 months
measure: Changes in Adverse Events - Safety monitoring laboratory tests
timeFrame: From Baseline to 13 months and as clinically warranted
measure: Changes in total days hospitalized for disease-related illnesses.
timeFrame: Baseline - 13 months
Other outcomes:
Locations:
Study officials:
affiliation: Children's Hospital of Philadelphia
name: Adeline Vanderver, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Institute of Health Genome Research Institute
name: William Gahl, MD. PhD
role: PRINCIPAL_INVESTIGATOR
References: