Reverse Transcriptase Inhibitors in Aicardi Goutières Syndrome

NCT03304717 | Withdrawn Phase 1 DMC FDA Drug

• 2 other identifiers: 17-013715U01HD082806-03
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Aicardi Goutières Syndrome

Keywords

Leukodystrophy; Antiretroviral Drugs

Outcome Measures

Primary Outcomes (1)

• Change in interferon activation as measured by interferon response genes

  The investigators propose to measure genes in the IFN stimulatory pathway in AGS patients, as a measure of disease activity and as a possible biomarker of therapeutic activity. Current data suggests that IFN related genes remain elevated in the late teens in AGS affected subjects, making it a more reliable measure of disease activity than IFN alpha. Validation of this preliminary data includes serial measurements in blood across several time points, to assess for variability.

  From Baseline to 13 months

Secondary Outcomes (7)

• Determination of immune cell composition in CSF

  From Baseline to 13 months

• Determination of immune cell composition in blood

  From Baseline to 13 months

• Accumulation of endogenous retroelements as measured in circulating immune cells

  From Baseline to 13 months

• Accumulation of endogenous retroelements as measured in circulating CSF

  From Baseline to 13 months

• Change in presence of non-specific and specific autoantibodies in blood

  From Baseline to 13 months

Study Arms (2)

TDF/FTC then Placebo

EXPERIMENTAL

This is a double-blind, placebo-controlled, 2 arm, cross-over trial involving 34 children with clinical findings and molecular confirmation of Aicardi Goutieres Syndrome, who also have an abnormal interferon signature. For arm 1, half of the patients will receive TDF/FTC (a combination of Tenofovir \[TDF\] and Emtricitabine \[FTC\]) for the first 6 months of the study. There will be a one month washout period before starting on placebo for 6 months.

Drug: Tenofovir (TDF) and Emtricitabine (FTC); Other: Placebo

Placebo then TDF/FTC

EXPERIMENTAL

For arm 2, half of the patients will receive placebo for the first 6 months of the study. There will be a one month washout period before starting on TDF/FTC (a combination of Tenofovir \[TDF\] and Emtricitabine \[FTC\]) for 6 months.

Drug: Tenofovir (TDF) and Emtricitabine (FTC); Other: Placebo

Interventions

Tenofovir (TDF) and Emtricitabine (FTC) DRUG

Tenofovir (TDF): a nucleotide reverse transcriptase inhibitor (NtRTI) an acyclic nucleotide analog of adenosine 5'-monophosphate. This is used in children as young as age 2. Emtricitabine (FTC): a nucleoside reverse transcriptase inhibitor (NRTI), a synthetic analog of cytidine which binds at the active site of the reverse transcriptase.

Also known as: Truvada (Tenofovir Disoproxil Fumarate and Emtricitabine), Viread (Brand for tenofovir disoproxil fumarate), Emtriva (Brand for emtricitabine)

Placebo then TDF/FTC; TDF/FTC then Placebo

Placebo OTHER

Placebo for Tenofovir and Placebo for Emtricitabine

Placebo then TDF/FTC; TDF/FTC then Placebo

Eligibility Criteria

• Age: 2 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Children's Hospital of Philadelphia: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• National Human Genome Research Institute (NHGRI): collaborator
• Gilead Sciences: collaborator
• Emerson Resources: collaborator
• National Institutes of Health (NIH): collaborator

MeSH Terms

Interventions

Tenofovir; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Emtricitabine

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Drug Combinations; Pharmaceutical Preparations

Study Officials

• Adeline Vanderver, MD

  Children's Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

• William Gahl, MD. PhD

  National Institute of Health Genome Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 4, 2017
• First Posted: October 9, 2017
• Study Start: December 1, 2025
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2029
• Last Updated: May 1, 2025

Record last verified: 2025-04