Reverse Transcriptase Inhibitors in Aicardi Goutières Syndrome (RTI in AGS)

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.

Study Overview

• Status: Withdrawn
• Conditions: Aicardi Goutières Syndrome
• Intervention / Treatment: Drug: Tenofovir (TDF) and Emtricitabine (FTC); Other: Placebo

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.

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TDF/FTC then Placebo; 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); 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.; Other Names: Truvada (Tenofovir Disoproxil Fumarate and Emtricitabine); Viread (Brand for tenofovir disoproxil fumarate); Emtriva (Brand for emtricitabine); Other: Placebo; Placebo for Tenofovir and Placebo for Emtricitabine
Experimental: Placebo then TDF/FTC; 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); 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.; Other Names: Truvada (Tenofovir Disoproxil Fumarate and Emtricitabine); Viread (Brand for tenofovir disoproxil fumarate); Emtriva (Brand for emtricitabine); Other: Placebo; Placebo for Tenofovir and Placebo for Emtricitabine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determination of immune cell composition in CSF	The investigators will pursue immunophenotyping of CSF cells in AGS subjects. Immunophenotyping and target antigens will further understanding of end organ damage in AGS. Additionally, this may provide biomarkers for therapeutic outcome and disease activity.	From Baseline to 13 months
Determination of immune cell composition in blood	The investigators will pursue immunophenotyping of peripheral blood monocytes in AGS participants. Immunophenotyping and target antigens will further our understanding of end organ damage in AGS. Additionally, this may provide biomarkers for therapeutic outcome and disease activity.	From Baseline to 13 months
Accumulation of endogenous retroelements as measured in circulating immune cells	Performed by assays from previously collected samples	From Baseline to 13 months
Accumulation of endogenous retroelements as measured in circulating CSF	Performed by assays from previously collected samples	From Baseline to 13 months
Change in presence of non-specific and specific autoantibodies in blood	Performed by assays from previously collected samples	From Baseline to 13 months
Changes in Adverse Events - Safety monitoring laboratory tests	Patient monitoring for adverse effects	From Baseline to 13 months and as clinically warranted
Changes in total days hospitalized for disease-related illnesses.	Assess the effects of the treatment	Baseline - 13 months

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Gilead Sciences; National Institutes of Health (NIH); National Human Genome Research Institute (NHGRI); Emerson Resources
• Investigators: Principal Investigator: William Gahl, MD. PhD, National Institute of Health Genome Research Institute; Principal Investigator: Adeline Vanderver, MD, Children's Hospital of Philadelphia

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2025
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: August 4, 2017
• First Submitted That Met QC Criteria: October 3, 2017
• First Posted (Actual): October 9, 2017

Study Record Updates

• Last Update Posted (Actual): May 1, 2025
• Last Update Submitted That Met QC Criteria: April 28, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Leukodystrophy; Antiretroviral Drugs
• Additional Relevant MeSH Terms: Nervous System Diseases; Pathologic Processes; Autoimmune Diseases; Immune System Diseases; Disease; Congenital Abnormalities; Syndrome; Autoimmune Diseases of the Nervous System; Nervous System Malformations; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Nucleic Acid Synthesis Inhibitors; Antiviral Agents; Reverse Transcriptase Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Tenofovir; Emtricitabine
• Other Study ID Numbers: 17-013715; U01HD082806-03 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No