Reverse Transcriptase Inhibitors in Aicardi Goutières Syndrome

NCT ID: NCT03304717

Last Updated: 2025-05-01

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE1/PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-12-31
• Study Completion Date: 2029-12-31

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.

Conditions

Aicardi Goutières Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Tenofovir (TDF) and Emtricitabine (FTC)

Intervention Type: 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.

Placebo

Intervention Type: OTHER

Placebo for Tenofovir and Placebo for Emtricitabine

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.

Group Type: EXPERIMENTAL

Tenofovir (TDF) and Emtricitabine (FTC)

Intervention Type: 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.

Placebo

Intervention Type: OTHER

Placebo for Tenofovir and Placebo for Emtricitabine

Interventions

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.

Intervention Type: DRUG

Placebo

Placebo for Tenofovir and Placebo for Emtricitabine

Intervention Type: OTHER

Other Intervention Names

Truvada (Tenofovir Disoproxil Fumarate and Emtricitabine); Viread (Brand for tenofovir disoproxil fumarate); Emtriva (Brand for emtricitabine)

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

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role: collaborator

National Human Genome Research Institute (NHGRI)

NIH

Sponsor Role: collaborator

Gilead Sciences

INDUSTRY

Sponsor Role: collaborator

Emerson Resources

UNKNOWN

Sponsor Role: collaborator

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

Children's Hospital of Philadelphia

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Adeline Vanderver, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital of Philadelphia

William Gahl, MD. PhD

Role: PRINCIPAL_INVESTIGATOR

National Institute of Health Genome Research Institute

Other Identifiers

U01HD082806-03

Identifier Type: NIH

Identifier Source: secondary_id

View Link

17-013715

Identifier Type: -

Identifier Source: org_study_id