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

Children's Hospital of Philadelphia (CHOP)

Status and phase: Withdrawn; Phase 2; Phase 1

Conditions: Aicardi Goutières Syndrome

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

Study type: Interventional

Funder types: Other; Industry; NIH

Identifiers

NCT03304717

U01HD082806-03 (U.S. NIH Grant/Contract)

17-013715

Details and patient eligibility

About

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.

Full 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.

Sex: All

Ages: 2 to 18 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Triple Blind

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0 participants in 2 patient groups

TDF/FTC then Placebo

Experimental group

Description:

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.

Treatment:

Other: Placebo

Drug: Tenofovir (TDF) and Emtricitabine (FTC)

Placebo then TDF/FTC

Experimental group

Description:

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.

Treatment:

Other: Placebo

Drug: Tenofovir (TDF) and Emtricitabine (FTC)