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

April 28, 2025 updated by: Children's Hospital of Philadelphia
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

Status

Indicates the current recruitment status or the expanded access status.
Withdrawn

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Change in interferon activation as measured by interferon response genes
Time Frame: From Baseline to 13 months
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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Determination of immune cell composition in CSF
Time Frame: From Baseline to 13 months
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
Time Frame: From Baseline to 13 months
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
Time Frame: From Baseline to 13 months
Performed by assays from previously collected samples
From Baseline to 13 months
Accumulation of endogenous retroelements as measured in circulating CSF
Time Frame: From Baseline to 13 months
Performed by assays from previously collected samples
From Baseline to 13 months
Change in presence of non-specific and specific autoantibodies in blood
Time Frame: From Baseline to 13 months
Performed by assays from previously collected samples
From Baseline to 13 months
Changes in Adverse Events - Safety monitoring laboratory tests
Time Frame: From Baseline to 13 months and as clinically warranted
Patient monitoring for adverse effects
From Baseline to 13 months and as clinically warranted
Changes in total days hospitalized for disease-related illnesses.
Time Frame: Baseline - 13 months
Assess the effects of the treatment
Baseline - 13 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Children's Hospital of Philadelphia

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
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

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • 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

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 1, 2025

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 1, 2029

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2029

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 4, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 3, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 9, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 1, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 28, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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