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

Primary Purpose

Aicardi Goutières Syndrome

Status
Not yet recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Tenofovir (TDF) and Emtricitabine (FTC)
Placebo
Sponsored by
Children's Hospital of Philadelphia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Aicardi Goutières Syndrome focused on measuring Leukodystrophy, Antiretroviral Drugs

Eligibility Criteria

2 Years - 18 Years (Child, Adult)All SexesDoes not accept 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

Sites / Locations

  • Children's Hospital of Philadelphia

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

TDF/FTC then Placebo

Placebo then TDF/FTC

Arm 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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
Accumulation of endogenous retroelements as measured in circulating immune cells
Performed by assays from previously collected samples
Accumulation of endogenous retroelements as measured in circulating CSF
Performed by assays from previously collected samples
Change in presence of non-specific and specific autoantibodies in blood
Performed by assays from previously collected samples
Changes in Adverse Events - Safety monitoring laboratory tests
Patient monitoring for adverse effects
Changes in total days hospitalized for disease-related illnesses.
Assess the effects of the treatment

Full Information

First Posted
August 4, 2017
Last Updated
January 17, 2023
Sponsor
Children's Hospital of Philadelphia
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Human Genome Research Institute (NHGRI), Gilead Sciences, Emerson Resources, National Institutes of Health (NIH)
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1. Study Identification

Unique Protocol Identification Number
NCT03304717
Brief Title
Reverse Transcriptase Inhibitors in Aicardi Goutières Syndrome
Acronym
RTI in AGS
Official Title
Reverse Transcriptase Inhibitors in Aicardi Goutières Syndrome
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
December 2023 (Anticipated)
Primary Completion Date
December 2028 (Anticipated)
Study Completion Date
December 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Children's Hospital of Philadelphia
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Human Genome Research Institute (NHGRI), Gilead Sciences, Emerson Resources, National Institutes of Health (NIH)

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Aicardi Goutières Syndrome
Keywords
Leukodystrophy, Antiretroviral Drugs

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
34 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
TDF/FTC then Placebo
Arm Type
Experimental
Arm 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.
Arm Title
Placebo then TDF/FTC
Arm Type
Experimental
Arm 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.
Intervention Type
Drug
Intervention Name(s)
Tenofovir (TDF) and Emtricitabine (FTC)
Other Intervention Name(s)
Truvada (Tenofovir Disoproxil Fumarate and Emtricitabine), Viread (Brand for tenofovir disoproxil fumarate), Emtriva (Brand for emtricitabine)
Intervention Description
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
Other
Intervention Name(s)
Placebo
Intervention Description
Placebo for Tenofovir and Placebo for Emtricitabine
Primary Outcome Measure Information:
Title
Change in interferon activation as measured by interferon response genes
Description
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.
Time Frame
From Baseline to 13 months
Secondary Outcome Measure Information:
Title
Determination of immune cell composition in CSF
Description
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.
Time Frame
From Baseline to 13 months
Title
Determination of immune cell composition in blood
Description
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.
Time Frame
From Baseline to 13 months
Title
Accumulation of endogenous retroelements as measured in circulating immune cells
Description
Performed by assays from previously collected samples
Time Frame
From Baseline to 13 months
Title
Accumulation of endogenous retroelements as measured in circulating CSF
Description
Performed by assays from previously collected samples
Time Frame
From Baseline to 13 months
Title
Change in presence of non-specific and specific autoantibodies in blood
Description
Performed by assays from previously collected samples
Time Frame
From Baseline to 13 months
Title
Changes in Adverse Events - Safety monitoring laboratory tests
Description
Patient monitoring for adverse effects
Time Frame
From Baseline to 13 months and as clinically warranted
Title
Changes in total days hospitalized for disease-related illnesses.
Description
Assess the effects of the treatment
Time Frame
Baseline - 13 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Constance Besnier
Phone
215-590-0373
Email
besnierc@chop.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Adeline Vanderver, MD
Organizational Affiliation
Children's Hospital of Philadelphia
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
William Gahl, MD. PhD
Organizational Affiliation
National Institute of Health Genome Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Adeline Vanderver, MD
Phone
215-590-1719
Email
vandervera@chop.edu
First Name & Middle Initial & Last Name & Degree
Adeline Vanderver, MD

12. IPD Sharing Statement

Learn more about this trial

Reverse Transcriptase Inhibitors in Aicardi Goutières Syndrome

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