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

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ClinicalTrials.gov Identifier: NCT03304717
Recruitment Status : Not yet recruiting
First Posted : October 9, 2017
Last Update Posted : March 8, 2021
Sponsor:
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)
Information provided by (Responsible Party):
Children's Hospital of Philadelphia

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.

Condition or disease Intervention/treatment Phase
Aicardi Goutières Syndrome Drug: Tenofovir (TDF) and Emtricitabine (FTC) Other: Placebo Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 34 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Reverse Transcriptase Inhibitors in Aicardi Goutières Syndrome
Estimated Study Start Date : December 2021
Estimated Primary Completion Date : December 2026
Estimated Study Completion Date : December 2026


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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. Accumulation of endogenous retroelements as measured in circulating immune cells [ Time Frame: From Baseline to 13 months ]
    Performed by assays from previously collected samples

  4. Accumulation of endogenous retroelements as measured in circulating CSF [ Time Frame: From Baseline to 13 months ]
    Performed by assays from previously collected samples

  5. 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

  6. Changes in Adverse Events - Safety monitoring laboratory tests [ Time Frame: From Baseline to 13 months and as clinically warranted ]
    Patient monitoring for adverse effects

  7. Changes in total days hospitalized for disease-related illnesses. [ Time Frame: Baseline - 13 months ]
    Assess the effects of the treatment



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03304717


Contacts
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Contact: Constance Besnier 215-590-0373 besnierc@chop.edu

Locations
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United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Contact: Adeline Vanderver, MD    215-590-1719    vandervera@chop.edu   
Principal Investigator: Adeline Vanderver, MD         
Sponsors and Collaborators
Children's Hospital of Philadelphia
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)
Investigators
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Principal Investigator: Adeline Vanderver, MD Children's Hospital of Philadelphia
Principal Investigator: William Gahl, MD. PhD National Institute of Health Genome Research Institute
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Responsible Party: Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT03304717    
Other Study ID Numbers: 17-013715
U01HD082806-03 ( U.S. NIH Grant/Contract )
First Posted: October 9, 2017    Key Record Dates
Last Update Posted: March 8, 2021
Last Verified: March 2021

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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
Keywords provided by Children's Hospital of Philadelphia:
Leukodystrophy
Antiretroviral Drugs
Additional relevant MeSH terms:
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Nervous System Malformations
Autoimmune Diseases of the Nervous System
Syndrome
Disease
Pathologic Processes
Nervous System Diseases
Congenital Abnormalities
Autoimmune Diseases
Immune System Diseases
Tenofovir
Emtricitabine
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents