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Reverse Transcriptase Inhibitors in AGS (RTIs in AGS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02363452
Recruitment Status : Completed
First Posted : February 16, 2015
Last Update Posted : March 15, 2019
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:
The purpose of this study is to determine if treatment with reverse transcriptase inhibitors returns the interferon signature observed in patients with AGS to normal levels.

Condition or disease Intervention/treatment Phase
Aicardi-Goutières Syndrome (AGS) Drug: Reverse transcriptase inhibitors: Zidovudine, Lamivudine, Abacavir Phase 2

Detailed Description:

AGS is a genetically heterogeneous disease resulting from mutations in any one of the genes encoding the 3-prime repair exonuclease TREX1 (AGS1), the three non-allelic components of the RNASEH2 endonuclease complex (AGS2, 3 and 4), the Sam domain and HD domain containing protein (SAMHD1; AGS5) which functions as a deoxynucleoside triphosphate triphosphohydrolase, the double stranded RNA editing enzyme ADAR1, or the cytosolic dsRNA sensor IFIH1. It is hypothesized that AGS1-6 are involved in limiting the accumulation of intracellular nucleic acid species, a failure of which process results in triggering of an innate immune response that is more normally induced by viral nucleic acids. That is, in the absence of AGS-related protein activity, endogenous nucleic acids accumulate and are sensed as viral or 'non-self', leading to the induction of an interferon (IFN) alpha mediated immune response and the production of antibodies against self nucleic acids. AGS is associated with increased levels of interferon alpha in the cerebrospinal fluid (CSF) and serum. Available data suggest that AGS might be treated with (particular) reverse transcriptase inhibitors (which compounds can potentially disrupt both exogenous retroviral and endogenous retroelement cycling). No systematic approach to treatment in AGS has been explored. The investigators hypothesis is that reverse transcriptase inhibitors will also inhibit the reverse transcription of endogenous retroelements which are deemed to be responsible for initiating the tissue damage seen in AGS. Consequently, for the purpose of the investigators pilot study, it would be ideal to assess the effects of therapy by monitoring a reactive biomarker.

This is a single centre, open, single arm, phase II study in children with AGS. This study design is justified because no data are available about antiretroviral drug efficacy in children with AGS. Moreover, this study is the first step before a phase III study of drug efficacy.

The investigators propose a pilot clinical trial of selected reverse transcriptase inhibitors in AGS patients, with the specific endpoint of assessing the effect of treatment on the disease-associated interferon signature. The investigators propose to evaluate the safety of combination therapy comprising the three nucleoside analog reverse-transcriptase inhibitors (NRTIs) zidovudine (AZT), lamivudine (3TC), abacavir (ABC) in patients with AGS over a 52 week period of treatment. The inclusion period is 12 months. Patients can not participate in a biomedical trial of another drug during the 18 month follow-up (12 months of treatment period plus 6 months post treatment period).

A total of six visits (including a final visit) are scheduled for this trial over a period of 18 months (M1, M3, M6, M9, M12, M18) for all patients.

Drugs will be dispensed for medication at home, at usual doses recommended in HIV infection. Subjects will be dosed according to French guidelines. Dosing will be reviewed at each study visit against current weight, and modified as necessary in accordance with French dosing guidelines.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Clinical Trial of Reverse Transcriptase Inhibitors in Children With Aicardi-Goutières Syndrome (AGS)
Actual Study Start Date : September 10, 2015
Actual Primary Completion Date : January 2018
Actual Study Completion Date : June 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Zidovudine

Arm Intervention/treatment
Experimental: AGS
Reverse transcriptase inhibitors
Drug: Reverse transcriptase inhibitors: Zidovudine, Lamivudine, Abacavir
Oral Solution (syrup) or Tablets

Primary Outcome Measures :
  1. Interferon signature [ Time Frame: Before and after 12 months of treatment ]
    Interferon Score

Secondary Outcome Measures :
  1. Interferon signature [ Time Frame: Month 18 ]
    Interferon Score

  2. Adverse Events [ Time Frame: Baseline until Month 18 ]
  3. Interferon Activity Level in cerebrospinal fluid (UI/L) [ Time Frame: Within the 12 month on treatment ]
  4. Interferon Activity Level in blood (UI/L) [ Time Frame: Within the 12 month on treatment ]
  5. Interferon Activity Level in blood (UI/L) [ Time Frame: month 18 ]
  6. Interferon Protein in cerebrospinal fluid (Fg/mL) [ Time Frame: within the 12 month on treatment ]
  7. Interferon Protein in blood (FG/mL) [ Time Frame: Within the 12 month on treatment ]
  8. Interferon Protein in blood (Fg/mL) [ Time Frame: Month 18 ]
  9. Neurological assessment [ Time Frame: Baseline ]
    Scale for Evaluation of Movement Disorders Vineland Adaptive Behaviour Scales

  10. Neurological assessment [ Time Frame: Month 12 ]
    Scale for Evaluation of Movement Disorders Vineland Adaptive Behaviour Scales

  11. Neurological assessment [ Time Frame: Month 18 ]
    Scale for Evaluation of Movement Disorders Vineland Adaptive Behaviour Scales

  12. Radiological assessment [ Time Frame: Baseline ]
    MRI, CT Scan

  13. Radiological assessment [ Time Frame: Month 12 ]
    MRI, CT Scan

  14. dosages of abacavir [ Time Frame: Month 1 ]
    Blood sample

  15. dosages of zidovudine [ Time Frame: Month 1 ]
    Blood sample

  16. dosages of lamivudine [ Time Frame: Month 1 ]
    Blood sample

  17. dosages of zidovudine [ Time Frame: Month 3 ]
    Blood sample

  18. dosages of lamivudine [ Time Frame: Month 3 ]
    Blood sample

  19. dosages of abacavir [ Time Frame: Month 3 ]
    Blood sample

  20. dosages of abacavir [ Time Frame: Month 6 ]
    Blood sample

  21. dosages of zidovudine [ Time Frame: Month 6 ]
    Blood sample

  22. dosages of lamivudine [ Time Frame: Month 6 ]
    Blood sample

  23. Number of chilblains lesions [ Time Frame: baseline ]
  24. Number of chilblains lesions [ Time Frame: Month 1 ]
  25. Number of chilblains lesions [ Time Frame: Month 3 ]
  26. Number of chilblains lesions [ Time Frame: Month 6 ]
  27. Number of chilblains lesions [ Time Frame: Month 9 ]
  28. Number of chilblains lesions [ Time Frame: Month 12 ]
  29. Number of chilblains lesions [ Time Frame: Month 18 ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   1 Month to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • A molecular diagnosis of AGS i.e. biallelic or known dominant mutations, with pathogenicity assessed using our extensive mutation database / functional data, in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C and SAMHD1 genes
  • A pre-defined interferon signature (consistently present, moderate or high, on at least three occasions, over a period of 6 months prior to enrolment in the study)
  • Age ≥ 1 month and < 18 years (either sex)
  • Patient beneficiary or affiliated to " health insurance"
  • Written informed consent

Exclusion Criteria:

  • Pre-existing disease, not due to AGS, which would preclude the use of zidovudine, Lamivudine and abacavir (as currently assessed in routine clinical HIV-related practice)
  • HLA B57-01 positive result, which indicates a greater risk of abacavir hypersensitivity reaction
  • Patients with abnormally low neutrophile counts (<0.75 x 109/l), or abnormally low haemoglobin levels (<7.5 g/dl or 4.65 mmol/l)(zidovudine contraindication)
  • Positive serology for HIV, HBV
  • Known history of cirrhosis and history of clinically relevant hepatitis within last 6 months
  • Moderate to severe renal impairment
  • Pregnancy, breastfeeding
  • Patient participating to a biomedical research with drug

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 identifier (NCT number): NCT02363452

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Hôpital Necker - Enfants Malades
Paris, France, 75015
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
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Study Chair: Yanick CROW, MD, PhD Hôpital Necker - Enfants Malades Public Hospitals of Paris
Principal Investigator: Stéphane BLANCHE, MD,PhD Hôpital Necker - Enfants Malades Public Hospitals of Paris
Publications of Results:
Other Publications:
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Responsible Party: Assistance Publique - Hôpitaux de Paris Identifier: NCT02363452    
Other Study ID Numbers: P140203
First Posted: February 16, 2015    Key Record Dates
Last Update Posted: March 15, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Aicardi-Goutières syndrome
Reverse transcriptase inhibitors
open single study
interferon signature
Additional relevant MeSH terms:
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Nervous System Malformations
Autoimmune Diseases of the Nervous System
Pathologic Processes
Nervous System Diseases
Congenital Abnormalities
Autoimmune Diseases
Immune System Diseases
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Anti-HIV Agents
Anti-Retroviral Agents