Clinical Trial: Reverse Transcriptase Inhibitors in AGS

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: A Pilot Clinical Trial of Reverse Transcriptase Inhibitors in Children With Aicardi-Goutières Syndrome (AGS)

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.

Detailed Summary:

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 A
Sponsor: Assistance Publique - Hôpitaux de Paris

Current Primary Outcome: Interferon signature [ Time Frame: Before and after 12 months of treatment ]

Interferon Score


Original Primary Outcome:

  • Interferon signature [ Time Frame: Before and after 12 months of treatment ]
    Interferon Score
  • Interferon signature [ Time Frame: Month 6 ]
    Interferon Score
  • Interferon signature [ Time Frame: Month 18 ]
    Interferon Score


Current Secondary Outcome:

  • Interferon signature [ Time Frame: Month 18 ]
    Interferon Score
  • Adverse Events [ Time Frame: Baseline until Month 18 ]
  • Interferon Activity Level in cerebrospinal fluid (UI/L) [ Time Frame: Within the 12 month on treatment ]
  • Interferon Activity Level in blood (UI/L) [ Time Frame: Within the 12 month on treatment ]
  • Interferon Activity Level in blood (UI/L) [ Time Frame: month 18 ]
  • Interferon Protein in cerebrospinal fluid (Fg/mL) [ Time Frame: within the 12 month on treatment ]
  • Interferon Protein in blood (FG/mL) [ Time Frame: Within the 12 month on treatment ]
  • Interferon Protein in blood (Fg/mL) [ Time Frame: Month 18 ]
  • Neurological assessment [ Time Frame: Baseline ]
    Scale for Evaluation of Movement Disorders Vineland Adaptive Behaviour Scales
  • Neurological assessment [ Time Frame: Month 12 ]
    Scale for Evaluation of Movement Disorders Vineland Adaptive Behaviour Scales
  • Neurological assessment [ Time Frame: Month 18 ]
    Scale for Evaluation of Movement Disorders Vineland Adaptive Behaviour Scales
  • Radiological assessment [ Time Frame: Baseline ]
    MRI, CT Scan
  • Radiological assessment [ Time Frame: Month 12 ]
    MRI, CT Scan
  • dosages of abacavir [ Time Frame: Month 1 ]
    Blood sample
  • dosages of zidovudine [ Time Frame: Month 1 ]
    Blood sample
  • dosages of lamivudine [ Time Frame: Month 1 ]
    Blood sample
  • dosages of zidovudine [ Time Frame: Month 3 ]
    Blood sample
  • dosages of lamivudine [ Time Frame: Month 3 ]
    Blood sample
  • dosages of abacavir [ Time Frame: Month 3 ]
    Blood sample
  • dosages of abacavir [ Time Frame: Month 6 ]
    Blood sample
  • dosages of zidovudine [ Time Frame: Month 6 ]
    Blood sample
  • dosages of lamivudine [ Time Frame: Month 6 ]
    Blood sample
  • Number of chilblains lesions [ Time Frame: baseline ]
  • Number of chilblains lesions [ Time Frame: Month 1 ]
  • Number of chilblains lesions [ Time Frame: Month 3 ]
  • Number of chilblains lesions [ Time Frame: Month 6 ]
  • Number of chilblains lesions [ Time Frame: Month 9 ]
  • Number of chilblains lesions [ Time Frame: Month 12 ]
  • Number of chilblains lesions [ Time Frame: Month 18 ]


Original Secondary Outcome:

  • Adverse Events [ Time Frame: Baseline until Month 18 ]
  • Interferon Level [ Time Frame: Within the 12 month on treatment ]
    Blood, CSF
  • Neurological assessment [ Time Frame: Baseline ]
    Scale for Evaluation of Movement Disorders Vineland Adaptive Behaviour Scales
  • Neurological assessment [ Time Frame: Month 12 ]
    Scale for Evaluation of Movement Disorders Vineland Adaptive Behaviour Scales
  • Neurological assessment [ Time Frame: Month 18 ]
    Scale for Evaluation of Movement Disorders Vineland Adaptive Behaviour Scales
  • Radiological assessment [ Time Frame: Baseline ]
    MRI, CT Scan
  • Radiological assessment [ Time Frame: Month 12 ]
    MRI, CT Scan
  • dosages of abacavir [ Time Frame: Month 1 ]
    Blood sample
  • dosages of zidovudine [ Time Frame: Month 1 ]
    Blood sample
  • dosages of lamivudine [ Time Frame: Month 1 ]
    Blood sample
  • dosages of zidovudine [ Time Frame: Month 3 ]
    Blood sample
  • dosages of lamivudine [ Time Frame: Month 3 ]
    Blood sample
  • dosages of abacavir [ Time Frame: Month 3 ]
    Blood sample
  • dosages of abacavir [ Time Frame: Month 6 ]
    Blood sample
  • dosages of zidovudine [ Time Frame: Month 6 ]
    Blood sample
  • dosages of lamivudine [ Time Frame: Month 6 ]
    Blood sample


Information By: Assistance Publique - Hôpitaux de Paris

Dates:
Date Received: January 15, 2015
Date Started: September 2015
Date Completion: June 2018
Last Updated: May 17, 2016
Last Verified: May 2016