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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.
 
ClinicalTrials.gov Identifier: NCT02363452
Recruitment Status : Completed
First Posted : February 16, 2015
Last Update Posted : March 15, 2019
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE January 15, 2015
First Posted Date  ICMJE February 16, 2015
Last Update Posted Date March 15, 2019
Actual Study Start Date  ICMJE September 10, 2015
Actual Primary Completion Date January 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 29, 2016)
Interferon signature [ Time Frame: Before and after 12 months of treatment ]
Interferon Score
Original Primary Outcome Measures  ICMJE
 (submitted: February 13, 2015)
  • 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
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 29, 2016)
  • 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 Measures  ICMJE
 (submitted: February 13, 2015)
  • 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Reverse Transcriptase Inhibitors in AGS
Official Title  ICMJE 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 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Aicardi-Goutières Syndrome (AGS)
Intervention  ICMJE Drug: Reverse transcriptase inhibitors: Zidovudine, Lamivudine, Abacavir
Oral Solution (syrup) or Tablets
Study Arms  ICMJE Experimental: AGS
Reverse transcriptase inhibitors
Intervention: Drug: Reverse transcriptase inhibitors: Zidovudine, Lamivudine, Abacavir
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 20, 2017)
11
Original Estimated Enrollment  ICMJE
 (submitted: February 13, 2015)
24
Actual Study Completion Date  ICMJE June 2018
Actual Primary Completion Date January 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Month to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02363452
Other Study ID Numbers  ICMJE P140203
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE Not Provided
Investigators  ICMJE
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
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP