Reverse Transcriptase Inhibitors in AGS (RTIs in AGS)
Primary Purpose
Aicardi-Goutières Syndrome (AGS)
Status
Completed
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Reverse transcriptase inhibitors: Zidovudine, Lamivudine, Abacavir
Sponsored by
About this trial
This is an interventional treatment trial for Aicardi-Goutières Syndrome (AGS) focused on measuring Aicardi-Goutières syndrome, Reverse transcriptase inhibitors, open single study, interferon signature
Eligibility Criteria
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
Sites / Locations
- Hôpital Necker - Enfants Malades
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
AGS
Arm Description
Reverse transcriptase inhibitors
Outcomes
Primary Outcome Measures
Interferon signature
Interferon Score
Secondary Outcome Measures
Interferon signature
Interferon Score
Adverse Events
Interferon Activity Level in cerebrospinal fluid (UI/L)
Interferon Activity Level in blood (UI/L)
Interferon Activity Level in blood (UI/L)
Interferon Protein in cerebrospinal fluid (Fg/mL)
Interferon Protein in blood (FG/mL)
Interferon Protein in blood (Fg/mL)
Neurological assessment
Scale for Evaluation of Movement Disorders Vineland Adaptive Behaviour Scales
Neurological assessment
Scale for Evaluation of Movement Disorders Vineland Adaptive Behaviour Scales
Neurological assessment
Scale for Evaluation of Movement Disorders Vineland Adaptive Behaviour Scales
Radiological assessment
MRI, CT Scan
Radiological assessment
MRI, CT Scan
dosages of abacavir
Blood sample
dosages of zidovudine
Blood sample
dosages of lamivudine
Blood sample
dosages of zidovudine
Blood sample
dosages of lamivudine
Blood sample
dosages of abacavir
Blood sample
dosages of abacavir
Blood sample
dosages of zidovudine
Blood sample
dosages of lamivudine
Blood sample
Number of chilblains lesions
Number of chilblains lesions
Number of chilblains lesions
Number of chilblains lesions
Number of chilblains lesions
Number of chilblains lesions
Number of chilblains lesions
Full Information
NCT ID
NCT02363452
First Posted
January 15, 2015
Last Updated
March 14, 2019
Sponsor
Assistance Publique - Hôpitaux de Paris
1. Study Identification
Unique Protocol Identification Number
NCT02363452
Brief Title
Reverse Transcriptase Inhibitors in AGS
Acronym
RTIs in AGS
Official Title
A Pilot Clinical Trial of Reverse Transcriptase Inhibitors in Children With Aicardi-Goutières Syndrome (AGS)
Study Type
Interventional
2. Study Status
Record Verification Date
February 2019
Overall Recruitment Status
Completed
Study Start Date
September 10, 2015 (Actual)
Primary Completion Date
January 2018 (Actual)
Study Completion Date
June 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Aicardi-Goutières Syndrome (AGS)
Keywords
Aicardi-Goutières syndrome, Reverse transcriptase inhibitors, open single study, interferon signature
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
11 (Actual)
8. Arms, Groups, and Interventions
Arm Title
AGS
Arm Type
Experimental
Arm Description
Reverse transcriptase inhibitors
Intervention Type
Drug
Intervention Name(s)
Reverse transcriptase inhibitors: Zidovudine, Lamivudine, Abacavir
Intervention Description
Oral Solution (syrup) or Tablets
Primary Outcome Measure Information:
Title
Interferon signature
Description
Interferon Score
Time Frame
Before and after 12 months of treatment
Secondary Outcome Measure Information:
Title
Interferon signature
Description
Interferon Score
Time Frame
Month 18
Title
Adverse Events
Time Frame
Baseline until Month 18
Title
Interferon Activity Level in cerebrospinal fluid (UI/L)
Time Frame
Within the 12 month on treatment
Title
Interferon Activity Level in blood (UI/L)
Time Frame
Within the 12 month on treatment
Title
Interferon Activity Level in blood (UI/L)
Time Frame
month 18
Title
Interferon Protein in cerebrospinal fluid (Fg/mL)
Time Frame
within the 12 month on treatment
Title
Interferon Protein in blood (FG/mL)
Time Frame
Within the 12 month on treatment
Title
Interferon Protein in blood (Fg/mL)
Time Frame
Month 18
Title
Neurological assessment
Description
Scale for Evaluation of Movement Disorders Vineland Adaptive Behaviour Scales
Time Frame
Baseline
Title
Neurological assessment
Description
Scale for Evaluation of Movement Disorders Vineland Adaptive Behaviour Scales
Time Frame
Month 12
Title
Neurological assessment
Description
Scale for Evaluation of Movement Disorders Vineland Adaptive Behaviour Scales
Time Frame
Month 18
Title
Radiological assessment
Description
MRI, CT Scan
Time Frame
Baseline
Title
Radiological assessment
Description
MRI, CT Scan
Time Frame
Month 12
Title
dosages of abacavir
Description
Blood sample
Time Frame
Month 1
Title
dosages of zidovudine
Description
Blood sample
Time Frame
Month 1
Title
dosages of lamivudine
Description
Blood sample
Time Frame
Month 1
Title
dosages of zidovudine
Description
Blood sample
Time Frame
Month 3
Title
dosages of lamivudine
Description
Blood sample
Time Frame
Month 3
Title
dosages of abacavir
Description
Blood sample
Time Frame
Month 3
Title
dosages of abacavir
Description
Blood sample
Time Frame
Month 6
Title
dosages of zidovudine
Description
Blood sample
Time Frame
Month 6
Title
dosages of lamivudine
Description
Blood sample
Time Frame
Month 6
Title
Number of chilblains lesions
Time Frame
baseline
Title
Number of chilblains lesions
Time Frame
Month 1
Title
Number of chilblains lesions
Time Frame
Month 3
Title
Number of chilblains lesions
Time Frame
Month 6
Title
Number of chilblains lesions
Time Frame
Month 9
Title
Number of chilblains lesions
Time Frame
Month 12
Title
Number of chilblains lesions
Time Frame
Month 18
10. Eligibility
Sex
All
Minimum Age & Unit of Time
1 Month
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yanick CROW, MD, PhD
Organizational Affiliation
Hôpital Necker - Enfants Malades Public Hospitals of Paris
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Stéphane BLANCHE, MD,PhD
Organizational Affiliation
Hôpital Necker - Enfants Malades Public Hospitals of Paris
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hôpital Necker - Enfants Malades
City
Paris
ZIP/Postal Code
75015
Country
France
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
23607857
Citation
Crow YJ, Vanderver A, Orcesi S, Kuijpers TW, Rice GI. Therapies in Aicardi-Goutieres syndrome. Clin Exp Immunol. 2014 Jan;175(1):1-8. doi: 10.1111/cei.12115.
Results Reference
background
PubMed Identifier
30566312
Citation
Rice GI, Meyzer C, Bouazza N, Hully M, Boddaert N, Semeraro M, Zeef LAH, Rozenberg F, Bondet V, Duffy D, Llibre A, Baek J, Sambe MN, Henry E, Jolaine V, Barnerias C, Barth M, Belot A, Cances C, Debray FG, Doummar D, Fremond ML, Kitabayashi N, Lepelley A, Levrat V, Melki I, Meyer P, Nougues MC, Renaldo F, Rodero MP, Rodriguez D, Roubertie A, Seabra L, Uggenti C, Abdoul H, Treluyer JM, Desguerre I, Blanche S, Crow YJ. Reverse-Transcriptase Inhibitors in the Aicardi-Goutieres Syndrome. N Engl J Med. 2018 Dec 6;379(23):2275-7. doi: 10.1056/NEJMc1810983. No abstract available.
Results Reference
result
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Reverse Transcriptase Inhibitors in AGS
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