Reverse Transcriptase Inhibitors in AGS (RTIs in AGS)

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

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.

Study Overview

• Status: Completed
• Conditions: Aicardi-Goutières Syndrome (AGS)
• Intervention / Treatment: Drug: Reverse transcriptase inhibitors: Zidovudine, Lamivudine, Abacavir

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: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France, 75015
    • Hôpital Necker - Enfants Malades

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Interferon signature	Interferon Score	Before and after 12 months of treatment

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: 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 and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2015
• Primary Completion (Actual): January 1, 2018
• Study Completion (Actual): June 1, 2018

Study Registration Dates

• First Submitted: January 15, 2015
• First Submitted That Met QC Criteria: February 13, 2015
• First Posted (Estimate): February 16, 2015

Study Record Updates

• Last Update Posted (Actual): March 15, 2019
• Last Update Submitted That Met QC Criteria: March 14, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: Aicardi-Goutières syndrome; Reverse transcriptase inhibitors; open single study; interferon signature
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Autoimmune Diseases; Disease; Congenital Abnormalities; Syndrome; Autoimmune Diseases of the Nervous System; Nervous System Malformations; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Lamivudine; Zidovudine; Reverse Transcriptase Inhibitors; Abacavir
• Other Study ID Numbers: P140203

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No