Inhibition of Reverse Transcription in Aicardi-Goutières Syndrome

NCT04731103 | Completed Phase 2 DMC

• 1 other identifier: AC19167
• Study Type: interventional
• Actual enrollment (reported): 13
• Locations: 1 country
• Sites: 1
• Actual (reported): Study Start
• Actual (reported): Primary Completion
• Actual (reported): Study Completion

Brief Summary

Aicardi-Goutières syndrome (AGS) is a disease of children, particularly affecting the brain and the skin. There is a close link between AGS and increased amounts of a chemical called interferon. Normally humans only produce interferon when they are infected with a virus. In AGS, there is no viral infection. Instead, the cells in the cells of affected patients are confused into thinking that their own genetic material is coming from a virus. As a result they produce interferon all the time, which acts as a poison that damages the cells. The Investigators wish to treat AGS patients with drugs called reverse transcriptase inhibitors (RTIs), used to fight the HIV-1 virus that causes AIDS. The investigators will monitor the effect of treatment on interferon levels, and look at other markers which might give us clues to how the drugs are working. The trial is funded by the Medical Research Council, and involves experts based in Edinburgh, Birmingham, Manchester and Great Ormond Street Hospital.

Conditions

Aicardi-Goutières Syndrome

Keywords

Type 1 Interferon; Reverse Transcriptase Inhibitor(s)

Outcome Measures

Primary Outcomes (1)

• Determine if the use of the reverse transcriptase inhibitors abacavir (ABC), lamivudine (3TC) and zidovudine (AZT) reduces Interferon (IFN) signalling in patients with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C or SAMHD1

  The primary outcome is a change in the Interferon(IFN) score over baseline at 6 weeks end of treatment.

  At 6 weeks

Secondary Outcomes (2)

• A change in interferon alpha protein levels

  6 weeks

• A change in cerebral blood flow

  6 weeks

Study Arms (3)

Abacavir (ABC)

ACTIVE COMPARATOR

Participants receive Abacavir (ABC) for 6 weeks and 4 weeks of washout.

Drug: Abacavir (ABC)

Lamivudine (3TC)

ACTIVE COMPARATOR

Participants receive Lamivudine (3TC) for 6 weeks and 4 weeks of washout.

Drug: Lamivudine (3TC)

Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT)

ACTIVE COMPARATOR

Participants receive Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT) for 6 weeks and 4 weeks of washout.

Drug: Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT)

Interventions

Abacavir (ABC) DRUG

Tablets or oral solution

Abacavir (ABC)

Lamivudine (3TC) DRUG

Tablet or oral solution

Lamivudine (3TC)

Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT) DRUG

Tablet or oral solution

Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT)

Eligibility Criteria

• Age: 3 Months - 15 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Patients with mutations in any of TREX1, the three components of the RNase H2 complex (RNASEH2A, RNASEH2B, RNASEH2C: considered as one genotype) or SAMHD1.
• Greater than age 3 months and less than 16 years of age at the time of recruitment
• Resident in the United Kingdom (UK)
• Informed Consent obtained from parent or personal legal representative

You may not qualify if:

• Patients with AGS due to mutations in ADAR1 and IFIH1 will not be considered, given that the induction of interferon relating to these genotypes does not involve a reverse transcription step.
• Pre-existing disease, not due to AGS, which would preclude the use of zidovudine, lamivudine and abacavir
• Patients with abnormally low neutrophil counts (\<0.75 x 109/l) and / or abnormally low haemoglobin levels (\<7.5 g/dl)(particularly relevant to zidovudine), significant renal (creatinine clearance \< 50 ml/min; particularly relevant to lamivudine) or significant hepatic impairment (particularly relevant to abacavir; avoid if Child Pugh \> 5)
• Participation in another Clinical Trial of an Investigational Medicinal Product (CTIMP) trial
• Pregnancy
• Breast feeding
• Hepatitis B and C infection
• Potential hypersensitivity to abacavir, assessed according to HLA-B\*5701 status
• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 of the Summary of Product Characteristics (SPC)
• Where, in the opinion of the Investigator the participant cannot fulfil the requirements of the trial protocol

Sponsors & Collaborators

• University of Edinburgh: lead
• NHS Lothian: collaborator
• Medical Research Council: collaborator

Study Sites (1)

Yanick Crow

Edinburgh, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 30566312 BACKGROUND

MeSH Terms

Interventions

abacavir; Lamivudine

Intervention Hierarchy (Ancestors)

Zalcitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Dideoxynucleosides

Study Officials

• Yanick Crow

  University of Edinburgh

  PRINCIPAL INVESTIGATOR

Enrollment

13 participants — actual enrollment reported by the registry.

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Open label, non-placebo controlled. We propose a trial design involving an initial no-drug period of six weeks followed by three treatment arms each of six weeks, with a washout period of four weeks between treatment arms (considering documented drug half-lives).

Study Record Dates

• First Submitted: July 14, 2020
• First Posted: January 29, 2021
• Last Updated: May 9, 2024

Study Start

August 24, 2022

Actual (reported)

Primary Completion

March 11, 2024

Actual (reported)

Study Completion

March 11, 2024

Actual (reported)

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)