- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04731103
Inhibition of Reverse Transcription in Aicardi-Goutières Syndrome (AGS-RTI)
Inhibition of Reverse Transcription in Type I Interferon Mediated Neuropathology
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Aicardi-Goutières syndrome (AGS) is a severe childhood disease of the brain associated with very high levels of a chemical called type I interferon. Normally humans only produce interferon when they are infected with a virus. In AGS, there is no obvious viral infection. Instead, due to changes (mutations) in the genetic code in these individuals, it is believed that the cells in the body are fooled into thinking that the person's own DNA is viral - that is to say, there is a confusion in telling 'self' from 'non-self'.
In fact, a large amount of our own DNA is made up of ancient virus (called 'endogenous retrovirus' and sometimes also referred to as 'junk DNA'), that have been included into our own genetic material over millions of years. These endogenous retroviruses can still act like a virus coming from outside of the body, so that they need to be controlled. The Investigators have wondered if the genetic changes causing AGS mean that these normal control mechanisms don't work. If that is true, the endogenous retroviruses could start to make copies of themselves which might be recognised by our immune system as 'non-self' ('foreign' i.e. viral), leading to the continuous production of interferon which then damages the cells in our body.
Since humans cannot repair the genetic code in every cell, the investigators wish to treat AGS patients with drugs called reverse transcriptase inhibitors (RTIs). RTIs are used to fight the HIV-1 virus that causes AIDS. In the case of AGS, it is not treating HIV-1, but the investigators wonder if the same drugs might be able to control endogenous retroviruses that are driving interferon production. Indeed, in a recently completed study the investigators gathered early information to suggest that treatment of patients with AGS with RTIs for one year did lead to a reduction in interferon, with levels increasing again when we stopped the drugs.
The current study will involve three treatment arms, and an assessment of interferon status and other markers which we think will give us information about AGS, and about how RTIs may work in the treatment of AGS.
This study is of potential importance for patients with AGS and their families since there are no licenced drugs for this disorder at the present time. Scientifically, the project will be of considerable interest if the results support the possibility that 'junk DNA' can be associated with human disease. RTIs are very safe drugs, that have been used in millions of people with HIV-1 around the world. If the results turn out to be convincing, the investigators believe that it might be worth thinking about using RTIs to treat other diseases that have also been linked to increased levels of type I interferon, for example the relatively common immune condition called systemic lupus erythematosus.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Yanick Crow, MBBS; MRCP
- Phone Number: 07595398159
- Email: Yanick.Crow@ed.ac.uk
Study Contact Backup
- Name: Claire Battison, BA(Hons)
- Email: agsrti.trial@ed.ac.uk
Study Locations
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-
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Edinburgh, United Kingdom
- Recruiting
- Yanick Crow
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Contact:
- Yanick Crow
- Email: Yanick.Crow@ed.ac.uk
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- 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
- For inclusion in the study, a patient has either to have completed the vaccination programme two weeks prior to starting the trial, or remain unvaccinated until the end of the trial, or agree to defer vaccination until immediately after a study drug arm, so that there is a period of at least two weeks following vaccination and before the start of the following drug arm.
Exclusion Criteria:
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Crossover Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Abacavir (ABC)
Participants receive Abacavir (ABC) for 6 weeks and 4 weeks of washout.
|
Tablets or oral solution
|
Active Comparator: Lamivudine (3TC)
Participants receive Lamivudine (3TC) for 6 weeks and 4 weeks of washout.
|
Tablet or oral solution
|
Active Comparator: Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT)
Participants receive Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT) for 6 weeks and 4 weeks of washout.
|
Tablet or oral solution
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
Time Frame: At 6 weeks
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The primary outcome is a change in the Interferon(IFN) score over baseline at 6 weeks end of treatment.
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At 6 weeks
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
A change in interferon alpha protein levels
Time Frame: 6 weeks
|
Change in interferon alpha protein levels (fg/ml) over 6 weeks per treatment arm.
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6 weeks
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A change in cerebral blood flow
Time Frame: 6 weeks
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Change in cerebral blood flow (ml/min/100g of tissue) over 6 weeks per treatment arm.
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6 weeks
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Correlate changes in markers of brain cellular health
Time Frame: 6 weeks
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Change in levels of NfL and GFAP (pg/ml) over 6 weeks per treatment arm.
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6 weeks
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Yanick Crow, University of Edinburgh
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
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
- Reverse Transcriptase Inhibitors
- Nucleic Acid Synthesis Inhibitors
- Enzyme Inhibitors
- Anti-HIV Agents
- Anti-Retroviral Agents
- Antimetabolites
- Lamivudine
- Zidovudine
- Abacavir
- Dideoxynucleosides
Other Study ID Numbers
- AC19167
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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