Aicardi-Goutières SyndromePhase 2AGS-RTINCT04731103
Inhibition of Reverse Transcription in Aicardi-Goutières Syndrome
A Phase 2 study testing Abacavir (ABC), Lamivudine (3TC) and Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT) in people with Aicardi-Goutières Syndrome, run by University of Edinburgh at 1 site in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 3 months to 15 years
- Conditions the study is for
- Aicardi-Goutières Syndrome
- What is being tested?
- Abacavir (ABC), Lamivudine (3TC) and Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 13 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 24 Aug 2022to 11 Mar 2024
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 3 months to 15 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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.
Who cannot join
- 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
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- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Inhibition of Reverse Transcription in Type I Interferon Mediated Neuropathology
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.
Read the 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.
- Conditions
- Aicardi-Goutières Syndrome
- Being tested
- Abacavir (ABC), Lamivudine (3TC), Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT)
- Keywords
- Type 1 Interferon, Reverse Transcriptase Inhibitor(s)
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Abacavir (ABC)Drug
Tablets or oral solution
Lamivudine (3TC)Drug
Tablet or oral solution
Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT)Drug
Tablet or oral solution
| Study group | Role | What they receive |
|---|---|---|
| Abacavir (ABC) | Active comparator | Participants receive Abacavir (ABC) for 6 weeks and 4 weeks of washout. Receives: Drug: Abacavir (ABC) |
| Lamivudine (3TC) | Active comparator | Participants receive Lamivudine (3TC) for 6 weeks and 4 weeks of washout. Receives: 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. Receives: Drug: Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: At 6 weeks
Secondary outcomes (2)
A change in interferon alpha protein levels
Change in interferon alpha protein levels (fg/ml) over 6 weeks per treatment arm.
Measured: 6 weeks
A change in cerebral blood flow
Change in cerebral blood flow (ml/min/100g of tissue) over 6 weeks per treatment arm.
Measured: 6 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jan 2021
- Study start24 Aug 2022
- Primary completion11 Mar 2024
- Study completion11 Mar 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Aicardi-Goutières SyndromeStudies of the same condition, open and under way.
- More trials run by University of EdinburghThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Model description
- 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).
- Masking
- None (open label)
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Edinburgh
- Sponsor type
- University, hospital or other
- Collaborators
- NHS Lothian, Medical Research Council
- Responsible party
- Sponsor
- Investigators
- Yanick Crow, Principal investigator, University of Edinburgh
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04731103
- Sponsor's protocol ID
- AC19167
- Acronym
- AGS-RTI
- Status last verified
- Jun 2023
- First submitted
- 14 Jul 2020
- Last updated
- 9 May 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 30566312
Study at a glance
From the registry record, last updated by the sponsor on 9 May 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Inhibition of Reverse Transcription in Type I Interferon Mediated Neuropathology
- ClinicalTrials.gov ID
- NCT04731103
- Acronym / sponsor ID
- AGS-RTI / AC19167
- Conditions
- Aicardi-Goutières Syndrome
- Keywords
- Type 1 Interferon, Reverse Transcriptase Inhibitor(s)
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 13 participants (actual)
- Lead sponsor
- University of EdinburghUniversity, hospital or other
- Collaborators
- NHS Lothian, Medical Research Council
- Study start
- 24 Aug 2022 (actual)
- Primary completion
- 11 Mar 2024 (actual)
- Study completion
- 11 Mar 2024 (actual)
- First posted
- 29 Jan 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- 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).
| Arm | Type | Receives |
|---|---|---|
| Abacavir (ABC) | Active comparator | Drug: Abacavir (ABC)Participants receive Abacavir (ABC) for 6 weeks and 4 weeks of washout. |
| Lamivudine (3TC) | Active comparator | Drug: Lamivudine (3TC)Participants receive Lamivudine (3TC) for 6 weeks and 4 weeks of washout. |
| Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT) | Active comparator | Drug: Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT)Participants receive Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT) for 6 weeks and 4 weeks of washout. |
Who may qualify
- Ages
- 3 months to 15 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (10 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Abacavir (ABC)Tablets or oral solution | Drug | Abacavir (ABC) |
| Lamivudine (3TC)Tablet or oral solution | Drug | Lamivudine (3TC) |
| Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT)Tablet or oral solution | Drug | Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT) |
Primary outcome
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
The primary outcome is a change in the Interferon(IFN) score over baseline at 6 weeks end of treatment.
2 secondary outcomes
A change in interferon alpha protein levels
Time frame: 6 weeks
A change in cerebral blood flow
Time frame: 6 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 May 2024.
- Background: PubMed 30566312Rice 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.
- Individual participant dataSharing planned: No
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Yanick Crow principal investigator
University of Edinburgh
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Abacavir (ABC), Lamivudine (3TC) and Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT) in people with Aicardi-Goutières Syndrome, run by University of Edinburgh at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 May 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04731103, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 May 2024.