Assessing the effect of Triumeq in amyotrophic lateral sclerosis
| ISRCTN | ISRCTN88446415 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN88446415 |
| EudraCT/CTIS number | 2020-005069-15 |
| IRAS number | 271218 |
| ClinicalTrials.gov number | NCT05193994 |
| Secondary identifying numbers | IRAS 271218 |
- Submission date
- 22/02/2021
- Registration date
- 14/12/2021
- Last edited
- 07/08/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Nervous System Diseases
Plain English Summary
Background and study aims
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease. Unfortunately, there are limited medications available for ALS. The only available treatment is riluzole, which tends to provide only minimal benefit. Therefore, there is a high need for further research using other medications, to help improve the options for treatment for this disease.
There has been laboratory research that suggests that a virus called an endogenous retrovirus may be the cause or trigger for ALS in some people. This virus may be of the same family (although quite different) to the virus that causes HIV (also called ‘AIDS’). Researchers are intending to test if an anti-viral medication that is a very effective treatment for HIV, may also be effective for people who have ALS.
Triumeq, commonly prescribed for HIV treatment, is an antiviral medication that is a combination of three medications: dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg. Triumeq is approved by the Therapeutic Goods Administration (TGA) to treat HIV patients. However, it is not approved to treat ALS. Therefore, it is an experimental treatment for ALS.
The aim of this study is to determine whether Triumeq is effective at delaying the progression of ALS, and whether it is safe and well-tolerated in patients with ALS. The Lighthouse study demonstrated Triumeq to be safe and well tolerated in people with ALS.
Who can participate?
Patients aged 18 years and over with ALS
What does the study involve?
The entire study will last for around 2 years. Participation is voluntary. Participation in this study will involve up to 10 visits (about 2 hours each) roughly every 3 months, and as many telephone calls as participants would like, to make sure they are comfortable with the research process. Participants will be assessed throughout the project using assessment scales to determine if it is suitable for them to continue the medication.
Participants will be randomly allocated to receive either Triumeq or a matching placebo (dummy drug) once daily in addition to standard care. The random allocation will be done using a computer maintained by the King’s Clinical Trials Unit. Two thirds of research participants will receive active Triumeq and one third will receive matched placebo capsules. A placebo is a medication with no active ingredients and so has no medical benefit. It looks like the real thing, but it is not. The study is a ‘double-blind’ study. This means that neither participants nor the study doctor will know which treatment they are receiving. However, in certain circumstances the study doctor can find out which treatment participants are receiving. This study has been designed to make sure the researchers interpret the results fairly without any bias and avoids study doctors or participants jumping to conclusions.
There are a number of procedures and reviews that will be carried out at different times over the 24 months:
1. Demographics
2. Review of medical history
3. Physical examination/vital signs
4. Neurological exam
5. Blood collection
6. Urine collection
7. Throat or nasal swab: the doctor/nurse/research coordinator will perform either a throat or nasal swab to check for COVID-19 infection
8. Spirometry (breathing) test
9. Questionnaire completion
10. ECG test
What are the possible benefits and risks of participating?
The researchers cannot guarantee or promise that participants will receive any benefits from this research; however, possible benefits may include some relief of ALS symptoms. The tests provided may help participants learn about their general health. This study may assist doctors and scientists to help people suffering from symptoms with ALS in the future.
Medical treatments often cause side effects. Participants may have none, some or all of the effects listed below, and they may be mild, moderate or severe. There may be side effects that the researchers do not expect or do not know about and that may be serious. Many side effects go away shortly after treatment ends. However, sometimes side effects can be serious, long-lasting or permanent. If a severe side effect or reaction occurs, the study doctor may need to stop the treatment.
The following side effects have been experienced by people taking Triumeq:
Common side effects (occur in 1 out of 10 people): fever, not feeling well, discouragement, nausea, rash, irritability, loss of interest and/or pleasure, trouble concentrating and/or sleeping.
Uncommon side effects (occur in 1 out of 100 people): neuropathy (tingling in fingers and toes), anxiety, difficulty moving, weight loss, itching and hair loss as well as high blood sugar.
Rare side effects (occur in 1 out of 10, 0000 people): abnormal liver function tests, low blood pressure dizziness or light-headedness, fainting or lack of concentration or fatigue, acute inflammation of the pancreas, nausea, fever and a swollen and or tender abdomen and hepatitis, joint pain, abdominal pain and yellowing of the skin.
Where is the study run from?
King’s College London (UK)
When is the study starting and how long is it expected to run for?
January 2020 to August 2026
Who is funding the study?
1. National Institute for Health Research (NIHR) (UK)
2. FightMND (Australia)
3. Motor Neurone Disease Research Institute of Australia (Australia)
4. Treatment Research Initiative to Cure ALS (TRICALS)
Who is the main contact?
Sylvia Wilczynska
sylvia.1.wilczynska@kcl.ac.uk
Contact information
Public
King’s College London
Institute of Psychiatry, Psychology & Neuroscience
Department of Basic and Clinical Neuroscience
London
SE5 8AB
United Kingdom
| Phone | +44 (0)20 7848 0532 |
|---|---|
| sylvia.1.wilczynska@kcl.ac.uk |
Study information
| Study design | Double-blind (participant, investigators) 2:1 randomized placebo-controlled international multi-centre trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | Randomized double-blind placebo-controlled Phase III trial of Triumeq in amyotrophic lateral sclerosis |
| Study acronym | Lighthouse II |
| Study hypothesis | Activation of a human endogenous retrovirus is a key component of the pathogenesis of amyotrophic lateral sclerosis (ALS), and blocking its lifecycle with antiretroviral therapy will therefore provide an effective treatment. |
| Ethics approval(s) | Approved 01/02/2022, London - Westminster Research Ethics Committee (Equinox House, City Link, Nottingham, NG2 4LA, UK; +44 (0)207 104 8066, +44 (0)207 104 8236, +44 (0)207 104 8283; westminster.rec@hra.nhs.uk), ref: 22/LO/0059 |
| Condition | Amyotrophic Lateral Sclerosis (ALS) |
| Intervention | Lighthouse II is an international, phase III, multi-centre, parallel-group, placebo-controlled, blinded (participant, investigators, analyst) randomised controlled trial of Triumeq (abacavir 600 mg, lamivudine 300 mg and dolutegravir 50 mg) or matched placebo, once daily in addition to standard care, in a 2:1 treatment/placebo allocation ratio in participants with ALS, in order to determine the superiority of treatment versus placebo. If the trial is not terminated at a planned interim analysis, the trial will continue until 24 months after the last enrolled participant or a minimum of 212 events have occurred, whichever is first. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Abacavir, lamivudine, dolutegravir |
| Primary outcome measure | Overall survival, defined as time to mortality from any cause. This will be recorded and reported on an ongoing basis from the participant randomisation. The primary outcome timepoint is at 24 months. |
| Secondary outcome measures | 1. Combined assessment of survival and measures of daily functioning using the ALSFRS-R total score (CAFS) at baseline, 3, 6, 9, 12, 15, 18, 21 and 24 months 2. Daily functioning is measured by using the ALSFRS-R total score at baseline, 3, 6, 9, 12, 15, 18, 21 and 24 months 3. Respiratory function is measured by slow vital capacity (SVC) (% predicted of normal according to the GLI-2012 reference standard) at baseline, 3, 6, 9, 12, 15, 18, 21 and 24 months 4. Plasma creatinine levels are measured using safety blood test at baseline, 3, 6, 9, 12, 15, 18, 21 and 24 months 5. Clinical disease stage, defined as mean time spent in each stage of the King’s Staging Scale and the ALS Milano-Torino staging systems (MITOS, derived from ALSFRS-R) at baseline, 3, 6, 9, 12, 15, 18, 21 and 24 months 6. Safety based on safety assessments including: 6.1. Physical examinations at baseline, 3, 6, 9, 12, 15, 18, 21 and 24 months 6.2. Clinical laboratory evaluations at baseline, 3, 6, 9, 12, 15, 18, 21 and 24 months 6.3. Vital signs at baseline, 3, 6, 9, 12, 15, 18, 21 and 24 months 6.4. Frequency of adverse events (AEs) or serious adverse events (SAEs) – ongoing from participant randomisation 7. Tolerability measured by medication discontinuation – ongoing from participant randomisation 8. Cognitive function measured by using Edinburgh Cognitive and Behavioural ALS Screen (ECAS) at baseline, 12 and 24 months 9. Quality of life, defined as total scores on the Visual Analogue Scale (single-item scale) and EQ-5D-5L questionnaire at baseline, 3, 6, 9, 12, 15, 18, 21 and 24 months 10. Laboratory parameters, e.g. urine P75ECD, plasma neurofilament light and heavy chain, HERVK expression and genotyping (UNC13a / C9orf72), measured by blood and urine tests at baseline, 3, 6, 9, 12, 15, 18, 21 and 24 months |
| Overall study start date | 01/01/2020 |
| Overall study end date | 01/08/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 390 |
| Participant inclusion criteria | Current inclusion criteria as of 13/02/2024: 1. Age ≥ 18 years at the time of screening 2. Diagnosis of ALS according to the Gold Coast Criteria 3. Capable of providing informed consent and complying with trial procedures 4. TRICALS risk profile > -6.0 and < -2.0 5. Those taking Riluzole must be on a stable dose for at least 30 days prior to the baseline visit or must have stopped taking Riluzole at least 30 days prior to the baseline visit 6. Women must not become pregnant (e.g., post-menopausal, surgically sterile, using highly effective birth control methods or not having potentially reproductive sex) for the duration of the study plus five days. Highly effective methods of birth control are those with a failure rate of < 1% per year when employed consistently and correctly, e.g. combined (oestrogen and progestogen containing) hormonal contraception or progestogen-only hormonal contraception 7. Women of childbearing potential must have a negative serum pregnancy test at screening and be non-lactating. Patients will be advised regarding appropriate contraception. A menstruation history will be taken at each visit. Women of childbearing potential are defined as females who are fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy 8. For participants taking antacids (regularly or as required), the participant is willing and able to avoid taking antacids for at least 6 hours before and 2 hours after Triumeq 9. Participants taking taurursodiol supplements (TUDCA) can participate in this trial if the supplement does not contain sodium phenylbutyrate. 10. Participants taking taurursodiol supplements (TUDCA) that also contain sodium phenylbutyrate must be willing to stop supplementation 30 days prior to randomisation. Previous inclusion criteria: 1. Age ≥ 18 years at the time of screening 2. Diagnosis of ALS according to the Gold Coast Criteria 3. Capable of providing informed consent and complying with trial procedures 4. TRICALS risk profile > -6.0 and < -2.0 5. Those taking Riluzole must be on a stable dose for at least 30 days prior to the baseline visit or must have stopped taking Riluzole at least 30 days prior to the baseline visit 6. Women must not become pregnant (e.g., post-menopausal, surgically sterile, using highly effective birth control methods or not having potentially reproductive sex) for the duration of the study. Highly effective methods of birth control are those with a failure rate of < 1% per year when employed consistently and correctly, e.g. combined (oestrogen and progestogen containing) hormonal contraception or progestogen-only hormonal contraception 7. Women of childbearing potential must have a negative serum pregnancy test at screening and baseline and be non-lactating. Women of childbearing potential are defined as females who have experienced menarche and are not surgically sterilised (e.g. hysterectomy or bilateral salpingectomy) or post-menopausal (defined as at least 1 year since last regular menstrual period) 8. For participants taking antacids (regularly or as required), participant is willing and able to avoid taking antacids for at least 2 hours before and 6 hours after Triumeq |
| Participant exclusion criteria | Current exclusion criteria as of 13/02/2024: 1. People who are HLA-B*5701 positive 2. Known hypersensitivity to dolutegravir, abacavir or lamivudine, or to any of the excipients 3. Safety Laboratory Criteria at screening: 3.1. ALT ≥ 5 times upper limit of normal (ULN) 3.2. AST ≥ 3 times ULN 3.3. Bilirubin ≥ 1.5 times ULN with clinical indicators of liver disease 3.4. Creatinine clearance < 30 ml/min 3.5. Platelet concentration of < 100 x109 per l 3.6. Absolute neutrophil count of < 1x109 per l 3.7. Haemoglobin < 100 g/l 3.8. Amylase ≥ 2 times ULN 3.9. Lactate ≥ 2 times ULN 4. Moderate to severe hepatic impairment, as defined by local clinical guidelines 5. Presence of HIV antibodies at screening 6. Presence of Hepatitis C antibodies at screening unless participants have had effective treatment for Hepatitis C 7. Presence of Hepatitis B core or surface antigen at screening 8. Participation in any other investigational drug trial or using investigational drug within 30 days prior to screening 9. Use of NIV ≥22 h per day or having a tracheostomy 10. Edaravone dose within 30 days prior to screening. Edaravone is approved by the FDA and in Japan, but remains an investigational product in Europe and Australia 11. Clinically significant history of unstable or severe cardiac, oncological, psychiatric, hepatic, or renal disease or other medically significant illness 12. Taking medication contraindicated with Triumeq: dofetilide or fampridine (dalfampridine) 13. Taking Tofersen within 3 months prior to screening. Previous exclusion criteria: 1. People who are HLA-B*5701 positive 2. Known hypersensitivity to dolutegravir, abacavir or lamivudine, or to any of the excipients 3. Safety Laboratory Criteria at screening: 3.1. ALT ≥ 5 times upper limit of normal (ULN) 3.2. AST ≥ 3 times ULN 3.3. Bilirubin ≥ 1.5 times ULN 3.4. Creatinine clearance < 30 ml/min 3.5. Platelet concentration of < 100 x109 per l 3.6. Absolute neutrophil count of < 1x109 per l 3.7. Haemoglobin < 100 g/l 3.8. Amylase & lipase ≥ 2 times ULN 3.9. Lactate ≥ 2 times ULN 4. Moderate to severe hepatic impairment, as defined by local clinical guidelines 5. Presence of HIV antibodies at screening 6. Presence of Hepatitis C antibodies at screening unless participants have had effective treatment for Hepatitis C 7. Presence of Hepatitis B core or surface antigen at screening 8. Participation in any other investigational drug trial or using investigational drug within 30 days prior to screening 9. Use of NIV ≥22 h per day or having a tracheostomy 10. Edaravone dose within 30 days prior to screening. Edaravone is approved by the FDA and in Japan, but remains an investigational product in Europe and Australia 11. Clinically significant history of unstable or severe cardiac, oncological, psychiatric, hepatic, or renal disease or other medically significant illness 12. Taking medication contraindicated with Triumeq: dofetilideor fampridine (dalfampridine) |
| Recruitment start date | 31/01/2022 |
| Recruitment end date | 29/09/2024 |
Locations
Countries of recruitment
- Australia
- England
- Ireland
- Netherlands
- New Zealand
- Slovenia
- Spain
- Sweden
- United Kingdom
Study participating centres
Denmark Hill
London
SE5 9RS
United Kingdom
Glossop Road
Sheffield
S10 2JF
United Kingdom
Headley Way
Oxford
OX3 9DU
United Kingdom
Liverpool
L9 7LJ
United Kingdom
Sharoe Green Lane
Fulwood
Preston
PR2 9HT
United Kingdom
Queen Square
London
WC1N 3BG
United Kingdom
QEII Medical centre
8 Verdun Street
Nedlands
Nedlands
WA 6009
Australia
Suite 204, Level 2, F10A Building
2 Technology Place
Sydney
NSW 2109
Australia
Launceston
TAS 7250
Australia
94 Mallett Street
Camperdown
Sydney
NSW 2050
Australia
Bedford Park
South Australia
SA 5042
Australia
Level 7, Ned Hanlon Building, Butterfield Street
Herston
Brisbane
4029
Australia
3584 CX
Netherlands
D09V2N0
Ireland
SE-171 76
Sweden
Melbourne
3162
Australia
Christchurch
4710
New Zealand
Barcelona
08003
Spain
Dunedin
9016
New Zealand
Plymouth
PL6 8DH
United Kingdom
Stoke-on-trent
ST4 6QG
United Kingdom
London
SW17 0QT
United Kingdom
Ljubljana
1000
Slovenia
Queensland
4575
Australia
Tauranga
3112
New Zealand
Edinburgh
EH16 4SB
United Kingdom
Wellington
6021
New Zealand
Valencia
46026
Spain
Pamplona
31008
Spain
Sponsor information
University/education
Great Maze Pond
London
SE1 9RT
England
United Kingdom
| Phone | +44 (0)20 7818 8330 |
|---|---|
| amy.holton@kcl.ac.uk | |
| Website | http://www.kcl.ac.uk/index.aspx |
"ROR" |
https://ror.org/0220mzb33 |
University/education
F10A Building 2 Technology Place
Sydney
NSW 2109
Australia
| Phone | +61 (0)298 122968 |
|---|---|
| nicola.chapman@mq.edu.au | |
| Website | http://mq.edu.au/ |
Research organisation
Goeman Borgesiuslaan 77
Utrecht
3515 ET
Netherlands
| Phone | +31 (0)88 75 554 94 |
|---|---|
| operations@tricals.org | |
| Website | https://www.tricals.org/about/ |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- NIHR Efficacy and Mechanism Evaluation Programme, EME
- Location
- United Kingdom
Government organisation / Trusts, charities, foundations (both public and private)
- Alternative name(s)
- Fight MND
- Location
- Australia
Private sector organisation / Other non-profit organizations
- Alternative name(s)
- MND Research Institute of Australia, MND Research Institute, MNDRIA
- Location
- Australia
No information available
Results and Publications
| Intention to publish date | 31/01/2027 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Stored in repository |
| Publication and dissemination plan | The primary and secondary outcomes will be published in a peer-reviewed open-source medical journal within 12 months of the end of trial. Recruiting sites will be informed of the results and will be asked to disseminate the findings to participants. Patient groups will be informed of the results for dissemination among their members. The sharing dataset will be passed to the UK Chief Investigator by the analyst and all future data sharing will be managed by the TRICALS consortium and Macquarie University. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study will be stored in a repository. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version 2.6 | 20/10/2021 | 26/01/2023 | No | No |
| Protocol file | version 4.0 | 19/10/2023 | 23/02/2024 | No | No |
Additional files
Editorial Notes
07/08/2024: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/08/2024 to 29/09/2024.
2. The study participating centre Navarra Hospital Complex was added.
3. The intention to publish date was changed from 15/06/2025 to 31/01/2027.
11/04/2024: The ClinicalTrials.gov number was added.
03/04/2024: The following changes were made:
1. Study website added.
2. Belgium was removed from the Countries of recruitment.
3. New Zealand, Slovenia and Spain were added to the Countries of recruitment.
4. UZ Leuven was removed from the study participating centres.
5. Calvary Health Care Bethlehem, Christchurch Hospital, Del Mar Hospital, Dunedin Hospital, Derriford Hospital, Royal Stoke University Hospital, St George's Hospital, UMC Ljubljana, Sunshine Coast Hospital, Tauranga Hospital, The Ann Rowling Clinic/University of Edinburgh, Wellington Hospital and La Fe Hospital were added from the study participating centres.
23/02/2024: Uploaded protocol (not peer-reviewed) version 4.0 as an additional file.
13/02/2024: The inclusion and exclusion criteria were updated. The recruitment end date was changed from 31/01/2024 to 31/08/2024. Ethics approval details added.
26/01/2023: Uploaded protocol (not peer-reviewed) as an additional file.
10/01/2022: The recruitment start date was changed from 10/01/2022 to 31/01/2022.
14/12/2021: Trial's existence confirmed by the NIHR.
