Lighthouse II

Randomised Double-Blind Placebo-Controlled Phase 3 Trial Of Triumeq In Amyotrophic Lateral Sclerosis

Triumeq in Amyotrophic Lateral Sclerosis (LIGHTHOUSE II)

UK Chief Investigator

Professor Ammar Al-Chalabi

Research summary

What do you want to do?  We want to see if Triumeq, a drug used to block viruses, might be effective in amyotrophic lateral sclerosis (ALS). To find out, we will be doing a clinical trial in which some people receive Triumeq, and others do not, so that we can compare the two groups of people.

Why are you testing Triumeq in ALS?  Every cell in the body contains instructions called genes, stored as DNA. Everybody’s DNA also carries genes for ancient viruses. These lie dormant but “hitch-hike” along with our genes. We know that these viruses can kill the nerve cells involved in ALS. We think that in people with ALS these viruses are activated, and help to cause the disease. Triumeq is very effective against these hitchhiking viruses, so it makes sense to test it in people with ALS. We have already shown that people with ALS can take Triumeq safely. Our next step is to try it in 300 people with ALS to see if it is effective.

How will you test it?  We will carry out a clinical trial. People who take part will be chosen randomly to either receive Triumeq or a placebo. The placebo looks and tastes the same as Triumeq but does not have any Triumeq in it. Neither ourselves nor the people taking part will know who is taking Triumeq until the study ends. We will monitor the people in the trial for up to four years to see if taking Triumeq makes people live longer and slows down ALS.  

Current status

Open to recruitment

Recruitment target

200 participants in the UK; up to 390 participants globally

Click here to see how many patients have been recruited into this study in the UK to date (external link to the NIHR public study search) 

Recruitment group(s)

Patients with MND

Locations

• King's College Hospital, London (Principal Investigator: Ammar Al-Chalabi)

• Sheffield (Principal Investigator: Pam Shaw)

• University College London (Principal Investigator: Richard Orrell)

• Plymouth (Principal Investigator: Oliver Hanemann) 

• Liverpool (Principal Investigator: Sivakumar Sathasivam)

• Stoke (Principal Investigator: Tom Lambert)

• St George's Hospital, London (Principal Investigator: Pablo Garcia Reitboeck)

• Edinburgh (Principal Investigator: Suvankar Pal)

• Preston (Principal Investigator: Suresh Chhetri)

• Oxford (Principal Investigator: Martin Turner)

Information about study sites

Contact details

Elliott Phillips, Trial Manager - email: elliott.phillips@kcl.ac.uk

Medeah Yaqub, Trial Manager - email: medeah.yaqub@kcl.ac.uk

Shared trial inbox - email: lighthouseii@kcl.ac.uk

Key dates

Recruitment open date: August 2022

Planned recruitment end date: 31 August 2024

Inclusion / exclusion criteria

Key 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  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 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 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 randomisation.

Key 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: ALT ≥ 5 times upper limit of normal (ULN), AST ≥ 3 times ULN, Bilirubin ≥ 1.5 times ULN with clinical indicators of liver disease, Creatinine clearance < 30 mL / min, Platelet concentration of < 100 x109 per L, Absolute neutrophil count of < 1x109 per L, Haemoglobin < 100 g/L, Amylase ≥ 2 times ULN, 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) 

13. Taking Tofersen wihtin 3 months prior to screening.

Funder

National Institute for Health and Care Research (NIHR)

Sponsor

King's College London 

Study design

Interventional, randomised controlled trial

Intervention

• Drug: Triumeq (olutegravir, Abacavir and Lamivudine)

• Placebo

Phase

3

Outcome measures

Primary outcome measure

• Measure overall survival at 24 months or after a minimum of 212 events 

Secondary outcome measures

1. Measure scoring in the ALS-Functional Rating Scale Revised (ALSFRS-R) at 3 monthly intervals. The ALSFRS-R is a 12 item participant self-report measure that monitors ALS disease progression, where a higher score reflects a better outcome.

2. Number of participants with abnormal Slow Vital Capacity measured by hand spirometry at 3 monthly interval. Slow vital capacity is measured in litres, and as a % of predicted.

3. Measure plasma creatinine at 3 monthly intervals. Plasma creatinine is assessed to monitor kidney function.

4. Assign a value using the King's Staging Scale to describe degree of disease advancement over time. The King's Staging Scale is a clinical staging system defining four stages of ALS assessed by way of a semi-structured interview with the participant.

5. Evaluate the incidence of treatment-emergent adverse events.  Based on physical examinations and patient reported symptoms.

6. Measure study medication discontinuation. The number of participants who discontinue study medication will be assessed to assess tolerability.

7. Measure the score obtained with the Edinburgh Cognitive and Behavioural Assessment Screen (ECAS). ECAS is a multidomain assessment questionnaire used in ALS to assess cognitive and behavioural changes where a higher score relates to a better outcome.

8. Measure the responses in the EQ-5D-5L quality of life health questionnaire. The EQ-5D-5L questionnaire is a standardised measure of health-related Quality of Life, also incorporating a Visual Analogue Scale. A higher score relates to a better outcome.

9. Measurement of several biomarkers from blood and urine samples. Urinary P75ECD, plasma neurofilament light and heavy chain, HERV-K expression and genotyping (UNC13a / C9orf72) will be measured for post-trial exploratory analyses.