Title: A Randomised Double-Blind Placebo-Controlled Phase 3 Trial Of Triumeq In Amyotrophic Lateral Sclerosis
Funder: Medical Research Council

Abstract: A Randomized Clinical Trial of Triumeq in ALS_x000D_ Plain English Summary_x000D_ _x000D_ What do you want to do?_x000D_ 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._x000D_ _x000D_ What is ALS?_x000D_ ALS is also called MND or motor neuron disease. In people with ALS, nerve cells which control muscles die off - we do not know why. An affected person becomes progressively weaker and eventually dies because they are unable to breathe. Usually someone with ALS dies within two years of diagnosis, but some people can live for much longer. _x000D_ _x000D_ ALS will kill 1 in every 300 people. It can strike at any age, although most often in the 50s or 60s. There is no cure. The only treatment in the UK is Riluzole, a medicine that only slows the disease a little. We desperately need to find new treatments._x000D_ _x000D_ Why are you testing Triumeq in ALS?_x000D_ 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 hitch-hiking viruses, so it makes sense to test it in people with ALS. _x000D_ _x000D_ 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._x000D_ _x000D_ How will you test it? _x000D_ 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._x000D_ _x000D_ Have people with ALS been involved in designing this study?_x000D_ Yes. People with ALS and close relatives of people with ALS have been involved throughout the study design. They will also be involved as the study goes ahead. The Sheffield Motor Neurone Disorders Research Advisory Group includes people with ALS and both past and present carers. They have looked at our plans and we have followed their advice. We also have two patient representatives directly involved as members of the study team. People with ALS are also members of the Trial Management Group, which makes day-to-day decisions about the study. They will also help us in telling patients and the wider public about the trial and its results._x000D_ _x000D_ How will you tell people about the trial results?_x000D_ Once we know if Triumeq is useful or not, we will write a press release, and publish the results in scientific journals, through the MND Association website and on social media.

Lay abstract: Research Question:_x000D_ Is the antiretroviral therapy Triumeq an effective treatment for amyotrophic lateral sclerosis (ALS)?_x000D_ _x000D_ Background:_x000D_ Amyotrophic lateral sclerosis(ALS), also known as Motor Neuron Disease (MND), is an adult-onset neurodegenerative disease of the corticospinal motor system, resulting in progressive paralysis of voluntary muscles until death occurs, usually from respiratory failure, typically within 3 years of onset. It has a mean age of onset of 56 years, and the risk increases with age. The incidence is 1-2 per 100,000 person-years, prevalence about 5 per 100,000, and lifetime risk 1 in 300, with a male:female ratio of 3:2. There is no cure, and the only disease-modifying therapy, Riluzole, improves 1 year survival by about 38%. It is a greatly feared diagnosis, and the most frequent cause of assisted suicide. There is therefore a significant unmet need for an effective disease modifying therapy._x000D_ _x000D_ In 5% of people there is a family history of ALS, and for about 80% of such cases, and for about 18% of those without a family history, a genetic cause has been identified. Regardless of genetic background, we and others have shown that a human endogenous retrovirus (HERV), may contribute to disease onset, becoming activated, and leading to the death of motor neurons. This type of virus is in the same class of viruses as HIV, which also shows the same ability to integrate itself into the genome. A specific HERV, known as HERV-K, has been implicated in ALS._x000D_ _x000D_ A combination antiretroviral drug with a good safety record, Triumeq, is effective against HIV and is able to cross the blood brain barrier. Triumeq also shows efficacy against HERV-K. In the Lighthouse I Study, a phase 2a safety and tolerability trial of Triumeq in ALS carried out in Australia, it met its primary outcomes. Even though the study was not designed to assess efficacy, the results were promising in all parameters of outcome, including suppression of HERV-K, and need urgent follow up in a larger Phase 2b trial._x000D_ _x000D_ Aims and Objectives:_x000D_ To carry out a Phase 2b clinical trial of the antiretroviral drug, Triumeq, in people with ALS._x000D_ _x000D_ Methods:_x000D_ We therefore plan to test Triumeq in ALS in a randomized, double-blind, placebo-controlled trial in multiple specialist and non-specialist centres in the UK, recruiting 300 patients, half to be given placebo and half active therapy, with at least 2 years follow up. The study will test whether there is an improvement in the survival rate and function of people on Triumeq, and will explore whether biomarkers (blood and urine measurements of disease status) are effective for monitoring disease progression. We will also measure the quality of life of people with ALS taking part in the study. If there is a positive effect, we will apply to extend licensing in ALS. Patients will be monitored every three months to minimise the need for face-to-face attendance at clinics. _x000D_ _x000D_ Timelines for Delivery:_x000D_ Patients will be followed up for a minimum of two years. Patients will follow standard care, with outpatient clinics every 3 months._x000D_ _x000D_ Anticipated Impact and Dissemination:_x000D_ A treatment benefit will be a significant advance in our knowledge and treatment of ALS. Results will be made available through scientific journals, the MND Association website, press release, and social media.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL