A study to investigate the efficacy of fenebrutinib in relapsing multiple sclerosis (FENopta)

1. Why is this study needed?

Multiple sclerosis (MS) is a health condition in which the immune system (the body's natural defence) attacks the protective covering of nerve fibres in the brain and spinal cord. This leads to communication problems between the brain and the rest of the body. In relapsing multiple sclerosis (RMS), the signs or symptoms of MS return after they have improved for a while. This is known as a ‘relapse’. This can cause physical and cognitive (i.e. mental processes) impairment and disability. New drugs which help to prevent disease worsening are needed.

This study is testing a medicine called fenebrutinib, you say this ‘feh-NEH-broo-tuh-nib’. It is being developed to treat RMS. Fenebrutinib is an experimental medicine. This means health authorities (like the U.S. Food and Drug Administration and European Medicines Agency) have not approved fenebrutinib for the treatment of RMS.

This study aims to compare the effects of fenebrutinib against placebo in people with RMS. Placebo is a medicine that contains no active ingredients but looks the same as the study drug and is taken in the same way. This means that it does not have any medicine-related effect on the body.

2. Who can take part in this study?

People of 18 to 55 years of age with RMS can take part in the study. They must have a score on the Expanded Disability Status Scale (EDSS) of no more than 5.5. The EDSS measures changes in a person’s disability level over time. People with an EDSS score of 5.5 or less can walk 100 metres without the use of walking aids or needing to rest.

People who take part in the study must also have had either:

• 2 relapses in the last 2 years
• 1 relapse in the last year, OR
• At least 1 area of inflammation in the brain – known as an ‘active lesion’, visible on an MRI scan, within the past 6 months

People may not be able to take part in this study if their symptoms of MS have been very mild for more than 10 years. People with a type of MS called ‘primary progressive MS’, or people who have had certain treatments cannot take part. People also cannot join the study if they have certain infections, a history of cancer, or other conditions including a disease of the brain or spinal cord. People who are pregnant, or currently breastfeeding cannot take part in the study.

3. How does this study work?

People will be screened to check if they are able to participate in the study. The screening period will take place from 4 weeks before the start of treatment.

Everyone who joins this study will be placed into 1 of 2 groups randomly (like flipping a coin) and given either:

• Fenebrutinib pills taken twice a day, OR
• Placebo pills taken twice a day

Participants will have a 1 in 3 chance of receiving placebo and a 2 in 3 chance of receiving fenebrutinib.

The first part of this study is ‘double-blind’. This means that neither the participants in the study nor the team running it will know which treatment is being given until the double-blind period is over. This is done to make sure that the results of the treatment are not affected by what people expected from the received treatment. However, the study doctor can find out which group the participant is in, if the participants' safety is at risk.

The study doctor will see participants every 2 weeks during the double-blind period. They will see how well the treatment is working and any unwanted effects participants may have. After the double-blind period, participants will be given the choice to either stop study treatment or be given ‘open-label’ fenebrutinib. Open-label means everyone involved, including the participant and the study doctor, will know the study treatment the participant has been given. The study doctor and the participant will decide together if open-label fenebrutinib should be given if the study doctor believes a participant could benefit from it, and depending on symptoms.

Participants will have a follow-up visit 1 month after their last dose of study treatment, during which the study doctor will check on the participant’s wellbeing. Total time of participation in the study will be about 3 months to 4 years, depending on when a person joins the study and if they have open-label treatment. Participants have the right to stop study treatment and leave the study at any time, if they wish to do so.

4. What are the main results measured in the study?

The main result measured in the study to assess how the medicine has worked is the total number of new lesions seen on contrast-enhanced MRI scans of the brain at Months 1, 2, and 3.

Other key results measured in the study include:

• The total number of growing lesions seen on MRI scans of the brain at Months 1, 2, and 3
• The number of participants who do not have any new or growing lesions at Months 1, 2, and 3
• The number and seriousness of any unwanted effects
• How fenebrutinib gets to different parts of the body, and how the body changes and gets rid of it

5. Are there any risks or benefits in taking part in this study?

Taking part in the study may or may not make participants feel better. But the information collected in the study can help other people with similar health conditions in the future. It may not be fully known at the time of the study how safe and how well the study treatment works. The study involves some risks to the participant. But these risks are generally not greater than those related to routine medical care or the natural progression of the health condition. People interested in taking part will be informed about the risks and benefits, as well as any additional procedures or tests they may need to undergo. All details of the study will be described in an informed consent document. This includes information about possible effects and other options of treatment.

Risks associated with the study drugs

Participants may have unwanted effects of the drugs used in this study. These unwanted effects can be mild to severe, even life-threatening, and vary from person to person. During this study, participants will have regular check-ups to see if there are any unwanted effects.

Participants will be told about the known unwanted effects of fenebrutinib and possible unwanted effects based on human and laboratory studies or knowledge of similar medicines. The only known unwanted effect of fenebrutinib is a high level of liver markers in the blood.