A study to look at how safe and well emicizumab treatment works to prevent bleeds for people living with Type 3 Von Willebrand disease and understand what happens to it in the body and the effects it has

1. Why is this study needed?

People with Von Willebrand disease (VWD) have blood that does not clot as well as it should. This means that they may bleed more easily. There are 3 types of VWD, with Type 3 VWD being the rarest and most severe.

Symptoms include easy bruising, nose bleeds, bleeding gums, heavy menstrual periods, and prolonged bleeding from small cuts or after dental work, childbirth, or surgery. People with more severe symptoms can experience spontaneous bleeding in organs, joints and muscles, causing pain, swelling, and stiffness.

Treatment is available to help blood to clot and prevent bleeds. Preventative treatments are often taken for a long period of time and require a drip into a vein (an ‘infusion’) 1 to 3 times a week, which can impact a person's quality of life. Treatment can also be given to manage bleeds when they happen - known as ‘on-demand’ therapy.

This study is testing a medicine called emicizumab. It is being developed to prevent bleeds caused by Type 3 VWD. Emicizumab is an experimental medicine. This means health authorities (like the U.S. Food and Drug Administration and European Medicines Agency) have not approved emicizumab for the treatment of VWD. Emicizumab is approved for treating another blood-clotting disorder called ‘haemophilia A’.

This study aims to test how safe emicizumab is, how well it works to prevent bleeds in people with Type 3 VWD, and to understand what happens to emicizumab once it is in the body and the effects it has on the body.

2. Who can take part in the study?

People with Type 3 VWD can take part in the study if they are at least 1 month old and are not currently receiving standard preventative treatment. They must have needed on-demand therapy at least twice in the past 6 months, but no more than once a week.

People of at least 2 years of age with Type 3 VWD can take part if they have been receiving standard treatment to prevent bleeds for at least 6 months as part of study WP45335.

People may not be able to take part in this study if they have recently used certain medicines, such as emicizumab, or if they have certain other medical conditions, such as another bleeding disorder, liver disease or autoimmune disease. 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 1 month before the start of treatment.

People who are at least 1 month old who join this study and who are currently on standard on-demand therapy will be placed randomly into 1 of 2 groups.

• Group A: emicizumab as an injection under the skin every week for the first 4 weeks, then every 2 weeks
• Group B: standard on-demand therapy given according to approval or local guidelines

These participants will have a 2 in 3 chance of being placed in Group A and a 1 in 3 chance of being placed in Group B. This means they are twice as likely to receive emicizumab than standard on-demand treatment.

People who are at least 2 years old and previously took part in study WP45335 will be placed into Group C.

• Group C: emicizumab as an injection under the skin every week for the first 4 weeks, then every 2 weeks

After 6 months of treatment, participants may be invited to join an extension phase of this study and be given emicizumab for about 2 more years. Participants from Groups A or C who were given emicizumab during the main treatment phase can continue to receive emicizumab treatment during the extension phase, if they benefited from it previously.

This is an open-label study. This means everyone involved, including the participant and the study doctor, will know the study treatment the participant has been given.

During this study, the study doctor will see participants regularly. They will see how well the treatment is working and any unwanted effects participants may have. Participants will have a follow-up visit 6 months after their final dose of emicizumab or 1 week after their final dose of standard on-demand therapy (if they do not start emicizumab treatment), during which the study doctor will check on the participant’s wellbeing. Total time of participation in the study will be about 6 months, or 2 and a half years including the extension phase. 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 this study?

The main results measured in the study to assess if the medicine has worked are the number of bleeds people have that require treatment.

Other key results measured in the study include:

• The number of all bleeds people have (whether a treatment is given or not)
• The number of joint bleeds that require treatment
• The number of bleeds, requiring a treatment, that do not have a clear cause
• The number and seriousness of any unwanted effects
• Changes in pain and tiredness from the start of treatment
• How emicizumab gets to different parts of the body, and how the body changes and gets rid of it
• How emicizumab affects the body’s natural defence (immune system)

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.

Risks associated with emicizumab
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 emicizumab and possible unwanted effects based on human and laboratory studies or knowledge of similar medicines. Known unwanted effects include pain or discomfort in the head, joint pain and a reaction on the skin where it has been pricked with a needle to give a treatment.

Emicizumab will be given as an injection under the skin. Known unwanted effects include redness, swelling or rash on the skin where it has been pricked with a needle to give a treatment.

The study medicine(s) may be harmful to an unborn baby. Women and men must take precautions to avoid exposing an unborn baby to the study treatment.