A Study Evaluating the Efficacy and Safety of Crovalimab in Pediatric Patients with Atypical Hemolytic Uremic Syndrome (aHUS)

1. Why is this study needed?

Atypical Hemolytic Uremic Syndrome (aHUS) is a rare type of blood disease. Complement-mediated aHUS is a specific type of aHUS. It is called complement-mediated aHUS because it is linked to a part of your immune system called the complement system. When this system gets overactive, it can lead to the creation of tiny blood clots to form in the small blood vessels of the body. These blood clots can block blood flow to important organs, such as the kidneys. This can damage the kidneys and lead to kidney failure.

Currently aHUS is treated using a type of medication known as ‘C5 inhibitors’ which blocks a part of the complement system. These medications have proven to be effective at decreasing the symptoms of aHUS and reducing complications. However, there is still a need for new and improved treatments for aHUS to help improve people’s quality of life – that’s why we’re conducting the COMMUTE-a clinical study.

This study is testing a new medicine called Crovalimab, an investigational ‘C5 inhibitor’, developed to treat aHUS. Crovalimab is an experimental medicine. This means health authorities (like the U.S. Food and Drug Administration and European Medicines Agency) have not approved Crovalimab for the treatment of aHUS.

The purpose of this clinical trial is to test whether Crovalimab could be safe and beneficial for pediatric patients living with aHUS.

2. Who can take part in the study?

People with atypical hemolytic uremic syndrome (aHUS) of less than 18 years old (infants must be at least 28 days old) and weighing more than 5 kg can take part in the study.

People with a history of kidney disease or any other condition, apart from aHUS, that causes the kidneys to not work as well as they should may not be able to take part in this study.

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. If eligible people can join the study as one of three groups

• The Naive group: For Patients who have never taken a C5 inhibitor
• The Switch group: For patients changing from another C5 inhibitor to the study drug (Crovalimab)
• The Pretreated group: For patients who previously used a C5 inhibitor, stopped the treatment for a period of time and have a new episode of aHUS or for patients who have or a certain genetic mutation (called a C5 polymorphism)

The screening period is up to 7 days for patients in the Naive group and in the Pretreated group and up to 28 days for patients in the Switch group. Everyone who joins this study will be given Crovalimab. The first treatment will be given as an infusion into a vein, followed by injections under the skin, initially given once a week and then every 2 or 4 weeks depending on the weight.

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 every week for the first 5 weeks and then every 2 or 4 weeks depending on the weight. They will see how well the treatment is working and monitor for any unwanted effects participants may have. Participants will have a safety follow-up visit 6 months after the last dose of Crovalimab and will receive a safety telephone call 11 months after the last dose of Crovalimab during which the study doctor will check on the participant’s wellbeing. Total time of participation in the study will be up to 8 years. 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 is the number of patients who have responded to treatment (no signs of aHUS). Other key results measured in the study include the change in markers of kidney function and fatigue after 24 weeks of treatment.

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 drug
Participants may have unwanted effects of the drug 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.

Crovalimab
Participants will be told about the known unwanted effects of Crovalimab, and possible unwanted effects based on human and laboratory studies or knowledge of similar medicines. Known possible unwanted effects include the increased risk of getting infections, in particular the risk of infection by the bacteria Neisseria meningitidis. Due to this risk all people enrolled in the study must follow the study’s vaccination requirements.

Crovalimab will be given as an infusion into the vein (intravenous administration) and as an injection under the skin (subcutaneous injection). Known unwanted effects of the intravenous administration include fever, shivering or chills, nausea, and vomiting. Possible known unwanted effects of the subcutaneous administration include slight irritation, redness, rash, discomfort, or pain at the site of the injection.

In patients switching from another C5 inhibitor (Eculizumab or Ravulizumab) ) to Crovalimab, or vice versa, the switch may lead to a possible unwanted reaction. Most of these are mild to moderate and include rashes and joint pain reactions during the first weeks of the switch.

In participants who discontinue Crovalimab and who do not start another treatment, there is a risk that the symptoms of aHUS may return. This can lead to tiny blood vessels in the body being blocked by small blood clots, which can cause kidney problems, higher levels of lactate dehydrogenase (a marker of red blood cell damage), difficulty breathing, changes in mental state, seizures or chest pain.

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.