Librexia-AF

The purpose of this research study is to compare the effects of an experimental drug: MILVEXIAN to a similar drug, APIXIBAN to determine if it is safe and useful in reducing the risk of stroke and blood clots outside the brain in participants with atrial fibrillation.

Not everyone in the study will get milvexian. There are 2 treatment groups in this study: milvexian and apixaban. You will randomly (like flipping a coin), be put into either the milvexian or apixaban group. You will have a 50% chance of being put into either group. You will either receive milvexian and placebo or apixaban and placebo. Placebo is a tablet without medicine in it. You will take both placebo and study drug to ensure neither you nor the study staff will know which group you are in. However, if needed for a medical emergency, the study doctor/staff can quickly find out which treatment group you are in.
There are 3 parts to this study:
Screening time: Usually one visit

• Review and sign consent form
• Review of your medical history and medications
• Brief physical exam
• Body weight and height
• ECG (electrical tracing from your heart)
• Blood draw, including pregnancy test for applicable women
• Urine sample
• Questionnaires
• Stroke disability scale if needed

Treatment time: Up to 4 years depending on when you enter the study

• Take study medication everyday
• Visits every 3-6 months which include:
  • Medication review
  • Vital signs
  • Review of any side-effects
  • Stroke disability scale if needed
  • Questionnaires if needed
  • Blood draw

The study drug is supplied as a tablet and a capsule. You will take them orally (by mouth), two times daily. You should never take more or less each day than instructed by your study doctor. Please take the study medication as directed on the label. Please finish all the tablets/capsules in the bottles before opening new ones. At all times, you should have only one bottle of each open, 75cc and 160cc.
If you miss a dose of the study drug or if you vomit all or part of the study drug, let the study doctor/staff know.
Follow-up Time: 30 days after you stop taking study drug

• Take NO study medication (Other blood thinning medication may be provided if indicated by your doctor)
• Two visits (at beginning and end of period) which include:
  • Medication review
  • Vital signs
  • Review of any side-effects
  • Stroke disability scale if needed
  • Blood draw
  • Questionnaires

To participate in the study, you must follow the below list of things to do and not do:
Overall study rules
Do:

• Give correct information about your health history and health condition
• Tell the study doctor/staff about any health problems you have during the study
• Participate in all study visit appointments
• Carry your study participation card
• Take specified measures to help prevent pregnancy

Do not:

• Take part in any other medical research studies
• Get pregnant or cause your partner to become pregnant

Medicines
Do:

• Tell the study doctor/staff about any new medicine/drug or supplements/herbal medicines you take during the study or any changes to your medicines or drugs
• Take the study drug as instructed
• Return unused study drug and all empty packages at visits as instructed by study doctor/staff
• Keep study drug out of reach of children

Do not:

• Take any other drugs or remedies unless the study doctor/staff has approved them beforehand, including prescription and over-the-counter drugs such as vitamins and herbs
• Give your study drug to anyone else

TELEMEDICINE
You have the option to do some study visits virtually (for example, by telephone or video call). The study staff will provide more information to you on how these virtual visits will be conducted and about the tools that they use.

All drugs can cause side effects in some people. You must tell the study staff about any side effect you have. If you do not tell the study staff about the side effects, you may harm yourself by continuing to take part in this study.

Milvexian is a blood thinner (anticoagulant) which is in a class of drugs associated with a risk of bleeding:

• Minor bleeding (nosebleed, bleeding gums, bruising)
• Serious bleeding in the brain, stomach or bowel which could lead to hospitalization
• Rash, swelling (mainly in the feet, legs and/or ankles)
• Liver and kidney blood test changes

Of note, there have been reported cases of rash requiring hospitalization in patients taking multiple medications in addition to milvexian. Although the milvexian may not have caused these reactions, we can’t be sure at this time. Therefore, stop taking study drug and call your study doctor right away if you develop a rash that involves any of the following conditions:

• covers a large area of your body
• painful or blistered
• sores (lesions) in other areas (eyes, inside the mouth or nose, vagina, urethral opening, glans penis, anus)
• sudden malaise (not feeling well), unusual tiredness, fever, loss of appetite, stinging, redness, or burning of eyes, sore mouth, or difficulty swallowing experienced shortly before the rash.

Increased bleeding may also happen during surgery or invasive procedures. A serious bleeding event can be dangerous, permanently disabling, or fatal.

Twenty clinical trials have been completed as of December 2022. In those completed trials, a total of 3,369 participants had received milvexian. Based on what we have learned up to this point about milvexian, adverse drug reactions (potentially related to milvexian) include rash (0.7%), swelling (1.2%) (mainly in the feet, legs and/or ankles), and different types of bleeding events.

Reported bleeding events ranged from mild bleeding (for example nosebleed, bleeding gums, bruising and bleeding at an injection [area where a shot or needle had been given] or surgical [operation] site) to serious bleeding leading to hospitalization (for example bleeding from the stomach, bowels, bleeding hemorrhoids, blood in the urine or bowel movement, bleeding in the head or within the area of a previous stroke and bleeding during surgical operation). The most common bleeding events (>1%) that occurred in milvexian studies are contusion (1.8%), gastrointestinal bleeding (1.5%), and skin bleeding (1.2%).

These bleeding events happened while patients were either taking milvexian alone or with other blood thinner medications. Therefore, the role of milvexian in these events cannot be excluded or confirmed.

Liver (hepatic) laboratory value elevations have been observed in milvexian clinical studies. Although milvexian may not have caused these increases, its contribution cannot be excluded at this time. Your study doctor will be monitoring your liver function during your participation in the study. Please tell your study doctor if you have any yellowing of your skin or your eyes, light colored stool, itching or unusual and extreme tiredness, loss of appetite, continued nausea and/or vomiting, abdominal pain, dark urine or if you have been told you have increased liver laboratory values.

Kidney (renal) disorder cases mainly revealed by abnormal kidney laboratory values have been observed in milvexian clinical studies. Medically significant changes were seen more frequently in patients receiving milvexian 200 mg twice daily than in those receiving lower doses of milvexian or placebo (inactive tablet). This high dose will not be used in studies enrolling patients. Your study doctor will be monitoring your kidney function during your participation in the study. Please tell your study doctor if you have been told you have abnormal kidney laboratory values.

All drugs have a potential risk of an allergic reaction, which could become life threatening. You should stop the study drug and seek medical help immediately if you think you have any of the following symptoms of a serious allergic reaction: trouble breathing; swelling of the face, mouth, lips, gums, tongue, or neck; or seizures. Loss of consciousness, shock and death may result from heart and lung failure in rare cases.

You must review all current medications with your study doctor at the beginning of the study and inform the study doctor during the study if there are any changes to your existing medications or new medications added.

Certain medications, such as the ones listed below, can have a possible increased risk of bleeding while taking milvexian. If you are taking any of the medications listed now or are asked to start them during the study, you must discuss this with your study doctor immediately:

• Salicylates (aspirin and aspirin-containing products)
• NSAID (non-steroidal anti-inflammatory drug) such as Motrin®, Aleve®, Advil®
• Isoniazid, a medication used for tuberculosis
• Any blood thinners such as:
  • Vitamin K antagonists (for example, warfarin, Coumadin®)
  • Direct oral anticoagulants (for example, Xarelto® [rivaroxaban], Eliquis® [apixaban], Pradaxa® [dabigatran])
  • Clopidogrel (for example, Plavix®)
  • Ticagrelor (for example, Brilinta®, Brilique®)
  • Prasugrel (for example, Effient®)

There may be risks with the use of milvexian alone or with other drugs that are not yet known. During the study, the sponsor will learn new information about the study drug and the risks. It is possible that this new information might make you change your mind about being in the study. If new relevant information is discovered, your study doctor will tell you about it in a timely manner.

Apixiban Risks:

• Minor or serious bleeding events as with Milvexian
• Nausea
• Anemia
• Bruising
• Skin rash
• Abnormal liver tests
• Allergic reaction, potentially severe

Stopping apixaban suddenly increases the risk of blood clot related events.
Patients having spinal/epidural anesthesia or lumbar puncture are at increased risk of bleeding into the spinal area and forming a blood clot that can cause long-term or permanent loss of the ability to move (paralysis).

Apixaban should not be used if you currently have certain types of abnormal bleeding or have had a serious allergic reaction to apixaban.

ECG Risks: Adhesive patches/sensors will be applied to your skin. You may have temporary discomfort (pulling on the skin or hair) when the patches are taken off. You may also develop some minor skin irritation from the ECG patch glue.

Blood Draw Risks: Blood samples will be collected. Using a needle to remove blood from a vein is called “a blood draw”. It may be necessary to try more than once to draw blood. A new needle will be used for each blood draw. You might feel pain or be light-headed from this.
You may have the following where the needle stick is inserted:

• Bleeding at the place where the blood is drawn
• Temporary discomfort
• Bruising
• Infection (rarely)

COVID 19 Related Risks: As the majority of visits for this study must be done in person to allow for exchange of the study medication, blood draws and physical examinations, there is an added risk of you being exposed to COVID 19 from other people within the facility or by use of public transit to attend your appointment. We have several measures in place to reduce this risk as much as possible including screening each patient who attends our facility, use of PPE for all staff and patients, restrictions on the number of people allowed within the space, enhanced general cleaning procedures and sanitization of any space a patient occupies immediately following their visit.

Taking part in this study may help prevent a stroke due to your atrial fibrillation while potentially lowering bleeding risk. These benefits are not guaranteed and there may not be any benefit to you by being in this study. During the study, your condition may stay the same or get worse. However, your participation may help future patients.