In this trial, we investigate how safe the new compound is and how well it is tolerated when it is administered to healthy participants. It will be tested how quickly and to what extent the study compound is absorbed, transported, and eliminated from the body. Furthermore, we investigate the effect of the study compound on how the body processes the approved medications rosuvastatin and pitavastatin. Both of these medications are used for treatment of high cholesterol. Cholesterol is a building block for cells and hormones, but elevated cholesterol levels increase the risk of cardiovascular diseases. Blood values of previously approved medications (rosuvastatin and pitavastatin) will be measured when they are given alone. Then it is compared to when they are given together with the study compound. We compare the effects of the compound with the effects of a placebo. A placebo is a compound without any active ingredient. We also investigate whether your hereditary characteristics have an effect on how your body reacts to the compound. This part of the trial is mandatory.

The study compound has been extensively tested in the laboratory and in animals. In addition, it has been administered before in healthy individuals. In general, the study compound was well tolerated when given as single or multiple administrations.

This trial is not intended to improve your health but is necessary for the further development of this compound. The trial will only take place after it has been approved by the Independent Ethics Committee (METC) or the Central Committee on Research Involving Human Subjects (CCMO).

This trial will be executed in healthy male and female participants. You can participate only once in this trial.

To check if you are eligible to participate a medical screening will take place before the start of the trial. Depending on availability, this can be performed in Groningen or Utrecht. This screening will take place within 26 days before the start of the clinical trial.

The clinical trial consists of 2 stays in the research facility in Groningen (location van Swietenlaan 6). The first stay will be for 13 days (12 nights), the second stay for 47 days (46 nights). Depending on how you respond to the study compound the second period of stay could also be shorter than 47 days.

The clinical trial consists of 5 consecutive periods, all of different lengths, during each of which you will receive a different (combination of) compound(s):

• Period 1: one dose of rosuvastatin
• Period 2: one dose of pitavastatin
• Period 3: daily administration of the study compound or placebo
• Period 4: one dose of rosuvastatin and daily administration of the study compound or placebo
• Period 5: one dose of pitavastatin and daily administration of the study compound or placebo.

You will be given both the study compound or placebo and rosuvastatin as capsules by mouth, and pitavastatin as tablets by mouth. During period 3 you will receive a daily administration of the study compound. Every few days the dose will be increased to build up the amounts of study compound in the blood over time

During the trial, blood will regularly be drawn and urine will be collected. Prior to screening, at (each) admission in the research facility, and at the follow-up, you have to stay fasted for 4 hours. You can only drink water prior to your visit. This means that we will ask you to fast prior to any participation in the trial. You have not yet signed the form for participation in the trial. After the screening it will be announced whether you can participate.

On day -1 of period 1, on day 1 of every period, and on certain days during your stay when specific measurements are done, you will receive a light breakfast after 10 hours of fasting during the night. The breakfast must be started exactly on time and must be finished in 30 minutes. You will receive the medication 30 minutes after the start of the breakfast.

Consumption of other medication and grapefruit (including juice) are not allowed during the entire length of the trial. Consumption of alcohol, coffee and tea, cola, power drinks and chocolate (including chocolate milk), poppy seeds and tobacco/nicotine-containing products are not allowed during your stay at the research facility, but are allowed (in limited amounts) when you are not at the research facility. Also, before the start of the trial, there will be restrictions for these products. Use of decaffeinated coffee and (herbal) teas without caffeine (also called theine) is allowed.

All potential medicines can cause side effects. The compound has been studied extensively in the laboratory and in animals and has already been studied in healthy persons. The following side effects are most often observed: nausea, vomiting and diarrhea. These side effects were mostly of mild intensity.

Rosuvastatin may also cause side effects. The most common ones (in more than 1 in 100 patients but less than 1 in 10 patients) are:

• Elevated blood sugar levels
• Headache, dizziness
• Constipation, nausea, abdominal pain
• Muscle ache
• Feeling of weakness, lack of energy

Pitavastatin may also cause side effects. The most common ones (in more than 1 in 100 patients) are:

• Joint pain
• Muscle pain
• Constipation
• Diarrhea
• Nausea
• Headache

You should take into account that (serious) side effects may occur that are still unknown. In addition to unknown side effects, there is a (small) chance that an allergic reaction will occur. This can be caused by the study compound or other ingredients that are used to prepare the formulation. During the study, you will be under strict medical supervision. The doctors and investigators of ICON are always well-informed about the compound being studied. With this knowledge they can estimate the effects and side effects reasonably well.

• You are a healthy male or female.
• You are at least 18 and no more than 65 years old.
• You are not of Asian heritage. Based on studies it is known that people of Asian heritage respond more strongly to rosuvastatin in the blood than people of other heritage. Asian participants would therefore be at risk of being exposed to significantly higher rosuvastatin levels.
• Your Body Mass Index (BMI) is higher or equal to 27.0 kg/m2 .
• Both non-smokers and light smokers (up to 5 cigarettes per day) are allowed to participate in this clinical trial. You are not allowed to smoke during you stay in our research facility.

Note:

• You cannot participate in the trial if you have participated in another clinical trial in the 90 days prior to this clinical trial (counting from the follow-up visit).
• For this trial, you cannot (have) receive(d) a vaccine within 4 weeks prior to the start and during this trial.
• To determine if you are suitable to participate in this trial, you will undergo a medical screening. Depending on availability, this can be performed in Groningen or in Utrecht.
• As a female you can only participate if you are not pregnant, not breast feeding and meet one of the following conditions:
  • You are using hormonal contraception (for example an intra-uterine device containing hormones) in combination with a condom; Please note: hormonal contraception taken by mouth is not allowed in this trial.
  • You are using a copper intra-uterine device in combination with a condom;
  • You have passed the menopause (no periods for at least 12 months);
  • You have been sterilized or your male partner has been sterilized;
  • You are not sexually active according to your lifestyle;
  • You are only sexually active with a partner of the same sex. 
• As a male you can only participate if you meet one of the following conditions:
  • You are using a condom in combination with an additional contraception method used by your female partner;
  • You are using a condom and have been sterilized;
  • You are using a condom and your female partner is sterilized or has passed the menopause (no periods for at least 12 months);
  • You are using a condom if your female partner is pregnant;
  • You are not sexually active according to your lifestyle;
  • You are using a condom and are only sexually active with a partner of the same sex

You will receive a gross compensation of €15422 for participation in this study. Travel expenses will be reimbursed based on the distance traveled (€ 0.21 net per kilometer) with a minimum of € 13 and a maximum of € 176.40 (840 kilometers) per round trip, regardless of the mode of transportation.

You can participate in a trial a maximum of four times a year. There must be at least 30 days between two trials. Some trials have a longer waiting period.

During the trial, you may suffer from mild symptoms like headache or nausea. That may be caused by the medication. It might also be caused by needing to fast for the trial, for example. Those side effects are no fun, but fortunately are not dangerous.

Before a medication is tested on people, it has already been studied extensively in a lab. This enables us to predict well which side effects you might get and we can prepare you for them. It almost never happens that participants suffer from unexpected side effects. For example, an allergic reaction to the medication occurs on average once a year.

Your participation in a clinical trial is always voluntary. You can therefore decide to stop at any time. Sometimes you have to stop. For example because of family circumstances or if the doctor decides it is better for your health. If you stop, we will look at what portion of the compensation you are entitled to. It's only fair!