Preliminary Human Trials of F230 Tablets

F230 is a new Class 1 chemical drug jointly developed by Beijing Contini Pharmaceutical Co., Ltd. for the treatment of pulmonary hypertension (Notification number: 2024LP01242, 2024LP01243). The in vitro activity and in vivo toxicology tests of F230, the lead compound for the treatment of PAH developed by Beijing Contini Pharmaceutical Co., LTD., showed that F230 had the same in vitro activity as the endothelin antagonist on the market. The pharmacodynamics of F230 in rats with nephrogenic hypertension induced by Sunitinib showed that F230 could reduce proteinuria and improve renal index.It is expected to bring higher treatment and survival benefits to the corresponding patients. According to the spirit of NMPA new drug approval, on the basis of the completion of preclinical studies of this drug, the safety, tolerability and pharmacokinetic characteristics of single administration and multiple administration of this drug in healthy volunteers should be investigated first, and the influence of food on the pharmacokinetic characteristics of F230 in humans should be investigated, so as to recommend a safe and effective administration regimen for phase II clinical trials.

This study consists of three parts: the first part is a single administration study (SAD test), the second part is a multiple administration study (MAD test), and the third part is a Food Effect study, which is divided into multiple cohorts according to dose groups and administration regimens.

Single Administration Trial (SAD) : This randomized, double-blind, placebo-controlled, dose-increasing, single-center clinical study was designed to evaluate the safety, tolerability, and pharmacokinetic profile of F230 single administration in healthy volunteers. A total of 68 healthy adult volunteers were planned to be included.This part is expected to develop 6 dose groups: 3mg, 6mg, 12mg, 20mg, 30mg, 40mg, and the groups are indicated by A1-A6. Group A1 planned to include 8 healthy volunteers (stratified by sex, F230 tablets: placebo =3:1), and group A2-A6 planned to include 12 healthy volunteers (stratified by sex, F230 tablets: placebo =5:1), increasing from the initial dose group to the maximum dose group, with each group receiving only a single dose.Qualified volunteers who met the inclusion criteria and did not meet the exclusion criteria were admitted to the phase I laboratory one day before the experiment (D-1) and randomly grouped. The researchers conducted education on the environment, regulations, etc., unified dinner, fasting after 21:00, and did not refrain from drinking water. On the day of administration, F230 tablets or placebo were taken orally on an empty stomach. From the night before the start of the trial to the end of the trial evaluation period (D-1 \~ D3), the volunteers were kept in the phase I research room. During the study period, safety assessment and PK biological sample collection were conducted according to the protocol. Volunteers completed a safety check on day 3 (D3, 48h after the last dose) and were allowed to leave the study center after a comprehensive assessment by the investigator, and then returned to the study center on day 4 (D4, 72h after the last dose) or by telephone for safety follow-up.

Multiple dose trial (MAD) : This randomized, double-blind, placebo-controlled, dose-increasing, single-center clinical study was designed to evaluate the safety, tolerability, and pharmacokinetics of multiple dose F230 tablets in healthy volunteers. 36 healthy adult volunteers were scheduled to participate.

According to the preliminary results of the SAD study, this study is expected to carry out 3 dose groups: 6 mg, 12mg and 20mg groups are represented by B1, B2 and B3, and the administration frequency is determined according to the SAD test results for 7 consecutive days. 12 volunteers are included in each dose group (stratified by sex, F230 tablets: placebo =5:1).Qualified volunteers who met both the inclusion criteria and did not meet any of the exclusion criteria were admitted to the Phase I research room 1 day before the experiment (D-1) and randomly grouped. The researchers conducted education on the environment, regulations, etc., unified dinner, and fasting after 21:00 without drinking water. The volunteers were given F230 tablets or placebo orally on an empty stomach in the morning, and the frequency of administration was determined according to the SAD test results, and they were given continuously for 7 days. All volunteers were in the research center from the day before administration (D-1) to 48h after the last administration (D9). During the study period, safety assessment and PK biological sample collection were conducted according to the protocol, and the procedures prescribed in the protocol and related safety checks were completed on the 9th day of the study (D9, 48h after the last administration). The volunteers were allowed to leave the study center after a comprehensive assessment by the investigator, and then returned to the study center on day 10 (D10, 72h after the last dose) or by telephone for safety follow-up.

Research on the Effect of Food on Drugs:

This part is a randomized, open, two-cycle, double-cross clinical study design, referred to as the food impact study. According to the preliminary results of SAD study, it is expected to carry out a dose group: X mg, and a total of 12 healthy volunteers are planned to be included. The volunteers are randomly divided into K-C and C-K groups by stratified block randomization method, taking gender as a stratified factor, and are randomly divided into two groups at 1:1 ratio, with 6 cases in each group.

Qualified volunteers who met both the inclusion criteria and did not meet any of the exclusion criteria were admitted to the Phase I research room 1 day before the experiment (D-1) and randomly grouped. The researchers conducted education on the environment, regulations, etc., unified dinner, and fasting after 21:00 without drinking water. In the first cycle, K-C group was given fasting, C-K group was given within half an hour after eating a high-fat meal, and group exit examination was conducted on day 3 (D3). After 3 days (72h) of elution, the volunteers underwent a second cycle of dosing on day 7 (D7). In the second cycle, K-C group was administered within half an hour after eating a high-fat meal, and C-K group was administered on an empty stomach. Safety assessment and PK biological sample collection will be conducted during the study in accordance with protocol requirements.

Eligibility Criteria:
Inclusion Criteria:

Volunteers must meet all of the following criteria to be selected:

1. Healthy volunteers, half male and half female, should be replaced by volunteers of the same sex;
2. Age: 18 \~ 45 years old;
3. Weight: male ≥50kg, female ≥45kg, 19≤BMI≤26 (BMI= weight (kg)/height 2 (m2));
4. Pass the comprehensive health examination: vital signs, physical examination, blood urine routine, blood pregnancy, blood glucose, blood lipid, blood electrolyte, hepatitis B surface antigen, liver and kidney function, hepatitis C, HIV and syphilis antibody test, 12-lead electrocardiogram, nicotine, urine drug screening, alcohol breath test, abdominal B-ultrasound, chest X-ray examination, etc., no abnormalities or abnormalities have no clinical significance;
5. Before participating in the study, have a detailed understanding of the nature, significance, possible benefits, possible inconveniences and potential dangers of the trial, and voluntarily participate in this clinical trial, can communicate well with the investigators, comply with the requirements of the entire study, and have the ability to understand and sign the written informed consent.

Exclusion Criteria:

* Volunteers who meet one of the following conditions are not eligible for this study:

  1. Participants in any other clinical trial within three months prior to the trial;
  2. Serum ALT \> upper limit of normal (ULN), AST \> Upper limit of normal (ULN), TBil \> upper limit of normal (ULN);
  3. (Consultation) whether there are underlying liver diseases, such as chronic hepatitis B, chronic hepatitis C, alcoholic liver disease and non-alcoholic fatty liver disease, and cirrhosis;
  4. (Consultation) Have any disease that may affect the safety of the trial or the process of the drug in vivo, including but not limited to: Heart, liver, kidney, endocrine, digestive, immune, respiratory, nervous or psychiatric systems, or other pre-existing or existing diseases of the above systems \[especially cardiovascular disease including those at risk for cardiovascular disease, any gastrointestinal disease that interferes with drug absorption (e.g. symptoms of irritable bowel syndrome, history of inflammatory bowel disease), active pathological bleeding (e.g. peptic ulcer), urticaria, epilepsy, epilepsy, etc. Sensitive rhinitis, eczematous dermatitis, asthma, active pulmonary tuberculosis, etc.
  5. (Consultation) Allergy: If there is a history of drug, food allergy or skin allergy;
  6. (Interview) Any drug that inhibits or induces liver metabolism of the drug in the 28 days prior to the use of the study drug (common liver enzyme inducers: barbiturates such as phenobarbital, carbamazepine, aminomide, grofulvin, methylaminopropyl, phenytoin, Grumette, rifampin, dexamethasone; Common liver enzyme inhibitors: chlorpromazine, cimetidine, ciprofloxacin, metronidazole, chloramphenicol, isoniazid, sulfonamide);