First-in-human Trial to Evaluate the Safety, Tolerability and Pharmacokinetics of C106 in Healthy Subjects

Study Overview
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Brief Summary
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This is a FIH, double-blind, placebo-controlled, within-group randomised, trial designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending oral doses of compound 106 (C106) in healthy females of non-childbearing potential and healthy males. The trial will be conducted in 2 parts: Part A, single ascending dose (SAD) including a food interaction cohort: safety, tolerability, and PK in healthy males and healthy females of non-childbearing potential receiving single ascending doses of C106. Part B, multiple ascending dose (MAD): safety, tolerability, and PK in healthy males and healthy females of non-childbearing potential receiving twice daily multiple ascending doses of C106 for 8 days.

Official Title
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A Double-blind, Placebo-controlled, Randomised, First in Human Trial to Evaluate the Safety, Tolerability and Pharmacokinetics of Single and Multiple Ascending Oral Doses of C106 in Healthy Male and Female Subjects

Conditions
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Safety Issues, Tolerance, Idiopathic Pulmonary Fibrosis, Pulmonary Hypertension

Intervention / Treatment
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* Drug: C106 solution
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to give written informed consent for participation in the trial. Healthy males and females of non-childbearing potential aged 18-65 years inclusive. Body Mass Index (BMI) ≥ 18.5 and ≤ 30.0 kg/m2 Clinically normal medical history, physical findings, vital signs, ECG, and laboratory values at the time of screening, as judged by the Investigator Women of non-childbearing potential, defined as pre-menopausal females who are sterilized (tubal ligation or permanent bilateral occlusion of fallopian tubes); or females who have undergone hysterectomy or bilateral oophorectomy; or post-menopausal defined as 12 months of amenorrhea (in questionable cases a blood sample with simultaneous detection of follicle stimulating hormone [FSH] ≥ 25 IU/L is confirmatory). Male subjects must be willing to use condom or be vasectomised or practice sexual abstinence to prevent pregnancy and drug exposure of a partner and refrain from donating sperm from the date of dosing until 3 months after (last) dosing with the IMP. Their female partner of child-bearing potential must use highly effective contraceptive methods with a failure rate of < 1% to prevent pregnancy (combined [oestrogen and progestogen containing] hormonal contraception associated with inhibition of ovulation [oral, intravaginal, transdermal], progestogen-only hormonal contraception associated with inhibition of ovulation [oral, injectable, implantable], intrauterine device [IUD]or intrauterine hormone-releasing system [IUS]) from at least 4 weeks prior to dose to 3 months after last dose. Exclusion Criteria: History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the trial, or influence the results or the subject's ability to participate in the trial. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP. Malignancy within the past 5 years except for in situ removal of basal cell carcinoma. Any planned major surgery within the duration of the trial. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody and Human Immunodeficiency Virus (HIV). After 10 minutes supine rest at the time of screening, any vital signs values outside the following ranges: Systolic blood pressure <90 or >140 mmHg, or Diastolic blood pressure <50 or >90 mmHg, or Pulse <40 or >90 bpm Prolonged QTcF (>450 ms), PR interval < 120 ms or > 240 ms, QRS>115 ms, clinically significant cardiac arrhythmias or any clinically significant abnormalities in the resting ECG at the time of screening, as judged by the Investigator. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to C106. Regular use of any prescribed or non-prescribed medication including antacids, analgesics, herbal remedies, vitamins and minerals within 2 weeks prior to the (first) administration of IMP, at the discretion of the Investigator. Planned treatment or treatment with another investigational drug within 3 months prior to Day -1. Subjects consented and screened but not dosed in previous clinical trials are not excluded. Current smokers or users of nicotine products. Irregular use of nicotine (e.g., smoking, snuffing, chewing tobacco) less than three times per week is allowed before screening visit. Positive screen for drugs of abuse or alcohol at screening or on admission to the unit prior to administration of the IMP. History of alcohol abuse or excessive intake of alcohol, as judged by the Investigator. Presence or history of drug abuse, as judged by the Investigator. History of, or current use of, anabolic steroids. Excessive caffeine consumption defined by a daily intake of >5 cups of caffeine containing beverages. Plasma donation within one month of screening or blood donation (or corresponding blood loss) during the three months prior to screening. Investigator considers the subject unlikely to comply with trial procedures, restrictions, and requirements.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Part A, single ascending dose (SAD) including a food interaction cohort Part B, multiple ascending dose (MAD)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: C106 solution<br>Part A: Oral administration start dose, Single dose 5 mg Part B: Oral administration start dose 20 mg twice daily for 8 days | Drug: C106 solution<br>* selective nonpeptide angiotensin II type 2 receptor (AT2R) agonist<br>|
| Placebo Comparator: Placebo<br>Part A and B: Placebo to C106 without the active pharmaceutical ingredient | Drug: Placebo<br>* Placebo for C106 solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinically significant changes in vital signs, pulse | Will be measured in supine position after 10 minutes of rest. | Part A: Up to Day 3, Part B: Up to Day 10 | 
| Clinically significant changes in vital signs, respiratory rate | Will be assessed in supine position after 10 minutes of rest. | Part A:Up Day 3, Part B: Up to Day 10 | 
| Clinically significant changes in vital signs, temperature | Measured with digital thermometer | Part A:Up Day 3, Part B: Up to Day 10 | 
| Number of subjects with abnormal and clinically significant safety laboratory test results post-dose | Any lab values outside the normal ranges will be judged as not clinically significant or clinically significant. Abnormal post-dose findings assessed by the Investigator as clinically significant will be reported as AEs. Laboratory Safety variables are (haematology, coagulation, clinical chemistry and urine analysis | Part A: Up to Day 3, Part B: Up to Day 10 | 
| Number of subjects with abnormal and significant physical examination findings post-dose | Any abnormalities will be specified and documented as clinically significant or not clinically significant. Abnormal post-dose findings assessed by the Investigator as clinically significant will be reported as AEs. A complete physical examination will include assessments of the head, eyes, ears, nose, throat, skin, neurological, lungs, cardiovascular, and abdomen | Part A: Day 7, Part B: Day 22 | 
| Treatment Emergent adverse events (AEs) and serious AEs (SAEs) | AE reporting and questioning. AEs must be recorded in the AE Log of the eCRF. The Investigator must provide information on the AE, preferably with a diagnosis or at least with signs and symptoms; start and stop dates, start and stop time; intensity; causal relationship to IMP; action taken, and outcome. If the AE is serious, this must be indicated in the eCRF. AEs, including out-of-range clinically significant clinical safety laboratory values, must be recorded individually, except when considered manifestations of the same medical condition or disease state; in such cases, they must be recorded under a single diagnosis. | From date of signing informed consent until End of Study, assessed up to Day 22 | 
| Number of reported clinically significant changes from baseline in 12-lead electrocardiograms (ECGs) | Single 12-lead ECG will be recorded in supine position after 10 minutes of rest using an ECG machine. Abnormalities will be specified and documented as clinically significant or not clinically significant | Part A: Up to Day 10. Part B: Up to Day 22. | 
| Clinically significant changes in vital signs, systolic and diastolic blood pressure | Will be measured in supine position after 10 minutes of rest. | Part A: Up to Day 3, Part B: Up to Day 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of the PK profile (Cmax) | To assess the maximum Plasma Concentration (Cmax) | Part A up to Day 3, Part B up to Day 10 | 
| Measurement of the PK profile (t1/2) | To assess the plasma half life (t1/2) of the drug | Up to Day 3 | 
| Measurement of the PK profile (total clearance) | To assess the total clearance of the drug | Up to Day 3 | 
| Measurement of PK profile (dose proportionality) | To assess the dose proportionality of the drug | Part A: Up to Day 3, Part B: Up to Day 10 | 
| Measure % of dose excreted unchanged in urine of single and multiple oral doses of C106 of healthy subjects. | PK sampling in urine in Part A and B. | Part A: Up to Day 3, Part B: Up to Day 10 | 
| To evaluate the effect of a high fat meal on the single oral dose PK of C106 in healthy subjects (Part A) by relative bioavailibity of C106 in fasted versus fed conditions. | PK sampling in plasma and urine after single oral doses of C106 in healthy subjects, PK parameters as for Part A. | Up to Day 3 | 
| Investigate Renal Clearance in Part A and B of single and multiple oral doses of C106 of healthy subjects. | PK sampling in blood and urine | Part A: Up to Day 3 Part B: Up to 8 | 
| Identify accumulation ratios (based on AUCtau and Cmax) | PK sampling in blood and urine after multiple oral doses of C106 in healthy subjects. | Up to Day 10 | 
| Evaluate the observed concentration at the end of a dosing interval, immediately before next administration (Ctrough) | PK sampling in blood and urine after multiple doses of C106 in healthy subjects | Up to Day 10 |