Clinical trial NCT04613999: A Study of Ralinepag in Healthy Chinese Adult Subjects
Official title: A Phase 1 Open-label, Non-randomized, Single Ascending Dose Escalation Study To Evaluate The Pharmacokinetics, Safety, And Tolerability Of A Ralinepag Extended Release (XR) Tablet Formulation In Healthy Chinese Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteer
Pharmacokinetic Study
Keywords: Healthy volunteer
Pharmacokinetic, safety and tolerability
Ralinepag
Lead sponsor: Everstar Therapeutics Limited
Sponsor class: INDUSTRY
First posted: 2020-11-03
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: The study is planned to enroll 15 subjects with open-label, fixed sequence, non-randomized to take a single dose of ralinepag at 3 separate dose intervals. Ralinepag will be administered at doses of 50, 100 and 150 mcg single oral each time. Subjects will receive Regimen A (single dose of ralinepag 50 mcg) in the morning of Day 1 and pharmacokinetic assessments will be conducted pre-dose and over the 96 hours post-dose. There will be a washout period of 7 days between each IMP administration. Regimens B and C (single dose of ralinepag 100 mcg and ralinepag 150 mcg) will be administered following an overnight fast on Day 8 and 15, respectively, with 96 hours of pharmacokinetic assessments as performed with Regimen A. A Follow-up phone call will take place 10±1 days post-last dose to ensure the ongoing well-being of the subjects.
Primary purpose: TREATMENT

Brief summary: A Phase 1 Open-label, Non-randomized, Single Ascending Dose Escalation Study To Evaluate The Pharmacokinetics, Safety, And Tolerability Of A Ralinepag Extended Release (XR) Tablet Formulation In Healthy Chinese Subjects.

Detailed description: This is a single center, open-label, fixed sequence, non-randomized study of healthy subjects. The study is planned to enroll 15 subjects to ensure data for 8 evaluable subjects.

Subjects will visit the clinical unit for a screening visit up to 28 days before dosing. Eligible subjects will be admitted to the clinical unit prior to investigational medicinal product (IMP) administration (Day -1) and will remain onsite through the study discharge on Day 19. Following an overnight fast of at least 8 hours, subjects will receive Regimen A (single dose of ralinepag 50 mcg) in the morning of Day 1 and pharmacokinetic assessments will be conducted pre-dose and over the 96 hours post-dose. There will be a washout period of 7 days between each IMP administration. Regimens B and C (single dose of ralinepag 100 mcg and ralinepag 150 mcg) will be administered following an overnight fast on Day 8 and 15, respectively, with 96 hours of pharmacokinetic assessments as performed with Regimen A. A Follow-up phone call will take place 10±1 days post-last dose to ensure the ongoing well-being of the subjects. Ralinepag (APD811) will be supplied as 50 mcg round, orange, XR tablets for oral administration.

It is planned that every subject will receive each of the following regimens in the fasted state:

* Regimen A (50 mcg): 1 × 50 mcg ralinepag XR tablet
* Regimen B (100 mcg): 2 × 50 mcg ralinepag XR tablets
* Regimen C (150 mcg): 3 × 50 mcg ralinepag XR tablets Subjects will receive Regimens A, B and C in a sequential manner in consecutive treatment periods. Subjects who have tolerated the IMP in all prior regimens will continue in the study to receive each subsequent dose.

Eligibility criteria: Inclusion Criteria:

* 1. Healthy subjects aged 18 to 45 years at the time of signing the informed consent form (ICF).

  2. Body mass index of 19.0 to 25.0 kg/m2.

  3. In good general health, free from clinically significant medical or psychiatric illness or disease (as determined by medical/surgical history, physical examination, weight, 12-lead ECG and clinical laboratory tests).

  4. HIV, Syphilitics, Hepatitis B and Hepatitis C negative at the screening evaluation.

  5. Adequate venous access in the left or right arm to allow for collection of a number of blood samples

  6. Provides written informed consent.

  7. Willing to comply with all study procedures and requirements.

  8. Subjects of reproductive potential must agree to use an approved method of contraception from Day -1 until 30 days after study discharge:
  1. Barrier method (e.g., condom) plus an approved method of highly effective contraception or
  2. Female/male partner is surgically sterile.

     Exclusion Criteria:
* 1. History or presence of malignancy, with the exception of adequately treated localized skin cancer (basal cell or squamous cell carcinoma), which is allowed.

  2. History or presence of any clinically significant psychiatric condition (including depression or prior suicidal behaviour).

  3. Evidence of clinically relevant medical illness, cardiovascular, hematological, gastrointestinal, hepatic, renal, rheumatologic, endocrine, pulmonary, neurologic, psychiatric or skin disorder (excluding skin cancer as described in Exclusion Criterion 1) or history of hypertension or heart disease including any abnormal laboratory results deemed clinically significant by the study investigator at screening.

  4. History of dysphagia.

  5. Clinically significant surgical procedure or traumatic injury within 3 months of screening.

  6. History of epilepsy (other than febrile seizures during childhood).

  7. Clinically significant infection within 28 days of start of dosing.

  8. Currently suffers from clinically significant systemic allergic disease or has a history of significant drug allergies including a history of anaphylactic reaction (particularly reactions to general anesthetic agents); allergic reaction due to any drug which led to significant morbidity.

  9. History or presence of cardiac arrhythmia or congenital long QT syndrome.

  10. QTcF \>450 msec, PR \>220 msec and QRS \>120 msec on screening ECG (ECG may be repeated after consultation with the Medical Monitor).

  11. Use of tobacco or nicotine containing products in the previous 6 months prior to dosing or use of a nicotine patch within 14 days prior to screening.

  12. Regular alcohol consumption \> 2 units/day (1 unit = 300 mL of beer or 45 mL of alcohol 40% or 150mL of wine) or alcohol consumption within 48 hours of start of dosing.

  13. Positive urine drug or alcohol breathalyzer test prior to study entry or history of alcohol or drug abuse in the last 12 months.

  14. Use of any prescription medication within 14 days prior to screening.

  15. Use of any over the counter (OTC) medication, herbal or hormone supplements, or diet aids within 14 days prior to screening

  16. Participation in any other investigational trial in which the last dose of study drug occurred within 30 days or 5 half-lives (whichever is longer) before Check-in for Inpatient Period (Day -1)

  17. Donation of blood from 30 days before Check-in for Inpatient Period (Day -1) or of plasma from 2 weeks before Check-in for Inpatient Period (Day -1)

  18. Receipt of blood products within 2 months before Check-in for Inpatient Period (Day -1)

  19. Abnormal supine BP (defined as either systolic BP \> 140 millimetres (mm) Hg or \< 90 mmHg or diastolic BP \> 90 mmHg or \< 50 mmHg) or abnormal pulse rate (\> 100 beats per minute \[bpm\] or \< 50 bpm), confirmed by at least 1 repeat measurement

  20. Abnormal orthostatic BP at Screening or CPC Check-in on Day -1 (defined as confirmed drop in SBP \> 20 mmHg or drop in DBP \> 10 mmHg with standing). The assessment may be repeated once to assure adequate hydration.

  21. Women who are pregnant, lactating or breast-feeding.

  22. Known hypersensitivity to any of the excipients of Ralinepag.

  23. Any inappropriate condition to participate in the study considered by investigator.

Primary outcomes:
measure: Cmax
timeFrame: Baseline to 96 hours
measure: Tmax
timeFrame: Baseline to 96 hours
measure: T1/2
timeFrame: Baseline to 96 hours
measure: AUC0-24
timeFrame: Baseline to 96 hours
measure: AUClast
timeFrame: Baseline to 96 hours
measure: AUCinf
timeFrame: Baseline to 96 hours
Secondary outcomes:
measure: Adverse event reporting
timeFrame: From signing ICF to 10 days after last dose.
measure: Assessment of general appearance of dermatologic.
timeFrame: From signing ICF to 10 days after last dose.
measure: Assessment of general appearance of head.
timeFrame: From signing ICF to 10 days after last dose.
measure: Assessment of general appearance of eyes.
timeFrame: From signing ICF to 10 days after last dose.
measure: Assessment of general appearance of ears.
timeFrame: From signing ICF to 10 days after last dose.
measure: Assessment of general appearance of mouth.
timeFrame: From signing ICF to 10 days after last dose.
measure: Assessment of general appearance of throat.
timeFrame: From signing ICF to 10 days after last dose.
measure: Assessment of general appearance of neck.
timeFrame: From signing ICF to 10 days after last dose.
measure: Assessment of general appearance of thyroid.
timeFrame: From signing ICF to 10 days after last dose.
measure: Assessment of general appearance of lymph nodes.
timeFrame: From signing ICF to 10 days after last dose.
measure: Assessment of general appearance of respiratory system.
timeFrame: From signing ICF to 10 days after last dose.
measure: Assessment of general appearance of cardiovascular system.
timeFrame: From signing ICF to 10 days after last dose.
measure: Assessment of general appearance of gastrointestinal system.
timeFrame: From signing ICF to 10 days after last dose.
measure: Assessment of general appearance of extremities.
timeFrame: From signing ICF to 10 days after last dose.
measure: Assessment of general appearance of musculoskeletal system.
timeFrame: From signing ICF to 10 days after last dose.
measure: Assessment of general appearance of neurologic system.
timeFrame: From signing ICF to 10 days after last dose.
measure: Assessment of general appearance of psychiatric system.
timeFrame: From signing ICF to 10 days after last dose.
measure: Serum alanine aminotransferase (ALT)
timeFrame: From signing ICF to 10 days after last dose.
measure: Serum glucose
timeFrame: From signing ICF to 10 days after last dose.
measure: Serum albumin
timeFrame: From signing ICF to 10 days after last dose.
measure: Serum lactate dehydrogenase (LDH)
timeFrame: From signing ICF to 10 days after last dose.
measure: Serum alkaline phosphatase (ALP)
timeFrame: From signing ICF to 10 days after last dose.
measure: Serum phosphorus
timeFrame: From signing ICF to 10 days after last dose.
measure: Serum aspartate aminotransferase (AST)
timeFrame: From signing ICF to 10 days after last dose.
measure: Serum potassium
timeFrame: From signing ICF to 10 days after last dose.
measure: Serum blood urea
timeFrame: From signing ICF to 10 days after last dose.
measure: Serum sodium
timeFrame: From signing ICF to 10 days after last dose.
measure: Serum calcium
timeFrame: From signing ICF to 10 days after last dose.
measure: Serum total bilirubin
timeFrame: From signing ICF to 10 days after last dose.
measure: Serum cholesterol
timeFrame: From signing ICF to 10 days after last dose.
measure: Serum triglycerides
timeFrame: From signing ICF to 10 days after last dose.
measure: Serum creatinine
timeFrame: From signing ICF to 10 days after last dose.
measure: Serum uric acid
timeFrame: From signing ICF to 10 days after last dose.
measure: Serum creatine phosphokinase (CPK)
timeFrame: From signing ICF to 10 days after last dose.
measure: Serum gamma glutamyl transferase (GGT
timeFrame: From signing ICF to 10 days after last dose.
measure: White blood cell (WBC) count
timeFrame: From signing ICF to 10 days after last dose.
measure: Neutrophils (percentage and absolute count)
timeFrame: From signing ICF to 10 days after last dose.
measure: Red blood cell (RBC) count
timeFrame: From signing ICF to 10 days after last dose.
measure: Lymphocytes (percentage）
timeFrame: From signing ICF to 10 days after last dose.
measure: Lymphocytes (absolute count)
timeFrame: From signing ICF to 10 days after last dose.
measure: Hemoglobin (Hb)
timeFrame: From signing ICF to 10 days after last dose.
measure: Monocytes (percentage)
timeFrame: From signing ICF to 10 days after last dose.
measure: Monocytes (absolute count)
timeFrame: From signing ICF to 10 days after last dose.
measure: Hematocrit (HCT)
timeFrame: From signing ICF to 10 days after last dose.
measure: Eosinophils (percentage)
timeFrame: From signing ICF to 10 days after last dose.
measure: Eosinophils (absolute count)
timeFrame: From signing ICF to 10 days after last dose.
measure: Mean corpuscular volume (MCV)
timeFrame: From signing ICF to 10 days after last dose.
measure: Basophils (percentage)
timeFrame: From signing ICF to 10 days after last dose.
measure: Basophils (absolute count)
timeFrame: From signing ICF to 10 days after last dose.
measure: Mean corpuscular hemoglobin (MCH)
timeFrame: From signing ICF to 10 days after last dose.
measure: Platelet count
timeFrame: From signing ICF to 10 days after last dose.
measure: Mean corpuscular hemoglobin concentration (MCHC)
timeFrame: From signing ICF to 10 days after last dose.
measure: RBC distribution width
timeFrame: From signing ICF to 10 days after last dose.
measure: Urine bilirubin
timeFrame: From signing ICF to 10 days after last dose.
measure: Urine blood
timeFrame: From signing ICF to 10 days after last dose.
measure: Urine glucose
timeFrame: From signing ICF to 10 days after last dose.
measure: Urine PH
timeFrame: From signing ICF to 10 days after last dose.
measure: Urine specific gravity
timeFrame: From signing ICF to 10 days after last dose.
measure: Urine ketones
timeFrame: From signing ICF to 10 days after last dose.
measure: Urine protein
timeFrame: From signing ICF to 10 days after last dose.
measure: Urine leukocytes
timeFrame: From signing ICF to 10 days after last dose.
measure: Urine urobilinogen
timeFrame: From signing ICF to 10 days after last dose.
measure: Urine nitrite
timeFrame: From signing ICF to 10 days after last dose.
measure: Urine microscopic (only for abnormal urine stick test findings).
timeFrame: From signing ICF to 10 days after last dose.
measure: Supine BP
timeFrame: From signing ICF to 10 days after last dose.
measure: Pulse
timeFrame: From signing ICF to 10 days after last dose.
measure: Body temperature
timeFrame: From signing ICF to 10 days after last dose.
measure: Respiratory rate
timeFrame: From signing ICF to 10 days after last dose.
measure: ECG PR interval
timeFrame: From signing ICF to 10 days after last dose.
measure: ECG QRS interval
timeFrame: From signing ICF to 10 days after last dose.
measure: ECG RR interval
timeFrame: From signing ICF to 10 days after last dose.
measure: ECG QT interval
timeFrame: From signing ICF to 10 days after last dose.
measure: ECG QT interval corrected for heart rate (QTc)
timeFrame: From signing ICF to 10 days after last dose.
Other outcomes:
Locations:
city: Beijing
country: China
facility: Peking University Third Hospital
state: Beijing
Study officials:
affiliation: Peking University Third Hospital
name: Haiyan Li
role: PRINCIPAL_INVESTIGATOR
References: