Two Part Study to Assess Comparative Bioavailability, Pharmacokinetics of a Single Dose of ACM-001.1, Two Single Doses of Pindolol (Part1) Followed by Evaluation of Steady State Pharmacokinetics, Pharmacodynamics of ACM-001.1 in HV (Part2)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 51
- 试验地点
- 1
- 主要终点
- Part 1 Composite of PK parameters following single doses
研究概览
简要总结
The aim of this early phase two-part study was to compare the bioavailability (BA) pharmacokinetics (PK) and pharmacodynamics (PD) of racemic pindolol with the benzoate salt of the S-enantiomer of pindolol (ACM-001.1) and provide safety information. A total of 51 healthy male and female subjects were enrolled, and 48 healthy subjects completed the study.
Part 1 consisted of two Groups to compare BA and PK, Group 1 received two treatment sequences of a single dose of ACM-001.1 versus racemic pindolol; Group 2 ran in parallel with Group 1 and assessed the PK of a single dose of racemic pindolol in a single period.
Part 2 consisted of four groups, to evaluate the steady state PK and PD of ACM-001.1 with multiple ascending doses over 4 days.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
Part 2 was single - blind study (subject blinded). Masking was not triple for all parts of the study or all arms.
入排标准
- 年龄范围
- 20 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy males or non-pregnant, non-lactating healthy females
- •Aged 20 to 45 years inclusive at the time of signing informed consent
- •Body Mass Index (BMI) of 18.0 to 30.0 kg/m2 as measured at screening
- •Weight of 50 to 100 kg at screening
排除标准
- •Subjects who had received any investigational medicinal product in a clinical research study within the 90 days prior to Day 1,
- •Subjects for whom pindolol was contraindicated: hypersensitivity to the active substance or to any of its listed excipients.
- •Evidence of current Severe Acute Respiratory Coronavirus 2 infection.
- •History of any drug or alcohol abuse in the past 2 years.
- •Females of childbearing potential who were pregnant or lactating.
- •History of clinically significant cardiovascular disease, Raynaud's disease or phenomenon, renal, hepatic, dermatological, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder.
- •Subjects who were found to have mean heart rate less than 50 bpm at rest or mean systolic blood pressure (BP) less than 100 mmHg or mean diastolic heart rate less than 50 mmHg.
- •Subjects who were taking, or had taken, any prescribed or over-the-counter drug or herbal remedies (other than paracetamol, hormonal replacement therapy/hormonal contraception). Pindolol should not be taken in conjunction with agents which inhibit calcium transport.
研究组 & 干预措施
Part 1 Group1 (AB)
Part 1 Group1 Subjects were randomised to two treatment regimens (A and B) and received treatment sequence AB in a 2-period cross over.
Regimen A = 15 mg ACM-001.1 and matching placebo. Regimen B = 30 mg pindolol.
干预措施: Part 1 Group 1 Regime A (ACM-001.1) (Drug)
Part 1 Group1 (AB)
Part 1 Group1 Subjects were randomised to two treatment regimens (A and B) and received treatment sequence AB in a 2-period cross over.
Regimen A = 15 mg ACM-001.1 and matching placebo. Regimen B = 30 mg pindolol.
干预措施: Part 1 Group 1 Regimen B (Pindolol) (Drug)
Part 1 Group1 (AB)
Part 1 Group1 Subjects were randomised to two treatment regimens (A and B) and received treatment sequence AB in a 2-period cross over.
Regimen A = 15 mg ACM-001.1 and matching placebo. Regimen B = 30 mg pindolol.
干预措施: Part 1 Group 1 Regimen A (Placebo) (Other)
Part 1 Group 1 (BA)
Subjects were randomised to two treatment regimens (A and B) and received treatment sequence BA in a 2-period cross over.
Regimen B = 30 mg pindolol. Regimen A = 15 mg ACM-001.1 and matching placebo.
干预措施: Part 1 Group 1 Regime A (ACM-001.1) (Drug)
Part 1 Group 1 (BA)
Subjects were randomised to two treatment regimens (A and B) and received treatment sequence BA in a 2-period cross over.
Regimen B = 30 mg pindolol. Regimen A = 15 mg ACM-001.1 and matching placebo.
干预措施: Part 1 Group 1 Regimen B (Pindolol) (Drug)
Part 1 Group 1 (BA)
Subjects were randomised to two treatment regimens (A and B) and received treatment sequence BA in a 2-period cross over.
Regimen B = 30 mg pindolol. Regimen A = 15 mg ACM-001.1 and matching placebo.
干预措施: Part 1 Group 1 Regimen A (Placebo) (Other)
Part 1 Group 2 (C)
Subjects were non-randomised; received regimen C in parallel with Group 1 in a single period.
Regimen C = 15 mg pindolol.
干预措施: Part 1 Group 2 Regimen C (Pindolol) (Drug)
Part 2 Group D
Subjects received one of the four regimens over a four day treatment period. Regimen D = 20 mg pindolol BID (bis in die) for four days.
干预措施: Part 2 Group D (Pindolol) (Drug)
Part 2 Group E
Subjects received one of the four regimens over a four day treatment period. Regimen E = 5 mg ACM-001.1 and placebo BID for four days.
干预措施: Part 2 Group E (ACM-001.1) (Drug)
Part 2 Group E
Subjects received one of the four regimens over a four day treatment period. Regimen E = 5 mg ACM-001.1 and placebo BID for four days.
干预措施: Part 2 Group E (Placebo) (Other)
Part 2 Group F
Subjects received one of the four regimens over a four day treatment period. Regimen F = 10 mg ACM-001.1 and placebo BID for four days.
干预措施: Part 2 Group F (ACM-001.1 ) (Drug)
Part 2 Group F
Subjects received one of the four regimens over a four day treatment period. Regimen F = 10 mg ACM-001.1 and placebo BID for four days.
干预措施: Part 2 Group F (Placebo) (Other)
Part 2 Group G
Subjects received one of the four regimens over a four day treatment period. Regimen G = 15 mg ACM-001.1 and placebo BID for four days.
干预措施: Part 2 Group G (ACM-001.1) (Drug)
Part 2 Group G
Subjects received one of the four regimens over a four day treatment period. Regimen G = 15 mg ACM-001.1 and placebo BID for four days.
干预措施: Part 2 Group G ( Placebo) (Other)
结局指标
主要结局
Part 1 Composite of PK parameters following single doses
时间窗: Up to 5 days
Comparative bioavailability of S- pindolol and pindolol include: area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC\[0-infinite\].
PK parameters following single doses
时间窗: Up to 5 days
Comparative PK parameters of S- pindolol and racemic pindolol include: t time of occurrence of Cmax (Tmax)
Serum biomarker- DHEA/Cortisol
时间窗: Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours
Dehydroepiandrosterone (DHEA)/Cortisol (ng/mL). Serum concentrations were determined using validated analytical method.
Part 1 PK parameters following single doses
时间窗: Up to 5 days
Comparative bioavailability of S- pindolol and pindolol include:time of occurrence of Cmax (Tmax)
Serum biomarker - monokine-induced by gamma interferon (MIG/CXL9) Leptin
时间窗: Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.
Leptin (pg/mL).Serum concentrations were determined using validated analytical method.
Serum biomarker - Growth Hormone Receptor Hormone
时间窗: Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.
Growth Hormone Receptor Hormone (ng/mL).Serum concentrations were determined using validated analytical method.
Serum biomarker- Myostatin
时间窗: Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.
Myostatin (pg/mL).Serum concentrations were determined using validated analytical method.
Serum biomarker-IGF1
时间窗: Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.
Insulin-like growth factor (IGF)1 (pg/mL).Serum concentrations were determined using validated analytical method.
Serum biomarker - Somatostatin
时间窗: Day 1 at pre-dose (baseline). Day 4 at pre-dose, 1.5 hours.
Somatostatin (pg/mL).Serum concentrations were determined using validated analytical method.
Stoichiometric dose relationship measured using PK parameters following single doses
时间窗: Up to 5 days
PK parameters of S- pindolol and racemic pindolol include: maximum observed concentration (Cmax).
Cardiovascular vital parameter- blood pressure
时间窗: Up to 6 days
Systolic blood pressure (mmHG) and diastolic blood pressure (mmHG)
Serum biomarker- Folistatin
时间窗: Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.
Folistatin (pg/mL).Serum concentrations were determined using validated analytical method.
Serum biomarker - epithelial neutrophil activating peptide 78 (ENA78)
时间窗: Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.
ENA78 (pg/mL).Serum concentrations were determined using validated analytical method.
Serum biomarker - Ghrelin
时间窗: Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.
Ghrelin (pg/mL).Serum concentrations were determined using validated analytical method.
Part 2 Composite of PK parameters following multiple doses in plasma
时间窗: Up to 6 days
PK parameters of S- pindolol/racemic pindolol: Time to first occurrence of Cmax from plasma concentration-time data(Tmax).
Pharmacodynamics of ACM-001.1: Cardiovascular vital parameter- heart rate
时间窗: Up to 6 days
Heart rate (beats per minute)
Serum biomarker - (Type 3 procollagen peptide) PIIINP
时间窗: Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.
PIIINP (pg/mL).Serum concentrations were determined using validated analytical method.
次要结局
- Part 2 Composite PK parameters in urine following multiple doses and pindolol(Up to 7 days)
- Part 1 and Part 2 Analysis of S-pindolol and R-pindolol concentrations in plasma for any in vivo conversion(Up to 4 days)
- Part 1 Number of participants with adverse events following single doses as a measure of safety and tolerability(From screening: day -28 to follow up call on day 8 (part 1), up to 36 days.)
- Part 1 Composite PK parameters in urine following single doses(Up to 5 days)
- Part 2 Number of participants with adverse events following single doses as a measure of safety and tolerability(From screening: day -28 to follow up call on day 11 (part 2), up to 39 days.)
- Part 2 only - Pulmonary function test(Up to 32 days)