Study of Comparative Bioavailability and Pharmacokinetics of ACM-001.1) and Pindolol in Healthy Volunteers (HV)
- Conditions
- Cachexia
- Interventions
- Drug: Part 1 Group 2 Regimen C (Pindolol)Drug: Part 1 Group 1 Regime A (ACM-001.1)Drug: Part 2 Group G (ACM-001.1)Drug: Part 2 Group D (Pindolol)Drug: Part 2 Group E (ACM-001.1)Drug: Part 2 Group F (ACM-001.1 )Drug: Part 1 Group 1 Regimen B (Pindolol)Other: Part 2 Group G ( Placebo)Other: Part 2 Group E (Placebo)Other: Part 2 Group F (Placebo)Other: Part 1 Group 1 Regimen A (Placebo)
- Registration Number
- NCT06028321
- Lead Sponsor
- Actimed Therapeutics Ltd
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 51
- 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
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Part 1 Group 1 (BA) Part 1 Group 1 Regimen B (Pindolol) 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. Part 1 Group1 (AB) Part 1 Group 1 Regimen B (Pindolol) 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. Part 1 Group1 (AB) Part 1 Group 1 Regimen A (Placebo) 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. Part 1 Group 1 (BA) Part 1 Group 1 Regimen A (Placebo) 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. Part 1 Group 2 (C) Part 1 Group 2 Regimen C (Pindolol) Subjects were non-randomised; received regimen C in parallel with Group 1 in a single period. Regimen C = 15 mg pindolol. Part 1 Group 1 (BA) Part 1 Group 1 Regime A (ACM-001.1) 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. Part 2 Group G Part 2 Group G ( Placebo) 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. Part 2 Group E Part 2 Group E (Placebo) 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. Part 2 Group G Part 2 Group G (ACM-001.1) 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. Part 1 Group1 (AB) Part 1 Group 1 Regime A (ACM-001.1) 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. Part 2 Group F Part 2 Group F (Placebo) 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. Part 2 Group D Part 2 Group D (Pindolol) 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. Part 2 Group E Part 2 Group E (ACM-001.1) 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. Part 2 Group F Part 2 Group F (ACM-001.1 ) 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.
- Primary Outcome Measures
Name Time Method Part 1 Composite of PK parameters following single doses 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 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 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 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 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 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 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 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 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 Up to 5 days PK parameters of S- pindolol and racemic pindolol include: maximum observed concentration (Cmax).
Cardiovascular vital parameter- blood pressure Up to 6 days Systolic blood pressure (mmHG) and diastolic blood pressure (mmHG)
Serum biomarker- Folistatin 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) 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 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 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 Up to 6 days Heart rate (beats per minute)
Serum biomarker - (Type 3 procollagen peptide) PIIINP Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours. PIIINP (pg/mL).Serum concentrations were determined using validated analytical method.
- Secondary Outcome Measures
Name Time Method Part 2 Composite PK parameters in urine following multiple doses and pindolol Up to 7 days PK parameters of S-pindolol, R-pindolol and pindolol: Amount excreted (Ae), Cumulative amount excreted (CumAe), Fraction of dose excreted (%Ae) and Cumulative fraction of dose excreted (%CumAe)
Part 1 and Part 2 Analysis of S-pindolol and R-pindolol concentrations in plasma for any in vivo conversion Up to 4 days Plasma concentrations were determined using validated analytical methods.
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. AEs will be collected from provision of written informed consent until discharge at the follow-up contact.
Part 1 Composite PK parameters in urine following single doses Up to 5 days PK parameters of S-pindolol, R-pindolol and pindolol: Amount excreted (Ae), Cumulative amount excreted (CumAe), Fraction of dose excreted (%Ae) and Cumulative fraction of dose excreted (%CumAe)
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. AEs will be collected from provision of written informed consent until discharge at the follow-up contact
Part 2 only - Pulmonary function test Up to 32 days Forced expiratory spirometry to determine parameters FEV1, FVC, FEV1/FVC
Trial Locations
- Locations (1)
Quotient Sciences Ltd
🇬🇧Ruddington, United Kingdom