Study of Comparative Bioavailability and Pharmacokinetics of ACM-001.1) and Pindolol in Healthy Volunteers (HV)

Cachexia Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT06028321
• Other study ID #: ACM-2021-1-CT
• Secondary ID: QSC205141
• Status: Completed
• Phase: Phase 1
• Start date: November 26, 2021
• Est. completion date: June 2, 2022

Study information

• Verified date: October 2023
• Source: Actimed Therapeutics Ltd
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 51
• Est. completion date: June 2, 2022
• Est. primary completion date: June 2, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 20 Years to 45 Years

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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.

Related Conditions & MeSH terms

• Cachexia

Intervention

Drug:
• Part 1 Group 1 Regime A (ACM-001.1)
Drug: ACM-001.1 immediate release tablets for oral use and matching placebo, and pindolol tablets for oral use. Subjects randomised to Regimen A received placebo tablets to match the tablet number received by subjects in Regimen B.
• Part 1 Group 2 Regimen C (Pindolol)
Drug: Pindolol tablets for oral use.
• Part 2 Group D (Pindolol)
Drug: Pindolol tablets for oral use. Subjects were dosed over a four day treatment period twice daily. Subjects receiving ACM-001.1 in regimens E, F and G also received placebo tablets to match the tablet number received by subjects receiving pindolol in Regimen D.
• Part 2 Group E (ACM-001.1)
Drug: ACM-001.1 immediate release tablets for oral use and matching placebo. Subjects were dosed over a four day treatment period twice daily. Subjects receiving ACM-001.1 in regimens E, F and G also received placebo tablets to match the tablet number received by subjects receiving pindolol in Regimen D.
• Part 2 Group F (ACM-001.1 )
Drug: ACM-001.1 immediate release tablets for oral use and matching placebo. Subjects were dosed over a four day treatment period twice daily. Subjects receiving ACM-001.1 in regimens E, F and G also received placebo tablets to match the tablet number received by subjects receiving pindolol in Regimen D.
• Part 2 Group G (ACM-001.1)
Drug: ACM-001.1 immediate release tablets for oral use and matching placebo. Subjects were dosed over a four day treatment period twice daily. Subjects receiving ACM-001.1 in regimens E, F and G also received placebo tablets to match the tablet number received by subjects receiving pindolol in Regimen D.
• Part 1 Group 1 Regimen B (Pindolol)
Drug: pindolol tablets for oral use. Subjects randomised to Regimen A received placebo tablets to match the tablet number received by subjects in Regimen B.

Other:
• Part 1 Group 1 Regimen A (Placebo)
Placebo for oral use. Subjects randomised to Regimen A received placebo tablets to match the tablet number received by subjects in Regimen B.
• Part 2 Group E (Placebo)
Placebo for oral use. Subjects were dosed over a four day treatment period twice daily. Subjects receiving ACM-001.1 in regimens E, F and G also received placebo tablets to match the tablet number received by subjects receiving pindolol in Regimen D.
• Part 2 Group F (Placebo)
Placebo for oral use. Subjects were dosed over a four day treatment period twice daily. Subjects receiving ACM-001.1 in regimens E, F and G also received placebo tablets to match the tablet number received by subjects receiving pindolol in Regimen D.
• Part 2 Group G ( Placebo)
Placebo for oral use. Subjects were dosed over a four day treatment period twice daily. Subjects receiving ACM-001.1 in regimens E, F and G also received placebo tablets to match the tablet number received by subjects receiving pindolol in Regimen D.

Locations

Country	Name	City	State
United Kingdom	Quotient Sciences Ltd	Ruddington

Sponsors (2)

Lead Sponsor	Collaborator
Actimed Therapeutics Ltd	Quotient Sciences

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1 Composite of PK parameters following single doses	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].	Up to 5 days
Primary	Part 1 PK parameters following single doses	Comparative bioavailability of S- pindolol and pindolol include:maximum observed concentration (Cmax)	Up to 5 days
Primary	Part 1 PK parameters following single doses	Comparative bioavailability of S- pindolol and pindolol include:time of occurrence of Cmax (Tmax)	Up to 5 days
Primary	PK parameters following single doses	Comparative PK parameters of S- pindolol and racemic pindolol include: area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC[0-infinite]).	Up to 5 days
Primary	PK parameters following single doses	Comparative PK parameters of S- pindolol and racemic pindolol include: maximum observed concentration (Cmax)	Up to 5 days
Primary	PK parameters following single doses	Comparative PK parameters of S- pindolol and racemic pindolol include: t time of occurrence of Cmax (Tmax)	Up to 5 days
Primary	Stoichiometric dose relationship measured using PK parameters following single doses	PK parameters of S- pindolol and racemic pindolol include: area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC[0-infinite])	Up to 5 days
Primary	Stoichiometric dose relationship measured using PK parameters following single doses	PK parameters of S- pindolol and racemic pindolol include: maximum observed concentration (Cmax).	Up to 5 days
Primary	Part 2 Composite of PK parameters following multiple doses in plasma	PK parameters of S- pindolol/racemic pindolol:Area under the curve for interval between doses (tau) (AUC(0 tau);Area under the concentration-time curve from time zero (pre-dose) to last time of measurable concentration (AUC[0-t])	Up to 6 days
Primary	Part 2 Composite of PK parameters following multiple doses in plasma	PK parameters of S- pindolol/racemic pindolol: Maximum observed concentration (Cmax),	Up to 6 days
Primary	Part 2 Composite of PK parameters following multiple doses in plasma	PK parameters of S- pindolol/racemic pindolol: Time to first occurrence of Cmax from plasma concentration-time data(Tmax).	Up to 6 days
Primary	Pharmacodynamics of ACM-001.1: Cardiovascular vital parameter- heart rate	Heart rate (beats per minute)	Up to 6 days
Primary	Cardiovascular vital parameter- blood pressure	Systolic blood pressure (mmHG) and diastolic blood pressure (mmHG)	Up to 6 days
Primary	Serum biomarker- DHEA/Cortisol	Dehydroepiandrosterone (DHEA)/Cortisol (ng/mL). Serum concentrations were determined using validated analytical method.	Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours
Primary	Serum biomarker- Myostatin	Myostatin (pg/mL).Serum concentrations were determined using validated analytical method.	Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.
Primary	Serum biomarker- Folistatin	Folistatin (pg/mL).Serum concentrations were determined using validated analytical method.	Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.
Primary	Serum biomarker-IGF1	Insulin-like growth factor (IGF)1 (pg/mL).Serum concentrations were determined using validated analytical method.	Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.
Primary	Serum biomarker - (Type 3 procollagen peptide) PIIINP	PIIINP (pg/mL).Serum concentrations were determined using validated analytical method.	Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.
Primary	Serum biomarker - monokine-induced by gamma interferon (MIG/CXL9) Leptin	Leptin (pg/mL).Serum concentrations were determined using validated analytical method.	Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.
Primary	Serum biomarker - epithelial neutrophil activating peptide 78 (ENA78)	ENA78 (pg/mL).Serum concentrations were determined using validated analytical method.	Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.
Primary	Serum biomarker - Ghrelin	Ghrelin (pg/mL).Serum concentrations were determined using validated analytical method.	Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.
Primary	Serum biomarker - Growth Hormone Receptor Hormone	Growth Hormone Receptor Hormone (ng/mL).Serum concentrations were determined using validated analytical method.	Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.
Primary	Serum biomarker - Somatostatin	Somatostatin (pg/mL).Serum concentrations were determined using validated analytical method.	Day 1 at pre-dose (baseline). Day 4 at pre-dose, 1.5 hours.
Secondary	Part 1 Composite PK parameters in urine following single doses	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)	Up to 5 days
Secondary	Part 2 Composite PK parameters in urine following multiple doses and pindolol	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)	Up to 7 days
Secondary	Part 1 and Part 2 Analysis of S-pindolol and R-pindolol concentrations in plasma for any in vivo conversion	Plasma concentrations were determined using validated analytical methods.	Up to 4 days
Secondary	Part 1 Number of participants with adverse events following single doses as a measure of safety and tolerability	AEs will be collected from provision of written informed consent until discharge at the follow-up contact.	From screening: day -28 to follow up call on day 8 (part 1), up to 36 days.
Secondary	Part 2 Number of participants with adverse events following single doses as a measure of safety and tolerability	AEs will be collected from provision of written informed consent until discharge at the follow-up contact	From screening: day -28 to follow up call on day 11 (part 2), up to 39 days.
Secondary	Part 2 only - Pulmonary function test	Forced expiratory spirometry to determine parameters FEV1, FVC, FEV1/FVC	Up to 32 days