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

NCT06028321 | Completed Phase 1

• 2 other identifiers: ACM-2021-1-CTQSC205141
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 1

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.

Conditions

Cachexia

Outcome Measures

Primary Outcomes (23)

• 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

• Part 1 PK parameters following single doses

  Comparative bioavailability of S- pindolol and pindolol include:maximum observed concentration (Cmax)

  Up to 5 days

• 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

• 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

• PK parameters following single doses

  Comparative PK parameters of S- pindolol and racemic pindolol include: maximum observed concentration (Cmax)

  Up to 5 days

• 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

• 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

• 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

• 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

• 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

• 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

• Pharmacodynamics of ACM-001.1: Cardiovascular vital parameter- heart rate

  Heart rate (beats per minute)

  Up to 6 days

• Cardiovascular vital parameter- blood pressure

  Systolic blood pressure (mmHG) and diastolic blood pressure (mmHG)

  Up to 6 days

• 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

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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 Outcomes (6)

• Part 1 Composite PK parameters in urine following single doses

  Up to 5 days

• 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 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.

Study Arms (7)

Part 1 Group1 (AB)

EXPERIMENTAL

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.

Drug: Part 1 Group 1 Regime A (ACM-001.1); Drug: Part 1 Group 1 Regimen B (Pindolol); Other: Part 1 Group 1 Regimen A (Placebo)

Part 1 Group 1 (BA)

EXPERIMENTAL

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.

Drug: Part 1 Group 1 Regime A (ACM-001.1); Drug: Part 1 Group 1 Regimen B (Pindolol); Other: Part 1 Group 1 Regimen A (Placebo)

Part 1 Group 2 (C)

EXPERIMENTAL

Subjects were non-randomised; received regimen C in parallel with Group 1 in a single period. Regimen C = 15 mg pindolol.

Drug: Part 1 Group 2 Regimen C (Pindolol)

Part 2 Group D

EXPERIMENTAL

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.

Drug: Part 2 Group D (Pindolol)

Part 2 Group E

EXPERIMENTAL

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.

Drug: Part 2 Group E (ACM-001.1); Other: Part 2 Group E (Placebo)

Part 2 Group F

EXPERIMENTAL

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.

Drug: Part 2 Group F (ACM-001.1 ); Other: Part 2 Group F (Placebo)

Part 2 Group G

EXPERIMENTAL

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.

Drug: Part 2 Group G (ACM-001.1); Other: Part 2 Group G ( Placebo)

Interventions

Part 1 Group 1 Regime A (ACM-001.1) DRUG

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 1 (BA); Part 1 Group1 (AB)

Part 1 Group 2 Regimen C (Pindolol) DRUG

Drug: Pindolol tablets for oral use.

Part 1 Group 2 (C)

Part 2 Group D (Pindolol) DRUG

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 D

Part 2 Group E (ACM-001.1) DRUG

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 E

Part 2 Group F (ACM-001.1 ) DRUG

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

Part 2 Group G (ACM-001.1) DRUG

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

Part 1 Group 1 Regimen B (Pindolol) DRUG

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.

Part 1 Group 1 (BA); Part 1 Group1 (AB)

Part 1 Group 1 Regimen A (Placebo) OTHER

Placebo 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 1 (BA); Part 1 Group1 (AB)

Part 2 Group E (Placebo) OTHER

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 E

Part 2 Group F (Placebo) OTHER

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

Part 2 Group G ( Placebo) OTHER

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

Eligibility Criteria

• Age: 20 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Actimed Therapeutics Ltd: lead
• Quotient Sciences: collaborator

Study Sites (1)

Quotient Sciences Ltd

Ruddington, NG11 9JS, United Kingdom

Location

MeSH Terms

Conditions

Cachexia

Interventions

Pindolol

Condition Hierarchy (Ancestors)

Weight Loss; Body Weight Changes; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Thinness

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Part 2 was single - blind study (subject blinded). Masking was not triple for all parts of the study or all arms.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Part 1: part - blinded, part randomized, partial cross- over study. Group 1: double - blinded and randomized to two treatment sequences in a two period cross- over. Group 2: open label, non-randomized and in parallel with Group 1. Part 2: single-blind (subject blinded), randomized, parallel-group.

Study Record Dates

• First Submitted: July 6, 2023
• First Posted: September 8, 2023
• Study Start: November 26, 2021
• Primary Completion: June 2, 2022
• Study Completion: June 2, 2022
• Last Updated: October 10, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)