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Completed

NCT Number: NCT06028321

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

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.

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Key information

Conditions

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

Age range

20 year–45 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Quotient Sciences Ltd

Ruddington, NG11 9JS, United Kingdom

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

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 2 Regimen C (Pindolol)

Drug

Drug: Pindolol tablets for oral use.

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 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 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 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 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 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 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 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 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.

Primary outcomes

  1. Part 1 Composite of PK parameters following single doses

    Time frame: 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].

  2. Part 1 PK parameters following single doses

    Time frame: Up to 5 days

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

  3. Part 1 PK parameters following single doses

    Time frame: Up to 5 days

    Comparative bioavailability of S- pindolol and pindolol include:time of occurrence of Cmax (Tmax)

  4. PK parameters following single doses

    Time frame: Up to 5 days

    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]).

  5. PK parameters following single doses

    Time frame: Up to 5 days

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

  6. PK parameters following single doses

    Time frame: Up to 5 days

    Comparative PK parameters of S- pindolol and racemic pindolol include: t time of occurrence of Cmax (Tmax)

  7. Stoichiometric dose relationship measured using PK parameters following single doses

    Time frame: Up to 5 days

    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])

  8. Stoichiometric dose relationship measured using PK parameters following single doses

    Time frame: Up to 5 days

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

  9. Part 2 Composite of PK parameters following multiple doses in plasma

    Time frame: Up to 6 days

    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])

  10. Part 2 Composite of PK parameters following multiple doses in plasma

    Time frame: Up to 6 days

    PK parameters of S- pindolol/racemic pindolol: Maximum observed concentration (Cmax),

  11. Part 2 Composite of PK parameters following multiple doses in plasma

    Time frame: Up to 6 days

    PK parameters of S- pindolol/racemic pindolol: Time to first occurrence of Cmax from plasma concentration-time data(Tmax).

  12. Pharmacodynamics of ACM-001.1: Cardiovascular vital parameter- heart rate

    Time frame: Up to 6 days

    Heart rate (beats per minute)

  13. Cardiovascular vital parameter- blood pressure

    Time frame: Up to 6 days

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

  14. Serum biomarker- DHEA/Cortisol

    Time frame: 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.

  15. Serum biomarker- Myostatin

    Time frame: Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.

    Myostatin (pg/mL).Serum concentrations were determined using validated analytical method.

  16. Serum biomarker- Folistatin

    Time frame: Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.

    Folistatin (pg/mL).Serum concentrations were determined using validated analytical method.

  17. Serum biomarker-IGF1

    Time frame: 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.

  18. Serum biomarker - (Type 3 procollagen peptide) PIIINP

    Time frame: Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.

    PIIINP (pg/mL).Serum concentrations were determined using validated analytical method.

  19. Serum biomarker - monokine-induced by gamma interferon (MIG/CXL9) Leptin

    Time frame: Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.

    Leptin (pg/mL).Serum concentrations were determined using validated analytical method.

  20. Serum biomarker - epithelial neutrophil activating peptide 78 (ENA78)

    Time frame: Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.

    ENA78 (pg/mL).Serum concentrations were determined using validated analytical method.

  21. Serum biomarker - Ghrelin

    Time frame: Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours.

    Ghrelin (pg/mL).Serum concentrations were determined using validated analytical method.

  22. Serum biomarker - Growth Hormone Receptor Hormone

    Time frame: 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.

  23. Serum biomarker - Somatostatin

    Time frame: 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.

Secondary outcomes

  1. Part 1 Composite PK parameters in urine following single doses

    Time frame: 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)

  2. Part 2 Composite PK parameters in urine following multiple doses and pindolol

    Time frame: 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)

  3. Part 1 and Part 2 Analysis of S-pindolol and R-pindolol concentrations in plasma for any in vivo conversion

    Time frame: Up to 4 days

    Plasma concentrations were determined using validated analytical methods.

  4. Part 1 Number of participants with adverse events following single doses as a measure of safety and tolerability

    Time frame: 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.

  5. Part 2 Number of participants with adverse events following single doses as a measure of safety and tolerability

    Time frame: 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

  6. Part 2 only - Pulmonary function test

    Time frame: Up to 32 days

    Forced expiratory spirometry to determine parameters FEV1, FVC, FEV1/FVC

Sponsors and collaborators

Lead sponsor

Actimed Therapeutics Ltd

Industry

Collaborators

  • Quotient Sciences

Registry information

Official study 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)

Important dates

Study start
2021
Primary completion
2022
Study completion
2022
First posted
Sep 8, 2023
Registry last updated
Oct 10, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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