Cachexia
Conditions
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.
Interventions
DRUGPart 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.
DRUGPart 1 Group 2 Regimen C (Pindolol)
Drug: Pindolol tablets for oral use.
DRUGPart 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.
DRUGPart 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.
DRUGPart 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.
DRUGPart 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.
DRUGPart 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.
OTHERPart 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.
OTHERPart 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.
OTHERPart 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.
OTHERPart 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.
Sponsors
Quotient Sciences
Actimed Therapeutics Ltd
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
Part 2 was single - blind study (subject blinded). Masking was not triple for all parts of the study or all arms.
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
20 Years to 45 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 - (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. |
| 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 - 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. |
| 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. |
| 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\[0-infinite\]. |
| Part 1 PK parameters following single doses | Up to 5 days | Comparative bioavailability of S- pindolol and pindolol include:maximum observed concentration (Cmax) |
| PK parameters following single doses | 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\[0-infinite\]). |
| Stoichiometric dose relationship measured using PK parameters following single doses | 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\[0-infinite\]) |
| Part 2 Composite of PK parameters following multiple doses in plasma | 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\[0-t\]) |
| Pharmacodynamics of ACM-001.1: Cardiovascular vital parameter- heart rate | Up to 6 days | Heart rate (beats per minute) |
| Cardiovascular vital parameter- blood pressure | Up to 6 days | Systolic blood pressure (mmHG) and diastolic blood pressure (mmHG) |
| 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. |
| 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- 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 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 |
| 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) |
Countries
United Kingdom
Outcome results
None listed