check_circleStudy Completed

Clinical Pharmacology

Bayer Identifier:

13785

ClinicalTrials.gov Identifier:

Not Available

EudraCT Number:

2010-021029-11

EU CT Number:

Not Available
Phase I Multiple dose escalation study

Trial purpose

Primary objective: To investigate the safety and tolerability of BAY 94-8862 after multiple oral doses of 10 mg twice a day (bid), 20 mg bid and 40 mg once a day given as 10 mg immediate release tablets over 10 days in 12 healthy male subjects (9-verum and 3 placebo) per dose step in a randomized, single-blind, placebo-controlled, group-comparison design.
Secondary objectives: To assess
- The pharmacodynamics of BAY 94-8862 and pharmacokinetics (PK) of BAY 94-8862 and three metabolites
- The influence of multiple oral doses of BAY 94-8862 given as 20 mg bid over 10 days on the PK of a single oral dose of the CYP3A4 substrate midazolam in 9 healthy male subjects.

Key Participants Requirements

Sex

Male

Age

18 - 45 Years
  • - Healthy male white subjects, 18 to 45 years of age, body mass index ( ≥ 18.0 and ≤ 29.9 kg/m²

  • - Subjects with conspicuous findings in medical history and pre-study examination
    - Recent donation of blood/blood components
    - Clinically relevant changes/deviations from normal electrocardiography, physical examination, clinical chemistry, hematology, urinalysis, and/or blood pressure, heart rate (vital signs)
    - Regular daily consumption of an amount of beer, alcohol, xanthine-containing beverages, foods or beverages containing grapefruit and/or cigarettes that may affect study results
    - History of/current relevant diseases of vital or other organs and of the central nervous system and/or medical conditions that would impair subject’s ability to participate in the trial or that may affect study results
    - Subjects with a history of severe allergies, non-allergic drug reactions, or multiple drug allergies or with hypersensitivity to the investigational drugs, the control agent and/or to inactive constituents
    - Regular use of therapeutic or recreational drugs
    - Use of medication within the 2 weeks preceding the study, especially concomitant administration of potassium-sparing diuretics, ACE inhibitors, angiotensin-II-receptor blockers, potassium or calcium supplements, nonsteroidal anti-inflammatory drugs like acetylsalicylic acid, indomethacin or ibuprofen, concomitant use of strong CYP3A4 inducers and inhibitors, weak to moderate CYP3A4 inhibitors
    - Subjects testing positive in the drug screening
    - Subject testing positive for human immunodeficiency virus type 1 and 2 antibody, hepatitis B surface antigen or hepatitis C virus antibody
    - Serum potassium level greater than equal to 5.0 mmol/L, serum sodium level less than equal to 130 mmol/L
    - History of myasthenia gravis, narrow angle glaucoma
    - Known sleep apnea syndrome
    - Known hereditary galactose intolerance, lactase deficiency or glucose-galactase deficiency
    - Regular intake of liquorice or intake of liquorice within the last 14 days prior study treatment

Trial summary

Enrollment Goal
47
Trial Dates
August 2010 - December 2010
Phase
Phase 1
Could I Receive a placebo
No
Products
Finerenone (BAY94-8862)
Accepts Healthy Volunteer
Yes

Where to participate

StatusInstitutionLocation
Completed
Wuppertal, 42096, Germany

Primary Outcome

  • Cmax (Maximum drug concentration in plasma after single dose administration for BAY 94-8862 and its metabolites for Part A and midazolam and its metabolite for Part B)
    date_rangeTime Frame:
    For Part A, in dose steps 1 and 2, for BAY 94-8862 pre-dose (morning) and up to 12 h post-dose on 0d. For dose step 3, pre-dose and up to 15 h post-dose on 0d. For midazolam on day -1d, 1d and 9d at pre dose and up to 15 h post dose.
    enhanced_encryption
    Safety Issue:
    No
  • Cmax/D (Maximum drug concentration in plasma after single dose administration divided by dose for BAY 94-8862 and its metabolites in Part A on 0d)
    date_rangeTime Frame:
    For Part A, in dose steps 1 and 2, for BAY 94-8862 pre-dose (morning) and up to 12 h post-dose on 0d. For dose step 3, pre-dose and up to 15 h post-dose on 0d.
    enhanced_encryption
    Safety Issue:
    No
  • AUC (Area under the plasma concentration vs time curve from zero to infinity after single (first) dose for BAY 94-8862 and its metabolites for Part A and midazolam and its metabolite for Part B)
    date_rangeTime Frame:
    For Part A, in dose steps 1 and 2, for BAY 94-8862 pre-dose (morning) and up to 12 h post-dose on 0d. For dose step 3, pre-dose and up to 15 h post-dose on 0d. For midazolam on day -1d, 1d and 9d at pre dose and up to 15 h post dose.
    enhanced_encryption
    Safety Issue:
    No
  • AUC/D (AUC divided by dose for BAY 94-8862 and its metabolites in Part A on 0d)
    date_rangeTime Frame:
    For Part A, in dose steps 1 and 2, for BAY 94-8862 pre-dose (morning) and up to 12 h post-dose on 0d. For dose step 3, pre-dose and up to 15 h post-dose on 0d.
    enhanced_encryption
    Safety Issue:
    No
  • AUCτ,md (AUC for the actual dosing interval after multiple dose administration for BAY 94-8862 and its metabolites for Part A on 9d and only for BAY 94-8862 for Part B)
    date_rangeTime Frame:
    For Part A and Part B pre-dose (morning) and up to 48 h post-dose on 9d
    enhanced_encryption
    Safety Issue:
    No
  • AUCτ,md/D (AUCτ,md divided by dose for BAY 94-8862 and its metabolites for Part A and only for BAY 94-8862 for Part B)
    date_rangeTime Frame:
    For Part A and Part B pre-dose (morning) and up to 48 h post-dose on 9d
    enhanced_encryption
    Safety Issue:
    No
  • Cmax,md (Maximum drug concentration in plasma after multiple dose administration for BAY 94-8862 and its metabolites for Part A and only for BAY 94-8862 for Part B)
    date_rangeTime Frame:
    For Part A and Part B pre-dose (morning) and up to 48 h post-dose on 9d
    enhanced_encryption
    Safety Issue:
    No
  • Cmax,md/D (Cmax,md divided by dose for BAY 94-8862 and its metabolites for Part A and only for BAY 94-8862 for Part B)
    date_rangeTime Frame:
    For Part A and Part B pre-dose (morning) and up to 48 h post-dose on 9d
    enhanced_encryption
    Safety Issue:
    No
  • Number of participants with adverse events
    date_rangeTime Frame:
    Approximately 5 weeks per subject
    enhanced_encryption
    Safety Issue:
    Yes

Secondary Outcome

  • AUC(0-tlast) (AUC from time 0 to the last data point for BAY 94-8862 and its metabolites for Part A on 0d and midazolam and its metabolite for Part B)
    date_rangeTime Frame:
    For Part A, in dose steps 1 and 2, for BAY 94-8862 pre-dose (morning) and up to 12 h post-dose on 0d. For dose step 3, pre-dose and up to 15 h post-dose on 0d. For midazolam on day -1d, 1d and 9d at pre dose and up to 15 h post-dose
    enhanced_encryption
    Safety Issue:
    No
  • AUC(0-tlast)/D (AUC(0-tlast) divided by dose for BAY 94-8862 and its metabolites in Part A on 0d)
    date_rangeTime Frame:
    For Part A, in dose steps 1 and 2, for BAY 94-8862 pre-dose (morning) and up to 12 h post-dose on 0d. For dose step 3, pre-dose and up to 15 h post-dose on 0d.
    enhanced_encryption
    Safety Issue:
    No
  • AUCnorm (Area under the curve divided by dose per kg body weight after single (first) dose for BAY 94-8862 and its metabolites in Part A)
    date_rangeTime Frame:
    For Part A, in dose steps 1 and 2, for BAY 94-8862 pre-dose (morning) and up to 12 h post-dose on 0d. For dose step 3, pre-dose and up to 15 h post-dose on 0d.
    enhanced_encryption
    Safety Issue:
    No
  • Cmax,norm (Maximum drug concentration in plasma after single dose administration divided by dose (mg) per kg body weight for BAY 94-8862 and its metabolites in Part A)
    date_rangeTime Frame:
    For Part A, in dose steps 1 and 2, for BAY 94-8862 pre-dose (morning) and up to 12 h post-dose on 0d. For dose step 3, pre-dose and up to 15 h post-dose on 0d.
    enhanced_encryption
    Safety Issue:
    No
  • t½ (Half-life associated with the terminal slope for both study days for BAY 94-8862 and its metabolites for Part A on 0d and 9d and only for BAY 94-8862 and midazolam and its metabolite for Part B)
    date_rangeTime Frame:
    For Part A, (dose steps 1 and 2) up to 12 h post-dose on 0d; dose step 3, up to 15 h post-dose on 0d; up to 48 h post-dose on 9d in 3 dose steps. In Part B, for BAY 94-8862 on 9d, up to 48 h post-dose. Midazolam up to 15 h post-dose.
    enhanced_encryption
    Safety Issue:
    No
  • tmax (Time to reach maximum drug concentration in plasma after both study days for BAY 94-8862 and its metabolites for Part A on 0d and 9d and only for BAY 94-8862 and midazolam and its metabolite for Part B)
    date_rangeTime Frame:
    For Part A, (dose steps 1 and 2) up to 12 h post-dose on 0d; dose step 3, up to 15 h post-dose on 0d; up to 48 h post-dose on 9d in 3 dose steps. In Part B, for BAY 94-8862 on 9d, up to 48 h post-dose. Midazolam up to 15 h post-dose.
    enhanced_encryption
    Safety Issue:
    No
  • MRT (Mean residence time for both study days for BAY 94-8862 and its metabolites for Part A on 0d and 9d and only for BAY 94-8862 for Part B)
    date_rangeTime Frame:
    For Part A, (dose steps 1 and 2) up to 12 h post-dose on 0d; dose step 3, up to 15 h post-dose on 0d; up to 48 h post-dose on 9d in 3 dose steps. In Part B, for BAY 94-8862 on 9d, up to 48 h post-dose.
    enhanced_encryption
    Safety Issue:
    No
  • CL/f (Total body clearance of drug from plasma calculated after oral administration (apparent oral clearance) for BAY 94-8862 and its metabolites in Part A on 0d)
    date_rangeTime Frame:
    For Part A, in dose steps 1 and 2, for BAY 94-8862 pre-dose (morning) and up to 12 h post-dose on 0d. For dose step 3, pre-dose and up to 15 h post-dose on 0d.
    enhanced_encryption
    Safety Issue:
    No
  • AUCτ,md,norm (AUCτ,md divided per kg body weight for BAY 94-8862 and its metabolites in Part A on 9d)
    date_rangeTime Frame:
    For Part A pre-dose (morning) and up to 48 h post-dose on 9d
    enhanced_encryption
    Safety Issue:
    No
  • Cmax,md,norm (Cmax,md divided by dose (mg) per kg body weight for BAY 94-8862 and its metabolites for Part A and only for BAY 94-8862 for Part B)
    date_rangeTime Frame:
    For Part A and Part B pre-dose (morning) and up to 48 h post-dose on 9d
    enhanced_encryption
    Safety Issue:
    No
  • PTF (Peak trough fluctuation calculated as Cmax,md - Cmin/Cav with Cav =AUCτ/τ for BAY 94-8862 and its metabolites for Part A and only for BAY 94-8862 for Part B)
    date_rangeTime Frame:
    For Part A and Part B pre-dose (morning) and up to 48 h post-dose on 9d
    enhanced_encryption
    Safety Issue:
    No
  • Cτ/Cmax (Observed concentration at the end of the dosing interval divided by maximum observed drug concentration for BAY 94-8862 and its metabolites for Part A and only for BAY 94-8862 for Part B)
    date_rangeTime Frame:
    For Part A and Part B pre-dose (morning) and up to 48 h post-dose on 9d
    enhanced_encryption
    Safety Issue:
    No
  • RACmax (Accumulation ratio = Cmax,md divided by Cmax for BAY 94-8862 and its metabolites in Part A on 9d)
    date_rangeTime Frame:
    For Part A pre-dose (morning) and up to 48 h post-dose on 9d
    enhanced_encryption
    Safety Issue:
    No
  • RLin (Accumulation ratio = AUCτ,md divided by AUC for BAY 94-8862 and its metabolites in Part A on 9d)
    date_rangeTime Frame:
    For Part A pre-dose (morning) and up to 48 h post-dose on 9d
    enhanced_encryption
    Safety Issue:
    No
  • RAAUC (Accumulation ratio = AUCτ,md divided by AUCτ on Day 0 for BAY 94-8862 and its metabolites in Part A on 9d)
    date_rangeTime Frame:
    For Part A pre-dose (morning) and up to 48 h post-dose on 9d
    enhanced_encryption
    Safety Issue:
    No
  • Aeur(0-24) (Amount excreted into urine from 0 to 24 h (od regimen) for BAY 94-8862 and its metabolites in Part A on 9d)
    date_rangeTime Frame:
    Pre-dose and up to 24 h post-dose on 9d
    enhanced_encryption
    Safety Issue:
    No
  • Aeur(0-12) (Amount excreted into urine from 0 to 12 h (bid regimen) for BAY 94-8862 and its metabolites in Part A on 9d)
    date_rangeTime Frame:
    Pre-dose and up to 12 h post-dose on 9d
    enhanced_encryption
    Safety Issue:
    No
  • CLR (Renal body clearance of drug for BAY 94-8862 and its metabolites on day 9d in Part A)
    date_rangeTime Frame:
    Pre-dose to 12 h post-dose in bid doses and up to 24 post-dose in od dosing
    enhanced_encryption
    Safety Issue:
    No
  • Cτ,md,norm (Cτ,md divided by dose (mg) per kg body weight for BAY 94-8862 in Part B only)
    date_rangeTime Frame:
    Pre-dose and up to 48 h post-dose
    enhanced_encryption
    Safety Issue:
    No
  • AUC-ratio (α-hydroxymidazolam / midazolam)
    date_rangeTime Frame:
    On Day -1, Day 2 and Day 10
    enhanced_encryption
    Safety Issue:
    No
  • HR over 1 min
    Heart rate over 1 min
    date_rangeTime Frame:
    From 24 h prior to dosing and up to 4 post-dose on 0d. On 9d, pre-dose and up to 48 h post-dose. In between 1d and 8d at 00 h.
    enhanced_encryption
    Safety Issue:
    Yes
  • HR (Heart rate)
    date_rangeTime Frame:
    Approximately 5 weeks per subject
    enhanced_encryption
    Safety Issue:
    Yes
  • BP (Blood pressure)
    date_rangeTime Frame:
    Approximately 5 weeks per subject
    enhanced_encryption
    Safety Issue:
    Yes
  • Neurohormones (Plasma renin activity, plasma angiotensin II, serum aldosterone and plasma noradrenaline)
    date_rangeTime Frame:
    At -1d, pre-dose on 0d, 9d, and 11d
    enhanced_encryption
    Safety Issue:
    No
  • Urinary electrolytes (Sodium (Na), potassium (K), magnesium)
    date_rangeTime Frame:
    From 24 h prior to dosing and up to 24 h post-dose on both the profile days, 0d and 9d and additionally single samples were collected at 00 h from 2d to 7d
    enhanced_encryption
    Safety Issue:
    Yes
  • Urinary creatinine
    date_rangeTime Frame:
    From 24 h prior to dosing and up to 24 h post dose on both the profile days, 0d and 9d and additionally single samples were collected at 00 h from 2d to 7d
    enhanced_encryption
    Safety Issue:
    Yes
  • Urinary volume
    date_rangeTime Frame:
    From 24 h prior to dosing and up to 24 h post-dose on both the profile days, 0d and 9d and additionally single samples were collected at 00 h from 2d to 7d
    enhanced_encryption
    Safety Issue:
    Yes
  • PTF (Peak trough fluctuation calculated as Cmax,md Cmin/Cav with Cav =AUCτ/τ for BAY 94-8862 and its metabolites for Part A on 9d and for BAY 94-8862 in Part B)
    date_rangeTime Frame:
    Pre-dose and up to 48 h post-dose in both Part A and B on 9d
    enhanced_encryption
    Safety Issue:
    No
  • Ctrough (For BAY 94-8862 and its metabolites in Part A, and BAY 94-8862 in Part B)
    date_rangeTime Frame:
    Between 0d and 9d in both Part A and B
    enhanced_encryption
    Safety Issue:
    No

Trial design

Multiple dose basic phase I dose escalation study, to investigate safety, tolerability, pharmacokinetics and pharmacodynamics of BAY 94-8862 after oral dosing of 10 mg bid, 20 mg bid or 40 mg od over 10 days given as 10 mg IR-tablets in 12 healthy male subjects per dose step in a randomized, single-blind, placebo-controlled, group-comparison design
Trial Type
Interventional
Intervention Type
Drug
Trial Purpose
Other
Allocation
Randomized
Blinding
Single Blind
Assignment
Parallel Assignment
Trial Arms
3