Pharmacodynamic Effects, Safety and Tolerability of Cilobradine, Compared to Metoprolol Succinate and Placebo in Healthy Volunteers

Pharmacodynamic Effects, Safety and Tolerability of 0.25 mg, 0.5 mg, 1 mg and 2 mg Cilobradine, Compared to 190 mg Metoprolol Succinate and Placebo, Administered p.o. Once Daily Over 14 Days to Healthy Volunteers in a Randomised, Placebo-controlled, Partly Double Blind Study, With a 4 mg/14 mg and 10 mg/20 mg Cilobradine Single Dose Versus Placebo Substudy (Double Blind, Three-fold Cross-over)

Pharmacodynamic effects on heart rate (HR) at rest and during exercise and on flicker fusion frequency (FFF), FFF method evaluation

Safety, tolerability and pharmacokinetics of cilobradine

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Placebo; Drug: Cilobradine low dose 1; Drug: Cilobradine low dose 2; Drug: Cilobradine medium dose; Drug: Cilobradine high dose 1; Drug: Cilobradine high dose 2; Drug: Metoprolol succinate tablets

• Study Type: Interventional
• Enrollment (Actual): 119
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• All participants in the study should be healthy males and females. Volunteers will

  • be 21 to 55 years of age
  • have a Body Mass Index (BMI) of 19.9 to 29.9 kg/m2 and
  • have a resting heart rate (HR) (after 10 min. in the supine position) of more than 55 beats per minute (bpm)
• Only post-menopausal females, or those who had had a hysterectomy, could participate. All females had to have a negative pregnancy test
• In accordance with good clinical practice (GCP) and the local legislation all volunteers had to give their written informed consent prior to admission to the study

Exclusion Criteria:

• Any finding of the medical examination (including BP, HR and ECG) deviating from normal and of clinical relevance
• Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
• Diseases of the central nervous system or psychiatric disorders or neurological disorders
• History of relevant orthostatic hypotension, fainting spells or blackouts
• Chronic or relevant acute infections
• History of allergy/hypersensitivity (including drug allergy) which is deemed relevant to the trial as judged by the Investigator
• Intake of drugs with a long half-life (> 24 hours) within ten half-lives of the respective drug before enrolment in the study
• Use of any drugs which might influence the results of the trial within two weeks prior to administration or during the trial
• Participation in another trial with an investigational drug (≤ two months prior to administration or during the trial)
• Smoker (> 10 cigarettes or > 3 cigars of > 3 pipes/day)
• Inability to refrain from smoking on trial days
• Alcohol abuse (> 60 g/day)
• Drug abuse
• Blood donation (≥ 100 ml within four weeks prior to administration or during the trial)
• Excessive physical activities (within the last week before the study)
• Any laboratory value outside the reference range of clinical relevance

Not necessarily clinically relevant abnormalities, but specific Exclusion criteria for the drugs under study or for the study:

• Consumption of more than 2 cups of coffee or black tea, or cola drinks, per day during the last 6 weeks. However, subjects may participate if abstinence from the before mentioned beverages is well tolerated during an interval of at least 2 weeks between screening and first treatment
• ECG: PQ interval > 210 ms
• HR at rest < 55 bpm
• Systolic BP < 115 mmHg
• Colour vision test abnormal. However, subjects may participate if they are able to perform the flicker fusion test without difficulty
• Psoriasis (own medical history or relative)
• Relevant ophthalmological disease
• History of asthma or obstructive pulmonary disease
• History (including childhood) of traumatic injury to the head or brain
• History (including childhood) of reduced seizure threshold

• The following subjects will not be allowed to participate in the study

  • Any subject involved in professional transportation of human subjects
  • Any subject involved in operating dangerous machinery

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo
Experimental: Cilobradine low dose 1	Drug: Cilobradine low dose 1
Experimental: Cilobradine low dose 2	Drug: Cilobradine low dose 2
Experimental: Cilobradine medium dose	Drug: Cilobradine medium dose
Experimental: Cilobradine high dose 1	Drug: Cilobradine high dose 1
Experimental: Cilobradine high dose 2	Drug: Cilobradine high dose 2
Active Comparator: Metoprolol succinate; 1 tablet on day 1, day 2 followed by two tablets from day 3 to day 14	Drug: Metoprolol succinate tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Changes in heart rate at rest	Pre-dose, up to day 20 after first drug administration
Changes in heart rate during exercise	Pre-dose, up to day 20 after first drug administration
Changes in flicker fusion frequency test (FFF)	Pre-dose, up to day 20 after first drug administration

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of patients with clinically relevant changes in laboratory tests	Pre-dose, up to 12 days after last drug administration
Number of patients with clinically relevant changes in vital signs (blood pressure, heart rate)	Pre-dose, up to 12 days after last drug administration
Number of patients with clinically relevant changes in 12-lead ECG	Pre-dose, up to 12 days after last drug administration
Number of patients with adverse events	Up to 12 days after last drug administration
Assessment of global tolerability by the investigator	Up to 12 days after last drug administration
Changes in peripheral FFF	Pre-dose, up to day 20 after first drug administration
Area under the concentration-time curve of the analytes in plasma (AUC)	Up to day 20 after start of first drug administration
Maximum measured concentration of the analytes in plasma (Cmax)	Up to day 20 after start of first drug administration
Time from dosing to the maximum concentration of the analytes in plasma (tmax)	Up to day 20 after start of first drug administration
Terminal half-life of the analytes in plasma (t½)	Up to day 20 after start of first drug administration
Mean residence time of the analytes in the body after oral administration (MRTpo)	Up to day 20 after start of first drug administration
Total clearance of the analytes in plasma following extravascular administration (CL/F)	Up to day 20 after start of first drug administration
Apparent volume of distribution of the analytes during the terminal phase λz following extravascular administration (Vz/F)	Up to day 20 after start of first drug administration

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: February 1, 2003
• Primary Completion (Actual): November 1, 2003

Study Registration Dates

• First Submitted: October 13, 2014
• First Submitted That Met QC Criteria: October 13, 2014
• First Posted (Estimate): October 15, 2014

Study Record Updates

• Last Update Posted (Estimate): October 15, 2014
• Last Update Submitted That Met QC Criteria: October 13, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Metoprolol
• Other Study ID Numbers: 503.203