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

Study Overview
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Brief Summary
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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

Official Title
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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)

Conditions
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Healthy

Intervention / Treatment
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* 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
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 |