Effect of Riociguat on Bone Metabolism

Study Overview
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Brief Summary
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Investigation of the effect of Riociguat, administered as 2.5 mg IR-tablets TID over 14 days, on bone metabolism.

Detailed Description
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Clinical pharmacology

Official Title
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Investigation of the Effect of Riociguat, Administered as 2.5 mg IR-tablets TID Over 14 Days, on Bone Metabolism in a Randomized, Placebo-controlled, Double-blind, 2-fold Cross-over Design in Healthy Male Subjects

Conditions
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Pharmacology, Clinical

Intervention / Treatment
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* Drug: Riociguat (Adempas, BAY63-2521) immediate release tablet of 2.5 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male white subjects 18 to 45 years of age BMI between 18 and 28 kg/m2 Subjects who are able to understand and follow instructions and who are able to participate in the study for the entire period Exclusion Criteria: Relevant deviation from the normal range in the clinical examination; in clinical chemistry, hematology, or urinalysis Resting heart rate in the awake subject below 45 BPM or above 90 BPM Systolic blood pressure below 100 mmHg or above 145 mmHg Diastolic blood pressure above 95 mmHg Relevant pathological changes in the ECG such as a second or third-degree AV block, prolongation of the QRS complex over 120 msec or of the QT / QTc-interval over 450 msec for males History of genetic muscle or bone disease of any kind Completely sedentary or extremely fit subjects Fractures in the preceding 12 months Psychiatric diseases History of peptic ulcers or relevant gastro-esophageal reflux disease Subjects with hypersensitivity to the investigational drug riociguat or ranitidine, or to inactive constituents Regular daily consumption of more than half a liter of usual beer or the equivalent quantity of approximately 20 g of alcohol in another form, more than 1 L of xanthine-containing beverages, recent smoking history Use of medication within the 2 weeks preceding the study which could have interfered with the investigational drug riociguat or ranitidine Subjects with a medical disorder, condition or history of such that would have impaired the subject's ability to participate or complete this study in the opinion of the investigator or the sponsor

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Riociguat<br>Subjects received multiple doses of riociguat (thrice a day) with concomitant administration of ranitidine (once daily) for 14 days | Drug: Riociguat (Adempas, BAY63-2521) immediate release tablet of 2.5 mg<br>* Riociguat administered in a dose of 2.5 mg (single tablet), thrice daily, over 14 days.<br>|
| Placebo Comparator: Placebo<br>Subjects received placebo (thrice a day) with concomitant administration of ranitidine (once daily) for 14 days | Drug: Placebo<br>* Placebo administered as a single tablet, thrice daily, over 14 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary excretion (over 24 hours) of C-terminal cross-linking telopeptides of type I collagen (CTX) | Marker of bone resorption | From Day -01 to 16 | 
| AUC(0-7) | Area under the plasma concentration vs time curve (AUC) from zero to 7 hours after single (first) dose for riociguat and its metabolite M-1 (BAY60-4552) | Pre-dose and up to 7 hours post-dose on Day 0 | 
| AUC(0-7)ss | AUC(0-7) at steady state | Pre-dose and up to 7 hours post-dose on Day 13 | 
| Cmax | Maximum drug concentration in plasma after single dose administration for riociguat and its metabolite M-1 (BAY60-4552) | Pre-dose and up to 7 hours post-dose on Day 0 | 
| Cmax,ss | Maximum drug concentration in plasma at steady state during a dosage interval for riociguat and its metabolite M-1 (BAY60-4552) | Pre-dose and up to 7 hours post-dose on Day 13 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events |  | Approximately 12 weeks | 
| Ctrough | Drug concentration in plasma at expected time of minimum (trough) concentration for riociguat and its metabolite M-1 (BAY60-4552) | On Days 03 and 08 | 
| AUC(0-7)norm | AUC(0-7) divided by dose per kg body weight for riociguat and its metabolite M-1 (BAY60-4552) | Pre-dose and up to 7 hours post-dose on Day 0 | 
| AUC(0-7)ss,norm | AUC(0-7)ss divided by dose per kg body weight for riociguat and its metabolite M-1 (BAY60-4552) | Pre-dose and up to 7 hours post-dose on Day 13 | 
| Cmax,norm | Maximum drug concentration in plasma after (first) single dose administration divided by dose (mg) per kg body weight for riociguat and its metabolite M-1 (BAY60-4552) | Pre-dose and up to 7 hours post-dose on Day 0 | 
| Cmax,ss,norm | Maximum drug concentration in plasma at steady state during a dosage interval divided by dose (mg) per kg body weight for riociguat and its metabolite M-1 (BAY60-4552) | Pre-dose and up to 7 hours post-dose on Day 13 | 
| tmax | Time to reach maximum drug concentration in plasma after single (first) dose for riociguat and its metabolite M-1 (BAY60-4552) | Pre-dose and up to 7 hours post-dose on Day 0 | 
| tmax,ss | tmax at steady state for riociguat and its metabolite M-1 (BAY60-4552) | Pre-dose and up to 7 hours post-dose on Day 13 | 
| Aeur(0-7) | Amount of drug excreted via urine from zero to 7 hours after administration for riociguat and its metabolite M-1 (BAY60-4552) | Pre-dose and up to 7 hours post-dose | 
| %Aeur(0-7) | Aeur(0-7) expressed as percent of dose administered for riociguat and its metabolite M-1 (BAY60-4552) | Pre-dose and up to 7 hours post-dose | 
| Urinary excretion (over 24 hours) of N-terminal cross-linking telopeptides of type I collagen (NTX) | Marker of bone resorption | From -01 to 16 Days | 
| Serum CTX | Marker of bone resorption | From -01 to 16 Days | 
| Serum N-terminal propeptide of type I collagen (PINP) | Marker of bone formation | From -01 to 16 Days | 
| Serum bone-specific alkaline phosphatase (bAP) | Marker of bone formation | From -01 to 16 Days | 
| Serum albumin, protein | Determination of albumin, protein in serum | From -01 to 16 Days | 
| Cyclic guanosine monophosphate (cGMP) | Determination of cGMP in plasma and urinary excretion (over 24 hours) | From -01 to 16 Days | 
| Calcium, sodium, potassium | Determination of calcium, sodium, potassium in serum and urinary excretion (over 24 hours) | From -01 to 16 Days | 
| Urine volume | Volume of urine excreted (over 24 hours) | From -01 to 16 Days | 
| Renin | Determination of plasma renin level | From -01 to 16 Days | 
| Creatinine clearance | For estimation of glomerular filtration rate | From -01 to 16 Days | 
| Serum osteocalcin | Determination of osteocalcin in serum | From -01 to 16 Days | 
| Creatinine | Determination of creatinine in serum and urinary excretion (over 24 hours) | From -01 to 16 Days | 
| Phosphate | Determination of phosphate in serum only | From -01 to 16 Days | 
| Parathyroid hormone (PTH) | Determination of PTH in serum only | From -01 to 16 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bone Metabolism