Effect of Riociguat on Bone Metabolism

Phase 1

Completed

• Conditions: Pharmacology, Clinical
• Interventions: Drug: Placebo; Drug: Riociguat (Adempas, BAY63-2521) immediate release tablet of 2.5 mg

• Registration Number: NCT00855660
• Lead Sponsor: Bayer

Brief Summary

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

Detailed Description

Clinical pharmacology

Basic Information
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Recruitment & Eligibility
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Study & Design

Study Timeline

• Study Start: 2009-03
• Study First Submitted: 2009-03-03
• Study First Submitted QC: 2009-03-03
• Study First Posted: 2009-03-04
• Primary Completion: 2009-12
• Study Completion: 2010-07
• Status Verified: 2016-01
• Last Update Submitted: 2016-01-07
• Last Update Posted: 2016-01-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 17

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Subjects received placebo (thrice a day) with concomitant administration of ranitidine (once daily) for 14 days
Riociguat	Riociguat (Adempas, BAY63-2521) immediate release tablet of 2.5 mg	Subjects received multiple doses of riociguat (thrice a day) with concomitant administration of ranitidine (once daily) for 14 days

Primary Outcome Measures

Name	Time	Method
Cmax	Pre-dose and up to 7 hours post-dose on Day 0	Maximum drug concentration in plasma after single dose administration for riociguat and its metabolite M-1 (BAY60-4552)
Cmax,ss	Pre-dose and up to 7 hours post-dose on Day 13	Maximum drug concentration in plasma at steady state during a dosage interval for riociguat and its metabolite M-1 (BAY60-4552)
AUC(0-7)	Pre-dose and up to 7 hours post-dose on Day 0	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)
AUC(0-7)ss	Pre-dose and up to 7 hours post-dose on Day 13	AUC(0-7) at steady state
Urinary excretion (over 24 hours) of C-terminal cross-linking telopeptides of type I collagen (CTX)	From Day -01 to 16	Marker of bone resorption

Secondary Outcome Measures

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