Effect of Riociguat on Bone Metabolism

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

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

Study Overview

• Status: Completed
• Conditions: Pharmacology, Clinical
• Intervention / Treatment: Drug: Riociguat (Adempas, BAY63-2521) immediate release tablet of 2.5 mg; Drug: Placebo

Detailed Description

Clinical pharmacology

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Nordrhein-Westfalen
    • Köln, Nordrhein-Westfalen, Germany, 51147

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Riociguat; 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; Riociguat administered in a dose of 2.5 mg (single tablet), thrice daily, over 14 days.
Placebo Comparator: Placebo; Subjects received placebo (thrice a day) with concomitant administration of ranitidine (once daily) for 14 days	Drug: Placebo; Placebo administered as a single tablet, thrice daily, over 14 days.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

Helpful Links

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe.

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (Actual): December 1, 2009
• Study Completion (Actual): July 1, 2010

Study Registration Dates

• First Submitted: March 3, 2009
• First Submitted That Met QC Criteria: March 3, 2009
• First Posted (Estimate): March 4, 2009

Study Record Updates

• Last Update Posted (Estimate): January 11, 2016
• Last Update Submitted That Met QC Criteria: January 7, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: Bone Metabolism
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Activators; Riociguat
• Other Study ID Numbers: 13790; 2008-005569-70 (EudraCT Number)