Riociguat in Children With Pulmonary Arterial Hypertension (PAH)

NCT02562235 | Active Not Recruiting Phase 3 Results DMC FDA Drug

• 2 other identifiers: 156812014-003952-29
• Study Type: interventional
• Target: 24
• Locations: 9 countries
• Sites: 16

Brief Summary

This study was designed to evaluate the safety, tolerability, pharmacodynamics and pharmacokinetics of riociguat at age-, sex- and body-weight-adjusted doses of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID in children from ≥6 to less than 18 years with pulmonary arterial hypertension (PAH) group 1. The study design consisted of a main study part followed by an optional long-term extension part. The main treatment period consisted of two phases: titration phase up to 8 weeks and a maintenance phase up to 16 weeks.

Conditions

Hypertension, Pulmonary

Keywords

Pulmonary arterial hypertension

Outcome Measures

Primary Outcomes (21)

• Number of Participants With Any Treatment-emergent Adverse Events

  An adverse event (AE), including AE in relation to a medical device (i.e. Raumedic dosing pipette), is any untoward medical occurrence in a participant administered with a pharmaceutical product and does not necessarily have to have a causal relationship with this treatment. A serious AE (SAE) is any untoward medical occurrence that at any dose is resulting in death, is lifethreatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity. AEs occurring between start of study drug and up to 2 days after the last dose were defined as treatment-emergent AEs (TEAEs).

  From start of study drug up to 2 days after the last dose of study drug in the main study part, up to 24 weeks plus/minus 5 days.

• Change in Heart Rate From Baseline

  Mean change in heart rate from baseline is reported.

  Baseline and Week 24 (plus/minus 5 days)

• Change in Blood Pressure From Baseline

  Mean changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline are reported.

  Baseline and Week 24 (plus/minus 5 days)

• Change in Respiratory Rate From Baseline

  Mean change in respiratory rate from baseline is reported.

  Baseline and Week 24 (plus/minus 5 days)

• Number of Subjects With Transitions From Baseline in Bone Age Compared to Chronological Age

  X-ray of left hand was performed for each participant and bone age was determined centrally by a specialist. For each participant, the bone age was compared to the chronological age and assigned to one of the categories - "delayed", "in accordance" or "advanced", indicating the advancement or delay in the growth of the bone. Number of participants who transitioned to another category different from baseline was calculated and is reported.

  Baseline and Week 24 (plus/minus 5 days)

• Change in Hematology Parameters (Platelets) From Baseline

  Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set.

  Baseline and Week 24 (plus/minus 5 days)

• Change in Hematology Parameters (Lymphocytes/Leucocytes Ratio) From Baseline

  Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set.

  Baseline and Week 24 (plus/minus 5 days)

• Change in Hematology Parameter (Neutrophils/Leucocytes Ratio) From Baseline

  Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set.

  Baseline and Week 24 (plus/minus 5 days)

• Change in Clinical Chemistry (Alanine Aminotransferase) From Baseline

  Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.

  Baseline and Week 24 (plus/minus 5 days)

• Change in Clinical Chemistry (Aspartate Aminotransferase) From Baseline

  Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.

  Baseline and Week 24 (plus/minus 5 days)

• Change in Clinical Chemistry (Sodium) From Baseline

  Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.

  Baseline and Week 24 (plus/minus 5 days)

• Change in Clinical Chemistry (Blood Urea Nitrogen) From Baseline

  Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.

  Baseline and Week 24 (plus/minus 5 days)

• Change in Clinical Chemistry (eGFR) From Baseline

  Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set. eGFR = estimated glomerular filtration rate

  Baseline and Week 24 (plus/minus 5 days)

• Change in Clinical Chemistry (Urea) From Baseline

  Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.

  Baseline and Week 24 (plus/minus 5 days)

• Change in Clinical Chemistry (Gamma Glutamyl Transferase) From Baseline

  Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.

  Baseline and Week 24 (plus/minus 5 days)

• Plasma Concentration of Riociguat at Week 0

  For each participant, one blood sample was collected at one given time point. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported. W = Week.

  Week 0 (30-90 minutes post-dose; 2.5-4 hours post-dose)

• Plasma Concentration of Riociguat at Week 4

  For each participant, one blood sample was collected at one given time point. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported.

  Week 4 (pre-dose)

• Plasma Concentration of Riociguat at Week 8

  For each participant, one blood sample was collected at one given time point. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported.

  Week 8 (pre-dose)

• Plasma Concentration of BAY60-4552 at Week 0

  BAY60-4552 is riociguat's active metabolite. For each participant, one blood sample was collected at one given time point and in that sample both riociguat and BAY60-4552 were measured. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported. W = Week

  Week 0 (30-90 minutes post-dose; 2.5-4 hours post-dose)

• Plasma Concentration of BAY60-4552 at Week 4

  BAY60-4552 is riociguat's active metabolite. For each participant, one blood sample was collected at one given time point and in that sample both riociguat and BAY60-4552 were measured. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported.

  Week 4 (pre-dose)

• Plasma Concentration of BAY60-4552 at Week 8

  BAY60-4552 is riociguat's active metabolite. For each participant, one blood sample was collected at one given time point and in that sample both riociguat and BAY60-4552 were measured. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported.

  Week 8 (pre-dose)

Secondary Outcomes (25)

• Change in 6-minute Walking Distance From Baseline

  Baseline and Week 24 (plus/minus 5 days)

• Number of Subjects With Change in WHO Functional Class From Baseline

  Baseline and Week 24 (plus/minus 5 days)

• Change in NT-proBNP From Baseline

  Baseline and Week 24 (plus/minus 5 days)

• Change in BNP From Baseline

  Baseline and Week 24 (plus/minus 5 days)

• Change in Quality of Life Evaluated by SF-10 Questionnaire From Baseline

  Baseline and Week 24 (plus/minus 5 days)

Other Outcomes (10)

• Taste and Texture (Questions 1 to 4) of the Oral Suspension of Riociguat at Week 0

  At the beginning of the treatment (Week 0)

• Taste and Texture (Questions 1 to 4) the Oral Suspension of Riociguat at Week 24

  Week 24 (plus/minus 5 days)

• Taste and Texture (Question 5) of the Oral Suspension of Riociguat at Week 0

  At the beginning of the treatment (Week 0)

Study Arms (1)

Riociguat

EXPERIMENTAL

Participants with age ≥6 to \<18 years received riociguat up to 2.5 mg three times a day (titration between 1.0 mg and 2.5 mg) for up to 8 weeks during the individual dose titration (IDT) phase, and followed with the last dose administered in the IDT phase for up to 16 weeks during the maintenance phase. Down-titration (up to 0.5 mg) of the dose for safety reasons was allowed at any time.

Drug: Riociguat (Adempas, BAY63-2521)

Interventions

Riociguat (Adempas, BAY63-2521) DRUG

For children with body-weight \<50 kg at screening: body-weight adjusted dose equivalent to the exposure of (0.5 mg) 1.0 - 2.5 mg three times a day, IDT in adults treated for PAH; oral suspension. For children ≥50 kg at screening: 1.0 to 2.5 mg three times a day; oral tablet.

Riociguat

Eligibility Criteria

• Age: 6 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Children from 6 years to less than 18 years of age with pulmonary arterial hypertension (PAH)
• Diagnosed with PAH :
• Idiopathic (IPAH)
• Hereditable (HPAH)
• PAH associated with (APAH)
• Connective tissue disease
• Congenital heart disease with shunt closure more than 6 months ago (no open shunts, confirmed by RHC no less than 4 months after surgery)
• PAH diagnosed by right heart catheterization (RHC) at any time prior to enrolment (for patients with closed shunts - RHC no less than 4 months after surgery)
• PAH confirmed by a RHC at any time prior to start of study, with mean pulmonary artery pressure (PAPmean) ≥25 mmHg at rest, pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) ≤15 mmHg, and pulmonary vascular resistance (PVR) \>240 dyn•sec•cm\^-5 (i.e., ≥3.0 wood units•m\^2)
• Patients must be on standard of care PAH medications, allowing Endothelin Receptor Antagonists (ERA) and/or Prostacyclin Analogues (PCA), for at least 12 weeks prior to baseline visit.
• Two groups of patients will be included:
• Prevalent: Patients currently on PAH medication (allowing ERA and/or PCA) who need additional treatment (discretion of the investigator)
• Incident: Treatment naïve patients initiated on PAH medication (allowing ERA and /or PCA) and then riociguat added once patients are stable on standard of care
• WHO functional class I-III
• Adolescent females of childbearing potential can only be included in the study if a pregnancy test is negative. Adolescent females of childbearing potential must agree to receive sexual counseling and use effective contraception as applicable. 'Effective contraception' is defined as progestogen-only hormonal contraception associated with inhibition of ovulation (implant), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), or any combination of adequate methods of birth control (e.g. condoms with hormonal contraception). Agreement to use contraception is required from the signing of the informed consent form up until 4 weeks after the last study drug administration.

You may not qualify if:

• Concomitant use of the following medications: phosphodiesterase (PDE) 5 inhibitors (such as sildenafil, tadalafil, vardenafil) and non-specific phosphodiesterase (PDE) inhibitors (theophylline, dipyridamole), nitrates or NO donors (such as amyl nitrite) in any form
• Active state of hemoptysis or pulmonary hemorrhage, including those events managed by bronchial artery embolization or any history of bronchial artery embolization or massive hemoptysis within 3 months prior to screening
• Systolic blood pressure (SBP) more than 5 mmHg lower than the age-, sex- and height-adapted level of the 50th SBP percentile (NHBPEP, 2004)
• History of left-sided heart disease, including valvular disease or heart failure
• WHO functional class IV
• Pulmonary veno-occlusive disease
• Screening aspartate transaminase (AST) and/ or alanine transaminase (ALT) more than 3 times the upper limit of normal (ULN)
• Severe restrictive lung disease
• Severe congenital abnormalities of the lung, thorax, and diaphragm
• Clinically relevant hepatic dysfunction (especially Child Pugh C)
• Renal insufficiency (estimated glomerular filtration rate \<30 mL/min/1.73m\^2 e.g. calculated based on Schwartz formula)
• PH associated with idiopathic interstitial pneumonia (PH-IIP)

Sponsors & Collaborators

• Bayer: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (16)

Clínica Imbanaco S.A.S

Cali, Valle del Cauca Department, 760042, Colombia

Location

Universitätsklinikum Heidelberg

Heidelberg, Baden-Wurttemberg, 69115, Germany

Location

Universitätsklinikum Ulm

Ulm, Baden-Wurttemberg, 89075, Germany

Location

Deutsches Herzzentrum der Charité (DHZC)

Berlin, 13353, Germany

Location

Gottsegen Gyorgy Orszagos Kardiovaszkularis Intezet

Budapest, 1096, Hungary

Location

Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ

Szeged, 6720, Hungary

Location

Azienda Ospedale-Università di Padova - UOC Cardiologia Pediatrica

Padova, Veneto, 35128, Italy

Location

Aichi Children's Health and Medical Center

Ōbu, Aichi-ken, 474-8710, Japan

Location

The University of Osaka Hospital

Suita, Osaka, 565-0871, Japan

Location

National Cerebral and Cardiovascular Center

Suita, Osaka, 565-8565, Japan

Location

Keio University Hospital

Shinjuku-ku, Tokyo, 160-8582, Japan

Location

Instituto Nacional de Cardiología "Ignacio Chávez"

México D.F., Mexico City, 14080, Mexico

Location

Operadora de Hospitales Angeles S. A. de C. V.

Huixquilucan, 52763, Mexico

Location

Wojewodzki Szpital Specjalistyczny - Wroclaw

Wroclaw, 51-124, Poland

Location

Veterans General Hospital

Kaohsiung City, 813414, Taiwan

Location

Hacettepe Universitesi Tip Fakultesi

Ankara, 06230, Turkey (Türkiye)

Location

Related Links

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

MeSH Terms

Conditions

Hypertension, Pulmonary; Pulmonary Arterial Hypertension

Interventions

riociguat

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases

Limitations and Caveats

The results should be interpreted with caution due to the limited number of subjects. The number of subjects with clinical worsening events was too low to produce valid Kaplan-Meier estimates for the time to clinical worsening.

Results Point of Contact

• Title: Therapeutic Area Head
• Organization: Bayer

clinical-trials-contact@bayer.com

1-888-8422937

Study Officials

• Bayer Study Director

  Bayer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 28, 2015
• First Posted: September 29, 2015
• Study Start: October 29, 2015
• Primary Completion: March 7, 2020
• Study Completion (Estimated): August 3, 2027
• Last Updated: May 12, 2026
• Results First Posted: May 17, 2021

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will not share

Locations

CO (1); ME (2); JP (4); DE (3); IT (1); TW (1); TU (1); HU (2); PL (1)