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Riociguat in Children With Pulmonary Arterial Hypertension (PAH) (PATENT-CHILD)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02562235
Recruitment Status : Active, not recruiting
First Posted : September 29, 2015
Results First Posted : May 17, 2021
Last Update Posted : September 20, 2021
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Bayer

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.

Condition or disease Intervention/treatment Phase
Hypertension, Pulmonary Drug: Riociguat (Adempas, BAY63-2521) Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Open-label, Individual Dose Titration Study to Evaluate Safety, Tolerability and Pharmacokinetics of Riociguat in Children From 6 to Less Than 18 Years of Age With Pulmonary Arterial Hypertension (PAH)
Actual Study Start Date : October 29, 2015
Actual Primary Completion Date : March 7, 2020
Estimated Study Completion Date : November 25, 2031


Arm Intervention/treatment
Experimental: Riociguat
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)
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.




Primary Outcome Measures :
  1. Number of Participants With Any Treatment-emergent Adverse Events [ Time Frame: 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. ]
    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).

  2. Change in Heart Rate From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Mean change in heart rate from baseline is reported.

  3. Change in Blood Pressure From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Mean changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline are reported.

  4. Change in Respiratory Rate From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Mean change in respiratory rate from baseline is reported.

  5. Number of Subjects With Transitions From Baseline in Bone Age Compared to Chronological Age [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    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.

  6. Change in Hematology Parameters (Platelets) From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set.

  7. Change in Hematology Parameters (Lymphocytes/Leucocytes Ratio) From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set.

  8. Change in Hematology Parameter (Neutrophils/Leucocytes Ratio) From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set.

  9. Change in Clinical Chemistry (Alanine Aminotransferase) From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    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.

  10. Change in Clinical Chemistry (Aspartate Aminotransferase) From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    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.

  11. Change in Clinical Chemistry (Sodium) From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    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.

  12. Change in Clinical Chemistry (Blood Urea Nitrogen) From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    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.

  13. Change in Clinical Chemistry (eGFR) From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    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

  14. Change in Clinical Chemistry (Urea) From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    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.

  15. Change in Clinical Chemistry (Gamma Glutamyl Transferase) From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    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.

  16. Plasma Concentration of Riociguat at Week 0 [ Time Frame: Week 0 (30-90 minutes post-dose; 2.5-4 hours post-dose) ]
    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.

  17. Plasma Concentration of Riociguat at Week 4 [ Time Frame: Week 4 (pre-dose) ]
    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.

  18. Plasma Concentration of Riociguat at Week 8 [ Time Frame: Week 8 (pre-dose) ]
    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.

  19. Plasma Concentration of BAY60-4552 at Week 0 [ Time Frame: Week 0 (30-90 minutes post-dose; 2.5-4 hours post-dose) ]
    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

  20. Plasma Concentration of BAY60-4552 at Week 4 [ Time Frame: Week 4 (pre-dose) ]
    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.

  21. Plasma Concentration of BAY60-4552 at Week 8 [ Time Frame: Week 8 (pre-dose) ]
    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.


Secondary Outcome Measures :
  1. Change in 6-minute Walking Distance From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    6-minute walking distance (6MWD) is a exercise test used to assess aerobic capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity. An increase in the distance walked indicates improvement in basic mobility.

  2. Number of Subjects With Change in WHO Functional Class From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    The World Health Organization (WHO) functional class describes how severe a patient's pulmonary hypertension (PH) symptoms are. There are four different classes - I is the mildest and IV the most severe form of PH. Number of participants per change in number of classes is reported.

  3. Change in NT-proBNP From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Laboratory biomarkers N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) or brain-type natriuretic peptide (BNP) were tested for the participants. When both tests were available, NT-proBNP was chosen over BNP and the same test was performed at every required visit.

  4. Change in BNP From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Laboratory biomarkers N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) or brain-type natriuretic peptide (BNP) were tested for the participants. When both tests were available, NT-proBNP was chosen over BNP and the same test was performed at every required visit.

  5. Change in Quality of Life Evaluated by SF-10 Questionnaire From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    SF-10 is a parent-completed health survey for children that contains 10 questions adapted from the Child Health Questionnaire. It is scored using nom-based scoring to produce physical and psychosocial health summary measures. The possible range for the physical measure is -10.9 to 57.2 scores and the possible range for the psychosocial measure is 8.8 to 62.3 scores. Higher scores indicate more favorable functioning.

  6. Change in Quality of Life Evaluated by PedsQL Scale [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    The PedsQL Generic Core Scales were designed to measure health-related quality of life in children and adolescents. It has 4 dimensions: physical functioning, emotional functioning, social functioning and school functioning. 3 Summary Scores of PedsQL were calculated from the scales including total scale score (23 questions), physical health summary score (physical functioning, 8 questions) and psychosocial health summary score (emotional, social and school functioning, 15 questions). Responses of the questions are transformed to a 0-100 scale. Higher scores indicate better quality of life.

  7. Number of Subjects With Clinical Worsening [ Time Frame: Up to Week 24 (plus/minus 5 days) ]
    Clinical worsening was defined as: hospitalization for right heart failure, death, lung transplantation, Pott's anastomosis and atrioseptostomy, worsening of pulmonary arterial hypertension (PAH) symptoms, which must include either an increase in World Health Organization (WHO) functional class or appearance/worsening symptoms of right heart failure and need for additional PAH therapy.

  8. Change in Estimated Right Atrial Pressure From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Estimated right atrial pressure was measured by echocardiography.

  9. Change in Left Ventricular Eccentricity Index From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Left ventricular (LV) eccentricity index (EI) was measured by echocardiography and defined as the ratio of the LV anteroposterior dimension to the septolateral dimension in the parasternal short-axis window by echocardiography. The value of EI greater than 1.0 is abnormal and suggests right ventricle (RV) overload.

  10. Change in Pericardial Effusion From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Pericardial effusion was measured by echocardiography.

  11. Change in Pulmonary Artery Acceleration Time From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Pulmonary artery acceleration time was measured by echocardiography.

  12. Change in Right Ventricular Cardiac Index From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Right ventricle (RV) cardiac index (CI) was measured by echocardiography and calculated by dividing the cardiac output (stroke volume × heart rate) by the body surface area. The change in RV CI should not be understood solely but associated with other conditions of the participants.

  13. Change in Right Ventricular Cardiac Output From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Right ventricular cardiac output was measured by echocardiography.

  14. Change in Right Atrial Diastolic Area From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Right atrial diastolic area was measured by echocardiography.

  15. Change in Right Atrial Diastolic Area Index From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Right atrial (RA) diastolic area index was measured by echocardiography and calculated by dividing the RA area at end-diastole by the body surface area. The RA area index is a reflection of RA volume at end-diastole. The change in the index should not be understood solely but associated with other conditions of the participants.

  16. Change in Right Atrial Systolic Area From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Right atrial systolic area was measured by echocardiography.

  17. Change in Right Atrial Systolic Area Index From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Right atrial (RA) systolic area index was measured by echocardiography and calculated by dividing the RA area at end-systole by the body surface area. The RA area index is a reflection of RA volume at end-systole. The change in the index should not be understood solely but associated with other conditions of the participants.

  18. Change in Right Ventricular Fractional Area Change From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Right ventricular fractional area change was measured by echocardiography.

  19. Change in Right Ventricular Diastolic Area From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Right ventricular diastolic area was measured by echocardiography.

  20. Change in Right Ventricular Diastolic Area Index From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Right ventricular (RV) diastolic area index was measured by echocardiography and calculated by dividing the RV area at end-diastole by the body surface area. The RV area index is a reflection of RV volume at end-diastole. The change in the index should not be understood solely but associated with other conditions of the participants.

  21. Change in Right Ventricular Systolic Area From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Right ventricular systolic area was measured by echocardiography.

  22. Change in Right Ventricular Systolic Area Index From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Right ventricular (RV) systolic area index was measured by echocardiography and calculated by dividing the RV area at end-systole by the body surface area. The RV area index is a reflection of RV volume at end-systole. The change in the index should not be understood solely but associated with other conditions of the participants.

  23. Change in Systolic Pulmonary Artery Pressure From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Systolic pulmonary artery pressure was measured by echocardiography.

  24. Change in Tricuspid Annular Plane Systolic Excursion From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Tricuspid annular plane systolic excursion (TAPSE) was measured by echocardiography.

  25. Change in Tricuspid Regurgitation Peak Velocity From Baseline [ Time Frame: Baseline and Week 24 (plus/minus 5 days) ]
    Tricuspid regurgitation peak velocity was measured by echocardiography.


Other Outcome Measures:
  1. Taste and Texture (Questions 1 to 4) of the Oral Suspension of Riociguat at Week 0 [ Time Frame: At the beginning of the treatment (Week 0) ]
    To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Responses to Questions 1 to 4 are reported in this endpoint. Questions 1 and 2 were asked before the participants received the suspension; whereas questions 3 and 4 were asked right after administration of the suspension. Participants were asked to respond to the 4 questions as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer).

  2. Taste and Texture (Questions 1 to 4) the Oral Suspension of Riociguat at Week 24 [ Time Frame: Week 24 (plus/minus 5 days) ]
    To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Responses to Questions 1 to 4 are reported in this endpoint. Questions 1 and 2 were asked before the participants received the suspension; whereas questions 3 and 4 were asked right after administration of the suspension. Participants were asked to respond to the 4 questions as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer).

  3. Taste and Texture (Question 5) of the Oral Suspension of Riociguat at Week 0 [ Time Frame: At the beginning of the treatment (Week 0) ]
    To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 5 "Taste of the drink" is reported in this endpoint. Question 5 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to answer "yes", "I do not know/unsure" or "No" to each taste including "sweet, sour, bitter, salty, disgusting and fruity".

  4. Taste and Texture (Question 5) of the Oral Suspension of Riociguat at Week 24 [ Time Frame: Week 24 (plus/minus 5 days) ]
    To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 5 "Taste of the drink" is reported in this endpoint. Question 5 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to answer "yes", "I do not know/unsure" or "No" to each taste including "sweet, sour, bitter, salty, disgusting and fruity".

  5. Taste and Texture (Question 6) of the Oral Suspension of Riociguat at Week 0 [ Time Frame: At the beginning of the treatment (Week 0) ]
    To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 6 "Drink feels in mouth" is reported in this endpoint. Question 6 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to answer "yes", "I do not know/unsure" or "No" to each feeling including "like sand, sticky, gooey, slimy, creamy".

  6. Taste and Texture (Question 6) of the Oral Suspension of Riociguat in Mouth at Week 24 [ Time Frame: Week 24 (plus/minus 5 days) ]
    To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 6 "Drink feels in mouth" is reported in this endpoint. Question 6 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to answer "yes", "I do not know/unsure" or "No" to each feeling including "like sand, sticky, gooey, slimy, creamy".

  7. Taste and Texture (Question 7) of the Oral Suspension of Riociguat in Mouth at Week 0 [ Time Frame: At the beginning of the treatment (Week 0) ]
    To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 7 "Did you like the taste after swallowing" is reported in this endpoint. Question 7 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to respond as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer).

  8. Taste and Texture (Question 7) of the Oral Suspension of Riociguat in Mouth at Week 24 [ Time Frame: Week 24 (plus/minus 5 days) ]
    To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 7 "Did you like the taste after swallowing" is reported in this endpoint. Question 7 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to respond as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer).

  9. Expression Assessment on the Taste and Texture of Oral Suspension of Riociguat - Week 0 [ Time Frame: At the beginning of the treatment (Week 0) ]
    The facial expression of the subjects concerning appearance, smell and taste of the suspension of Riociguat was captured by the investigators as "comfortable", "indifferent" and "displeased".

  10. Expression Assessment on the Taste and Texture of Oral Suspension of Riociguat - Week 24 [ Time Frame: Week 24 (plus/minus 5 days) ]
    The facial expression of the subjects concerning appearance, smell and taste of the suspension of Riociguat was captured by the investigators as "comfortable", "indifferent" and "displeased".



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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)

Regardless of the type of PAH, the following findings are not exclusionary:

--- Patent foramen ovale (PFO) and asymptomatic, isolated, ostium secundum atrial septal defect (OS-ASD) ≤ 1 cm (both confirmed by echocardiogram) and not associated with hemodynamic alterations indicative of significant shunt, e.g. Qp/Qs ratio less <1.5:1 are not exclusionary

  • 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.
    • Young men must agree to use adequate contraception when sexually active.
    • Written inform consent provided and if applicable child assent provided

Exclusion Criteria:

  • 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

    -- Pretreatment with NO donors (e.g. nitrates) within the last 2-weeks before visit 1. The use of any drug including NO acutely for testing during catheterization is not an exclusion criterion.

  • 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
  • Pulmonary hypertension related to conditions other than specified in the inclusion criteria
  • 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02562235


Locations
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Colombia
IPS Centro Médico Imbanaco de Cali S.A.
Cali, Valle Del Cauca, Colombia
Germany
Universitätsklinikum Heidelberg
Heidelberg, Baden-Württemberg, Germany, 69120
Universitätsklinikum Ulm
Ulm, Baden-Württemberg, Germany, 89075
Deutsches Herzzentrum
Berlin, Germany, 13353
Hungary
Gottsegen Gyorgy Orszagos Kardiologiai Intezet
Budapest, Hungary, 1096
SZTE ÁOK Szent Györgyi Albert Klinikai Kozpont
Szeged, Hungary, 6725
Italy
A.O.U. di Padova
Padova, Veneto, Italy, 35128
Japan
Aichi Children's Health and Medical Center
Obu, Aichi, Japan, 474-8710
National Cerebral and Cardiovascular Center
Suita, Osaka, Japan, 564-8565
Osaka University Hospital
Suita, Osaka, Japan, 565-0871
Keio University Hospital
Shinjuku-ku, Tokyo, Japan, 160-8582
Mexico
Operadora de Hospitales Angeles S. A. de C. V.
Huixquilucan, Mexico, 52763
Instituto Nacional de Cardiología "Ignacio Chávez"
Mexico D.F., Mexico, 14080
Poland
Wojewodzki Szpital Specjalistyczny
Wroclaw, Poland, 51-124
Taiwan
Veterans General Hospital
Kaoshiung, Taiwan, 81346
Turkey
Hacettepe Universitesi Tip Fakultesi
Ankara, Turkey, 06100
Sponsors and Collaborators
Bayer
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Bayer Study Director Bayer
  Study Documents (Full-Text)

Documents provided by Bayer:
Study Protocol  [PDF] July 20, 2020
Statistical Analysis Plan  [PDF] February 17, 2020

Additional Information:
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Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT02562235    
Other Study ID Numbers: 15681
2014-003952-29 ( EudraCT Number )
First Posted: September 29, 2015    Key Record Dates
Results First Posted: May 17, 2021
Last Update Posted: September 20, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description:

Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access.

As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.

Interested researchers can use www.clinicalstudydatarequest.com to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the Study sponsors section of the portal.


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Bayer:
Pulmonary arterial hypertension
Additional relevant MeSH terms:
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Pulmonary Arterial Hypertension
Hypertension, Pulmonary
Hypertension
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Riociguat
Enzyme Activators
Molecular Mechanisms of Pharmacological Action