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Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy (REPLACE)

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ClinicalTrials.gov Identifier: NCT02891850
Recruitment Status : Completed
First Posted : September 8, 2016
Results First Posted : January 22, 2021
Last Update Posted : January 22, 2021
Sponsor:
Information provided by (Responsible Party):
Bayer

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Pulmonary Arterial Hypertension
Interventions Drug: Riociguat (Adempas, BAY63-2521)
Drug: Sildenafil
Drug: Tadalafil
Enrollment 225
Recruitment Details Study was conducted at multiple centers in 21 countries between 11-JAN-2017 (first participant first visit) and 03-MAR-2020 (last participant last visit).
Pre-assignment Details 293 participants were screened in this study. Of these, 67 participants did not enter the treatment period (60 screening failures; 2 withdraw during screening; 2 withdraw following physician decision; 3 withdraw due to other reasons). 226 participants were randomized, of which 1 participant withdraw before treated.
Arm/Group Title Riociguat PDE-5i
Hide Arm/Group Description Participants received BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks. Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator.
Period Title: Overall Study
Started [1] 111 114
Completed 104 107
Not Completed 7 7
Reason Not Completed
Adverse Event             3             0
Death             0             4
Physician Decision             1             0
Pregnancy             1             0
Withdrawal by Subject             2             3
[1]
Treated
Arm/Group Title Riociguat PDE-5i Total
Hide Arm/Group Description Participants received BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks. Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator. Total of all reporting groups
Overall Number of Baseline Participants 111 114 225
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 111 participants 114 participants 225 participants
49.4  (16.16) 49.2  (15.64) 49.3  (15.86)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 111 participants 114 participants 225 participants
Female
82
  73.9%
95
  83.3%
177
  78.7%
Male
29
  26.1%
19
  16.7%
48
  21.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 111 participants 114 participants 225 participants
Hispanic or Latino
32
  28.8%
31
  27.2%
63
  28.0%
Not Hispanic or Latino
75
  67.6%
80
  70.2%
155
  68.9%
Unknown or Not Reported
4
   3.6%
3
   2.6%
7
   3.1%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 111 participants 114 participants 225 participants
American Indian or Alaska Native
1
   0.9%
0
   0.0%
1
   0.4%
Asian
17
  15.3%
19
  16.7%
36
  16.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
4
   3.6%
5
   4.4%
9
   4.0%
White
86
  77.5%
89
  78.1%
175
  77.8%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
3
   2.7%
1
   0.9%
4
   1.8%
1.Primary Outcome
Title Number of Participants With Satisfactory Clinical Response at Week 24
Hide Description

The treatment is assessed as efficient (participants with satisfactory clinical response) in case at least 2 out of the following 3 criteria were fulfilled

  • 6 Minute Walking Distance increase by ≥ 10% or ≥ 30 m from baseline to Week 24
  • World Health Organization Functional Class (WHO FC) I or II at Week 24
  • N-terminal pro-brain natriuretic peptide (NT-proBNP) reduction ≥ 30% from baseline to Week 24 (NT-proBNP ratio Week 24/baseline ≤ 0.7) and in absence of the defined criteria of clinical worsening
Time Frame At Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) with evaluable participants
Arm/Group Title Riociguat PDE-5i
Hide Arm/Group Description:
Participants received BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks.
Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator.
Overall Number of Participants Analyzed 111 113
Measure Type: Count of Participants
Unit of Measure: Participants
With satisfactory clinical response
45
  40.5%
23
  20.4%
Without satisfactory clinical response
66
  59.5%
90
  79.6%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat, PDE-5i
Comments [Not Specified]
Type of Statistical Test Equivalence
Comments The hypothesis was that there was no difference in the satisfactory clinical response rates in terms of odds ratio (OR) when treated with riociguat compared with participants who remained on their previous therapy.
Statistical Test of Hypothesis P-Value 0.0007
Comments [Not Specified]
Method Mantel Haenszel
Comments Stratified by PAH category at baseline
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.78
Confidence Interval (2-Sided) 95%
1.526 to 5.060
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change in 6 Minute Walking Distance (6MWD) With Last Observation Carried Forward From Baseline to 24 Weeks
Hide Description Six-minute walk distance (6MWD) was conducted to test the physical limitations of the participant by assessing the participant's exercise capacity. The distance walked by the participant in 6 minutes was measured.
Time Frame From baseline and up to 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) with evaluable participants
Arm/Group Title Riociguat PDE-5i
Hide Arm/Group Description:
Participants received BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks.
Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator.
Overall Number of Participants Analyzed 111 113
Mean (Standard Deviation)
Unit of Measure: meters (m)
36.448  (65.9748) 13.884  (67.1552)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat, PDE-5i
Comments [Not Specified]
Type of Statistical Test Equivalence
Comments The hypothesis was that there was no difference in the change of 6MWD in terms of mean difference when treated with riociguat compared with participants who remained on their previous therapy.
Statistical Test of Hypothesis P-Value 0.0542
Comments [Not Specified]
Method t-test, 2 sided
Comments Stratified by PAH category at baseline
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 22.56
Confidence Interval (2-Sided) 95%
5.03 to 40.10
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) With Last Observation Carried Forward at Week 24
Hide Description N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in the blood are used for screening, diagnosis of acute congestive heart failure (CHF) and may be useful to establish prognosis in heart failure.
Time Frame From baseline and up to 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) with evaluable participants
Arm/Group Title Riociguat PDE-5i
Hide Arm/Group Description:
Participants received BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks.
Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator.
Overall Number of Participants Analyzed 108 113
Mean (Standard Deviation)
Unit of Measure: picograms per milliliter (pg/mL)
-88.234  (533.9179) 81.414  (1267.6142)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat, PDE-5i
Comments [Not Specified]
Type of Statistical Test Equivalence
Comments The hypothesis was that there was no difference in the change of NT-proBNP in terms of mean difference when treated with riociguat compared with participants who remained on their previous therapy.
Statistical Test of Hypothesis P-Value 0.1067
Comments [Not Specified]
Method t-test, 2 sided
Comments Stratified by PAH category at baseline
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -169.65
Confidence Interval (2-Sided) 95%
-426.18 to 86.88
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Change in World Health Organization Functional Class (WHO FC) With Last Observation Carried Forward From Baseline to Week 24
Hide Description The participant's functional class was determined by using the WHO classification. Possible classes range from I (patients with pulmonary hypertension (PH) but without resulting limitation of physical activity) to IV (patients with PH with inability to carry out any physical activity without symptoms).
Time Frame From baseline and up to 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) with evaluable participants
Arm/Group Title Riociguat PDE-5i
Hide Arm/Group Description:
Participants received BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks.
Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator.
Overall Number of Participants Analyzed 111 113
Mean (Standard Deviation)
Unit of Measure: class
-0.5  (0.58) -0.2  (0.62)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat, PDE-5i
Comments [Not Specified]
Type of Statistical Test Equivalence
Comments The hypothesis was that there was no difference in the change from baseline in WHO FC in terms of mean difference when treated with riociguat compared with participants who remained on their previous therapy.
Statistical Test of Hypothesis P-Value 0.0007
Comments [Not Specified]
Method t-test, 2 sided
Comments Stratified by PAH category at baseline
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.26
Confidence Interval (2-Sided) 95%
-0.42 to -0.11
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Number of Participants With Adjudicated Clinical Worsening at Week 24
Hide Description Clinical worsening was defined as death of any cause, hospitalization due to worsening pulmonary arterial hypertension (PAH) (adjudicated) or disease progression (adjudicated).
Time Frame Up to 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) with evaluable participants
Arm/Group Title Riociguat PDE-5i
Hide Arm/Group Description:
Participants received BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks.
Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator.
Overall Number of Participants Analyzed 111 113
Measure Type: Count of Participants
Unit of Measure: Participants
1
   0.9%
10
   8.8%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat, PDE-5i
Comments [Not Specified]
Type of Statistical Test Equivalence
Comments The hypothesis was that there was no difference in the clinical worsening rates in terms of odds ratio (OR) when treated with riociguat compared with participants who remained on their previous therapy.
Statistical Test of Hypothesis P-Value 0.0047
Comments [Not Specified]
Method Mantel Haenszel
Comments Stratified by PAH category at baseline
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.10
Confidence Interval (2-Sided) 95%
0.013 to 0.725
Estimation Comments [Not Specified]
Time Frame The adverse events were considered to be treatment emergent if they had started or worsened after the first treatment administration up to 2 days after end of treatment.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Riociguat PDE-5i
Hide Arm/Group Description Participants received BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks. Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator.
All-Cause Mortality
Riociguat PDE-5i
Affected / at Risk (%) Affected / at Risk (%)
Total   0/111 (0.00%)      4/114 (3.51%)    
Hide Serious Adverse Events
Riociguat PDE-5i
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   8/111 (7.21%)      19/114 (16.67%)    
Blood and lymphatic system disorders     
Iron deficiency anaemia * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Cardiac disorders     
Arrhythmia supraventricular * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Atrial fibrillation * 1  0/111 (0.00%)  0 1/114 (0.88%)  2
Cardiac failure * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Right ventricular failure * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Gastrointestinal disorders     
Gastrointestinal haemorrhage * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Small intestinal obstruction * 1  1/111 (0.90%)  3 0/114 (0.00%)  0
General disorders     
Chest pain * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Infections and infestations     
Gastroenteritis * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Pneumonia * 1  0/111 (0.00%)  0 2/114 (1.75%)  2
Tracheobronchitis * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Viral infection * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Respiratory tract infection * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Investigations     
Pulmonary arterial pressure increased * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Metabolism and nutrition disorders     
Dehydration * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Musculoskeletal and connective tissue disorders     
Osteonecrosis * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Nervous system disorders     
Epilepsy * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Syncope * 1  1/111 (0.90%)  1 1/114 (0.88%)  1
Respiratory, thoracic and mediastinal disorders     
Dyspnoea * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Dyspnoea exertional * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Epistaxis * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Pulmonary hypertension * 1  0/111 (0.00%)  0 2/114 (1.75%)  2
Pulmonary arterial hypertension * 1  0/111 (0.00%)  0 2/114 (1.75%)  3
Surgical and medical procedures     
Drug therapy enhancement * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Vascular disorders     
Hypotension * 1  2/111 (1.80%)  3 0/114 (0.00%)  0
1
Term from vocabulary, MedDRA (22.1)
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Riociguat PDE-5i
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   77/111 (69.37%)      72/114 (63.16%)    
Blood and lymphatic system disorders     
Anaemia * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Anaemia megaloblastic * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Iron deficiency anaemia * 1  2/111 (1.80%)  2 0/114 (0.00%)  0
Leukopenia * 1  0/111 (0.00%)  0 2/114 (1.75%)  2
Lymphopenia * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Neutropenia * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Cardiac disorders     
Arrhythmia * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Atrial fibrillation * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Cardiac failure chronic * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Palpitations * 1  3/111 (2.70%)  4 4/114 (3.51%)  4
Sinus tachycardia * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Tachycardia * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Ventricular extrasystoles * 1  0/111 (0.00%)  0 2/114 (1.75%)  2
Ear and labyrinth disorders     
Vertigo * 1  2/111 (1.80%)  3 0/114 (0.00%)  0
Eye disorders     
Astigmatism * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Cataract * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Eye irritation * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Glaucoma * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Retinal disorder * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Ocular discomfort * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Gastrointestinal disorders     
Abdominal discomfort * 1  3/111 (2.70%)  3 0/114 (0.00%)  0
Abdominal distension * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Abdominal pain * 1  3/111 (2.70%)  3 0/114 (0.00%)  0
Abdominal pain lower * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Abdominal pain upper * 1  3/111 (2.70%)  3 1/114 (0.88%)  1
Constipation * 1  4/111 (3.60%)  5 0/114 (0.00%)  0
Diarrhoea * 1  6/111 (5.41%)  6 3/114 (2.63%)  3
Dyspepsia * 1  10/111 (9.01%)  10 0/114 (0.00%)  0
Flatulence * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Gastritis * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Gastrooesophageal reflux disease * 1  8/111 (7.21%)  10 1/114 (0.88%)  1
Gingival hypertrophy * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Irritable bowel syndrome * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Nausea * 1  5/111 (4.50%)  6 3/114 (2.63%)  3
Toothache * 1  0/111 (0.00%)  0 2/114 (1.75%)  2
Vomiting * 1  3/111 (2.70%)  3 0/114 (0.00%)  0
Gastrointestinal hypermotility * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Reflux gastritis * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
General disorders     
Asthenia * 1  0/111 (0.00%)  0 2/114 (1.75%)  2
Chest discomfort * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Chest pain * 1  5/111 (4.50%)  8 5/114 (4.39%)  5
Drug ineffective * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Fatigue * 1  6/111 (5.41%)  7 2/114 (1.75%)  2
Malaise * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Oedema * 1  2/111 (1.80%)  2 2/114 (1.75%)  2
Oedema mucosal * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Oedema peripheral * 1  3/111 (2.70%)  4 4/114 (3.51%)  4
Pyrexia * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Peripheral swelling * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Hepatobiliary disorders     
Hepatomegaly * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Immune system disorders     
Drug hypersensitivity * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Hypersensitivity * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Infections and infestations     
Acute sinusitis * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Body tinea * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Bronchitis * 1  1/111 (0.90%)  1 2/114 (1.75%)  2
Conjunctivitis * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Diverticulitis * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Enterobiasis * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Eye infection * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Fungal infection * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Gastroenteritis * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Hepatitis E * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Herpes zoster * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Influenza * 1  1/111 (0.90%)  1 2/114 (1.75%)  2
Laryngitis * 1  0/111 (0.00%)  0 2/114 (1.75%)  2
Lower respiratory tract infection * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Nasopharyngitis * 1  8/111 (7.21%)  8 5/114 (4.39%)  5
Otitis media * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Pneumonia * 1  2/111 (1.80%)  2 1/114 (0.88%)  1
Rhinitis * 1  0/111 (0.00%)  0 4/114 (3.51%)  4
Sinusitis * 1  2/111 (1.80%)  2 6/114 (5.26%)  8
Tonsillitis * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Upper respiratory tract infection * 1  4/111 (3.60%)  4 7/114 (6.14%)  8
Urinary tract infection * 1  2/111 (1.80%)  2 3/114 (2.63%)  3
Viral infection * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Pharyngotonsillitis * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Febrile infection * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Bronchitis viral * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Mycobacterial infection * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Respiratory tract infection * 1  1/111 (0.90%)  2 0/114 (0.00%)  0
Injury, poisoning and procedural complications     
Ligament sprain * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Muscle strain * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Limb injury * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Bone contusion * 1  1/111 (0.90%)  1 1/114 (0.88%)  1
Investigations     
Blood pressure decreased * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Blood pressure systolic increased * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Catheterisation cardiac * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Haemoglobin decreased * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Prothrombin time prolonged * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Hepatic enzyme increased * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
N-terminal prohormone brain natriuretic peptide increased * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Metabolism and nutrition disorders     
Dehydration * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Fluid retention * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Gout * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Hyperuricaemia * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Hypokalaemia * 1  0/111 (0.00%)  0 4/114 (3.51%)  4
Iron deficiency * 1  2/111 (1.80%)  2 4/114 (3.51%)  4
Decreased appetite * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Type 2 diabetes mellitus * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Musculoskeletal and connective tissue disorders     
Arthralgia * 1  1/111 (0.90%)  1 3/114 (2.63%)  3
Arthritis * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Back pain * 1  1/111 (0.90%)  1 6/114 (5.26%)  6
Muscle spasms * 1  2/111 (1.80%)  2 1/114 (0.88%)  1
Musculoskeletal pain * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Myalgia * 1  1/111 (0.90%)  1 1/114 (0.88%)  1
Neck pain * 1  2/111 (1.80%)  2 1/114 (0.88%)  1
Pain in extremity * 1  0/111 (0.00%)  0 1/114 (0.88%)  2
Pain in jaw * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Spinal osteoarthritis * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Systemic lupus erythematosus * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Intervertebral disc protrusion * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Nervous system disorders     
Diabetic neuropathy * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Dizziness * 1  5/111 (4.50%)  5 2/114 (1.75%)  2
Headache * 1  14/111 (12.61%)  16 8/114 (7.02%)  8
Hypoaesthesia * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Migraine * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Presyncope * 1  1/111 (0.90%)  1 2/114 (1.75%)  2
Syncope * 1  0/111 (0.00%)  0 2/114 (1.75%)  2
Psychiatric disorders     
Anxiety * 1  0/111 (0.00%)  0 1/114 (0.88%)  3
Depression * 1  2/111 (1.80%)  2 0/114 (0.00%)  0
Insomnia * 1  0/111 (0.00%)  0 3/114 (2.63%)  3
Sleep disorder * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Stress * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Renal and urinary disorders     
Polyuria * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Urinary incontinence * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Reproductive system and breast disorders     
Dysmenorrhoea * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Menometrorrhagia * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Adnexa uteri cyst * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Respiratory, thoracic and mediastinal disorders     
Asthma * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Cough * 1  0/111 (0.00%)  0 7/114 (6.14%)  7
Dry throat * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Dyspnoea * 1  3/111 (2.70%)  4 5/114 (4.39%)  6
Dyspnoea exertional * 1  2/111 (1.80%)  3 0/114 (0.00%)  0
Epistaxis * 1  3/111 (2.70%)  3 3/114 (2.63%)  4
Hypoxia * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Lung disorder * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Nasal congestion * 1  1/111 (0.90%)  1 1/114 (0.88%)  1
Nasal polyps * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Productive cough * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Pulmonary embolism * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Pulmonary hypertension * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Pulmonary oedema * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Rhinitis allergic * 1  2/111 (1.80%)  2 0/114 (0.00%)  0
Rhinorrhoea * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Sleep apnoea syndrome * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Throat irritation * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Paranasal sinus hypersecretion * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Pulmonary arterial hypertension * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Bronchial hyperreactivity * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Oropharyngeal pain * 1  0/111 (0.00%)  0 2/114 (1.75%)  2
Skin and subcutaneous tissue disorders     
Acne * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Erythema * 1  1/111 (0.90%)  1 0/114 (0.00%)  0
Hyperhidrosis * 1  1/111 (0.90%)  1 1/114 (0.88%)  1
Pruritus * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Rash * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Surgical and medical procedures     
Tooth extraction * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Vascular disorders     
Circulatory collapse * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Flushing * 1  1/111 (0.90%)  1 1/114 (0.88%)  1
Hypertension * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Hypotension * 1  13/111 (11.71%)  19 6/114 (5.26%)  11
Orthostatic hypotension * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
Jugular vein distension * 1  0/111 (0.00%)  0 1/114 (0.88%)  1
1
Term from vocabulary, MedDRA (22.1)
*
Indicates events were collected by non-systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Therapeutic Area Head
Organization: Bayer
Phone: (+) 1-888-8422937
EMail: clinical-trials-contact@bayer.com
Layout table for additonal information
Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT02891850    
Other Study ID Numbers: 18588
2016-001067-36 ( EudraCT Number )
First Submitted: August 26, 2016
First Posted: September 8, 2016
Results First Submitted: January 4, 2021
Results First Posted: January 22, 2021
Last Update Posted: January 22, 2021