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A Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects With Pulmonary Arterial Hypertension (PAH) (AMBITION)

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: NCT01178073
Recruitment Status : Completed
First Posted : August 9, 2010
Results First Posted : April 28, 2015
Last Update Posted : September 13, 2017
Sponsor:
Collaborator:
Gilead Sciences
Information provided by (Responsible Party):
GlaxoSmithKline

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Hypertension, Pulmonary
Interventions Drug: ambrisentan
Drug: tadalafil
Enrollment 610
Recruitment Details 500 participants (par.) in the ITT Population were also included in the modified ITT Population (those who also met the modified inclusion/exclusion criteria defined in the protocol amendment 2). Disposition results below have been presented for the ITT Population.
Pre-assignment Details A total of 610 par. were randomized; however, only 605 were included in the Intent-to-Treat (ITT) Population (randomized par. who received at least one dose of IP). All par. received a minimum of 24 weeks of therapy unless they died or withdrew.
Arm/Group Title Combination Therapy: Ambrisentan + Tadalafil Ambrisentan Monotherapy Tadalafil Monotherapy
Hide Arm/Group Description Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg. Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg. Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.
Period Title: Overall Study
Started 302 152 151
Completed 240 108 105
Not Completed 62 44 46
Reason Not Completed
Adverse Event             34             27             24
Protocol Violation             1             1             1
Lost to Follow-up             2             0             3
Physician Decision             14             10             10
Withdrawal by Subject             10             6             8
Missing Completion Status             1             0             0
Arm/Group Title Combination Therapy: Ambrisentan + Tadalafil Ambrisentan Monotherapy Tadalafil Monotherapy Total
Hide Arm/Group Description Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg. Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg. Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks. Total of all reporting groups
Overall Number of Baseline Participants 302 152 151 605
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 302 participants 152 participants 151 participants 605 participants
55.9  (13.86) 55.2  (14.41) 55.9  (14.75) 55.7  (14.21)
[1]
Measure Description: Intent-to-Treat Population
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 302 participants 152 participants 151 participants 605 participants
Female
223
  73.8%
117
  77.0%
121
  80.1%
461
  76.2%
Male
79
  26.2%
35
  23.0%
30
  19.9%
144
  23.8%
[1]
Measure Description: Intent-to-Treat Population
Race/Ethnicity, Customized   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 302 participants 152 participants 151 participants 605 participants
African American/African Heritage 11 14 13 38
American Indian or Alaskan Native 2 0 0 2
Asian - Central/South Asian Heritage 1 2 1 4
Asian - Japanese Heritage 3 0 1 4
Asian - South East Asian Heritage 1 2 1 4
Native Hawaiian or Other Pacific Islander 1 0 2 3
White - Arabic /North African Heritage 1 1 0 2
White - White/Caucasian/European Heritage 280 131 133 544
Mixed Race 2 1 0 3
Missing 0 1 0 1
[1]
Measure Description: Intent-to-Treat Population
1.Primary Outcome
Title Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV
Hide Description Time to the first adjudicated CF event (death, hospitalization for worsening pulmonary arterial hypertension [PAH], disease progression, or unsatisfactory long-term clinical response) after initiating either first-line combination therapy with AMB and TAD or first-line monotherapy with either drug (AMB or TAD) in par. with PAH was assessed. If data was not available for some par. following a loss to follow-up, their event times were treated as censored at their last assessment time for the statistical analyses. FAV occurred approximately 4 weeks after the predicted 105th adjudicated first CF event was reached. Par. who had an FAV, and who had no adjudicated events or whose first adjudicated event occurred after their FAV, were censored at their individual FAV. Modified Intent-to-Treat (mITT) Population: all randomized par. who met the PAH diagnosis and inclusion/exclusion criteria defined in protocol amendment 2 and who also received at least one dose of investigational product (IP).
Time Frame From Baseline up to the Final Assessment Visit (FAV) (average of 609 days)
Hide Outcome Measure Data
Hide Analysis Population Description
mITT Population
Arm/Group Title Combination Therapy: Ambrisentan + Tadalafil Monotherapy Pooled: Ambrisentan or Tadalafil Ambrisentan Monotherapy Tadalafil Monotherapy
Hide Arm/Group Description:
Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.
Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks; or one tablet of 20 mg TAD and one tablet of TAD-matching placebo QD for the first 4 weeks. For participants on TAD, the dose of TAD was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and for participants on AMB, the dose of AMB may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.
Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.
Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.
Overall Number of Participants Analyzed 253 247 126 121
Measure Type: Number
Unit of Measure: Participants
First adjudicated clinical failure event 46 77 43 34
Death (all-cause) 9 8 2 6
Hospitalization for worsening PAH 10 30 18 12
Disease progression 10 16 12 4
Unsatisfactory long-term clinical response 17 23 11 12
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Ambrisentan + Tadalafil, Monotherapy Pooled: Ambrisentan or Tadalafil
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments [Not Specified]
Method Stratified Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.502
Confidence Interval (2-Sided) 95%
0.348 to 0.724
Estimation Comments Analysis of time to first adjudicated clinical failure event through FAV. HR is calculated using the Cox proportional hazards model. HR is for Combination Therapy: Ambrisentan + Tadalafil / Monotherapy Pooled: Ambrisentan or Tadalafil.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Ambrisentan + Tadalafil, Ambrisentan Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments [Not Specified]
Method Stratified Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.477
Confidence Interval (2-Sided) 95%
0.314 to 0.723
Estimation Comments Analysis of time to first adjudicated clinical failure event through FAV. HR is calculated using the Cox proportional hazards model. HR is for Combination Therapy: Ambrisentan + Tadalafil / Ambrisentan Monotherapy.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Ambrisentan + Tadalafil, Tadalafil Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0045
Comments [Not Specified]
Method Stratified Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.528
Confidence Interval (2-Sided) 95%
0.338 to 0.827
Estimation Comments Analysis of time to first adjudicated clinical failure event through FAV. HR is calculated using the Cox proportional hazards model. HR is for Combination Therapy: Ambrisentan + Tadalafil / Tadalafil Monotherapy.
2.Secondary Outcome
Title Percent Change From Baseline in the N-Terminal Pro-B-Type Natriuretic Peptide at Week 24
Hide Description N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) is a surrogate marker of heart failure. The data were log-transformed. The geometric mean was calculated (based on the log-transformed data). The geometric mean ratio was calculated as the ratio between the Week 24 value and the Baseline value (based on the log-transformed data) and presented as percent change = 100 * (geometric mean ratio - 1). The Baseline value is the last value prior to administration of study drug; this may be prior to or on the day of study drug initiation. No imputation was performed for missing data. The secondary endpoints were analyzed according to a pre-specified hierarchical testing procedure.
Time Frame Baseline and Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
mITT Population. Only participants with data available at the specified time points were analyzed.
Arm/Group Title Combination Therapy: Ambrisentan + Tadalafil Monotherapy Pooled: Ambrisentan or Tadalafil Ambrisentan Monotherapy Tadalafil Monotherapy
Hide Arm/Group Description:
Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.
Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks; or one tablet of 20 mg TAD and one tablet of TAD-matching placebo QD for the first 4 weeks. For participants on TAD, the dose of TAD was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and for participants on AMB, the dose of AMB may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.
Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.
Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.
Overall Number of Participants Analyzed 204 199 99 100
Mean (Standard Error)
Unit of Measure: Percent change
-67.15  (0.069) -50.37  (0.070) -56.15  (0.096) -43.83  (0.095)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Ambrisentan + Tadalafil, Monotherapy Pooled: Ambrisentan or Tadalafil
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Percent Difference
Estimated Value -33.81
Confidence Interval (2-Sided) 95%
-44.78 to -20.66
Estimation Comments Mean percent difference is for Combination Therapy: Ambrisentan + Tadalafil - Monotherapy Pooled: Ambrisentan or Tadalafil.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Ambrisentan + Tadalafil, Ambrisentan Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0111
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Percent Difference
Estimated Value -25.09
Confidence Interval (2-Sided) 95%
-40.04 to -6.40
Estimation Comments Mean percent difference is for Combination Therapy: Ambrisentan + Tadalafil - Ambrisentan Monotherapy.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Ambrisentan + Tadalafil, Tadalafil Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Percent Difference
Estimated Value -41.51
Confidence Interval (2-Sided) 95%
-53.16 to -26.97
Estimation Comments Mean percent difference is for Combination Therapy: Ambrisentan + Tadalafil - Tadalafil Monotherapy.
3.Secondary Outcome
Title Percentage of Participants With a Satisfactory Clinical Response at Week 24
Hide Description A satisfactory clinical response at Week 24 is defined as a participant who meets all of the following criteria: 10% improvement in 6MWD compared with Baseline; improvement to or maintenance of World Health Organization (WHO) class I or II symptoms; no events of clinical worsening prior to or at the Week 24 visit. Clinical worsening events included: death, hospitalization for pulmonary arterial hypertension (PAH), and disease progression. Participants without an event of clinical worsening prior to or at the Week 24 visit who did not have a 6MWD value or a WHO functional class value at Week 24 were excluded from the analysis.
Time Frame Baseline and Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
mITT Population. Only those participants who had a "Yes"/"No" response were analyzed.
Arm/Group Title Combination Therapy: Ambrisentan + Tadalafil Monotherapy Pooled: Ambrisentan or Tadalafil Ambrisentan Monotherapy Tadalafil Monotherapy
Hide Arm/Group Description:
Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.
Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks; or one tablet of 20 mg TAD and one tablet of TAD-matching placebo QD for the first 4 weeks. For participants on TAD, the dose of TAD was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and for participants on AMB, the dose of AMB may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.
Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.
Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.
Overall Number of Participants Analyzed 234 226 113 113
Measure Type: Number
Unit of Measure: Percentage of participants
39 29 31 27
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Ambrisentan + Tadalafil, Monotherapy Pooled: Ambrisentan or Tadalafil
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0264
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.563
Confidence Interval (2-Sided) 95%
1.054 to 2.319
Estimation Comments Odds ratio is for Combination Therapy: Ambrisentan + Tadalafil / Monotherapy Pooled: Ambrisentan or Tadalafil.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Ambrisentan + Tadalafil, Ambrisentan Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1518
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.424
Confidence Interval (2-Sided) 95%
0.878 to 2.308
Estimation Comments Odds ratio is for Combination Therapy: Ambrisentan + Tadalafil / Ambrisentan Monotherapy.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Ambrisentan + Tadalafil, Tadalafil Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0321
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.723
Confidence Interval (2-Sided) 95%
1.047 to 2.833
Estimation Comments Odds ratio is for Combination Therapy: Ambrisentan + Tadalafil / Tadalafil Monotherapy.
4.Secondary Outcome
Title Change From Baseline in the 6 Minute Walk Distance Test at Week 24
Hide Description The 6-minute walk distance (6MWD) test measures the distance that a participant can walk in a period of 6 minutes. Change from Baseline was calculated as the Week 24 value minus the Baseline value. The analysis was performed based on last observation carried forward data, except in the case of an adjudicated clinical failure event of death or hospitalization preceding the missing data observation. In this case, the missing observation was assigned the worst-rank score relative to those actually observed and was assigned a rank reflecting the relative order of the actual event times. Baseline 6MWD comprised of an average of the last two consecutive measurements prior to randomization that varied by no greater than 10%. If only one measurement was available, that measurement was used. If no two consecutive measures vary by no greater than 10% then Baseline was based on the last two consecutive measures for a participant.
Time Frame Baseline and Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
mITT Population. Only participants with Baseline data were analyzed.
Arm/Group Title Combination Therapy: Ambrisentan + Tadalafil Monotherapy Pooled: Ambrisentan or Tadalafil Ambrisentan Monotherapy Tadalafil Monotherapy
Hide Arm/Group Description:
Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.
Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks; or one tablet of 20 mg TAD and one tablet of TAD-matching placebo QD for the first 4 weeks. For participants on TAD, the dose of TAD was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and for participants on AMB, the dose of AMB may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.
Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.
Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.
Overall Number of Participants Analyzed 248 244 124 120
Median (95% Confidence Interval)
Unit of Measure: Meters
48.98
(39.00 to 57.50)
23.80
(19.00 to 33.50)
27.00
(12.50 to 38.00)
22.70
(16.50 to 35.50)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Ambrisentan + Tadalafil, Monotherapy Pooled: Ambrisentan or Tadalafil
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Stratified Wilcoxon Rank Sum Test
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference
Estimated Value 22.75
Confidence Interval (2-Sided) 95%
12.00 to 33.50
Estimation Comments Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Monotherapy Pooled: Ambrisentan or Tadalafil.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Ambrisentan + Tadalafil, Ambrisentan Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0005
Comments [Not Specified]
Method Stratified Wilcoxon Rank Sum Test
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference
Estimated Value 24.75
Confidence Interval (2-Sided) 95%
11.00 to 38.50
Estimation Comments Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Ambrisentan Monotherapy.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Ambrisentan + Tadalafil, Tadalafil Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0030
Comments [Not Specified]
Method Stratified Wilcoxon Rank Sum Test
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference
Estimated Value 20.85
Confidence Interval (2-Sided) 95%
8.00 to 33.70
Estimation Comments Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Tadalafil Monotherapy.
5.Secondary Outcome
Title Change From Baseline in the World Health Organization Functional Class at Week 24
Hide Description The WHO Functional Class (FC) indicates the severity of PAH and is an adaptation of the New York Heart Association classification. It was assessed by the investigator. There are four grades for WHO FC based on severity of symptoms (Class I = none, Class IV = most severe). Baseline WHO FC is the latest assessment prior to dosing (i.e., at Randomization or Screening). Change from Baseline at Week 24 was calculated as the Week 24 value minus the Baseline value. The analysis was performed based on the last observation carried forward data, except in the case of an adjudicated clinical failure event of death or hospitalization preceding the missing data observation. In this case, the missing observations was assigned the worst-rank score relative to those actually observed and was assigned rank reflecting the relative order of the actual event times.
Time Frame Baseline and Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
mITT Population. Only participants with Baseline data were analyzed.
Arm/Group Title Combination Therapy: Ambrisentan + Tadalafil Monotherapy Pooled: Ambrisentan or Tadalafil Ambrisentan Monotherapy Tadalafil Monotherapy
Hide Arm/Group Description:
Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.
Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks; or one tablet of 20 mg TAD and one tablet of TAD-matching placebo QD for the first 4 weeks. For participants on TAD, the dose of TAD was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and for participants on AMB, the dose of AMB may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.
Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.
Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.
Overall Number of Participants Analyzed 252 244 124 120
Median (Inter-Quartile Range)
Unit of Measure: Scores on a scale
0.0
(-1.0 to 0.0)
0.0
(-1.0 to 0.0)
0.0
(-1.0 to 0.0)
0.0
(-1.0 to 0.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Ambrisentan + Tadalafil, Monotherapy Pooled: Ambrisentan or Tadalafil
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2287
Comments [Not Specified]
Method Stratified Wilcoxon Rank Sum Test
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference
Estimated Value 0.0
Confidence Interval (2-Sided) 95%
0.0 to 0.0
Estimation Comments Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Monotherapy Pooled: Ambrisentan or Tadalafil.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Ambrisentan + Tadalafil, Ambrisentan Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Stratified Wilcoxon Rank Sum Test
Comments This comparison was not formally tested according to the pre-defined hierarchical testing procedure.
Method of Estimation Estimation Parameter Median Difference
Estimated Value 0.0
Confidence Interval (2-Sided) 95%
0.0 to 0.0
Estimation Comments Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Ambrisentan Monotherapy.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Ambrisentan + Tadalafil, Tadalafil Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Stratified Wilcoxon Rank Sum Test
Comments This comparison was not formally tested according to the pre-defined hierarchical testing procedure.
Method of Estimation Estimation Parameter Median Difference
Estimated Value 0.0
Confidence Interval (2-Sided) 95%
0.0 to 0.0
Estimation Comments Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Tadalafil Monotherapy.
6.Secondary Outcome
Title Change From Baseline in Borg Dyspnea Index at Week 24
Hide Description Borg Dyspnea Index (BDI) indicates the degree of breathlessness after completion of the 6 minute walk test. The BDI was calculated by using the Borg category (C) ratio (R) CR10 scale which starts at 0 (nothing at all) and has no upper limit (extremely strong). Change from BL was calculated as the Week 24 values minus the BL value. The BDI scale was assessed by each participant. The BL BDI score is the average of the two BDI values obtained following the two 6MWD tests used in determining the BL 6MWD. A negative change from BL in the BDI score represented an improvement for the participant. The analysis was performed based on the last observation carried forward data, except in the case of an adjudicated clinical failure event of death or hospitalization preceding the missing data observation. In this case, the missing observation was assigned the worst-rank score relative to those actually observed and was assigned rank reflecting the relative order of the actual event times.
Time Frame Baseline (BL) and Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
mITT Population. Only participants with Baseline data were analyzed.
Arm/Group Title Combination Therapy: Ambrisentan + Tadalafil Monotherapy Pooled: Ambrisentan or Tadalafil Ambrisentan Monotherapy Tadalafil Monotherapy
Hide Arm/Group Description:
Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.
Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks; or one tablet of 20 mg TAD and one tablet of TAD-matching placebo QD for the first 4 weeks. For participants on TAD, the dose of TAD was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and for participants on AMB, the dose of AMB may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.
Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.
Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.
Overall Number of Participants Analyzed 247 244 124 120
Median (Inter-Quartile Range)
Unit of Measure: Scores on a scale
-1.00
(-2.00 to 0.50)
-0.50
(-1.50 to 0.50)
-0.50
(-1.50 to 0.50)
-0.50
(-2.00 to 0.88)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Ambrisentan + Tadalafil, Monotherapy Pooled: Ambrisentan or Tadalafil
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Stratified Wilcoxon Rank Sum Test
Comments This endpoint was not formally tested according to the pre-defined hierarchical testing procedure.
Method of Estimation Estimation Parameter Median Difference
Estimated Value -0.38
Confidence Interval (2-Sided) 95%
-0.75 to 0.00
Estimation Comments Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Monotherapy Pooled: Ambrisentan or Tadalafil.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Ambrisentan + Tadalafil, Ambrisentan Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Stratified Wilcoxon Rank Sum Test
Comments This endpoint was not formally tested according to the pre-defined hierarchical testing procedure.
Method of Estimation Estimation Parameter Median Difference
Estimated Value -0.50
Confidence Interval (2-Sided) 95%
-1.00 to 0.00
Estimation Comments Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Ambrisentan Monotherapy.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Ambrisentan + Tadalafil, Tadalafil Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Stratified Wilcoxon Rank Sum Test
Comments This endpoint was not formally tested according to the pre-defined hierarchical testing procedure.
Method of Estimation Estimation Parameter Median Difference
Estimated Value -0.50
Confidence Interval (2-Sided) 95%
-1.00 to 0.00
Estimation Comments Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Tadalafil Monotherapy.
Time Frame Serious adverse events (SAEs) and non-serious AEs were collected from the start of investigational product until 30 days after the last dose of investigational product (average of 639 days on investigational product).
Adverse Event Reporting Description SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of investigational product. Only AEs for the “On-Randomized Treatment” arms are tabulated.
 
Arm/Group Title Combination Therapy: Ambrisentan + Tadalafil Ambrisentan Monotherapy Tadalafil Monotherapy
Hide Arm/Group Description Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg. Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg. Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.
All-Cause Mortality
Combination Therapy: Ambrisentan + Tadalafil Ambrisentan Monotherapy Tadalafil Monotherapy
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Hide Serious Adverse Events
Combination Therapy: Ambrisentan + Tadalafil Ambrisentan Monotherapy Tadalafil Monotherapy
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   124/302 (41.06%)   63/152 (41.45%)   68/151 (45.03%) 
Blood and lymphatic system disorders       
Anaemia  1  10/302 (3.31%)  3/152 (1.97%)  5/151 (3.31%) 
Iron deficiency anaemia  1  2/302 (0.66%)  0/152 (0.00%)  0/151 (0.00%) 
Anaemia macrocytic  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Hypochromic anaemia  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Immune thrombocytopenic purpura  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Spontaneous haematoma  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Hyperchromic anaemia  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Leukocytosis  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Cardiac disorders       
Cardiac failure  1  6/302 (1.99%)  6/152 (3.95%)  3/151 (1.99%) 
Right ventricular failure  1  5/302 (1.66%)  8/152 (5.26%)  3/151 (1.99%) 
Atrial flutter  1  3/302 (0.99%)  1/152 (0.66%)  0/151 (0.00%) 
Cardiac failure congestive  1  3/302 (0.99%)  2/152 (1.32%)  1/151 (0.66%) 
Angina pectoris  1  2/302 (0.66%)  2/152 (1.32%)  0/151 (0.00%) 
Cardiac arrest  1  2/302 (0.66%)  0/152 (0.00%)  2/151 (1.32%) 
Coronary artery stenosis  1  2/302 (0.66%)  0/152 (0.00%)  0/151 (0.00%) 
Supraventricular tachyarrhythmia  1  2/302 (0.66%)  0/152 (0.00%)  0/151 (0.00%) 
Atrial fibrillation  1  1/302 (0.33%)  1/152 (0.66%)  3/151 (1.99%) 
Atrial tachycardia  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Bradycardia  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Cardiac disorder  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Cardiac failure acute  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Cor pulmonale  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Cor pulmonale acute  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Coronary artery occlusion  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Myocardial infarction  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Pericardial effusion  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Pleuropericarditis  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Arrhythmia  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Arrhythmia supraventricular  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Atrioventricular block complete  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Atrioventricular block second degree  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Cardiorenal syndrome  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Left ventricular dysfunction  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Mitral valve incompetence  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Nodal arrhythmia  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Palpitations  1  0/302 (0.00%)  1/152 (0.66%)  1/151 (0.66%) 
Supraventricular extrasystoles  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Supraventricular tachycardia  1  0/302 (0.00%)  0/152 (0.00%)  2/151 (1.32%) 
Ear and labyrinth disorders       
Sudden hearing loss  1  2/302 (0.66%)  0/152 (0.00%)  0/151 (0.00%) 
Vertigo  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Endocrine disorders       
Diabetes insipidus  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Eye disorders       
Retinal vein occlusion  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Retinal detachment  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Gastrointestinal disorders       
Gastrointestinal haemorrhage  1  3/302 (0.99%)  3/152 (1.97%)  1/151 (0.66%) 
Gastritis  1  2/302 (0.66%)  0/152 (0.00%)  0/151 (0.00%) 
Ileus  1  2/302 (0.66%)  0/152 (0.00%)  1/151 (0.66%) 
Abdominal hernia  1  1/302 (0.33%)  0/152 (0.00%)  1/151 (0.66%) 
Abdominal pain upper  1  1/302 (0.33%)  0/152 (0.00%)  1/151 (0.66%) 
Duodenogastric reflux  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Epiploic appendagitis  3  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Gastric ulcer  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Gastritis erosive  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Gastrointestinal angiodysplasia  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Gastrointestinal inflammation  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Gastrooesophageal reflux disease  1  1/302 (0.33%)  0/152 (0.00%)  2/151 (1.32%) 
Haemorrhoidal haemorrhage  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Hiatus hernia  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Large intestinal ulcer  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Pancreatitis  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Umbilical hernia  1  1/302 (0.33%)  0/152 (0.00%)  1/151 (0.66%) 
Upper gastrointestinal haemorrhage  1  1/302 (0.33%)  1/152 (0.66%)  0/151 (0.00%) 
Abdominal distension  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Abdominal pain  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Diverticulum  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Melaena  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Oesophageal haemorrhage  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Rectal haemorrhage  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
General disorders       
Non-cardiac chest pain  1  7/302 (2.32%)  0/152 (0.00%)  0/151 (0.00%) 
Oedema peripheral  1  5/302 (1.66%)  1/152 (0.66%)  0/151 (0.00%) 
Pyrexia  1  4/302 (1.32%)  1/152 (0.66%)  1/151 (0.66%) 
Death  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
General physical health deterioration  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Generalised oedema  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Asthenia  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Chest discomfort  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Chest pain  1  0/302 (0.00%)  0/152 (0.00%)  2/151 (1.32%) 
Drug withdrawal syndrome  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Euthanasia  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Infusion site phlebitis  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Sudden cardiac death  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Hepatobiliary disorders       
Cholelithiasis  1  2/302 (0.66%)  1/152 (0.66%)  0/151 (0.00%) 
Bile duct stone  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Biliary colic  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Cholecystitis acute  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Hepatitis acute  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Cholecystitis  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Cholecystitis chronic  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Immune system disorders       
Autoimmune disorder  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Infections and infestations       
Pneumonia  1  15/302 (4.97%)  10/152 (6.58%)  7/151 (4.64%) 
Respiratory tract infection  1  4/302 (1.32%)  1/152 (0.66%)  1/151 (0.66%) 
Lung infection  1  3/302 (0.99%)  0/152 (0.00%)  1/151 (0.66%) 
Cellulitis  1  2/302 (0.66%)  5/152 (3.29%)  3/151 (1.99%) 
Gastroenteritis  1  2/302 (0.66%)  0/152 (0.00%)  0/151 (0.00%) 
Urinary tract infection  1  2/302 (0.66%)  1/152 (0.66%)  1/151 (0.66%) 
Abscess limb  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Bronchitis  1  1/302 (0.33%)  0/152 (0.00%)  3/151 (1.99%) 
Catheter site infection  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Conjunctivitis viral  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Diverticulitis  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Erysipelas  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Hepatitis C  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Infective exacerbation of chronic obstructive airways diseas  2  1/302 (0.33%)  1/152 (0.66%)  0/151 (0.00%) 
Influenza  1  1/302 (0.33%)  0/152 (0.00%)  1/151 (0.66%) 
Pneumonia bacterial  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Pneumonia mycoplasmal  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Postoperative wound infection  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Sepsis  1  1/302 (0.33%)  1/152 (0.66%)  3/151 (1.99%) 
Septic shock  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Upper respiratory tract infection  1  1/302 (0.33%)  0/152 (0.00%)  2/151 (1.32%) 
Vaginal infection  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Viral infection  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Alveolar osteitis  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Bacterial pyelonephritis  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Bronchitis viral  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Catheter site cellulitis  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Cholecystitis infective  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Escherichia infection  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Herpes zoster  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Infected skin ulcer  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Infection  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Lobar pneumonia  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Lower respiratory tract infection  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Necrotising fasciitis  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Pyelonephritis  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Staphylococcal bacteraemia  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
West Nile viral infection  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Wound infection  1  0/302 (0.00%)  1/152 (0.66%)  1/151 (0.66%) 
Injury, poisoning and procedural complications       
Fall  1  1/302 (0.33%)  0/152 (0.00%)  1/151 (0.66%) 
Femoral neck fracture  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Hip fracture  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Muscle rupture  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Post procedural complication  1  1/302 (0.33%)  1/152 (0.66%)  1/151 (0.66%) 
Spinal fracture  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Subdural haematoma  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Upper limb fracture  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Vascular pseudoaneurysm  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Burns second degree  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Concussion  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Lower limb fracture  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Mountain sickness acute  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Muscle injury  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Post procedural haemorrhage  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Post procedural myocardial infarction  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Radiation pneumonitis  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Respiratory fume inhalation disorder  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Tendon rupture  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Toxicity to various agents  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Traumatic ulcer  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Investigations       
Transaminases increased  1  2/302 (0.66%)  0/152 (0.00%)  0/151 (0.00%) 
Blood pressure systolic increased  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Gamma-glutamyltransferase increased  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Oxygen saturation decreased  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Blood potassium decreased  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Metabolism and nutrition disorders       
Fluid overload  1  5/302 (1.66%)  1/152 (0.66%)  4/151 (2.65%) 
Fluid retention  1  3/302 (0.99%)  0/152 (0.00%)  0/151 (0.00%) 
Dehydration  1  1/302 (0.33%)  2/152 (1.32%)  1/151 (0.66%) 
Diabetes mellitus  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Electrolyte imbalance  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Hypokalaemia  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Diabetic ketoacidosis  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Hyperkalaemia  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Hypovolaemia  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Metabolic syndrome  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Musculoskeletal and connective tissue disorders       
Osteonecrosis  1  2/302 (0.66%)  1/152 (0.66%)  0/151 (0.00%) 
Arthritis  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Connective tissue disorder  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Intervertebral disc disorder  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Intervertebral disc protrusion  1  1/302 (0.33%)  1/152 (0.66%)  0/151 (0.00%) 
Juvenile idiopathic arthritis  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Mixed connective tissue disease  1  1/302 (0.33%)  0/152 (0.00%)  1/151 (0.66%) 
Musculoskeletal chest pain  1  1/302 (0.33%)  1/152 (0.66%)  0/151 (0.00%) 
Myopathy  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Osteoarthritis  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Systemic sclerosis  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Back pain  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Chondromalacia  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Musculoskeletal pain  1  0/302 (0.00%)  1/152 (0.66%)  1/151 (0.66%) 
Myalgia  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Myositis  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Periarthritis  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Colon adenoma  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Colon cancer  1  2/302 (0.66%)  0/152 (0.00%)  0/151 (0.00%) 
Metastases to liver  1  2/302 (0.66%)  1/152 (0.66%)  0/151 (0.00%) 
Adenocarcinoma of colon  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Endometrial adenocarcinoma  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Lipoma  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Metastatic neoplasm  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Pancreatic carcinoma stage IV  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Prostate cancer  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Salivary gland neoplasm  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Thyroid cancer  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Uterine cancer  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Adenocarcinoma of the cervix  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Basal cell carcinoma  1  0/302 (0.00%)  2/152 (1.32%)  0/151 (0.00%) 
Invasive ductal breast carcinoma  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Leukaemia  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Lung neoplasm  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Lung neoplasm malignant  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Nervous system disorders       
Syncope  1  9/302 (2.98%)  5/152 (3.29%)  7/151 (4.64%) 
Cerebrovascular accident  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Headache  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Presyncope  1  1/302 (0.33%)  2/152 (1.32%)  1/151 (0.66%) 
Restless legs syndrome  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Altered state of consciousness  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Carotid artery stenosis  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Convulsion  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Dizziness  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Ischaemic stroke  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Somnolence  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Transient ischaemic attack  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Psychiatric disorders       
Abnormal behaviour  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Depression  1  1/302 (0.33%)  0/152 (0.00%)  1/151 (0.66%) 
Psychotic disorder  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Suicidal ideation  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Renal and urinary disorders       
Renal failure acute  1  3/302 (0.99%)  0/152 (0.00%)  1/151 (0.66%) 
Renal failure  1  2/302 (0.66%)  2/152 (1.32%)  1/151 (0.66%) 
Haematuria  1  0/302 (0.00%)  1/152 (0.66%)  1/151 (0.66%) 
Nephrolithiasis  1  0/302 (0.00%)  1/152 (0.66%)  1/151 (0.66%) 
Renal impairment  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Reproductive system and breast disorders       
Vaginal haemorrhage  1  2/302 (0.66%)  0/152 (0.00%)  0/151 (0.00%) 
Ovarian cyst ruptured  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Prostatitis  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Respiratory, thoracic and mediastinal disorders       
Pulmonary hypertension  1  11/302 (3.64%)  16/152 (10.53%)  12/151 (7.95%) 
Dyspnoea  1  10/302 (3.31%)  2/152 (1.32%)  4/151 (2.65%) 
Respiratory failure  1  5/302 (1.66%)  2/152 (1.32%)  1/151 (0.66%) 
Pleural effusion  1  4/302 (1.32%)  0/152 (0.00%)  2/151 (1.32%) 
Pulmonary oedema  1  4/302 (1.32%)  2/152 (1.32%)  0/151 (0.00%) 
Acute respiratory failure  1  3/302 (0.99%)  1/152 (0.66%)  0/151 (0.00%) 
Pulmonary embolism  1  3/302 (0.99%)  0/152 (0.00%)  2/151 (1.32%) 
Atelectasis  1  2/302 (0.66%)  1/152 (0.66%)  0/151 (0.00%) 
Hypoxia  1  2/302 (0.66%)  1/152 (0.66%)  1/151 (0.66%) 
Pulmonary arterial hypertension  1  2/302 (0.66%)  1/152 (0.66%)  1/151 (0.66%) 
Aspiration  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Chronic obstructive pulmonary disease  1  1/302 (0.33%)  1/152 (0.66%)  1/151 (0.66%) 
Chronic respiratory failure  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Interstitial lung disease  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Pleurisy  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Pleuritic pain  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Pneumonia aspiration  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Pneumothorax spontaneous  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Pulmonary vasculitis  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Respiratory distress  1  1/302 (0.33%)  1/152 (0.66%)  1/151 (0.66%) 
Sleep apnoea syndrome  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Acute pulmonary oedema  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Dyspnoea exertional  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Haemoptysis  1  0/302 (0.00%)  2/152 (1.32%)  0/151 (0.00%) 
Hypoventilation  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Lung disorder  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Obliterative bronchiolitis  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Organising pneumonia  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Pulmonary fibrosis  1  0/302 (0.00%)  0/152 (0.00%)  2/151 (1.32%) 
Skin and subcutaneous tissue disorders       
Rash  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Drug eruption  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Skin ulcer  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Vascular disorders       
Hypotension  1  3/302 (0.99%)  2/152 (1.32%)  2/151 (1.32%) 
Circulatory collapse  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Venous thrombosis limb  1  1/302 (0.33%)  0/152 (0.00%)  0/151 (0.00%) 
Hypertension  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Hypovolaemic shock  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Subclavian artery stenosis  1  0/302 (0.00%)  1/152 (0.66%)  0/151 (0.00%) 
Vascular insufficiency  1  0/302 (0.00%)  0/152 (0.00%)  1/151 (0.66%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA, 16.0
2
Term from vocabulary, RA, 16.0
3
Term from vocabulary, MedDRA
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Combination Therapy: Ambrisentan + Tadalafil Ambrisentan Monotherapy Tadalafil Monotherapy
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   279/302 (92.38%)   140/152 (92.11%)   135/151 (89.40%) 
Blood and lymphatic system disorders       
Anaemia  1  38/302 (12.58%)  8/152 (5.26%)  11/151 (7.28%) 
Cardiac disorders       
Palpitations  1  33/302 (10.93%)  22/152 (14.47%)  20/151 (13.25%) 
Ear and labyrinth disorders       
Vertigo  1  5/302 (1.66%)  6/152 (3.95%)  8/151 (5.30%) 
Eye disorders       
Vision blurred  1  19/302 (6.29%)  8/152 (5.26%)  4/151 (2.65%) 
Gastrointestinal disorders       
Diarrhoea  1  63/302 (20.86%)  35/152 (23.03%)  26/151 (17.22%) 
Nausea  1  47/302 (15.56%)  23/152 (15.13%)  23/151 (15.23%) 
Vomiting  1  35/302 (11.59%)  13/152 (8.55%)  13/151 (8.61%) 
Dyspepsia  1  32/302 (10.60%)  6/152 (3.95%)  18/151 (11.92%) 
Gastrooesophageal reflux disease  1  23/302 (7.62%)  10/152 (6.58%)  15/151 (9.93%) 
Constipation  1  17/302 (5.63%)  10/152 (6.58%)  6/151 (3.97%) 
Abdominal pain  1  9/302 (2.98%)  9/152 (5.92%)  7/151 (4.64%) 
Abdominal pain upper  1  8/302 (2.65%)  6/152 (3.95%)  8/151 (5.30%) 
Dry mouth  1  8/302 (2.65%)  11/152 (7.24%)  3/151 (1.99%) 
Abdominal distension  1  4/302 (1.32%)  8/152 (5.26%)  11/151 (7.28%) 
General disorders       
Oedema peripheral  1  133/302 (44.04%)  60/152 (39.47%)  44/151 (29.14%) 
Fatigue  1  35/302 (11.59%)  22/152 (14.47%)  20/151 (13.25%) 
Non-cardiac chest pain  1  26/302 (8.61%)  14/152 (9.21%)  9/151 (5.96%) 
Pyrexia  1  17/302 (5.63%)  6/152 (3.95%)  2/151 (1.32%) 
Chest discomfort  1  16/302 (5.30%)  6/152 (3.95%)  5/151 (3.31%) 
Asthenia  1  9/302 (2.98%)  4/152 (2.63%)  8/151 (5.30%) 
Pain  1  8/302 (2.65%)  2/152 (1.32%)  8/151 (5.30%) 
Infections and infestations       
Nasopharyngitis  1  51/302 (16.89%)  32/152 (21.05%)  24/151 (15.89%) 
Upper respiratory tract infection  1  41/302 (13.58%)  23/152 (15.13%)  22/151 (14.57%) 
Bronchitis  1  34/302 (11.26%)  7/152 (4.61%)  10/151 (6.62%) 
Urinary tract infection  1  24/302 (7.95%)  12/152 (7.89%)  18/151 (11.92%) 
Sinusitis  1  22/302 (7.28%)  11/152 (7.24%)  11/151 (7.28%) 
Influenza  1  14/302 (4.64%)  9/152 (5.92%)  7/151 (4.64%) 
Metabolism and nutrition disorders       
Hypokalaemia  1  17/302 (5.63%)  8/152 (5.26%)  5/151 (3.31%) 
Fluid retention  1  16/302 (5.30%)  7/152 (4.61%)  9/151 (5.96%) 
Decreased appetite  1  10/302 (3.31%)  9/152 (5.92%)  8/151 (5.30%) 
Musculoskeletal and connective tissue disorders       
Pain in extremity  1  49/302 (16.23%)  16/152 (10.53%)  22/151 (14.57%) 
Back pain  1  43/302 (14.24%)  17/152 (11.18%)  23/151 (15.23%) 
Arthralgia  1  41/302 (13.58%)  21/152 (13.82%)  23/151 (15.23%) 
Myalgia  1  30/302 (9.93%)  12/152 (7.89%)  18/151 (11.92%) 
Muscle spasms  1  25/302 (8.28%)  8/152 (5.26%)  10/151 (6.62%) 
Neck pain  1  10/302 (3.31%)  4/152 (2.63%)  8/151 (5.30%) 
Nervous system disorders       
Headache  1  124/302 (41.06%)  51/152 (33.55%)  55/151 (36.42%) 
Dizziness  1  62/302 (20.53%)  31/152 (20.39%)  22/151 (14.57%) 
Presyncope  1  11/302 (3.64%)  6/152 (3.95%)  11/151 (7.28%) 
Syncope  1  9/302 (2.98%)  4/152 (2.63%)  8/151 (5.30%) 
Psychiatric disorders       
Insomnia  1  21/302 (6.95%)  6/152 (3.95%)  10/151 (6.62%) 
Depression  1  13/302 (4.30%)  3/152 (1.97%)  8/151 (5.30%) 
Respiratory, thoracic and mediastinal disorders       
Nasal congestion  1  58/302 (19.21%)  25/152 (16.45%)  17/151 (11.26%) 
Cough  1  53/302 (17.55%)  20/152 (13.16%)  25/151 (16.56%) 
Dyspnoea  1  46/302 (15.23%)  27/152 (17.76%)  28/151 (18.54%) 
Epistaxis  1  27/302 (8.94%)  7/152 (4.61%)  15/151 (9.93%) 
Sinus congestion  1  18/302 (5.96%)  9/152 (5.92%)  4/151 (2.65%) 
Oropharyngeal pain  1  7/302 (2.32%)  9/152 (5.92%)  9/151 (5.96%) 
Skin and subcutaneous tissue disorders       
Rash  1  24/302 (7.95%)  6/152 (3.95%)  5/151 (3.31%) 
Pruritus  1  13/302 (4.30%)  10/152 (6.58%)  6/151 (3.97%) 
Vascular disorders       
Flushing  1  41/302 (13.58%)  18/152 (11.84%)  15/151 (9.93%) 
Hypotension  1  21/302 (6.95%)  8/152 (5.26%)  9/151 (5.96%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA, 16.0
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.
GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: GSK Response Center
Organization: GlaxoSmithKline
Phone: 866-435-7343
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01178073    
Other Study ID Numbers: 112565
First Submitted: July 15, 2010
First Posted: August 9, 2010
Results First Submitted: March 23, 2015
Results First Posted: April 28, 2015
Last Update Posted: September 13, 2017