Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension

• ClinicalTrials.gov Identifier: NCT00323297
• Recruitment Status: Completed
• First Posted: May 9, 2006
• Results First Posted: November 19, 2013
• Last Update Posted: February 1, 2021
• Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
• Information provided by (Responsible Party): Pfizer ( Pfizer's Upjohn has merged with Mylan to form Viatris Inc. )

Tracking Information

• First Submitted Date: May 5, 2006
• First Posted Date: May 9, 2006
• Results First Submitted Date: August 23, 2013
• Results First Posted Date: November 19, 2013
• Last Update Posted Date: February 1, 2021
• Study Start Date: September 2006
• Actual Primary Completion Date: August 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 18, 2013)

Change From Baseline in the Total Distance Walked During 6 Minute Walk Time (6MWT) at Week 12 [ Time Frame: Week 12 ]

6MWT is the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. Continuous pulse oximetry was conducted during the test for safety.

• Original Primary Outcome Measures (submitted: May 5, 2006): To assess the effect on exercise capacity (as measured by the 6 Minute Walk Test) after 12 weeks of treatment of sildenafil (20mg TID) or placebo, when added to subjects with PAH who are stabilized on bosentan therapy

Current Secondary Outcome Measures (submitted: July 17, 2014)

• Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF [ Time Frame: Week 12 ]
  WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity) to Class IV (can not perform a physical activity without any symptoms, dyspnea at rest). Improvement=reduction in functional class; deterioration = increase in functional class, no change = no change in functional class.
• Clinical Worsening Events [ Time Frame: Week 12 ]
  No survival analysis was carried out for the study due to very few events of clinical worsening. Hence, we present a summary of clinical worsening events instead. Events of clinical worsening were categorized as (A). Death, (B). Heart/lung transplantation, (C). Hospitalization due to pulmonary arterial hypertension (PAH), and (D). Clinical deterioration of PAH requiring additional therapy.
• Change From Baseline in Borg Dyspnea Score at Week 12 [ Time Frame: Week 12 ]
  Borg dyspnea scale is a 10-point scale where following scores stands for severity of dyspnea: 0 (no breathlessness at all); 0.5 (very very slight [just noticeable]);

  1. (very slight);
  2. (slight breathlessness);
  3. (moderate); 4 (some what severe);

  5 (severe breathlessness); 7 (very severe breathlessness); 9 (very very severe [almost maximum]); and 10 (maximum).
• One Year Survival Probability From the Start of Sildenafil Treatment. [ Time Frame: One year from the time of starting sildenafil ]
  The survival probability of all participants up to 1-year post start of Sildenafil treatment; for participants who were randomized to Sildenafil, this was the week 52 from randomization, and for participants who were originally randomized to Placebo group, this was the Week 64 from Baseline (Week 52 from Week 12, when the first dose of Sildenafil was administered to these participants). Those participants who discontinued from the study prior to 1 year after start of sildenafil were considered as censored at the time of discontinuation and those who discontinued from the study post 1-year after start of sildenafil were considered as censored at the time of 1-year post start of sildenafil.
• One Year Survival From the Start of Sildenafil Treatment. [ Time Frame: One year from the time of starting sildenafil ]
  The survival status of all participants who discontinued from the study, including those participants who discontinued during the double-blind phase, was to be assessed at one year post their Week 12 visit/ End of treatment visit.

Original Secondary Outcome Measures (submitted: May 5, 2006)

• To assess the safety and tolerability of sildenafil (20mg TID) or placebo, when added to subjects with PAH who are currently treated with bosentan, after 12 weeks of treatment.
• To assess the safety and tolerability of the open label treatment of sildenafil (20mg TID) and bosentan therapy in subjects with PAH after 12 months of treatment.
• To assess the effect on other clinical outcome measures (clinical worsening, Borg dyspnoea score and PAH functional class) after 12 weeks of treatment of sildenafil (20mg TID) or placebo when added to bosentan therapy in subjects with PAH.
• To determine the population pharmacokinetic parameters of sildenafil and bosentan.
• To investigate the Pharmacokinetic/Pharmacodynamic (PK/PD) relationship between sildenafil and bosentan exposure on the 6-Minute Walk Test.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension
• Official Title: A Multinational, Multicentre, Randomized, Double-blind Study To Assess The Efficacy And Safety Of Oral Sildenafil 20mg Tid Or Placebo When Added To Bosentan In The Treatment Of Subjects, Aged 18 Years And Above, With Pulmonary Arterial Hypertension (Pah)
• Brief Summary: To assess the efficacy and safety of sildenafil when added to patients with PAH who are taking bosentan as all or part of their background therapy.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Pulmonary Arterial Hypertension

Intervention

• Drug: Bosentan
  Bosentan + Placebo for 12 weeks of the study (double blind), then 12 months open label phase (bosentan + sildenafil)
• Other: Placebo
  Bosentan + Placebo for 12 weeks of the study (double blind), then 12 months open label phase (bosentan + sildenafil)
• Drug: Bosentan
  Bosentan + Sildenafil for 12 weeks of the study (double blind), then 12 months open label phase
• Drug: Sildenafil Citrate
  Bosentan + Sildenafil for 12 weeks of the study (double blind), then 12 months open label phase

Study Arms

• Placebo Comparator: placebo
  Interventions:

  • Drug: Bosentan
  • Other: Placebo
• Experimental: Active
  Interventions:

  • Drug: Bosentan
  • Drug: Sildenafil Citrate

• Publications *: Vizza CD, Jansa P, Teal S, Dombi T, Zhou D. Sildenafil dosed concomitantly with bosentan for adult pulmonary arterial hypertension in a randomized controlled trial. BMC Cardiovasc Disord. 2017 Sep 6;17(1):239. doi: 10.1186/s12872-017-0674-3.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 27, 2014): 105
• Original Enrollment (submitted: May 5, 2006): 106
• Actual Study Completion Date: August 2013
• Actual Primary Completion Date: August 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Subjects aged 18 and over above with PAH and for which bosentan therapy is indicated according to national license
• Subjects with a mean pulmonary artery pressure of >25mmHg and a pulmonary artery wedge pressure of <15mmHg at rest via right heart catheterization within 3 years prior to randomization.
• Subjects whose baseline 6 Minute Walk Test distance is >100m and < 450m.

Exclusion Criteria:

• PAH secondary to any aetiology including congenital heart disease other than those specified in the inclusion criteria
• Subjects whose 6 Minute Walk Test may be limited by conditions other than PAH related dyspnoea or fatigue eg. claudication from vascular insufficiency or arthritis.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Czechia, France, Germany, Greece, Israel, Italy, Taiwan, United Kingdom, United States
• Removed Location Countries: Belgium, Czech Republic

Administrative Information

• NCT Number: NCT00323297
• Other Study ID Numbers: A1481243; 2006-001464-23 ( EudraCT Number ); PATHWAYS ( Other Identifier: Alias Study Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Pfizer ( Pfizer's Upjohn has merged with Mylan to form Viatris Inc. )
• Study Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: January 2021