Effect of Selexipag on Daily Life Physical Activity of Patients With Pulmonary Arterial Hypertension. (TRACE)

A Multi-center, Double-blind, Placebo-controlled Phase 4 Study in Patients With Pulmonary Arterial Hypertension to Assess the Effect of Selexipag on Daily Life Physical Activity and Patient's Self-reported Symptoms and Their Impacts

The primary objective of this study is to evaluate the effect of selexipag on the physical activity of patients with pulmonary arterial hypertension (PAH) in their daily life, by using a wearable wrist device (actigraph). The actigraph will collect data on daily life physical activity in the patient's real environment. In addition, the PAH symptoms and their impacts will be assessed by using an electronic patient reported outcome measure in the patient's real environment. Patients will be assigned randomly to either selexipag or placebo.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Selexipag; Drug: Placebo

Detailed Description

This study is designed as exploratory with the purpose to generate hypotheses on new endpoints

• Study Type: Interventional
• Enrollment (Actual): 108
• Phase: Phase 4

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria, 06020
    • Medizinische Universität Innsbruck (MUI), Abt. für Pneumologie, Haus 2
  • Linz, Austria, 4020
    • Krankenhaus der Elisabethinen, Servicestelle Klinische Studien
• France
  • Le Kremlin-Bicêtre, France, 94270
    • Hôpital Bicêtre, ervice de Pneumologie et Réanimation respiratoire
  • Lille, France, 59000
    • CHRU de Lille - Hôpital Albert Calmette, Service de cardiologie
  • Toulouse, France, 31059
    • Hospital Larrey CHU de Toulouse
• Germany
  • Giessen, Germany, 35392
    • Universitätsklinikum Gießen
  • Köln, Germany, 50937
    • Herzzentrum der Universität zu Köln, Klinik III für Innere Medizin
  • Leipzig, Germany, 04103
    • Universitätsklinikum Leipzig AöR, Abteilung Pneumologie
  • Lünen, Germany, 44534
    • Katholisches Klinikum Lünen/Werne GmbH, Haus E
• Ireland
  • Dublin, Ireland, D07 R2WY
    • Mater Misericordiae University Hospital
• Norway
  • Oslo, Norway, 0372
    • Oslo University Hospital, dept of cardiology
• Portugal
  • Coimbra, Portugal, 3000-075
    • Centro Hospitalar e Universitário de Coimbra, Serviço de Cardiologia
  • Porto, Portugal, 4099-001
    • Hospital Geral de Santo António-DEFI
• Sweden
  • Gothenburg, Sweden, 413 45
    • Sahlgrenska University Hospital, Gothenburg
  • Lund, Sweden, 221 85
    • Skåne University Hospital, VO Hjärt och Lungmedicin
• Switzerland
  • St. Gallen, Switzerland, 9007
    • Kantonsspital St. Gallen, Klinik für Pneumologie und Schlafmedizin
  • Zurich, Switzerland, 8091
    • Universitaetsspital Zurich, Klinik für Pneumologie C HOER 11
• United Kingdom
  • Cambridge, United Kingdom, Cb23 3RE
    • Papworth Hospital, Pulmonary Vascular Disease Unit
  • Clydebank, United Kingdom, G81 4DY
    • Golden Jubilee National Hospital, Scottish Pulmonary Vascular Unit
  • London, United Kingdom, W12 0HS
    • Hammersmith Hospital
  • London, United Kingdom, NW3 2QG
    • The Royal Free Hospital, Cardiology Department
  • London, United Kingdom, SW3 6NP
    • Royal Brompton Hospital, Hypertension
  • Newcastle Upon Tyne, United Kingdom, NE7 7DN
    • Freeman Hospital, Cardiothoracic Department
  • Sheffield, United Kingdom, S10 2JF
    • Royal Hallamshire Hospital, Pulmonary Vascular Medicine
• United States
  • California
    • Torrance, California, United States, 90502
      • LA Biomedical Research Institute
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Northside Hospital
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Kentuckiana Pulmonary Research Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center, Pulmonary/Critical Care & Sleep
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center, Pulmonary, Critical Care & Sleep Medicine Division
  • New York
    • Mineola, New York, United States, 11501
      • NYU Winthrop Hospital
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Pulmonary Speciality Clinic
    • Durham, North Carolina, United States, 27710
      • Duke University School of Medicine, Duke Pulmonary Vascular Disease center
  • Ohio
    • Cincinnati, Ohio, United States, 45267-0564
      • University of Cincinnati, Heart, Lung and Vascular Institute
    • Cleveland, Ohio, United States, 44307
      • CCF- Akron General Medical Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Integris Baptist Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania, Pulmonary Vascular Disease Program
  • Tennessee
    • Nashville, Tennessee, United States, 37232-2650
      • Vanderbilt University Medical Center, Care Medicine
  • Texas
    • San Antonio, Texas, United States, 78229
      • Methodist Clinical Trials
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center (San Antonio)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female between 18 and 75 years old inclusive.
• Women of childbearing potential must have a negative serum pregnancy test at planned visits and use an acceptable method of birth control from screening up to 30 days after study treatment discontinuation.

• Symptomatic pulmonary arterial hypertension (PAH) belonging to one of the following subgroups only:

  • Idiopathic
  • Heritable
  • Drug or toxin induced
  • Associated with one of the following: connective tissue disease; HIV infection; corrected simple congenital heart disease.

• With the following hemodynamic characteristics assessed by right heart catheterization (RHC) prior to randomization:

  • Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg
  • Pulmonary vascular resistance (PVR) ≥ 240 dyn•sec/cm5 (or 3 Wood Units)
  • Pulmonary artery wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) ≤ 15 mmHg.
• Treatment with an endothelin receptor antagonist (ERA) for at least 90 days and on a stable dose for 30 days prior to randomization.
• If an ERA is given in combination with a phosphodiesterase-5 (PDE-5) inhibitor or soluble guanylate cyclase (sGC) stimulator, these treatments must be ongoing for at least 90 days and on a stable dose for 30 days prior to randomization.
• WHO functional class (FC) II or III at randomization
• 6-minute walk distance (6MWD) ≥ 100 m at screening.
• Ability to walk without a walking aid.
• Valid baseline data for daily life physical activity (DLPA) and PAH-SYMPACT®.

Exclusion Criteria:

• Patients on a PAH-specific monotherapy targeting the nitric oxide pathway (i.e. PDE-5 inhibitor or sGC stimulator).
• Patients treated with prostacyclin, prostacyclin analog or selexipag within 3 months prior to screening.
• Any hospitalization during the last 30 days prior to screening.
• Severe coronary heart disease or unstable angina.
• Documented severe hepatic impairment or severe renal insufficiency at screening.
• Participation in a cardio-pulmonary rehabilitation program based on exercise training within 8 weeks prior to screening
• Any factor or condition likely to affect full participation in the study or compliance with the protocol (such as adherence to protocol mandated procedures), as judged by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Selexipag; Selexipag is up-titrated from Day 1 to Week 12 to the individualized highest tolerated dose (HTD), which can range from 200 mcg b.i.d. to 1600 mcg b.i.d., in 200 mcg steps starting with 200 mcg b.i.d. Then, the dose is increased in increments of 200 mcg b.i.d., usually at weekly intervals, depending on the dose tolerability. Up-titration is followed by a stable maintenance treatment period at the highest tolerated dose, from Week 13 to Week 24.	Drug: Selexipag; Film-coated tablets for oral use; one tablet (200 mcg) to eight tablets (1600 mcg) are administered depending on the individual tolerability.; Other Names: ACT-293987; Uptravi
Placebo Comparator: Placebo; Regimen and titration scheme similar to those in the selexipag group	Drug: Placebo; Matching film coated tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 24 in Actigraphy Assessed Daily Life Physical Activity (DLPA) for Variables Expressed in Minutes	Change from baseline to Week 24 of the DLPA activity parameters for daily time spent in non-sedentary activity (NSA) (as defined by Freedson '98 and Koster '16) and daily time spent in moderate-to-vigorous physical activity (MVPA) as defined by Freedson '98 were reported. These variables were assessed by actigraphy and were expressed in minutes. Freedson 1998 established ranges of activity counts obtained from a hip worn accelerometer corresponding to commonly employed MET categories. Based on this work, threshold between sedentary and NSA was defined. This threshold is often referred to as Freedson's 1998 publication. Koster 2016 defined the threshold between sedentary and NSA based on wrist-worn accelerometers on non-dominant hand, respectively. Positive change from baseline means improvement.	Baseline and Week 24 (data analysis was done during 14-Days each for Baseline and for Week 24 and mean value reported)
Change From Baseline to Week 24 in Actigraphy DLPA for Variables Expressed in Percentage (%)	Change from baseline to Week 24 of the DLPA activity parameters for daily time spent in non-sedentary activity (NSA) (Freedson '98), daily time spent in moderate-to-vigorous physical activity (MVPA) (Freedson '98) and dailytime spent in NSA (Koster '16) were reported. These variables were assessed by actigraphy and were expressed in percentage (%). Freedson 1998 established ranges of activity counts obtained from a hip worn accelerometer corresponding to commonly employed MET categories. Based on this work, threshold between sedentary and NSA was defined. This threshold is often referred to as Freedson's 1998 publication. Koster 2016 defined the threshold between sedentary and NSA based on wrist-worn accelerometers on non-dominant hand, respectively. Positive change from baseline means improvement.	Baseline and Week 24 (data analysis was done during 14-Days each for Baseline and for Week 24 and mean value reported)
Change From Baseline to Week 24 in Actigraphy DLPA for Variables Expressed in Counts Per Minute (Counts/Minute)	Change from baseline to Week 24 of the DLPA activity parameter for total daily activities and NSA (Koster '16) were reported. These variables were assessed by actigraphy and were expressed in counts/minutes. Koster 2016 defined the threshold between sedentary and NSA based on wrist-worn accelerometers on non-dominant hand, respectively. Positive change from baseline means improvement.	Baseline and Week 24 (data analysis was done during 14-Days each for Baseline and for Week 24 and mean value reported)
Change From Baseline to Week 24 in Actigraphy DLPA for Variables Expressed in Counts	Change from baseline to Week 24 of the DLPA activity parameters for volume of non-sedentary activity (Koster '16)were reported. These variables were assessed by actigraphy and were expressed in counts. Koster 2016 defined the threshold between sedentary and NSA based on wrist-worn accelerometers on non-dominant hand, respectively. Positive change from baseline means improvement.	Baseline and Week 24 (data analysis was done during 14-Days each for Baseline and for Week 24 and mean value reported)
Change From Baseline to Week 24 in Actigraphy DLPA for Variable Expressed in Step Counts	Change from baseline to Week 24 of the DLPA activity parameters for number of steps during awake time were reported. These variables were assessed by actigraphy and were expressed in step counts. Positive change from baseline means improvement.	Baseline and Week 24 (data analysis was done during 14-Days each for Baseline and for Week 24 and mean value reported)
Change From Baseline to Week 24 in Actigraphy DLPA for Variables Expressed in Step Counts/Minute	Change from baseline to Week 24 of the DLPA activity parameters for number of steps during awake time were reported. These variables were assessed by actigraphy and were expressed in step counts/minute. Positive change from baseline means improvement.	Baseline and Week 24 (data analysis was done during 14-Days each for Baseline and for Week 24 and mean value reported)
Change From Baseline to Week 24 in Total Sleep Time (TST)	TST (in minutes) was assessed by actigraphy.	Baseline and Week 24 (data analysis was done during 14-Days each for Baseline and for Week 24 and mean value reported)
Change From Baseline to Week 24 in Wake After Sleep Onset (WASO)	WASO (in minutes) was assessed by actigraphy.	Baseline and Week 24 (data collection was done during 14-Days each for Baseline and for Week 24)
Change From Baseline to Week 24 in Number of Awakenings	Number of awakenings was assessed by actigraphy.	Baseline and Week 24 (data collection was done during 14-Days each for Baseline and for Week 24)
Change From Baseline to Week 24 in Sleep Efficiency (SE)	SE (in percentage) was assessed by actigraphy. Sleep efficiency was defined as the TST divided by the time in bed (minutes) multiplied by 100. TST was the duration in minutes including REM sleep plus NREM sleep during the time spent in bed.	Baseline and Week 24 (data collection was done during 14-Days each for Baseline and for Week 24)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 24 in Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Score	PAH-SYMPACT has 2 main parts: symptoms (cardiopulmonary and cardiovascular) and impact (physical impacts and cognitive/emotional). The symptom part is a questionnaire completed daily for 7 consecutive days and contains 11 items. The impact part has a 7-day recall period and is completed on 7th day of symptoms questionnaire data collection period. It contains 11 items pertaining to impact of PAH. The average Cardiopulmonary Symptoms and cardiovascular symptoms domain scores are determined based on daily scores of 6 and 5 items, respectively, reported on a 5-point Likert scale with score range from 0=best to 4=worst. The Physical impacts and Cognitive/emotional domain consists of 7 items reported on a 5-point Likert scale (from 0 to 4). The value 0 = "not at all"/"with no difficulty at all" and value 4 = "very much"/"extremely"/ "not able at all". Mean value on each of 7-day period was calculated for each specific domain score and corresponding mean change from baseline was reported.	Baseline and Week 24
Number of Participants With Change From Baseline to Week 24 in World Health Organization Functional Class (WHO FC)	The WHO FC of pulmonary hypertension is a physical activity rating scale as follows: Class I (No limitation of physical activity); Class II (Slight limitation of physical activity); Class III (Marked limitation of physical activity); and Class IV (Inability to carry out any physical activity without symptoms). The change from baseline in WHO FC was classified into "Improved", "No change" and "Worsened" compared to baseline. Deterioration, No Change, and Improvement are based on shift of risk category (I, II, III, IV) from baseline in WHO Functional Class.	Baseline and Week 24
Change From Baseline to Week 24 in 6-Minute Walk Distance (6MWD)	The 6MWD was the total distance walked during 6 minutes. Mean change from baseline (distance walked at Week 24 minus distance walked at baseline) was reported.	Baseline and Week 24
Change From Baseline to Week 24 in Borg Dyspnea Score	The Borg dyspneas score was a self-rating scale to evaluate the severity of dyspnea (from 0 "no shortness of breath at all" to 10 "very, very severe / maximal") shortness of breath. It was completed immediately after the 6-minute walk test at Week 24 and at baseline. Mean change from baseline in scoring was reported.	Baseline and Week 24
Change From Baseline to Week 24 in N-Terminal Pro B-type Natriuretic Peptide (NT-proBNP)	Change from baseline to Week 24 in NT-pro BNP levels was reported. The negative change from baseline means improvement.	Baseline and Week 24

Collaborators and Investigators

• Sponsor: Actelion
• Investigators: Study Director: Thomas Pfister, Actelion

Publications and helpful links

General Publications

• Howard LS, Rosenkranz S, Frantz RP, Hemnes AR, Pfister T, Hsu Schmitz SF, Skara H, Humbert M, Preston IR. Assessing Daily Life Physical Activity by Actigraphy in Pulmonary Arterial Hypertension: Insights From the Randomized Controlled Study With Selexipag (TRACE). Chest. 2023 Feb;163(2):407-418. doi: 10.1016/j.chest.2022.08.2231. Epub 2022 Sep 8.

Study record dates

Study Major Dates

• Study Start (Actual): November 8, 2017
• Primary Completion (Actual): February 10, 2020
• Study Completion (Actual): February 10, 2020

Study Registration Dates

• First Submitted: March 6, 2017
• First Submitted That Met QC Criteria: March 13, 2017
• First Posted (Actual): March 14, 2017

Study Record Updates

• Last Update Posted (Actual): February 23, 2021
• Last Update Submitted That Met QC Criteria: February 4, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: physical activity; actigraphy; PAH-SYMPACT; daily life
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Antihypertensive Agents; Selexipag
• Other Study ID Numbers: AC-065A404

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No