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NCT01560624: FREEDOM-EV

Phase III Clinical Worsening Study of UT-15C in Subjects With PAH Receiving Background Oral Monotherapy

Completed Phase 3 Results posted Last updated 13 February 2020
What this trial tests

Phase 3 trial testing Treprostinil Diolamine in Pulmonary Arterial Hypertension in 690 participants. Completed in 24 June 2018.

Timeline
26 June 2012
Primary endpoint
24 June 2018
24 June 2018

Quick facts

Lead sponsorUnited Therapeutics
PhasePhase 3
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingquadruple
Primary purposetreatment
Enrollment690
Start date26 June 2012
Primary completion24 June 2018
Estimated completion24 June 2018
Sites155 locations across Italy, Taiwan, Poland, South Korea, Denmark, Netherlands, Sweden, Mexico

Drugs / interventions tested

Conditions studied

Sponsor

United Therapeutics — full company profile →

Who can join

Adults 18 to 75, any sex, with Pulmonary Arterial Hypertension. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Time to First Clinical Worsening Event Primary · From randomization to approximately 4 years

Clinical worsening was assessed continuously from randomization until the subject's last study visit. Clinical worsening events were defined as death (all causes), hospitalizations due to worsening pulmonary arterial hypertension (PAH), initiation of an inhaled or infused prostacyclin (PGI2) for the treatment of worsening PAH, disease progression, or unsatisfactory long-term clinical response. All clinical worsening events reported by the study sites were reviewed by the Sponsor Medical Monitors. Once a clinical worsening event occurred, it was entered in the eCRF and a narrative was submitted

GroupValue95% CI
UT-15C60.58± 42.93
Placebo49.31± 46.28
Change in 6-Minute Walk Distance Secondary · From Baseline to Week 24

The intent of the 6-Minute Walk Test (6MWT) is to evaluate exercise capacity associated with carrying out activities of daily living. A baseline 6MWT was performed prior to initiation of study drug on the day of randomization. 6MWTs were conducted at Weeks 4, 8, 12, 24, and every 12 weeks thereafter. The change between Baseline and Week 24 is reported.

Baseline
GroupValue95% CI
UT-15C392.9± 92.5
Placebo398.5± 100.00
Week 24
GroupValue95% CI
UT-15C395.4± 120.0
Placebo372.3± 163.0
Change in Plasma N-Terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 24 Secondary · From Baseline to Week 24

Plasma NT-proBNP concentration is a useful biomarker for the severity of PAH as it is associated with changes in right heart morphology and function. NT-proBNP sample collection occurred at Baseline (prior to starting study drug), Week 12, Week 24, the first Continued Visit, and every other Continued Visit thereafter (ie, Continued Visits 3, 5, 7, etc). NT-proBNP was also assessed at the Study Drug Termination Visit. The change between Baseline and Week 24 is reported.

GroupValue95% CI
UT-15C0.7859± 1.05470
Placebo1.1230± 1.05439
Change in World Health Organization Functional Class (WHO FC) From Baseline to Week 48 Secondary · Baseline to Week 48

The WHO FC for PAH was assessed at Baseline prior to starting study drug, at all subsequent scheduled study visits, and every time the 6MWT was performed for purposes of assessing clinical worsening status.

GroupValue95% CI
UT-15C46
Placebo38
UT-15C203
Placebo170
UT-15C66
Placebo103

Adverse events — posted to ClinicalTrials.gov

Time frame: The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

UT-15C
Serious: 116/346 (34%)
Deaths: 17/346
Placebo
Serious: 110/344 (32%)
Deaths: 18/344

Serious adverse events (187 terms)

ReactionSystemUT-15CPlacebo
Pulmonary hypertensionRespiratory, thoracic and mediastinal disorders
Right ventricular failureCardiac disorders
PneumoniaInfections and infestations
DyspnoeaRespiratory, thoracic and mediastinal disorders
Cardiac failureCardiac disorders
GastroenteritisInfections and infestations
Upper respiratory tract infectionInfections and infestations
Chest painGeneral disorders
BronchitisInfections and infestations
HeadacheNervous system disorders
Lung infectionInfections and infestations
HypotensionVascular disorders
SyncopeNervous system disorders
Cardiogenic shockCardiac disorders
Respiratory tract infectionInfections and infestations
SepsisInfections and infestations
HypoxiaRespiratory, thoracic and mediastinal disorders
Respiratory failureRespiratory, thoracic and mediastinal disorders
Septic shockInfections and infestations
Cardiac arrestCardiac disorders
Cardio-respiratory arrestRespiratory, thoracic and mediastinal disorders
HaemoptysisRespiratory, thoracic and mediastinal disorders
Acute kidney injuryRenal and urinary disorders
AppendicitisInfections and infestations
Atrial fibrillationCardiac disorders
Other adverse events (47 terms — click to expand)

ReactionSystemUT-15CPlacebo
HeadacheNervous system disorders
DiarrhoeaGastrointestinal disorders
FlushingVascular disorders
NauseaGastrointestinal disorders
VomitingGastrointestinal disorders
Upper respiratory tract infectionInfections and infestations
Oedema peripheralGeneral disorders
DizzinessNervous system disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
Pulmonary hypertensionRespiratory, thoracic and mediastinal disorders
CoughRespiratory, thoracic and mediastinal disorders
Pain in jawMusculoskeletal and connective tissue disorders
Pain in extremityMusculoskeletal and connective tissue disorders
Viral upper respiratory tract infectionInfections and infestations
MyalgiaMusculoskeletal and connective tissue disorders
PalpitationsCardiac disorders
FatigueGeneral disorders
Chest painGeneral disorders
ArthralgiaMusculoskeletal and connective tissue disorders
Abdominal pain upperGastrointestinal disorders
Decreased appetiteMetabolism and nutrition disorders
Back painMusculoskeletal and connective tissue disorders
EpistaxisRespiratory, thoracic and mediastinal disorders
Chest discomfortGastrointestinal disorders
Abdominal discomfortGastrointestinal disorders
Abdominal painGastrointestinal disorders
Abdominal distensionGastrointestinal disorders
PyrexiaGeneral disorders
Gastrooesophageal reflux diseaseGastrointestinal disorders
BronchitisInfections and infestations
HypotensionVascular disorders
AestheniaGeneral disorders
Right ventricular failureCardiac disorders
Muscle spasmsMusculoskeletal and connective tissue disorders
InsomniaPsychiatric disorders
DyspepsiaGastrointestinal disorders
SyncopeNervous system disorders
Nasal congestionRespiratory, thoracic and mediastinal disorders
RashSkin and subcutaneous tissue disorders
Oropharyngeal painRespiratory, thoracic and mediastinal disorders

Most-reported serious reactions: Pulmonary hypertension, Right ventricular failure, Pneumonia, Dyspnoea, Cardiac failure, Gastroenteritis, Upper respiratory tract infection, Chest pain.

Data from ClinicalTrials.gov NCT01560624 adverse events section.

Sponsor's own description

This is an international, multicenter, randomized, double-blind, placebo-controlled, event driven study in subjects with pulmonary arterial hypertension.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Combination Therapy with Oral Treprostinil for Pulmonary Arterial Hypertension. A Double-Blind Placebo-controlled Clinical Trial.
    White RJ, Jerjes-Sanchez C, Bohns Meyer GM, Pulido T, et al · · 2020 · cited 118× · PMID 31765604 · DOI 10.1164/rccm.201908-1640oc
  2. Recent advances in targeting the prostacyclin pathway in pulmonary arterial hypertension.
    Lang IM, Gaine SP. · · 2015 · cited 70× · PMID 26621977 · DOI 10.1183/16000617.0067-2015
  3. Oral treprostinil improves pulmonary vascular compliance in pulmonary arterial hypertension.
    Khan A, White RJ, Meyer G, Pulido Zamudio TR, et al · · 2022 · cited 14× · PMID 35134631 · DOI 10.1016/j.rmed.2022.106744
  4. Selexipag in the treatment of pulmonary arterial hypertension: design, development, and therapy.
    Hardin EA, Chin KM. · · 2016 · cited 12× · PMID 27895464 · DOI 10.2147/dddt.s103534
  5. The Changing Landscape of Pulmonary Arterial Hypertension in the Adult with Congenital Heart Disease.
    van Dissel AC, Mulder BJ, Bouma BJ. · · 2017 · cited 11× · PMID 28358329 · DOI 10.3390/jcm6040040
  6. Clinical use of extended-release oral treprostinil in the treatment of pulmonary arterial hypertension.
    Pugliese SC, Bull TM. · · 2016 · cited 8× · PMID 26869810 · DOI 10.2147/ibpc.s68230
  7. From short-term benefits to long-term outcomes: the evolution of clinical trials in pulmonary arterial hypertension.
    Chakinala MM, Barst R. · · 2013 · cited 7× · PMID 24618537 · DOI 10.1086/674456
  8. What's new in pulmonary hypertension clinical research: lessons from the best abstracts at the 2020 American Thoracic Society International Conference.
    Sweatt AJ, Reddy R, Rahaghi FN, Al-Naamani N, et al · · 2021 · cited 5× · PMID 34471517 · DOI 10.1177/20458940211040713

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