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Subcutaneous treprostinil for the treatment of severe non-operable chronic thromboembolic pulmonary hypertension (CTREPH): a double-blind, phase 3, randomised controlled trial.
Lancet Respir Med. 2019 03; 7(3):239-248.LR

Abstract

BACKGROUND

Treprostinil, a prostacyclin analogue, is effective for the treatment of pulmonary arterial hypertension. However, information is scarce regarding treprostinil for treatment of chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to examine the efficacy and safety of subcutaneous treprostinil in this setting.

METHODS

In this 24-week, randomised, double-blind controlled trial, we enrolled patients with CTEPH, classified as non-operable, or with persistent or recurrent pulmonary hypertension after pulmonary endarterectomy, in six European expert centres in Austria, Czech Republic, Germany, and Poland. Patients in WHO functional class III or IV with a 6-min walk distance of 150-400 m were randomly assigned at a 1:1 allocation ratio to continuous high-dose subcutaneous treprostinil (target dose around 30 ng/kg per min at week 12) or low-dose subcutaneous treprostinil (target dose around 3 ng/kg per min at week 12). The primary endpoint was the change from baseline in 6-min walk distance at week 24. All patients who received at least one dose of the study drug were included in the intention-to-treat efficacy and safety analyses based on assessment of adverse events. The trial was registered at ClinicalTrialsRegister.eu EudraCT number 2008-006441-10 and ClinicalTrials.gov, number NCT01416636.

FINDINGS

From March 9, 2009, to June 9, 2016, 105 patients were enrolled with 53 (50%) patients randomly assigned to high-dose and 52 (50%) patients to low-dose subcutaneous treprostinil. At week 24, marginal mean 6-min walk distance improved by 44·98 m (95% CI 27·52 to 62·45) in the high-dose group, and by 4·29 m (95% CI -13·34 to 21·92) in the low-dose group (treatment effect 40·69 m, 95% CI 15·86 to 65·53, p=0·0016). 12 serious adverse events were reported in ten (19%) of 52 patients from the low-dose group and 16 serious adverse events were reported in nine (17%) of 53 patients from the high-dose group. The most common treatment-related adverse events in both groups were infusion site pain and other infusion site reactions.

INTERPRETATION

Treatment with subcutaneous treprostinil was safe, and improved exercise capacity in patients with severe CTEPH. Subcutaneous treprostinil provides a parenteral treatment option for patients of WHO functional class III or IV and those who do not tolerate other therapies or need combination treatment.

FUNDING

SciPharm Sàrl.

Authors+Show Affiliations

Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.Clinical Department of Cardiology and Angiology of the 2nd Department of Medicine, General University Hospital, Prague, Czech Republic.Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, Centre for Rare Cardiovascular Diseases, John Paul II Hospital, Krakow, Poland.Department of Pulmonary Circulation and Thromboembolic Diseases, European Health Center, Otwock, Poland.Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.Department of Internal Medicine I, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.Department of Cardiology and Angiology of Medical Faculty, Slovak Medical University and National Institute of Cardiovascular Diseases, Bratislava, Slovakia.Department of Pulmonology, Semmelweis University, Budapest, Hungary.Department of Internal Medicine II, Ordensklinikum Linz Elisabethinen, Linz, Austria.Department of Pulmonary Diseases, Klinički Bolnički Centar Zagreb, Zagreb, Croatia.Department of Pulmonary Diseases and Allergy, Ljubljana University Medical Centre, Ljubljana, Slovenia.Department of Cardiothoracic Surgery, Medical University of Vienna, Vienna, Austria.Clinical Department of Cardiology and Angiology of the 2nd Department of Medicine, General University Hospital, Prague, Czech Republic.Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria. Electronic address: irene.lang@meduniwien.ac.at.

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30477763

Citation

Sadushi-Kolici, Roela, et al. "Subcutaneous Treprostinil for the Treatment of Severe Non-operable Chronic Thromboembolic Pulmonary Hypertension (CTREPH): a Double-blind, Phase 3, Randomised Controlled Trial." The Lancet. Respiratory Medicine, vol. 7, no. 3, 2019, pp. 239-248.
Sadushi-Kolici R, Jansa P, Kopec G, et al. Subcutaneous treprostinil for the treatment of severe non-operable chronic thromboembolic pulmonary hypertension (CTREPH): a double-blind, phase 3, randomised controlled trial. Lancet Respir Med. 2019;7(3):239-248.
Sadushi-Kolici, R., Jansa, P., Kopec, G., Torbicki, A., Skoro-Sajer, N., Campean, I. A., Halank, M., Simkova, I., Karlocai, K., Steringer-Mascherbauer, R., Samarzija, M., Salobir, B., Klepetko, W., Lindner, J., & Lang, I. M. (2019). Subcutaneous treprostinil for the treatment of severe non-operable chronic thromboembolic pulmonary hypertension (CTREPH): a double-blind, phase 3, randomised controlled trial. The Lancet. Respiratory Medicine, 7(3), 239-248. https://doi.org/10.1016/S2213-2600(18)30367-9
Sadushi-Kolici R, et al. Subcutaneous Treprostinil for the Treatment of Severe Non-operable Chronic Thromboembolic Pulmonary Hypertension (CTREPH): a Double-blind, Phase 3, Randomised Controlled Trial. Lancet Respir Med. 2019;7(3):239-248. PubMed PMID: 30477763.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Subcutaneous treprostinil for the treatment of severe non-operable chronic thromboembolic pulmonary hypertension (CTREPH): a double-blind, phase 3, randomised controlled trial. AU - Sadushi-Kolici,Roela, AU - Jansa,Pavel, AU - Kopec,Grzegorz, AU - Torbicki,Adam, AU - Skoro-Sajer,Nika, AU - Campean,Ioana-Alexandra, AU - Halank,Michael, AU - Simkova,Iveta, AU - Karlocai,Kristof, AU - Steringer-Mascherbauer,Regina, AU - Samarzija,Miroslav, AU - Salobir,Barbara, AU - Klepetko,Walter, AU - Lindner,Jaroslav, AU - Lang,Irene M, Y1 - 2018/11/23/ PY - 2018/06/30/received PY - 2018/08/20/revised PY - 2018/08/21/accepted PY - 2018/11/28/pubmed PY - 2020/4/16/medline PY - 2018/11/28/entrez SP - 239 EP - 248 JF - The Lancet. Respiratory medicine JO - Lancet Respir Med VL - 7 IS - 3 N2 - BACKGROUND: Treprostinil, a prostacyclin analogue, is effective for the treatment of pulmonary arterial hypertension. However, information is scarce regarding treprostinil for treatment of chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to examine the efficacy and safety of subcutaneous treprostinil in this setting. METHODS: In this 24-week, randomised, double-blind controlled trial, we enrolled patients with CTEPH, classified as non-operable, or with persistent or recurrent pulmonary hypertension after pulmonary endarterectomy, in six European expert centres in Austria, Czech Republic, Germany, and Poland. Patients in WHO functional class III or IV with a 6-min walk distance of 150-400 m were randomly assigned at a 1:1 allocation ratio to continuous high-dose subcutaneous treprostinil (target dose around 30 ng/kg per min at week 12) or low-dose subcutaneous treprostinil (target dose around 3 ng/kg per min at week 12). The primary endpoint was the change from baseline in 6-min walk distance at week 24. All patients who received at least one dose of the study drug were included in the intention-to-treat efficacy and safety analyses based on assessment of adverse events. The trial was registered at ClinicalTrialsRegister.eu EudraCT number 2008-006441-10 and ClinicalTrials.gov, number NCT01416636. FINDINGS: From March 9, 2009, to June 9, 2016, 105 patients were enrolled with 53 (50%) patients randomly assigned to high-dose and 52 (50%) patients to low-dose subcutaneous treprostinil. At week 24, marginal mean 6-min walk distance improved by 44·98 m (95% CI 27·52 to 62·45) in the high-dose group, and by 4·29 m (95% CI -13·34 to 21·92) in the low-dose group (treatment effect 40·69 m, 95% CI 15·86 to 65·53, p=0·0016). 12 serious adverse events were reported in ten (19%) of 52 patients from the low-dose group and 16 serious adverse events were reported in nine (17%) of 53 patients from the high-dose group. The most common treatment-related adverse events in both groups were infusion site pain and other infusion site reactions. INTERPRETATION: Treatment with subcutaneous treprostinil was safe, and improved exercise capacity in patients with severe CTEPH. Subcutaneous treprostinil provides a parenteral treatment option for patients of WHO functional class III or IV and those who do not tolerate other therapies or need combination treatment. FUNDING: SciPharm Sàrl. SN - 2213-2619 UR - https://www.unboundmedicine.com/medline/citation/30477763/Subcutaneous_treprostinil_for_the_treatment_of_severe_non_operable_chronic_thromboembolic_pulmonary_hypertension__CTREPH_:_a_double_blind_phase_3_randomised_controlled_trial_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2213-2600(18)30367-9 DB - PRIME DP - Unbound Medicine ER -