Efficacy and Tolerability of Subcutaneously Administered Treprostinil Sodium in Patients With Severe (Non-operable) Chronic Thromboembolic Pulmonary Hypertension (CTREPH) (CTREPH)
A Double Blind Controlled Clinical Study to Investigate the Efficacy and Tolerability of Subcutaneous Treprostinil Sodium in Patients With Severe Non-operable Chronic Thromboembolic Pulmonary Hypertension (CTREPH)
調査の概要
詳細な説明
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by non-resolving organized thromboembolic obstructing the pulmonary vascular bed. These thrombi are resistant to thrombolytic therapy and chronic plasmatic anticoagulation. An increase in pulmonary vascular resistance (PVR), right ventricular overload, and eventually right ventricular failure ensue.
The treatment of choice for CTEPH is pulmonary endarterectomy (PEA), providing a potential cure for the disease. However, about 50 % of patients are not candidates for surgery, mainly because of distal location of thromboemboli. Despite recent advances in the treatment of pulmonary arterial hypertension (PAH), medical treatments have not been recommended for inoperable CTEPH, because of the concept that a predominantly major vessel obstructive arteriopathy would not be suitable for vasodilators. Furthermore, a major drawback of i.v. prostacyclin therapy is the need for a permanent central venous access that increases the risk of infection (0.22-0.68 per patient per year), thrombosis and new major vessel thromboembolism.
研究の種類
入学 (実際)
段階
- フェーズ 3
連絡先と場所
研究場所
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Linz、オーストリア、4020
- Krankenhaus der Elisabethinen
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Vienna、オーストリア
- Medical University of Vienna AKH - Division Cardiology
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Prague、チェコ
- II. interní klinika Všeobecná fakultní nemocnice
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Dresden、ドイツ
- Medical University Carl Gustav Carus Medizinische Klinik und Poliklinik I Medizinische Fakultät der Technischen Universität Dresden
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Krakow、ポーランド、31-202
- Department of Cardiac and Vascular Diseases Centre for Rare Cardiovascular Diseases John Paul II Hospital
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Otwock、ポーランド、05-400
- NZOZ Europejskie Centrum Zdrowia Otwock
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参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
- Subject must be competent to understand the information given in the written informed consent and from the investigator and must sign and date the informed consent prior to any study mandated procedure.
- Subject must be at least 18 years of age and can be of any ethnical origin
- Women of child bearing potential must be surgically sterile or postmenopausal (amenorrhea for at least 12 months) or using an acceptable form of contraception. Reliable contraception is defined as a method which results in a low failure rate, i.e., less than 1% per year when used correctly such as, implants, injectables, oral contraceptive medications, sexual abstinence, or a vasectomised partner.
Subject must have a current diagnosis of CTEPH, as defined by the following criteria:
- A test result of perfusion scintigraphy and pulmonary angiography and/or multislice CT not older than 6 months, consistent with the diagnosis CTEPH. In case of recurrent PH after PEA, test results from before the surgery are acceptable if a typical specimen was harvested during PEA substantiating the diagnosis of CTEPH.
- A right heart catheterization, not older than 6 months, consistent with the diagnosis CTEPH but specifically with a mean pulmonary artery pressure (PAPm) of > 25 mmHg, and a PVR of > 300 dyn.s.cm-5
- At least three months of effective anticoagulation therapy (without improvement / to exclude subacute pulmonary emboli)
Subject must have CTEPH classified as severe, as defined by the following criteria:
- An un-encouraged 6MWT distance of between 150 and 400 meters
- Classification in the WHO/New York Heart Association (NYHA) functional class III or IV
The subject must not be suitable to undergo a PEA and is therefore defined as non-operable, due to at least one of the following reasons:
- Clot is not accessible
- Discrepancy between severity of PH and morphologic lesion
- Subject is not a good surgical candidate for other reasons:
PVR > 1500 dynes.s.cm-5 Age Comorbidity No functional lung parenchyma
- Unsuccessful PEA in the past with residual/recurrent CTEPH
- No consent for PEA given by subject
- Subject must be willing and able to follow all study procedures
Exclusion:
- Subject with any form of pulmonary arterial hypertension or any disease known to cause PAH (WHO Group I)
- Subjects with a total lung capacity (TLC) of < 70% predicted or a forced expiratory volume/forced vital capacity (FEV1/FVC < 50%)
- Subject who received any prostanoids, within the 30 days before screening or be scheduled to receive prostanoids during the course of the study
- Subject with a new type of chronic therapy (a different category of vasodilator or diuretic) for PAH added within the last month, except anticoagulants
- Subject with an increased risk for hemorrhage or stroke or with a major cardiovascular event during the past 6 months.
- Unstable subjects for any reason (according to the investigators discretion)
- Subject who received any investigational medication within 30 days prior to the screening visit of this study or be scheduled to receive another investigational drug during the course of this study
- Subject with a known intolerance to any drug relevant for this trial, especially to Treprostinil sodium or prostanoids
- Subject with a history or suspicion of non compliance
- Subject who has any musculoskeletal disease or any other disease that would limit ambulation
- Subject with other cardiovascular, liver, renal, hematologic, gastrointestinal immunologic, endocrine, metabolic, or central nervous system disease that, in the opinion of the investigator, may adversely affect the safety of the subject and /or efficacy of the study drug or limit the lifespan of the subject
- Female who is considering pregnancy or who is pregnant and/or lactating
- Subject who is an investigator or any other team member involved directly or indirectly in the conduct of the clinical study.
- Subject who is an inmate of a psychiatric ward, prison or is suspected not to be able to give consent of his free will
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：4倍
武器と介入
参加者グループ / アーム |
介入・治療 |
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アクティブコンパレータ：Treprostinil sodium low dose - Arm I
Arm I (low dose): Subject was treated with a low dose of Treprostinil sodium. Dose was escalated to an approximate target dose of 3 ng/kg/min after the first 12 weeks and was kept stable for another 12 weeks. Due to the predefined infusion rate setting schedule an interim dose of up to 6 ng/kg/min could be reached for few days at the end of the phases 1,2 and 3. This depended on the patient's exact weight and is caused by the limited infusion rate setting possibility of the infusion pump. |
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実験的：Treprostinil sodium high dose - Arm II
Subject was treated with a low dose of Treprostinil sodium. Dose was escalated to an approximate target dose of 3 ng/kg/min after the first 12 weeks and kept stable for another 12 weeks. Due to the predefined infusion rate setting schedule an interim dose of up to 6 ng/kg/min could be reached for few days at the end of the phases 1,2 and 3. This depended on the patient's exact weight and is caused by the limited infusion rate setting possibility of the infusion pump. |
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
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Change in 6-minute Walk Test Distance After 24 Weeks
時間枠：Baseline and 24 weeks
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To determine the effect of subcutaneous Treprostinil sodium on 6-minute walk test distance after 24 weeks in patients with severe non-operable chronic thromboembolic pulmonary hypertension severe (inoperable) Chronic Thromboembolic Pulmonary Hypertension Time frame of the 6-minute walk test: The 6-minute walk test was conducted at the following visits:
In case of missing values, Last-Observation-Carried-Forward imputation method was used. In such cases values documented at Visit 4 (day84) were used. |
Baseline and 24 weeks
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
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Number of Participants With Clinical Worsening
時間枠：12 weeks and 24 weeks
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Clinical worsening defined as a decrease of 6-minute walk test distance of more than 20% from baseline due to Chronic Thromboembolic Pulmonary Hypertension, decrease of New York Heart Association functional class, hospitalization with the requirement for additional Pulmonary Hypertension specific treatment and/or death due to worsening Chronic Thromboembolic Pulmonary Hypertension. Clinical Worsening was assessed after 12 weeks and 24 weeks, participants experiencing clinical worsening at any time-point are reported. |
12 weeks and 24 weeks
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Effect on Maximal Borg Score During 6-minutes Walk Test
時間枠：Baseline and 24 weeks
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The Borg scale was used for rating of dyspnea during 6-minutes walk test. The scale is defined from 0 to > 10 (upper bound) (0 = NOTHING AT ALL; 0.5 = VERY VERY SLIGHT (just noticeable); 1 = VERY SLIGHT; 2 = SLIGHT; 3 = MODERATE; 4 = SOMEWHAT SEVERE; 5 = SEVERE; 6-9 = VERY SEVERE; 10 = VERY VERY SEVERE (almost maximum); >10 MAXIMUM). As can be seen with the scale, the higher scale values represent a worse outcome. As no imputation rule applied only full-data sets were evaluated. Complete data sets were available for 48 patients randomized to high dose group and 48 patients in low dose group. |
Baseline and 24 weeks
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Change in WHO/NYHA (World Health Organization - New York Heart Association) Functional Class
時間枠：Baseline and 24 weeks
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Class I - Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or near syncope. Class II - Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope. Class III - Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain or near syncope Class IV - Patients with pulmonary hypertension in the inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity. |
Baseline and 24 weeks
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Effect on Quality of Life by the MINNESOTA Questionnaire
時間枠：Baseline and 24 weeks
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This questionnaire is composed of 21 questions relating to limitations in lifestyle associated with Heart Failure. Respondents use a 5-point scale that ranges from 0 (none) to 5 (too much), with a score of 0 representing no limitation and a score of 5 representing maximum limitation. The change in individual score sum was evaluated and is displayed in the results, with a possible range of 0-105. Higher values indicate more limitations in Quality of Life. As no imputation rule applied only full-data sets were evaluated. Complete data sets were available for 50 patients randomized to high dose group and 46 patients in low dose group. |
Baseline and 24 weeks
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Effect on N-terminal Pro-BNP Levels
時間枠：Baseline and 24 weeks
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baseline values, assessment after 12 and 24 weeks As no imputation rule applied only full-data sets were evaluated. Complete data sets were available for 46 patients randomized to high dose group and 46 patients in low dose group. |
Baseline and 24 weeks
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Effect on Hemodynamic Parameter (PVR - Pulmonary Vascular Resistance)
時間枠：Baseline and 24 weeks
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baseline values, assessment after 24 weeks As no imputation rule applied only full-data sets were evaluated. Complete data sets were available for 48 patients randomized to high dose group and 47 patients in low dose group. |
Baseline and 24 weeks
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Effect on Hemodynamic Parameter (CI - Cardiac Index)
時間枠：Baseline and 24 weeks
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baseline values, assessment after 24 weeks As no imputation rule applied only full-data sets were evaluated. Complete data sets were available for 48 patients randomized to high dose group and 47 patients in low dose group. |
Baseline and 24 weeks
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Effect on Hemodynamic Parameter (CO - Cardiac Output)
時間枠：Baseline and 24 weeks
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baseline values, assessment after 24 weeks As no imputation rule applied only full-data sets were evaluated. Complete data sets were available for 48 patients randomized to high dose group and 47 patients in low dose group. |
Baseline and 24 weeks
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Effect on Hemodynamic Parameter (mPAP - Mean Pulmonary Arterial Pressure)
時間枠：Baseline and 24 weeks
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baseline values, assessment after 24 weeks As no imputation rule applied only full-data sets were evaluated. Complete data sets were available for 47 patients randomized to high dose group and 47 patients in low dose group. |
Baseline and 24 weeks
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Effect on Hemodynamic Parameter (mRap - Mean Right Atrial Pressure)
時間枠：Baseline and 24 weeks
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baseline values, assessment after 24 weeks As no imputation rule applied only full-data sets were evaluated. Complete data sets were available for 48 patients randomized to high dose group and 47 patients in low dose group. |
Baseline and 24 weeks
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Effect on Signs & Symptoms of the CTEPH
時間枠：Baseline and 24 weeks
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baseline values, assessment after 24 weeks
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Baseline and 24 weeks
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協力者と研究者
スポンサー
捜査官
- 主任研究者：Irene Lang, MD、Medical University Vienna
出版物と役立つリンク
一般刊行物
- Kuhn KP, Byrne DW, Arbogast PG, Doyle TP, Loyd JE, Robbins IM. Outcome in 91 consecutive patients with pulmonary arterial hypertension receiving epoprostenol. Am J Respir Crit Care Med. 2003 Feb 15;167(4):580-6. doi: 10.1164/rccm.200204-333OC. Epub 2002 Nov 21.
- Lang IM, Marsh JJ, Olman MA, Moser KM, Loskutoff DJ, Schleef RR. Expression of type 1 plasminogen activator inhibitor in chronic pulmonary thromboemboli. Circulation. 1994 Jun;89(6):2715-21. doi: 10.1161/01.cir.89.6.2715.
- Klepetko W, Mayer E, Sandoval J, Trulock EP, Vachiery JL, Dartevelle P, Pepke-Zaba J, Jamieson SW, Lang I, Corris P. Interventional and surgical modalities of treatment for pulmonary arterial hypertension. J Am Coll Cardiol. 2004 Jun 16;43(12 Suppl S):73S-80S. doi: 10.1016/j.jacc.2004.02.039.
- McLaughlin VV, Presberg KW, Doyle RL, Abman SH, McCrory DC, Fortin T, Ahearn G; American College of Chest Physicians. Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004 Jul;126(1 Suppl):78S-92S. doi: 10.1378/chest.126.1_suppl.78S.
- Sadushi-Kolici R, Jansa P, Kopec G, Torbicki A, Skoro-Sajer N, Campean IA, Halank M, Simkova I, Karlocai K, Steringer-Mascherbauer R, Samarzija M, Salobir B, Klepetko W, Lindner J, Lang IM. 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 Mar;7(3):239-248. doi: 10.1016/S2213-2600(18)30367-9. Epub 2018 Nov 23.
研究記録日
主要日程の研究
研究開始
一次修了 (実際)
研究の完了 (実際)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (見積もり)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
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Treprostinil sodiumの臨床試験
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Insmed Incorporated利用可能肺動脈高血圧 | 肺高血圧、間質性肺疾患