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Riociguat Versus Balloon Pulmonary Angioplasty in Non-operable Chronic thromboEmbolic Pulmonary Hypertension (RACE)

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ClinicalTrials.gov Identifier: NCT02634203
Recruitment Status : Recruiting
First Posted : December 17, 2015
Last Update Posted : November 20, 2017
Sponsor:
Collaborator:
Bayer
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:

"Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe form of pulmonary hypertension characterized by obstruction of the pulmonary vasculature by residual organized thrombi, leading to increased pulmonary vascular resistance (PVR), progressive pulmonary hypertension, and right failure.

In patients deemed operable, pulmonary endarterectomy (PEA) is the gold standard treatment and is the only potentially curative treatment. However, some patients are ineligible for surgery owing to occlusion of distal vessels. The best treatment option for these non-operable CTEPH patients is not yet established.


Condition or disease Intervention/treatment Phase
Chronic Thromboembolic Pulmonary Hypertension Procedure: Balloon Pulmonary Angioplasty (BPA) Drug: Riociguat Not Applicable

Detailed Description:
Currently, riociguat is the only drug approved in Europe and US for the treatment of non-operable CTEPH. However, medical therapy with riociguat does not address obstructive lesions. In this sense, another treatment option, balloon pulmonary angioplasty (BPA), began recently to gain widespread interest after development in several centers. This procedure uses the standard balloon angioplasty technique to dilate selected pulmonary arteries. The main aim is to reopen vessels occluded by webs and bands. Several teams, mainly from Japan, have reported their experiences with BPA for the treatment of non-operable CTEPH and demonstrated impressive decrease in pulmonary vascular resistance and improvement in functional status and exercise capacity with an acceptable procedure-related risk. Although BPA has never been prospectively evaluated, most of the leading CTEPH centers worldwide have currently added BPA to their therapeutic options. However, no randomized controlled trial comparing safety and efficacy of medical therapy with riociguat versus pulmonary balloon angioplasty has been performed so far. Therefore, the respective places of medical treatment and of BPA in the management of inoperable patients with CTEPH need to be further evaluated.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 124 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Riociguat Versus Balloon Pulmonary Angioplasty in Non-operable Chronic thromboEmbolic Pulmonary Hypertension
Study Start Date : January 2016
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : September 2019


Arm Intervention/treatment
Experimental: Balloon Pulmonary Angioplasty (BPA)
Non-operable patients with CTEPH allocated to BPA arm
Procedure: Balloon Pulmonary Angioplasty (BPA)
Balloon pulmonary angioplasty (BPA) will be done via femoral vein. 2 sessions will be performed during the same hospitalization following by additional sessions at an interval of 2-3 weeks until a mean PAP< 30 mmHg is achieved A pulmonary angiography and a right heart catheterization will be performed at each BPA session

Active Comparator: Riociguat
Non-operable patients with CTEPH allocated to Riociguat arm
Drug: Riociguat
The starting dose will be 1 mg three times daily as recommended. The dose will be titrated every 2 weeks according to the peripheral systolic pressure. Dose should be increased by 0.5 mg three times daily every two weeks to a maximum of 2.5 mg three times daily, if systolic blood pressure is ≥95 mmHg and the patient has no signs or symptoms of hypotension.
Other Name: Medical therapy with Riociguat




Primary Outcome Measures :
  1. Change from baseline in Pulmonary Vascular Resistance (PVR) [ Time Frame: Baseline and at 26 weeks ]

Secondary Outcome Measures :
  1. Change from Baseline in 6 Minute Walking Distance (6MWD) [ Time Frame: Baseline and at 26 weeks ]
  2. Change from Baseline in WHO functional class (FC) [ Time Frame: Baseline and at 26 weeks ]
  3. Change from Baseline in brain natriuretic peptide (BNP) [ Time Frame: Baseline and at 26 weeks ]
  4. Change from Baseline in Borg dyspnea score (measured at the end of the 6MWD Test [ Time Frame: Baseline and at 26 weeks ]
  5. Time To Clinical Worsening defined by the occurence of - Death (all-cause mortality or Lung - or Heart-lung transplantation - or Hospitalization due to persistent worsening of PH or - Start of PAH specific treatment [ Time Frame: Up to 26 weeks ]


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 18 to 80 years of age at Visit 1
  • CTEPH patients considered as non-operable but eligible for balloon pulmonary angioplasty and riociguat by the multidisciplinary meeting, with pulmonary vascular resistance > 320 dyn.sec.cm-5 and mean PAP > 25 mmHg and PWP (Pulmonary capillary Wedge Pressure) ≤ 15 mmHg measured at least 3 months after start of full anticoagulation.
  • The diagnosis of CTEPH must have been established based on 2 of the 3 following methods before study entry: ventilation-perfusion scan, pulmonary angiography, spiral-CT scan.
  • The diagnosis of inoperability must have been established based on spiral-CT scan and/or pulmonary angiography before study entry.
  • Unspecific treatments which may also be used for the treatment of pulmonary hypertension (PH) such as oral anticoagulants, diuretics, digitalis, calcium channel blockers or oxygen supplementation are permitted. However treatment with anticoagulants must have been started at least 3 months before Visit 1.
  • Specific PH treatments (bosentan, ambrisentan, macitentan, sildenafil, tadalafil, epoprostenol, treprostinil, iloprost) are not permitted at Visit 1.
  • Patients who fulfill criteria for a supplemental long-term oxygen therapy (PaO2 < 55 mmHg at rest) need to be supplied sufficiently before study entry. The amount of supplemental oxygen and the delivery method need to be stable for at least one month before Visit 1.
  • Right-heart catheterization results for the definite diagnosis of PH must not be older than 6 weeks at Visit 1 (will be considered as baseline values), must have been measured after at least 3 months of full anticoagulation, and must have been measured in the participating center under standardized conditions.
  • Women without childbearing potential defined as postmenopausal women aged 55 years or older, women with bilateral tubal ligation, women with bilateral ovariectomy, and women with hysterectomy can be included in the study. Women with childbearing potential can be included in the study only if a serological pregnancy test is negative and a combination of condoms with a safe and highly effective contraception method is used.
  • Patients who are able to understand and follow instructions and who are able to participate in the study for the entire period.
  • Patients must have given their written informed consent to participate in the study after having received adequate previous information and prior to any study-specific procedures.

Exclusion Criteria:

  • General non-inclusion criteria:

    • Participation in another clinical trial during the preceding 3 months.
    • Pregnant women, or breast feeding women, or women with childbearing potential not using a combination of condoms and a safe and highly effective contraception method
    • Patients with a medical disorder, condition, or history of such that would impair the patient's ability to participate or complete this study in the opinion of the investigator.
    • Patients with underlying medical disorders and anticipated life expectancy below 2 years (eg active cancer disease with localized and/or metastasized tumor mass).
    • Patients with a history of severe allergic-like reaction to intravascular administration of iodinated contrast media
    • Significant obstructive or restrictive lung disease (forced expiratory volume < 60% predicted and/or total lung capacity < 70% predicted).
    • Severe hepatic impairment (Child-Pugh C)
    • Left heart failure with an ejection fraction less than 40%
    • Severe proven or suspected coronary artery disease (symptomatic patients with Canadian Cardiovascular Society Angina Classification class 2-4, and/or requiring nitrates, and/or myocardial infarction within the last 3 months before Visit 1).
    • Severe renal insufficiency (glomerular filtration rate ≤ 30mL/min eg calculated based on the Cockcroft formula).
  • Non-inclusion criteria related to treatment by riociguat:

    • Patients with hypersensitivity to riociguat or any of the excipients.
    • Treatment with :

      • PDE-5 Inhibitors (eg Sildenafil or Tadalafil)
      • NO donors (eg Nitrates)
    • Strong multi pathway cytochrome P450 (CYP) and P-glycoprotein (P-gp) / breast cancer resistance protein (BCRP) inhibitors such as azole antimycotics (e.g. ketoconazole, itraconazole) or HIV protease inhibitors (e.g. ritonavir)
    • Systolic blood pressure <95mmHg
    • Patients with a history of life-threatening hemoptysis (>100 mL in 24 h) or who have previously undergone bronchial arterial embolization for hemoptysis
  • Non-inclusion criteria related to BPA:

    • Patients who could not remain in a supine position for at least 120 min for any reason.
    • Very distal CTEPH disease without stenosis, webs, or slits on CT scan and CTEPH disease with predominant complete occlusions of segmental or sub- segmental arteries (defined by the multidisciplinary meeting)
  • Patients with significant interstitial lung disease on High-resolution computed tomography (HRCT)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02634203


Contacts
Contact: Xavier JAIS, MD, PhDI xavier.jais@aphp.fr
Contact: Gérald SIMONNEAU, MD, PhDI gerald.simonneau@aphp.fr

Locations
France
AP-HP, Bicêtre Hospital Recruiting
Le Kremlin Bicetre, France, 94275
Contact: Xavier JAIS, MD, PhDI       xavier.jais@aphp.fr   
Contact: Gerald SIMONNEAU, MD, PhDI       gerald.simonneau@aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Bayer
Investigators
Principal Investigator: Xavier JAIS, MD, PhDI AP-HP, Bicêtre Hospital

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02634203     History of Changes
Other Study ID Numbers: AOM14123
First Posted: December 17, 2015    Key Record Dates
Last Update Posted: November 20, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Chronic Thromboembolic Pulmonary Hypertension
Balloon Pulmonary Angioplasty
Riociguat

Additional relevant MeSH terms:
Hypertension
Hypertension, Pulmonary
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases