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Upfront Combination Pulmonary Arterial Hypertension Therapy

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ClinicalTrials.gov Identifier: NCT03809156
Recruitment Status : Unknown
Verified March 2020 by University of Calgary.
Recruitment status was:  Recruiting
First Posted : January 18, 2019
Last Update Posted : March 26, 2020
Information provided by (Responsible Party):
University of Calgary

Tracking Information
First Submitted Date  ICMJE January 9, 2019
First Posted Date  ICMJE January 18, 2019
Last Update Posted Date March 26, 2020
Actual Study Start Date  ICMJE April 26, 2016
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 15, 2019)
Pulmonary Vascular resistance [ Time Frame: 4 and 12 months ]
Change from baseline to month 4 and month 12 in pulmonary vascular resistance (PVR) as assessed by Right Heart Catheterization.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 15, 2019)
  • Hemodynamic Variables [ Time Frame: 4 and 12 months ]
    Change in hemodynamic variables (mPAP, RAP, CI) from baseline to month 4 and month 12 as assessed by Right Heart Catheterization.
  • Echocardiographic parameters [ Time Frame: 4 and 12 months ]
    Change in echocardiographic parameters (TAPSE, RV strain, Tei index, Left ventricular Eccentricity index, RV:LV area ratio) as assessed by Echocardiogram.
  • RV function [ Time Frame: 4 and 12 months ]
    Change from baseline to month 4 in RV function as assessed by cardiac MRI.
  • NT-PRo-BNP [ Time Frame: 4 and 12 Months ]
    Change from baseline NT-PRo-BNP value from baseline to month 4 and month 12
  • Exercise capacity [ Time Frame: 4 and 12 months ]
    Change from baseline to month 4 and month 12 in exercise capacity assessed by the 6 minute walk test
  • Dyspnea [ Time Frame: 4 and 12 months ]
    Change from baseline to month 4 and month 12 in dyspnea as assessed by study questionnaire.
  • Quality of Life Assessment [ Time Frame: 4 and 12 months ]
    Change from baseline to month 4 and month 12 in quality of life as assessed by study questionnaire.
  • Functional Class [ Time Frame: 4 and 12 months ]
    Change from baseline to month 4 and month 12 in functional class as assessed by study questionnaire.
  • Survival [ Time Frame: 12 months ]
    Survival at 12 months
  • Clinical worsening [ Time Frame: 12 months ]
    Time to clinical worsening over 12 months
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Upfront Combination Pulmonary Arterial Hypertension Therapy
Official Title  ICMJE Upfront Riociguat and Ambrisentan Combination Therapy for Pulmonary Arterial Hypertension: A Safety and Efficacy Pilot Study
Brief Summary To evaluate the safety and efficacy of first-line combination therapy using riociguat with ambrisentan in patients with Pulmonary Arterial Hypertension (PAH).
Detailed Description This is a prospective, multi-center, open-label, exploratory study with patients followed for a period of one year. The treatment duration period in this study begins at the initiation of ambrisentan plus riociguat and will continue for 12 months. Patients will come to clinic for a visit at month 4 and 12. Assessments will include Right Heart Catheterization, 6 Minute walk test, cardiac MRI, questionnaires and nt-Pro-BNP.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Pulmonary Hypertension
Intervention  ICMJE Drug: Riociguat Oral Product
Dual therapy of Riociguat and Ambrisentan at initiation of treatment.
Other Name: Ambrisentan Oral Product
Study Arms  ICMJE Experimental: Combo Riociguat and Ambrisentan Therapy
Riociguat Oral Product and Ambrisentan Oral Product to be given in combination to de novo (untreated) patients.
Intervention: Drug: Riociguat Oral Product
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: January 15, 2019)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 31, 2021
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Signed informed consent prior to initiation of any study mandated procedure;
  2. Males or females ≥ 18 years of age i. Women of childbearing potential must have a negative pre-treatment pregnancy test and must use reliable methods of contraception.

    ii. Women not of childbearing potential are defined as postmenopausal (i.e., amenorrhea for at least 1 year), or documented surgically or naturally sterile.

  3. Patients with symptomatic Functional Class III PAH in the following categories:

    i. Idiopathic (IPAH) ii. Familial (FPAH) iii. Associated with connective tissue disease iv. Associated with drugs or toxins;

  4. PAH diagnosed by right heart catheterization, defined as:

    i. Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg ii. PVR > 3 mmHg/l/min (Wood units) or > 240 dyn sec cm-5 iii. Pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg;

  5. 150 m ≤ 6 Minute Walk Test (6MWT) distance ≤ 480 m

Exclusion Criteria:

  1. PAH associated with any other condition than those described in the inclusion criteria (patients with PAH associated with portal hypertension, HIV and CHD should not be included);
  2. PAH associated with thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders and splenectomy;
  3. Valvular disease with valvular lesions to be excluded by echocardiogram within 2 years prior to randomization (i.e., patients with tricuspid or pulmonary insufficiency secondary to PAH can be included);
  4. Restrictive lung disease: total lung capacity (TLC) < 60% of normal predicted value;
  5. Obstructive lung disease: forced expiratory volume/forced vital capacity (FEV1/FVC) < 0.5;
  6. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C;
  7. Pregnancy or breast-feeding;
  8. Systolic blood pressure < 95 mmHg;
  9. Body weight < 40 kg;
  10. Hemoglobin > 25% below the lower limit of the normal range;
  11. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal ranges;
  12. Renal insufficiency as defined by creatinine clearance < 30 mL/min or on dialysis
  13. Treatment with phosphodiesterase type 5 inhibitors, any prostanoid (excluding acute administration during a catheterization procedure to test vascular reactivity) or with any other PH specific medication;
  14. Treatment or planned treatment with calcineurin-inhibitors (i.e., cyclosporine A and tacrolimus), CYP2C9 and CYP3A4 inhibitors (i.e., ketoconazole, fluconazole) within 1 week of study start;
  15. Treatment or planned treatment with nitrate drugs, short acting nitrate-containing medications, alpha blockers or protease inhibitors (i.e., ritonavir);
  16. Known hypersensitivity to ambrisentan, riociguat or any of their excipients;
  17. Patients with any contraindication to riociguat treatment or ERA treatment
  18. Patients with syncope, a rapid rate of symptom progression or with high or rising nt-BNP levels in the judgment of the investigators
  19. Any contraindications specified in the product monographs of either ambrisentan or riociguat, including:

1. Patients at increased risk of hypotension with concomitant or underlying conditions such as coronary artery disease, hypovolemia, severe left ventricular outflow obstruction or autonomic dysfunction; patients with resting hypotension 2. Patients with history of serious hemoptysis or patients who have previously undergone bronchial arterial embolization 20. Patients with pulmonary veno-occlusive disease 21. Ongoing participation in any interventional clinical studies.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03809156
Other Study ID Numbers  ICMJE 15-3056
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party University of Calgary
Original Responsible Party Same as current
Current Study Sponsor  ICMJE University of Calgary
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Bayer
Investigators  ICMJE
Principal Investigator: Naushad Hirani, MD University of Calgary
PRS Account University of Calgary
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP