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Upfront Combination Pulmonary Arterial Hypertension Therapy

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ClinicalTrials.gov Identifier: NCT03809156
Recruitment Status : Recruiting
First Posted : January 18, 2019
Last Update Posted : January 18, 2019
Sponsor:
Collaborator:
Bayer
Information provided by (Responsible Party):
University of Calgary

Brief Summary:
To evaluate the safety and efficacy of first-line combination therapy using riociguat with ambrisentan in patients with Pulmonary Arterial Hypertension (PAH).

Condition or disease Intervention/treatment Phase
Pulmonary Hypertension Drug: Riociguat Oral Product Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Upfront Riociguat and Ambrisentan Combination Therapy for Pulmonary Arterial Hypertension: A Safety and Efficacy Pilot Study
Actual Study Start Date : April 26, 2016
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : January 31, 2020


Arm Intervention/treatment
Experimental: Combo Riociguat and Ambrisentan Therapy
Riociguat Oral Product and Ambrisentan Oral Product to be given in combination to de novo (untreated) patients.
Drug: Riociguat Oral Product
Dual therapy of Riociguat and Ambrisentan at initiation of treatment.
Other Name: Ambrisentan Oral Product




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. RV function [ Time Frame: 4 and 12 months ]
    Change from baseline to month 4 in RV function as assessed by cardiac MRI.

  4. NT-PRo-BNP [ Time Frame: 4 and 12 Months ]
    Change from baseline NT-PRo-BNP value from baseline to month 4 and month 12

  5. 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

  6. Dyspnea [ Time Frame: 4 and 12 months ]
    Change from baseline to month 4 and month 12 in dyspnea as assessed by study questionnaire.

  7. 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.

  8. 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.

  9. Survival [ Time Frame: 12 months ]
    Survival at 12 months

  10. Clinical worsening [ Time Frame: 12 months ]
    Time to clinical worsening over 12 months



Information from the National Library of Medicine

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

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.


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): NCT03809156


Contacts
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Contact: Naushad Hirani, MD 403 943 4759
Contact: Jean Marks, BN (403) 943 4759 jean.marks@ahs.ca

Locations
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Canada, Alberta
Peter Lougheed Center Recruiting
Calgary, Alberta, Canada, T1Y 6J4
Contact: Naushad Hirani, MD    403 943 4759      
Canada, British Columbia
Vancouver General Hospital, The Lung Centre Recruiting
Vancouver, British Columbia, Canada, V5Z 1M9
Contact: John Swiston, MD    (604) 875 4122    swiston@mail.ubc.ca   
Contact: Mami Okada    (604) 875 4111 ext 69831    mami.okada@vch.ca   
Sub-Investigator: John Swiston, MD         
Sponsors and Collaborators
University of Calgary
Bayer
Investigators
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Principal Investigator: Naushad Hirani, MD University of Calgary

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Responsible Party: University of Calgary
ClinicalTrials.gov Identifier: NCT03809156     History of Changes
Other Study ID Numbers: 15-3056
First Posted: January 18, 2019    Key Record Dates
Last Update Posted: January 18, 2019
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Calgary:
Pulmonary Hypertension
Additional relevant MeSH terms:
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Hypertension, Pulmonary
Hypertension
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Ambrisentan
Riociguat
Antihypertensive Agents
Enzyme Activators
Molecular Mechanisms of Pharmacological Action