Upfront Combination Pulmonary Arterial Hypertension Therapy

Upfront Riociguat and Ambrisentan Combination Therapy for Pulmonary Arterial Hypertension: A Safety and Efficacy Pilot Study

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

Study Overview

• Status: Unknown
• Conditions: Pulmonary Hypertension
• Intervention / Treatment: Drug: Riociguat Oral Product

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: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Naushad Hirani, MD; Phone Number: 403 943 4759
• Study Contact Backup: Name: Jean Marks, BN; Phone Number: (403) 943 4759; Email: jean.marks@ahs.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T1Y 6J4
      • Recruiting
      • Peter Lougheed Center
      • Contact: Naushad Hirani, MD; Phone Number: 403 943 4759
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Recruiting
      • Vancouver General Hospital, The Lung Centre
      • Contact: John Swiston, MD; Phone Number: (604) 875 4122; Email: swiston@mail.ubc.ca
      • Contact: Mami Okada; Phone Number: 69831 (604) 875 4111; Email: mami.okada@vch.ca
      • Sub-Investigator: John Swiston, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: Ambrisentan Oral Product

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulmonary Vascular resistance	Change from baseline to month 4 and month 12 in pulmonary vascular resistance (PVR) as assessed by Right Heart Catheterization.	4 and 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hemodynamic Variables	Change in hemodynamic variables (mPAP, RAP, CI) from baseline to month 4 and month 12 as assessed by Right Heart Catheterization.	4 and 12 months
Echocardiographic parameters	Change in echocardiographic parameters (TAPSE, RV strain, Tei index, Left ventricular Eccentricity index, RV:LV area ratio) as assessed by Echocardiogram.	4 and 12 months
RV function	Change from baseline to month 4 in RV function as assessed by cardiac MRI.	4 and 12 months
NT-PRo-BNP	Change from baseline NT-PRo-BNP value from baseline to month 4 and month 12	4 and 12 Months
Exercise capacity	Change from baseline to month 4 and month 12 in exercise capacity assessed by the 6 minute walk test	4 and 12 months
Dyspnea	Change from baseline to month 4 and month 12 in dyspnea as assessed by study questionnaire.	4 and 12 months
Quality of Life Assessment	Change from baseline to month 4 and month 12 in quality of life as assessed by study questionnaire.	4 and 12 months
Functional Class	Change from baseline to month 4 and month 12 in functional class as assessed by study questionnaire.	4 and 12 months
Survival	Survival at 12 months	12 months
Clinical worsening	Time to clinical worsening over 12 months	12 months

Collaborators and Investigators

• Sponsor: University of Calgary
• Collaborators: Bayer
• Investigators: Principal Investigator: Naushad Hirani, MD, University of Calgary

Study record dates

Study Major Dates

• Study Start (Actual): April 26, 2016
• Primary Completion (Anticipated): December 31, 2020
• Study Completion (Anticipated): January 31, 2021

Study Registration Dates

• First Submitted: January 9, 2019
• First Submitted That Met QC Criteria: January 15, 2019
• First Posted (Actual): January 18, 2019

Study Record Updates

• Last Update Posted (Actual): March 26, 2020
• Last Update Submitted That Met QC Criteria: March 24, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Pulmonary Hypertension
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Activators; Riociguat; Ambrisentan
• Other Study ID Numbers: 15-3056

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No