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Olaparib for PAH: a Pilot Study (OPTION-p)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03251872
Recruitment Status : Terminated (OPTION pilot trial merged with the new NCT03782818 - OPTION multicenter trial)
First Posted : August 16, 2017
Last Update Posted : August 26, 2020
Information provided by (Responsible Party):
Steeve Provencher, Laval University

Brief Summary:

The main OBJECTIVE of this proposal is to extend our preclinical findings on the role of DNA damage and poly(ADP-ribose) polymerases (PARP) inhibition as a therapy for a devastating disease, pulmonary arterial hypertension (PAH), to early-phase clinical trials. We, and others, have published strong evidence that DNA damage accounts for disease progression in PAH and showed that PARP1 inhibition can reverse PAH in several animal models1. Interestingly, PARP1 inhibition is also cardioprotective. Olaparib, an orally available PARP1 inhibitor, can reverse cancer growth in animals and humans with a good safety profile, and is now approved for the treatment of ovarian cancer in Canada, Europe and the USA. The time is thus right to translate our findings in human PAH. The industry-sponsored clinical research on PARP1 inhibitor is currently entirely cancer-oriented. Nonetheless, AstraZeneca Canada accepted to support an early phase clinical trial through in-kind contribution, but the support from foundations and federal agencies is critical to catalyze early-stage development of PARP1 inhibitors for other indications, especially for orphan diseases. A CIHR Project Scheme grant will thus be submitted on September 15 2017, proposing a Phase 1, followed by a Phase 2 trial that will be conducted in recognized PAH programs throughout Canada. At this stage, however, we propose a pilot study to assess the feasibility of the proposed trials in the PAH population. The overall HYPOTHESIS is that PARP1 inhibition with olaparib is a safe and effective therapy for PAH.

The primary objective of the study is to confirm feasibility, to support the safety of using olaparib in PAH patients, and precise the sample size of the coming Phase 1B trial. The feasibility of the comprehensive patient phenotyping that will be proposed within the phase 1B trial will thus be assessed, in addition to adverse events and efficacy signals.

***OPTION pilot trial was merged with the new OPTION multicenter trial (NCT03782818)***

Condition or disease Intervention/treatment Phase
Pulmonary Arterial Hypertension Drug: Olaparib Early Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: The design is open-label. A 4-week pre-treatment phase will allow ensuring that patients are on stable doses of medication. Patients will be given progressive doses of olaparib up to 400mg BID for 16 weeks.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Olaparib for Pulmonary Arterial Hypertension: a Pilot Clinical Study
Actual Study Start Date : October 25, 2018
Actual Primary Completion Date : December 1, 2019
Actual Study Completion Date : December 1, 2019

Arm Intervention/treatment
Experimental: Drug: Olaparib
Olaparib up to 400 mg BID (100 to 400 mg) for 16 weeks
Drug: Olaparib
Olaparib tablets
Other Name: Lynparza

Primary Outcome Measures :
  1. Change in pulmonary vascular resistance (PVR) at week 16 [ Time Frame: 16 weeks ]
    At baseline and week 16, a cardiac catheterization and MRI will assess changes in pulmonary hemodynamics and RV function

Other Outcome Measures:
  1. Additional haemodynamic data by catheterization [ Time Frame: At baseline and week 16 ]
    A cardiac catheterization and MRI will assess changes in pulmonary hemodynamics and RV function

  2. 6-min walk distance (6MWD) [ Time Frame: At baseline and week 16 ]
    The six-minute walk test (6MWT) measures the distance (6MWD) that a person can quickly walk on a flat, hard surface in 6 min.

  3. RV volumes and mass (cardiac MRI) [ Time Frame: At baseline and week 16 ]
    A cardiac catheterization and MRI will assess changes in pulmonary hemodynamics and RV function

  4. WHO functional class [ Time Frame: At baseline and week 16 ]
    Assesses the severity of the disease using a range of clinical assessments, exercise tests, biochemical markers, and echocardiographic and haemodynamic assessments. The clinical assessment of the patient has a pivotal role in the choice of the initial treatment, the evaluation of the response to therapy, and the possible escalation of therapy if needed. The clinical severity of PAH is classified by the World Health Organization (WHO) according to a system that grades PAH severity according to the functional status of the patient. The grades range from Functional Class (FC) I, where the patient's disease does not affect their day-to-day activities, to FC IV, where patients are severely functionally impaired, even at rest. This functional classification system links symptoms with activity limitations, and allows clinicians to quickly predict disease progression and prognosis, as well as the need for specific treatment regimens, irrespective of the underlying aetiology of PAH.

  5. NT-proBNP levels [ Time Frame: At baseline and week 16 ]
    Blood test. B-type natriuretic peptide (brain natriuretic peptide: BNP) is a small, ringed peptide secreted by the heart to regulate blood pressure and fluid balance. This peptide is stored in and secreted predominantly from membrane granules in the heart ventricles in a pro form (proBNP). Once released from the heart in response to ventricle volume expansion or pressure overload, the N-terminal (NT) piece of 76 amino acids (NT-proBNP) is rapidly cleaved by the enzymes corin and furin to release the active 32-amino acid peptide (BNP). Both BNP and NT-proBNP are markers of atrial and ventricular distension due to increased intracardiac pressure.

  6. Quality of life - Clinical deterioration [ Time Frame: At baseline and week 16 ]
    Assessed using the CAMPHOR questionnaire

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • 1) adults (18-75 yrs) with PAH of idiopathic/ hereditary/drug or toxin-induced origin or associated with connective tissue diseases; 2) mean PA pressure ≥25mmHg, PA wedge pressure ≤15mmHg, PVR >480 and absence of acute vasoreactivity (we expect PARP1 inhibition will be most effective in patients with significant PA remodelling); 3) WHO functional class II or III; 4) clinically stable with unchanged vasoactive therapy for ≥4 months; 5) two 6MWD of 150-550m and within ±15% of each other (the latter being used as baseline value); 6) a negative serum pregnancy test prior to receiving the first dose of study treatment and willing to use adequate contraception from enrolment through 3 months after the last dose of study treatment for patients of childbearing potential

Exclusion Criteria:

  • 1) other types of pulmonary hypertension; 2) significant restrictive (total lung capacity <60% predicted) or obstructive (FEV1/FVC<60% after a bronchodilator) lung disease; 3) systolic blood pressure <90 mmHg; 4) acute RV failure within the last 3 months; 5) received any investigational drug within 30 days; 6) BMI <18 or >40 kg/m2; 7) cardiopulmonary rehabilitation program planned or started ≤12 weeks prior to Day 1; 8) presence of ≥3 risk factors for heart failure with preserved ejection fraction (BMI >30 kg/m2, diabetes mellitus, hypertension or coronary artery disease); 9) organ dysfunction other than RV failure; 10) anticipated survival <1 year due to concomitant disease

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 identifier (NCT number): NCT03251872

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Canada, Quebec
Quebec City, Quebec, Canada, G1V 4G5
Sponsors and Collaborators
Laval University
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Principal Investigator: Steeve Provencher, MD, MSc IUCPQ-UL
Principal Investigator: Sébastien Bonnet, PhD, FAHA IUCPQ-UL
Additional Information:

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Responsible Party: Steeve Provencher, Professor, Laval University Identifier: NCT03251872    
Other Study ID Numbers: CER-21658
First Posted: August 16, 2017    Key Record Dates
Last Update Posted: August 26, 2020
Last Verified: August 2020

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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 Steeve Provencher, Laval University:
pulmonary arterial hypertension
poly (ADP-ribose) polymerases inhibition
PARP-1 inhibition
DNA damage
Early-phase clinical trial pilot study
Safety and efficacy
Additional relevant MeSH terms:
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Familial Primary Pulmonary Hypertension
Vascular Diseases
Cardiovascular Diseases
Hypertension, Pulmonary
Lung Diseases
Respiratory Tract Diseases
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents