Olaparib for PAH: a Pilot Study (OPTION-p)
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|ClinicalTrials.gov Identifier: NCT03251872|
Recruitment Status : Recruiting
First Posted : August 16, 2017
Last Update Posted : June 7, 2019
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.
|Condition or disease||Intervention/treatment||Phase|
|Pulmonary Arterial Hypertension||Drug: Olaparib||Early Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||6 participants|
|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)|
|Official Title:||Olaparib for Pulmonary Arterial Hypertension: a Pilot Clinical Study|
|Actual Study Start Date :||October 25, 2018|
|Estimated Primary Completion Date :||December 2019|
|Estimated Study Completion Date :||December 2019|
Experimental: Drug: Olaparib
Olaparib up to 400 mg BID (100 to 400 mg) for 16 weeks
Other Name: Lynparza
- 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
- 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
- 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.
- 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
- 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.
- 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.
- Quality of life - Clinical deterioration [ Time Frame: At baseline and week 16 ]Assessed using the CAMPHOR questionnaire
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): NCT03251872
|Contact: Steeve Provencher, MD, MSc||418-956-8711 ext email@example.com|
|Contact: Sarah Bernard, MSc||4186568711 ext firstname.lastname@example.org|
|Quebec City, Quebec, Canada, G1V 4G5|
|Contact: Luce Bouffard, RN 418-656-8711 ext 2449 email@example.com|
|Principal Investigator: Steeve Provencher, MD, MSc|
|Principal Investigator:||Steeve Provencher, MD, MSc||IUCPQ-UL|
|Principal Investigator:||Sébastien Bonnet, PhD, FAHA||IUCPQ-UL|