Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 4 of 32 for:    Recruiting, Active, not recruiting, Enrolling by invitation Studies | Pulmonary Hypertension | Canada

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03251872
Recruitment Status : Recruiting
First Posted : August 16, 2017
Last Update Posted : June 7, 2019
Sponsor:
Information provided by (Responsible Party):
Steeve Provencher, Laval University

Tracking Information
First Submitted Date  ICMJE August 13, 2017
First Posted Date  ICMJE August 16, 2017
Last Update Posted Date June 7, 2019
Actual Study Start Date  ICMJE October 25, 2018
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 13, 2017)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures
 (submitted: July 26, 2018)
  • 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
Original Other Pre-specified Outcome Measures
 (submitted: August 13, 2017)
  • 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 [ Time Frame: At baseline and week 16 ]
    Assessed using the CAMPHOR questionnaire
 
Descriptive Information
Brief Title  ICMJE Olaparib for PAH: a Pilot Study
Official Title  ICMJE Olaparib for Pulmonary Arterial Hypertension: a Pilot Clinical Study
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.

Detailed Description

BACKGROUND PAH is a progressive and multifactorial condition characterized by the chronic elevation of pulmonary artery (PA) pressure leading to RV failure. In spite of currently approved therapies, patients with PAH have poor quality of life and the 3-year survival of idiopathic PAH remains ~55%. The identification and characterization of new therapeutic targets is thus an urgent need.

In recent years, it has become increasingly appreciated that, as in cancer cells, PAH-PA smooth muscle cells (PASMCs) are exposed to stressful conditions, jeopardizing their survival. To deal with these insults, these cells have developed complementary pathways, allowing them to survive and proliferate and leading to intense remodelling of distal PA. Central to these strategies are the activation of the DNA repair machinery. Survival of these cells is associated with an over-efficient activation of PAPR1, a predominant mechanism involved in DNA repair, and pharmacological inhibition of PARP1 reverses PAH in human cells and clinically relevant animal models.

Recently, Olaparib, an orally available PARP1 inhibitor, was shown to be safe, well tolerated and effective in treating cancers and was approved for the treatment of ovarian cancer.

OLAPARIB IN PAH: A PILOT STUDY The study population will include 6 well-characterized PAH patients that have been stable for >4 months on standard PAH-therapies, as per guidelines.

The primary objective of the study is to confirm the feasibility for a future early stage clinical trial and provide early evidence that Olaparib may be effective in PAH.

Exploratory efficacy end-point: The exploratory efficacy endpoint will be the change in pulmonary vascular resistance (PVR) at week 16. Other exploratory efficacy end-points will include changes in: 1) additional haemodynamic data by catheterization; 2) 6-min walk distance (6MWD); 3) RV volumes and mass (cardiac MRI) in eligible patients; 4) WHO functional class; 5) NT-proBNP levels; 6) Quality of life assessed using the CAMPHOR questionnaire.

Study design: This is a standard-design, dose-escalating pilot study. In line with most pilot and safety studies, 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. Patients will be regularly followed. At baseline and week 16, a cardiac catheterization and MRI will assess changes in pulmonary hemodynamics and RV function.

Toxicity monitoring/withdrawal: Based on experience to date with olaparib, doses up to 400mg BID should be tolerated. Subjects may experience mild side effects or other events that the investigator may consider related to study drug but not of sufficient clinical significance to warrant withdrawal from treatment. At the investigators' discretion, olaparib may be managed by dose reduction. If the lower dose is not tolerated, the patient will be withdrawn from the study. Subjects who require a dose reduction should be maintained at the reduced dose level through to the end of the 16-week treatment period. Adverse events will be submitted to our ethics committees.

Analysis: This pilot study is not meant to prove efficacy. As a result, power calculations were not determined. The safety and exploratory endpoint analysis will be only descriptive. Nonetheless, it is hoped that olaparib will be associated with hemodynamic improvements, giving precision about the dose to be tested and sample size calculation for subsequent studies. Thus, there is a need for assessment of the exploratory efficacy endpoints. These analyses will be based on the per protocol set (all treated patients who did not violate the protocol in a way that might influence the evaluation of the effect of the study drug on the primary endpoint).

Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE 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
Condition  ICMJE Pulmonary Arterial Hypertension
Intervention  ICMJE Drug: Olaparib
Olaparib tablets
Other Name: Lynparza
Study Arms  ICMJE Experimental: Drug: Olaparib
Olaparib up to 400 mg BID (100 to 400 mg) for 16 weeks
Intervention: Drug: Olaparib
Publications *

*   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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 13, 2017)
6
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2019
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 dyn.s.cm-5 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Steeve Provencher, MD, MSc 418-956-8711 ext 4747 steve.provencher@criucpq.ulaval.ca
Contact: Sarah Bernard, MSc 4186568711 ext 3617 sarah.bernard@criucpq.ulaval.ca
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03251872
Other Study ID Numbers  ICMJE CER-21658
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 Not Provided
Responsible Party Steeve Provencher, Laval University
Study Sponsor  ICMJE Laval University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Steeve Provencher, MD, MSc IUCPQ-UL
Principal Investigator: Sébastien Bonnet, PhD, FAHA IUCPQ-UL
PRS Account Laval University
Verification Date June 2019

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