Ignite Creation Date:
2024-05-06 @ 10:25 AM
Last Modification Date:
2024-10-26 @ 12:29 PM
Study NCT ID:
NCT03251872
Status:
TERMINATED
Last Update Posted:
2020-08-26
First Post:
2017-08-13
Brief Title:
Olaparib for PAH a Pilot Study
Sponsor:
Laval University
Organization:
Laval University
Study Overview
Official Title:
Olaparib for Pulmonary Arterial Hypertension a Pilot Clinical Study
Status:
TERMINATED
Status Verified Date:
2020-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
OPTION pilot trial merged with the new NCT03782818 - OPTION multicenter trial
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
OPTION-p
Brief Summary:
The main OBJECTIVE of this proposal is to extend our preclinical findings on the role of DNA damage and polyADP-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
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
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 monitoringwithdrawal 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
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 monitoringwithdrawal 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None