Pulmonary Arterial HypertensionEarly Phase 1OPTION-pNCT03251872
Olaparib for PAH: a Pilot Study
A Early Phase 1 study testing Olaparib in people with Pulmonary Arterial Hypertension, run by Laval University at 1 site in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Pulmonary Arterial Hypertension
- What is being tested?
- Olaparib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteCanada
- Study dates
- 25 Oct 2018to 1 Dec 2019
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Olaparib for Pulmonary Arterial Hypertension: a Pilot Clinical Study
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)*
Read the 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).
- Conditions
- Pulmonary Arterial Hypertension
- Being tested
- Olaparib
- Keywords
- pulmonary arterial hypertension, PAH, poly (ADP-ribose) polymerases inhibition, PARP-1 inhibition, DNA damage, Early-phase clinical trial pilot study, Olaparib, Safety and efficacy
- Medical subject headings
- Pulmonary Arterial Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
OlaparibDrug
Also called Lynparza
Olaparib tablets
| Study group | Role | What they receive |
|---|---|---|
| Drug: Olaparib | Experimental | Olaparib up to 400 mg BID (100 to 400 mg) for 16 weeks Receives: Drug: Olaparib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in pulmonary vascular resistance (PVR) at week 16
At baseline and week 16, a cardiac catheterization and MRI will assess changes in pulmonary hemodynamics and RV function
Measured: 16 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Aug 2017
- Study start25 Oct 2018
- Primary completion1 Dec 2019
- Study completion1 Dec 2019
Why it stopped: OPTION pilot trial merged with the new NCT03782818 - OPTION multicenter trial
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (16)Papers the sponsor has linked to this study.
- Other trials for Pulmonary Arterial HypertensionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- 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)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Laval University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Steeve Provencher, Laval University
- Investigators
- Steeve Provencher, MD, MSc, Principal investigator, IUCPQ-ULSébastien Bonnet, PhD, FAHA, Principal investigator, IUCPQ-UL
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03251872
- Sponsor's protocol ID
- CER-21658
- Acronym
- OPTION-p
- Status last verified
- Aug 2020
- First submitted
- 13 Aug 2017
- Last updated
- 26 Aug 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Chen PI, Cao A, Miyagawa K, Tojais NF, Hennigs JK, Li CG, Sweeney NM, Inglis AS, Wang L, Li D, Ye M, Feldman BJ, Rabinovitch M. Amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension. JCI Insight. 2017 Jan 26;2(2):e90427. doi: 10.1172/jci.insight.90427.
PubMed 28138562de Jesus Perez VA, Yuan K, Lyuksyutova MA, Dewey F, Orcholski ME, Shuffle EM, Mathur M, Yancy L Jr, Rojas V, Li CG, Cao A, Alastalo TP, Khazeni N, Cimprich KA, Butte AJ, Ashley E, Zamanian RT. Whole-exome sequencing reveals TopBP1 as a novel gene in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2014 May 15;189(10):1260-72. doi: 10.1164/rccm.201310-1749OC.
PubMed 24702692Dedes KJ, Wetterskog D, Mendes-Pereira AM, Natrajan R, Lambros MB, Geyer FC, Vatcheva R, Savage K, Mackay A, Lord CJ, Ashworth A, Reis-Filho JS. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci Transl Med. 2010 Oct 13;2(53):53ra75. doi: 10.1126/scitranslmed.3001538.
PubMed 20944090Federici C, Drake KM, Rigelsky CM, McNelly LN, Meade SL, Comhair SA, Erzurum SC, Aldred MA. Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2015 Jul 15;192(2):219-28. doi: 10.1164/rccm.201411-2128OC.
PubMed 25918951Happe CM, Szulcek R, Voelkel NF, Bogaard HJ. Reconciling paradigms of abnormal pulmonary blood flow and quasi-malignant cellular alterations in pulmonary arterial hypertension. Vascul Pharmacol. 2016 Aug;83:17-25. doi: 10.1016/j.vph.2016.01.004. Epub 2016 Jan 22.
PubMed 26804008Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M, Langleben D, Manes A, Satoh T, Torres F, Wilkins MR, Badesch DB. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D42-50. doi: 10.1016/j.jacc.2013.10.032.
PubMed 24355641Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, Matei D, Macpherson E, Watkins C, Carmichael J, Matulonis U. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012 Apr 12;366(15):1382-92. doi: 10.1056/NEJMoa1105535. Epub 2012 Mar 27.
PubMed 22452356Li M, Vattulainen S, Aho J, Orcholski M, Rojas V, Yuan K, Helenius M, Taimen P, Myllykangas S, De Jesus Perez V, Koskenvuo JW, Alastalo TP. Loss of bone morphogenetic protein receptor 2 is associated with abnormal DNA repair in pulmonary arterial hypertension. Am J Respir Cell Mol Biol. 2014 Jun;50(6):1118-28. doi: 10.1165/rcmb.2013-0349OC.
PubMed 24433082Meloche J, Le Guen M, Potus F, Vinck J, Ranchoux B, Johnson I, Antigny F, Tremblay E, Breuils-Bonnet S, Perros F, Provencher S, Bonnet S. miR-223 reverses experimental pulmonary arterial hypertension. Am J Physiol Cell Physiol. 2015 Sep 15;309(6):C363-72. doi: 10.1152/ajpcell.00149.2015. Epub 2015 Jun 17.
PubMed 26084306Meloche J, Pflieger A, Vaillancourt M, Paulin R, Potus F, Zervopoulos S, Graydon C, Courboulin A, Breuils-Bonnet S, Tremblay E, Couture C, Michelakis ED, Provencher S, Bonnet S. Role for DNA damage signaling in pulmonary arterial hypertension. Circulation. 2014 Feb 18;129(7):786-97. doi: 10.1161/CIRCULATIONAHA.113.006167. Epub 2013 Nov 22.
PubMed 24270264Moudry P, Watanabe K, Wolanin KM, Bartkova J, Wassing IE, Watanabe S, Strauss R, Troelsgaard Pedersen R, Oestergaard VH, Lisby M, Andujar-Sanchez M, Maya-Mendoza A, Esashi F, Lukas J, Bartek J. TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity. J Cell Biol. 2016 Feb 1;212(3):281-8. doi: 10.1083/jcb.201507042. Epub 2016 Jan 25.
PubMed 26811421Park ES, Kang DH, Kang JC, Jang YC, Lee MJ, Chung HJ, Yi KY, Kim DE, Kim B, Shin HS. Cardioprotective effect of KR-33889, a novel PARP inhibitor, against oxidative stress-induced apoptosis in H9c2 cells and isolated rat hearts. Arch Pharm Res. 2017 May;40(5):640-654. doi: 10.1007/s12272-017-0912-3. Epub 2017 Apr 4.
PubMed 28378219Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014 Jun 20;115(1):165-75. doi: 10.1161/CIRCRESAHA.113.301141.
PubMed 24951765Ramsey BW, Nepom GT, Lonial S. Academic, Foundation, and Industry Collaboration in Finding New Therapies. N Engl J Med. 2017 May 4;376(18):1762-1769. doi: 10.1056/NEJMra1612575. No abstract available.
PubMed 28467868Ranchoux B, Meloche J, Paulin R, Boucherat O, Provencher S, Bonnet S. DNA Damage and Pulmonary Hypertension. Int J Mol Sci. 2016 Jun 22;17(6):990. doi: 10.3390/ijms17060990.
PubMed 27338373
Study at a glance
From the registry record, last updated by the sponsor on 26 Aug 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Olaparib for Pulmonary Arterial Hypertension: a Pilot Clinical Study
- ClinicalTrials.gov ID
- NCT03251872
- Acronym / sponsor ID
- OPTION-p / CER-21658
- Conditions
- Pulmonary Arterial Hypertension
- Keywords
- pulmonary arterial hypertension, PAH, poly (ADP-ribose) polymerases inhibition, PARP-1 inhibition, DNA damage, Early-phase clinical trial pilot study, Olaparib, Safety and efficacy
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: OPTION pilot trial merged with the new NCT03782818 - OPTION multicenter trial
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Laval UniversityUniversity, hospital or other
- Study start
- 25 Oct 2018 (actual)
- Primary completion
- 1 Dec 2019 (actual)
- Study completion
- 1 Dec 2019 (actual)
- First posted
- 16 Aug 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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)*
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- 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.
| Arm | Type | Receives |
|---|---|---|
| Drug: Olaparib | Experimental | Drug: OlaparibOlaparib up to 400 mg BID (100 to 400 mg) for 16 weeks |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- 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
Key exclusion criteria (1 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| OlaparibAlso: LynparzaOlaparib tablets | Drug | Drug: Olaparib |
Primary outcome
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
Results and safety
The study was stopped early (reason given: OPTION pilot trial merged with the new NCT03782818 - OPTION multicenter trial). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Aug 2020.
- Background: PubMed 28138562Chen PI, Cao A, Miyagawa K, Tojais NF, Hennigs JK, Li CG, Sweeney NM, Inglis AS, Wang L, Li D, Ye M, Feldman BJ, Rabinovitch M. Amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension. JCI Insight. 2017 Jan 26;2(2):e90427. doi: 10.1172/jci.insight.90427.
- Background: PubMed 24702692de Jesus Perez VA, Yuan K, Lyuksyutova MA, Dewey F, Orcholski ME, Shuffle EM, Mathur M, Yancy L Jr, Rojas V, Li CG, Cao A, Alastalo TP, Khazeni N, Cimprich KA, Butte AJ, Ashley E, Zamanian RT. Whole-exome sequencing reveals TopBP1 as a novel gene in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2014 May 15;189(10):1260-72. doi: 10.1164/rccm.201310-1749OC.
- Background: PubMed 20944090Dedes KJ, Wetterskog D, Mendes-Pereira AM, Natrajan R, Lambros MB, Geyer FC, Vatcheva R, Savage K, Mackay A, Lord CJ, Ashworth A, Reis-Filho JS. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci Transl Med. 2010 Oct 13;2(53):53ra75. doi: 10.1126/scitranslmed.3001538.
- Background: PubMed 25918951Federici C, Drake KM, Rigelsky CM, McNelly LN, Meade SL, Comhair SA, Erzurum SC, Aldred MA. Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2015 Jul 15;192(2):219-28. doi: 10.1164/rccm.201411-2128OC.
- Background: PubMed 26804008Happe CM, Szulcek R, Voelkel NF, Bogaard HJ. Reconciling paradigms of abnormal pulmonary blood flow and quasi-malignant cellular alterations in pulmonary arterial hypertension. Vascul Pharmacol. 2016 Aug;83:17-25. doi: 10.1016/j.vph.2016.01.004. Epub 2016 Jan 22.
- Background: PubMed 24355641Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M, Langleben D, Manes A, Satoh T, Torres F, Wilkins MR, Badesch DB. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D42-50. doi: 10.1016/j.jacc.2013.10.032.
- Background: PubMed 22452356Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, Matei D, Macpherson E, Watkins C, Carmichael J, Matulonis U. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012 Apr 12;366(15):1382-92. doi: 10.1056/NEJMoa1105535. Epub 2012 Mar 27.
- Background: PubMed 24433082Li M, Vattulainen S, Aho J, Orcholski M, Rojas V, Yuan K, Helenius M, Taimen P, Myllykangas S, De Jesus Perez V, Koskenvuo JW, Alastalo TP. Loss of bone morphogenetic protein receptor 2 is associated with abnormal DNA repair in pulmonary arterial hypertension. Am J Respir Cell Mol Biol. 2014 Jun;50(6):1118-28. doi: 10.1165/rcmb.2013-0349OC.
- Background: PubMed 26084306Meloche J, Le Guen M, Potus F, Vinck J, Ranchoux B, Johnson I, Antigny F, Tremblay E, Breuils-Bonnet S, Perros F, Provencher S, Bonnet S. miR-223 reverses experimental pulmonary arterial hypertension. Am J Physiol Cell Physiol. 2015 Sep 15;309(6):C363-72. doi: 10.1152/ajpcell.00149.2015. Epub 2015 Jun 17.
- Background: PubMed 24270264Meloche J, Pflieger A, Vaillancourt M, Paulin R, Potus F, Zervopoulos S, Graydon C, Courboulin A, Breuils-Bonnet S, Tremblay E, Couture C, Michelakis ED, Provencher S, Bonnet S. Role for DNA damage signaling in pulmonary arterial hypertension. Circulation. 2014 Feb 18;129(7):786-97. doi: 10.1161/CIRCULATIONAHA.113.006167. Epub 2013 Nov 22.
- Background: PubMed 26811421Moudry P, Watanabe K, Wolanin KM, Bartkova J, Wassing IE, Watanabe S, Strauss R, Troelsgaard Pedersen R, Oestergaard VH, Lisby M, Andujar-Sanchez M, Maya-Mendoza A, Esashi F, Lukas J, Bartek J. TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity. J Cell Biol. 2016 Feb 1;212(3):281-8. doi: 10.1083/jcb.201507042. Epub 2016 Jan 25.
- Background: PubMed 28378219Park ES, Kang DH, Kang JC, Jang YC, Lee MJ, Chung HJ, Yi KY, Kim DE, Kim B, Shin HS. Cardioprotective effect of KR-33889, a novel PARP inhibitor, against oxidative stress-induced apoptosis in H9c2 cells and isolated rat hearts. Arch Pharm Res. 2017 May;40(5):640-654. doi: 10.1007/s12272-017-0912-3. Epub 2017 Apr 4.
- OPTION pilot trial merged to a new multicenter trial (OPTION multicenter - NTC03782818)Link provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Steeve Provencher, MD, MSc principal investigator
IUCPQ-UL
Sébastien Bonnet, PhD, FAHA principal investigator
IUCPQ-UL
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Olaparib in people with Pulmonary Arterial Hypertension, run by Laval University at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 26 Aug 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: OPTION pilot trial merged with the new NCT03782818 - OPTION multicenter trial). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in pulmonary vascular resistance (PVR) at week 16 (time frame: 16 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03251872, which also lists 16 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Aug 2020.