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Pulmonary Arterial HypertensionPhase 1/2OPTIONNCT03782818

Olaparib for PAH: a Multicenter Clinical Trial

A Phase 1/2 study testing Olaparib in people with Pulmonary Arterial Hypertension, run by Laval University at 3 sites in Canada.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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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
Could I receive a placebo?
No, everyone receives an active treatment
How many people
17 participants
Where
3 sitesCanada
Study dates
20 Nov 2019to 31 Oct 2024
Phase
Phase 1/2
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

  • Informed consent:
  • Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
  • Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses.
  • Type of patient and disease characteristics:
  • PAH of idiopathic/ hereditary/drug or toxin-induced origin or associated with connective tissue diseases;
  • 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);
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  • WHO functional class II or III, which is the traditional inclusion criteria in all PAH RCT);
  • Clinically stable with unchanged vasoactive therapy for ≥4 months; 5) two 6MWD of ≥150m and within ±15% of each other (the latter being used as baseline value);
  • Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
  • Haemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days
  • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
  • Platelet count ≥ 100 x 109/L
  • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal
  • Patients must have creatinine clearance estimated of ≥51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test :
  • Estimated creatinine clearance =( [(140-age [years]) x weight (kg)] / [serum creatinine (mg/dL) x 72]) (x F); (where F=0.85 for females and F=1 for males).
  • Patients must have a life expectancy ≥ 28 weeks.
  • Weight: Body mass index (BMI) within the range 18-40 kg/m2 (inclusive).
  • Reproduction:
  • Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1.
  • Postmenopausal is defined as:
  • Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
  • Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post menopausal range for women under 50
  • surgical sterilisation (bilateral oophorectomy or hysterectomy)
  • Male patients must use a condom during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential.

Who cannot join

  • Medical conditions
  • Other types of pulmonary hypertension [130], including pulmonary related to left heart diseases (group 2), lung diseases (group 3) or chronic thromboembolic disease (group 4);
  • Significant restrictive (total lung capacity <60% predicted) or obstructive (FEV1/FVC<60% after a bronchodilator) lung disease;
  • Systolic blood pressure <90 mmHg;
  • Acute RV failure within the last 3 months;
  • Received any investigational drug within 30 days;
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  • Cardiopulmonary rehabilitation program planned or started ≤12 weeks prior to Day 1;
  • Presence of ≥3 risk factors for heart failure with preserved ejection fraction, including: - BMI >30 kg/m2, - Diabetes mellitus, - Hypertension, - Coronary artery disease;
  • Other organ dysfunction other than RV failure including Childs-Pugh class B-C liver cirrhosis;
  • Recent cancer (<1yr)
  • Recent bacterial infection (<30 days);
  • History of hypertensive crisis;
  • Stage ≥1 systemic hypertension, defined as a systolic blood pressure ≥140mmHg or a diastolic blood pressure ≥90mmHg, or requiring anti-hypertensive therapies;
  • Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
  • Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML.
  • Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
  • Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
  • Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
  • Patients with known active hepatitis (i.e. Hepatitis B or C). Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  • Prior/concomitant therapy
  • Any previous treatment with PARP inhibitor, including Olaparib.
  • Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.
  • Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort ) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
  • Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
  • Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
  • Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable, for timing refer to inclusion criteria no.7).
  • Prior/concurrent clinical study experience:
  • Participation in another clinical study with an investigational product administered in the last 3 months
  • Patients with a known hypersensitivity to olaparib or any of the excipients of the product.
  • Other exclusions
  • Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
  • Breast feeding women.
  • Lifestyle restrictions:
  • Meals and dietary restrictions: It is prohibited to consume grapefruit juice while on olaparib therapy.
  • Activity: Women of childbearing potential and their partners, who are sexually active, must agree to the use of TWO highly effective forms of contraception in combination. This should be started from the signing of the informed consent and continue throughout the period of taking study treatment and for at least 1 month after last dose of study drug(s), or they must totally/truly abstain from any form of sexual intercourse.
  • Male patients must use a condom during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential. Male patients should not donate sperm throughout the period of taking olaparib and for 3 months following the last dose of olaparib.
  • For details of acceptable methods of contraception refer to Appendix B Acceptable Birth Control Methods.

Trial locations and contacts

3 sites in 1 country.

Canada3 sites

  • University of Alberta Hospital

    Edmonton, Alberta, T6G 2B7

  • IUCPQ-UL

    Québec, Quebec, G1V4G5

  • UHN-Toronto General Hospital

    Toronto, Ontario, M5G 2C4

Other trials in Canada

About this study

Official title: Olaparib for Pulmonary Arterial Hypertension: a Multicenter Clinical Trial

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 primary objective of this Phase 1B study is to confirm the safety of using olaparib in PAH patients, and precise the sample size of a future Phase 2 trial. In addition to safety, efficacy signals will thus be assessed.

Read the detailed description

Overall, 20 well-characterized PAH patients that have been stable for >4 months on standard PAH-therapies, as per guidelines will be recruited. The initial Health Canada approval will be obtained. Olaparib will be provided by AstraZeneca Canada, but AZ had no input into the trial design and will not be involved in the conduct of the trial, analysis, interpretation of the results or the final manuscript.

A 4-week pre-treatment phase will allow ensuring that patients are on stable doses of PAH medication.

Given that PAH is a chronic disease and that patients may be at higher risk for drug-related adverse events (e.g. anemia), olaparib will be started at low-dose (100mg BID), then up-titrated weekly by 100mg BID up to 200mg BID (n=5, group 1) or 300mg BID (n=15, group 2) for a total treatment duration (including the up-titration phase) of 24 weeks. Using 100mg and 150mg tablets will allow minimizing the number of tablets taken (e.g. 2 x 150mg tablets BID) or adjusting the dose in case of drug-related adverse events (e.g. 250mg BID using 100mg and 150mg tablets).

Patients will be regularly followed to assess whether side effects are observed and whether olaparib can be up-titrated.

At baseline and week 24, a cardiac catheterization will assess changes in pulmonary hemodynamics and RV function.

An end-of-study visit is planned at week 28 week.

Being tested
Olaparib
Keywords
Pulmonary Arterial Hypertension, PAH, poly (ADP-ribose) polymerases inhibition, PARP-1 inhibition, DNA damage, Multicenter 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 up to 300 mg BID for 24 weeks

Study groups in NCT03782818
Study groupRoleWhat they receive
OlaparibExperimentalAfter a 4-week pre-treatment phase to ensure that patients are on stable doses of PAH medication, patients will be given progressive doses of olaparib up to 300 mg BID for 24 weeks.
Receives: Drug: Olaparib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Occurrence of treatment-emergent AEs at week 24

    Description of treatment-emergent AEs leading to premature discontinuation of the study treatment.

    Measured: Week 24

Secondary outcomes (4)

  1. 6-min walk test (6MWT)

    The 6-minute walk test (6MWT) is a non-encouraged test which measures the distance in meters covered over a 6-minute walk.

    Measured: At baseline and visits 1, 3, 4, 5 and 6.

  2. WHO functional class

    WHO FC is a classification, which reflects disease severity based on symptoms. It is also a clinically relevant marker of prognosis and functional status.

    Measured: At baseline and visits 1, 3, 4, 5, 6 and 7.

  3. NT-proBNP levels

    NT-proBNP correlates with severity of RV failure in PAH, elevated or increasing plasma levels being associated with a worse prognosis.

    Measured: At baseline and visits 1, 3, 4, 5 and 6.

  4. Health related Quality of Life (HRQoL)

    The CAMPHOR is a PAH-specific QoL measure validated for the Canadian English and French languages. It has been used in numerous PAH trials.

    Measured: Visit 1 and visit 6

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Dec 2018
  2. Study start20 Nov 2019
  3. Primary completion31 Oct 2024
  4. Study completion31 Oct 2024

Why it stopped: The recruitment was stopped on October 31st 2024 due to limited recruitment within the last year, as well as the end of funding (Spring 2025).

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
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 300mg BID for 24 weeks.
Masking
None (open label)
Enrolment
17 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03782818
Sponsor's protocol ID
CER-21724
Acronym
OPTION
Status last verified
Feb 2025
First submitted
17 Dec 2018
Last updated
12 Feb 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Chaturvedi G, Dubey N, Panchbhai P, Singh S, Singh R, Baitha U, Parakh N, Narang R, Yadav HN. Mitochondrial-ER crosstalk: An emerging mechanism in the pathophysiology of pulmonary arterial hypertension. Mitochondrion. 2026 Jan;86:102094. doi: 10.1016/j.mito.2025.102094. Epub 2025 Nov 10.

    PubMed 41223909

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Olaparib in people with Pulmonary Arterial Hypertension, run by Laval University at 3 sites 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 25 inclusion and 37 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 12 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites 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 combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

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: The recruitment was stopped on October 31st 2024 due to limited recruitment within the last year, as well as the end of funding (Spring 2025).). 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?

Occurrence of treatment-emergent AEs at week 24 (time frame: Week 24). 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 NCT03782818, which also lists 1 linked publication.

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 12 Feb 2025.

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