To explore the efficacy and safety of an oral IP receptor agonist in an inoperable or persistent/recurrent CTEPH population treated with standard of care.
ID
Source
Brief title
Condition
- Pulmonary vascular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary efficacy endpoint(s):
PVR (pulmonary vascular resistance) at Week 20, assessed at rest, within 2-5
hours post dose, expressed as a percent of baseline PVR.
Timepoint(s) of evaluation of this end point
Assessed at rest in screening period (Day -60 to Day -14; baseline) and
assessed at rest within 2-5 hours post-dose at Week 20 during
treatment period.
Secondary outcome
Secondary efficacy endpoints
1 Change from baseline in 6MWD to Week 26 (key secondary endpoint).
2 TTCW: Time to clinical worsening (according to the CHMP definition, (key
secondary endpoint) up to Week 52, defined as at least one of the following
components confirmed by the CEC when applicable:
All-cause death;
Non-planned PH-related hospitalization;
PH-related deterioration identified by at least one of the following:
Increase from baseline in WHO FC4
Deterioration by at least 15% in exercise capacity as measured by the 6MWD;
New Signs or symptoms of right heart failure defined as a reported AE with one
of the following preferred terms: *CTEPH*, *pulmonary hypertension*, *right
ventricular failure*, *right ventricular dysfunction* and *acute right
ventricular failure*.
The investigation of a composite endpoint that reflects the TTCW has been
encouraged by the European Medicines Agency.
3 All cause death or hospitalisations related to PH worsening
4 Proportion of subjects with improvement in WHO FC from baseline to Week 26.
5 Change from baseline to Week 26 in PAH-SYMPACT* cardiopulmonary symptom
domain and cardiovascular symptom domain.
6 Change from baseline to Week 26 in the Borg dyspnea index (BDI)/Borg CR10.
7 Change from baseline to Week 26 in NT-proBNP.
Safety endpoints
- Treatment-emergent adverse events (AEs)2 up to 3 days after study treatment
discontinuation at each analysis time point.
- Serious adverse events (SAEs) up to 30 days after study treatment
discontinuation at each analysis time point.
- AEs leading to premature discontinuation of study treatment at each analysis
time point.
- Change in vital signs (systolic and diastolic arterial blood pressure and
pulse rate) and body weight from baseline to all assessed time points during
the study at each analysis time point.
- Treatment-emergent marked laboratory abnormalities up to 3 days after study
treatment discontinuation as detailed in Appendix 2 at each analysis time point.
- Treatment-emergent AEs2 of special interest (e.g., hypotension, anemia,
hyperthyroidism) up to 3 days after study treatment discontinuation at each
analysis time point.
Timepoint(s) of evaluation of this end point
1. Week 26, 2. end of double blind treatment period, 3. end of double blind
treatment period, 4. Week 26, 5. Week 26, 6. Week 26, 7. Week 26
Background summary
CTEPH is an important cause of severe Pulmonary Hypertension and is associated
with significant deterioration of quality of life and increased
mortality/morbidity. This study will be the first global, randomized,
controlled study to explore the efficacy and safety of an oral IP receptor
agonist in an inoperable (i.e. technically inoeprable) or persistent/recurrent
after surgical and/or interventional treatment CTEPH population treated with
standard of care. This study will provide insight into the long-term outcomes
of an IP receptor agonist, in particular when added sequentially to therapies
acting on other pathogenic pathways.
The histopathologic findings, including endothelial cell dysfunction and distal
pulmonary arterial remodeling, between PAH and CTEPH closely resemble each
other [Humbert 2010, see reference in the protocol]. The rationale for this
study is therefore based on efficacy of PH-specific therapies such as riociguat
and macitentan in inoperable and persistent/recurrent CTEPH. Selexipag is an
orally available, selective and long-acting non-prostanoid agonist of the
prostacyclin receptor (IP receptor) having the unique advantage to target the
prostacyclin pathway for the treatment of PAH and may also be beneficial in
patients with CTEPH. The purpose of the study is to evaluate the efficacy of
selexipag in CTEPH.
Study objective
To explore the efficacy and safety of an oral IP receptor agonist in an
inoperable or persistent/recurrent CTEPH population treated with standard of
care.
Study design
A prospective, multi-center, randomized, double-blind, placebo controlled,
add-on to standard of care, parallel-group, group sequential, adaptive Phase 3
study with an open-label extension period.
Up to 280 subjects will be randomized in a 1:1 ratio to receive either
selexipag or placebo during the DB period. Subjects completing the DB period
will enter the open-label extension period and will receive selexipag.
Subjects will be recruited in two sequential cohorts. Approximately the first
90 randomized subjects will constitute the hemodynamic cohort who, in addition
to the overall study assessments, will undergo an RHC (and left heart
catheterization *LHC*, if needed) at Week 20. The remaining subjects will
constitute the non-hemodynamic cohort. Both cohorts are combined for the
evaluation of secondary efficacy endpoints, which do not require a
post-baseline hemodynamic assessment. Treatment allocation will be stratified
by treatment with PH-specific therapies (ie, endothelin receptor antagonists
[ERAs], phosphodiesterase type-5 inhibitor (PDE-5i), soluble guanylate cyclase
stimulator [riociguat]; one versus two versus naive [naive capped at 40%]) and
by CTEPH population (inoperable [with or without BPA] versus
persistent/recurrent after PEA [including PEA followed by BPA]).
The database will be locked and analyzed at five time points during the study:
• Time point 1: when approximately 90 randomized subjects, the hemodynamic
cohort, have completed the Week 20 RHC (and LHC, if needed) or prematurely
discontinued from the study, the final analysis for the PVR endpoint will be
performed by an Independent Statistical Analysis Center (ISAC) for the IDMC.
• Time point 2: when approximately 160 randomized subjects have completed the
Week 26 6MWD assessment or prematurely discontinued from the study, an interim
analysis (IA) for the 6MWD endpoint and the TTCW endpoint will be performed by
the ISAC for the IDMC.
• Time point 3: when all (up to 280) randomized subjects have completed the
Week 26 6MWD assessment or prematurely discontinued from the study, the final
analysis for the 6MWD endpoint and an IA for the TTCW endpoint will be
performed by the ISAC for the IDMC.
•Time point 4: when all (up to 280) randomized subjects have completed the DB
treatment period or the post-treatment observation period (PTOP) or prematurely
discontinued from the study, the DB database will be locked, the data extract
will be performed and unblinding will occur. The final analysis for all
endpoints will be performed by the sponsor.
• Time point 5: when all (up to 280) randomized subjects have performed their
End-of-Study (EOS) visit, an analysis including OL period data will be
performed by the sponsor.
Intervention
Investigational treatment:
Double-blind and open-label selexipag 200 µg, oral tablets in childproof
bottles, up-titrated to allow each subject to reach their individual maximum
tolerated dose (iMTD), in the range of 200 µg to 1600 µg twice daily (b.i.d.).
Depending on the iMTD, a single dose of double-blind and open-label study
treatment will consist of 1 to 8 tablets (200 µg to 1600 µg).
Comparator and/or placebo:
Matching placebo, b.i.d.
Study burden and risks
The histopathologic findings, including endothelial cell dysfunction and distal
pulmonary arterial remodeling, between PAH and CTEPH closely resemble each
other [Humbert 2010, see reference in the protocol]. The rationale for this
study is therefore based on efficacy of PH-specific therapies such as riociguat
and macitentan in inoperable and persistent/recurrent CTEPH. Selexipag is an
orally available, selective and long-acting non-prostanoid agonist of the
prostacyclin receptor (IP receptor) having the unique advantage to target the
prostacyclin pathway for the treatment of PAH and may also be beneficial in
patients with CTEPH. The purpose of the study is to evaluate the efficacy of
selexipag in CTEPH.
Side effects standard of care, side effects lumicitabine, side effects
assessments, unknown risks may occur. Safety and tolerability will be evaluated
throughout the study from signing of the informed consent form onwards until
the last study-related activity (end of study/early withdrawal).
An IDMC will be established to monitor the safety of subjects and will review
data in an unblinded manner on a regular basis to ensure the continuing safety
of the subjects enrolled in this study and to evaluate whether efficacy
objectives are met. The IDMC will review the data and make recommendations to
the Sponsor Committee, which will be responsible for identifying appropriate
actions based on the recommendations of the IDMC.
Any clinically relevant changes occurring during the study must be recorded in
the AE section of the eCRF.
Any clinically significant abnormalities persisting at the end of the
study/early withdrawal will be followed by the investigator until resolution or
until a clinically stable endpoint is reached. Safety assessments will be based
on medical review of AE reports and the results of vital sign measurements,
ECGs, physical examinations, clinical laboratory tests, and other safety
evaluations.
Gewerbestrasse 16
Allschwil CH-4123
CH
Gewerbestrasse 16
Allschwil CH-4123
CH
Listed location countries
Age
Inclusion criteria
1. Signed and dated ICF.
2. Male and female subjects >=18 (or the legal age of consent in the
jurisdiction in which the study is taking place) and <= 85 years old at
screening (visit 1)
3. Subjects with diagnosis of CTEPH and inoperability confirmed by the
corresponding adjudication committee (AC; country-specific adjudication
committee [CSAC] or
central adjudication committee [CAC]), defined as one of the following options:
a) Inoperable CTEPH (i.e., technically non-operable) with:
- Diagnosis of CTEPH based on at least two of the following assessments
performed in the 14-month period prior to randomization (Visit 2):
ventilation/perfusion (V/Q) scan; pulmonary angiography (PA); computed
tomography pulmonary angiogram (CTPA) and/or magnetic resonance angiography
(MRA).
- RHC (and LHC if needed) 1 performed at least 90 days after start of full
anticoagulation showing: PVR at rest >= 400 dyn.sec/cm5 or >= 5 Wood units for
the hemodynamic cohort and PVR at rest >= 300 dyn.sec/cm5 or >=3.75 Wood units
for the non-hemodynamic cohort
- mean pulmonary arterial pressure (mPAP) >= 25 mmHg;
- Pulmonary arterial wedge pressure (PAWP) <= 15 mmHg or, if not available or
unreliable, a left ventricular end diastolic pressure (LVEDP) <= 15 mmHg.
b) Persistent/recurrent CTEPH after BPA and deemed inoperable, with:
- Diagnosis of CTEPH based on at least one of the following assessments
performed in the 14-month period prior to randomization (Visit 2) and after
last interventional (BPA) treatment: V/Q scan, PA, CTPA or MRA.
- RHC (and LHC if needed)performed at least 90 days after last interventional
(BPA) treatment and at least 90 days after start of full anticoagulation,
showing:
PVR at rest >= 400 dyn.sec/cm5 or >= 5 Wood units for the hemodynamic cohort and
PVR at rest >=300 dyn.sec/cm5 or >=3,75 Wood units for the non-hemodynamic
cohort;
mPAP >= 25 mmHg;
PAWP <= 15 mmHg, or, if not available or unreliable, an LVEDP <= 15 mmHg.
c) Persistent/recurrent CTEPH after PEA (including PEA followed by BPA) with:
- Diagnosis of CTEPH based on at least one of the following assessments
performed in the 14-month period prior to randomization (Visit 2) and after
last surgical (PEA) or interventional (BPA) treatment: V/Q scan, PA, CTPA or
MRA.
-RHC (and LHC if needed) performed at least 90 days after last surgical (PEA)
or interventional (BPA) treatment and at least 90 days after start of full
anticoagulation, showing: PVR at rest >= 400 dyn.sec/cm5 or 5 Wood units for the
hemodynamic cohort and PVR at rest >=300 dyn.sec/cm5 or >=3,75 Wood units for the
non-hemodynamic cohort;
mPAP >= 25 mmHg;
PAWP <= 15 mmHg, or, if not available or unreliable, an LVEDP <= 15 mmHg.
4. PH in WHO FC I-IV.
5. Subject able to perform the 6MWT with a minimum distance of 100 m and a
maximum distance of 450 m at screening visit (Visit 1).
6. A woman of childbearing potential [see definition in Section 4.5.1] is
eligible only if all the following applies:
a. Negative serum pregnancy test at Screening and a negative urine pregnancy
test at randomization.
b. Agreement to undertake monthly urine pregnancy tests during the study and up
to at least 30 days after study treatment discontinuation.
c. Agreement to use one of the methods of birth control described in Section
4.5 from Screening visit up to at least 30 days after study treatment
discontinuation
Exclusion criteria
1. Planned BPA within 26 weeks after randomization.
2. Change in dose or initiation of new PH-specific therapy within 90 days prior
to the baseline RHC (and LHC if needed) qualifying for enrollment for the
hemodynamic cohort and within 90 days prior to randomization (Visit 2) for the
non-hemodynamic cohort
3. Treatment with prostacyclin (epoprostenol), prostacyclin analogs (i.e.,
treprostinil, iloprost, beraprost) or prostacyclin receptor agonists (i.e.,
selexipag/Uptravi) within 90 days prior to randomization (Visit 2), except
those given at vasodilator testing during RHC
4. Change in dose or initiation of new diuretics and/or calcium channel
blockers within 1 week prior to baseline RHC (and LHC if needed).
Exclusion criteria related to comorbidities
5. Severe coronary heart disease or unstable angina as assessed by the
investigator.
6. Myocardial infarction within the last 6 months prior to screening.
7. Decompensated cardiac failure if not under close supervision.
8. Severe arrhythmias as assessed by the investigator.
9. Cerebrovascular events (e.g., transient ischemic attack, stroke) within the
last 3 months prior to screening.
10. Congenital or acquired valvular defects with clinically relevant myocardial
function disorders not related to pulmonary hypertension.
11. Known or suspicion of pulmonary veno-occlusive disease. Exclusion criteria
related to selexipag use
12. Known and documented severe hepatic impairment.
13. Severe renal failure (estimated glomerular filtration rate < 30 mL/min/1.73
m2 or serum creatinine > 2.5 mg/dL) at screening.
14. Known or suspected uncontrolled thyroid disease as per investigator
judgment.
15. Pregnant, planning to be become pregnant or lactating.
16. Treatment with strong inhibitors of cytochrome P-450 2C8 (CYP2C8; e.g.,
gemfibrozil) within 14 days prior to randomization.
17. Systolic blood pressure < 90 mmHg at screening (Visit 1) or at
randomization (Visit 2).
18. Known hypersensitivity to selexipag or drugs of the same class, or any of
their excipients.
19. Planned or current treatment with another investigational treatment up to 3
months prior to randomization.
20. Any co-morbid condition that may influence the ability to perform a
reliable and reproducible 6MWT, including use of walking aids (cane, walker,
etc.).
21. Any known factor or disease that might interfere with treatment compliance,
study conduct or interpretation of the results, such as drug or alcohol
dependence or psychiatric disease.
22. Known concomitant life-threatening disease with a life expectancy < 12
months.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-002823-41-NL |
| ClinicalTrials.gov | NCT03689244 |
| CCMO | NL67626.029.18 |