| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary arterial hypertension |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pulmonary arterial hypertension (Grade 1 Pulmonary Hypertension) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065150 |
| E.1.2 | Term | Associated with pulmonary arterial hypertension |
| E.1.2 | System Organ Class | 100000004855 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1. To evaluate the effect of MK-5475 versus placebo on the pulmonary vascular resistance (PVR) at Week 12 in the Phase 2 Cohort
2. To evaluate the effect of MK-5475 versus placebo on 6-minute walk distance (6MWD) at Week 12 in the Phase 3 Cohort |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the effect of MK-5475 versus placebo on 6-minute walk distance (6MWD) at Week 12 in the Phase 2 Cohort
2. To evaluate the effect of MK-5475 versus placebo on hemodynamic parameters other than pulmonary vascular resistance (PVR) at Week 12 in the Phase 2 Cohort
3. To evaluate the effect of MK-5475 versus placebo on 6-minute walk distance (6MWD) at Week 24 in the Phase 3 Cohort
4. To evaluate the effect of MK-5475 versus placebo on the World Health Organization (WHO) functional pulmonary arterial hypertension (PAH) class at week 12 in the Phase 3 Cohort
5. To evaluate the safety and tolerability of MK-5475 compared to placebo in the Phase 2 and Phase 3 Cohorts (independently) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has the following PAH groups, as defined by the Updated Clinical Classification of Pulmonary Hypertension:
a) Group 1.1 Idiopathic PAH
b) Group 1.2 Heritable PAH
c) Group 1.3 Drug and toxin-induced PAH
d) Group 1.4 PAH associated with:
● Connective tissue disease
● HIV infection
● Simple repaired congenital systemic-to-pulmonary shunt with persistent PH ≥1 year after surgical repair and with no clinically significant residual shunt
2. Has a diagnosis of PAH performed as standard of care, per scientific guidelines, and documented by historical RHC at any time prior to Screening; if participant is postsurgical repair of systemic-to pulmonary shunt, diagnostic RHC must have been performed at least 1 year after surgery
3. Has an eligibility RHC, meeting all the following criteria:
● mean pulmonary artery pressure (mPAP) ≥25 mmHg
● PVR of ≥3 Wood units
● PCWP or LVEDP ≤15 mmHg
For the Phase 2 Cohort, the eligibility RHC should be performed during Screening and will be centrally reviewed. A participant with RHC performed within 30 days prior to Visit 1/Screening may have the RHC results submitted for central review and, if deemed adequate, the RHC may count as baseline. In each case, the RHC should be performed after at least 90 days of stable PAH-specific therapy
For the Phase 3 Cohort, an RHC performed within 365 days prior to Visit 1/Screening may count for eligibility assessment. An RHC will be performed during Screening if an RHC performed within 365 days prior to Visit 1/Screening is not available
4. Has WHO-FC symptoms Class II to IV
5. Has two 6MWD measurements between 150 and 450 meters, 1 at Screening and 1 at Randomization. The relative difference between the 2 measurements must be ≤15%. If the relative difference between the two 6MWD measurements is >15%, the Randomization 6MWT may be repeated after at least 4 hours. If the relative difference between the 2 Randomization 6MWD measurements is ≤15%, the participant can be randomized and the last 6MWD will be considered the baseline value
6. Has stable concomitant background PAH-specific therapy with any of the following agents:
● an ERA and/or
● a PDE5i and/or
● an oral prostacyclin analogue or oral prostacyclin receptor agonist, an intravenous prostacyclin analogue or a subcutaneous prostacyclin
analogue
7. If on vasodilators other than PAH-specific therapy, has stable concomitant use
8. If on calcium channel blockers, a participant from Groups 1.1, 1.2, and 1.3 must have a history of being a nonresponder to acute pulmonary vasoreactivity testing
9. If on anticoagulants, has stable concomitant use for at least 30 days prior to and over the duration of Screening
10. Is male or female, from 18 years to 75 years of age inclusive, at the time of signing the informed consent
11. Has a BMI between 18.5 kg/m2 and 40 kg/m2
12. Is willing to comply with scheduled visits, treatment plan, laboratory tests, and/or other study procedures and study restrictions
13. Agrees to allowing site contact via phone or email for follow-up purposes
14. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 14 days after the last dose of study intervention:
● Be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent OR
● Must agree to use contraception unless confirmed to be azoospermic as detailed below:
- Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant
● Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
15. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
● Is not a WOCBP OR
● Is a WOCBP and using a contraceptive method that is highly effective, with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle during the intervention period and for at least 14 days after the last dose of study intervention
● A WOCBP must have a negative highly sensitive pregnancy test within 24 hours before the first dose of study intervention
● If a urine test cannot be confirmed as negative , a serum
pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
● Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
16. The participant has provided documented informed consent/assent for the study. The participant may also provide consent/assent for future biomedical research
17. Sponsor concurrence on key criteria must be obtained before the participant is randomized into the study |
|
| E.4 | Principal exclusion criteria |
1. Has Group 2 to 5 Pulmonary Hypertension in the Updated Clinical Classification of Pulmonary Hypertension
2. Has Group 1.5 PAH, long-term responders to calcium channel blockers, defined by sustained clinical improvement to WHO-FC I or II and sustained hemodynamic improvement after at least 1 year on CCBs only
3. Has Group 1.6 PAH, with overt features of venous/capillary (PVOD/PCH) involvement
4. For participants with Group 1.4 HIV-associated PAH, has any of the following within 90 days prior to and for the duration of Screening:
● concomitant active opportunistic infections
● plasma HIV-1 RNA≥50 copies/mL or CD4+ T-cell count<200/mm3
● changes in antiretroviral regimen
5. Has evidence of more-than-mild obstructive lung disease on PFT at Screening: FEV1/FVC <70%; and FEV1 <60% of predicted value after bronchodilator administration
6. Has evidence of more-than-mild parenchymal lung disease, based on medical history and chest imaging , and/or restrictive lung disease with Total Lung Capacity <60% of predicted on PFT at Screening
7. Has evidence of OSA that is untreated. Participants with well-controlled, treated OSA are eligible
8. Has evidence or history of left heart disease, including any of the following:
● left ventricular ejection fraction ≤45%
● moderate or severe left-sided valvular disease
● Grade 3 and 4 left ventricular diastolic function on echocardiographic evaluation
9. Has 3 or more of the following risk factors for heart failure with preserved ejection fraction:
● BMI >30 kg/m2
● history of essential systemic hypertension
● diabetes mellitus of any type
● history of coronary artery disease
10. Has oxygen saturation measured by pulse oximetry <90%, despite supplemental oxygen therapy
11. Had clinically unstable or acutely decompensated right heart failure within 30 days prior to and over the duration of Screening including, but not limited to, hospitalization or emergency room visit for acute decompensated heart failure
12. Has sitting systolic BP >160 mmHg or <90 mmHg or sitting diastolic BP >100 mmHg
13. Has significant chronic renal insufficiency, as defined by eGFR <30 mL/min or by ongoing dialytic support
14. Has evidence of chronic liver disease, portal hypertension,
cirrhosis, or hepatic laboratory abnormalities
15. Is included in a cardiopulmonary rehabilitation program initiated within 90 days prior to Screening or is planning to initiate cardiopulmonary rehabilitation during the study
16. Has acute or chronic impairment(s), limiting the ability to perform 6MWT
17. Is a current smoker or currently uses electronic cigarettes
18. Is unable to correctly use the DPI prior to randomization due to, but not limited to, cognitive impairment or physical limitations
19. Has other severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or that would confound study analysis or impair study participation or cooperation
20. Has a history of cancer. Exceptions:1) Adequately treated
nonmelanomatous skin carcinoma or carcinoma in situ of the cervix or;2) Other malignancies which have been successfully treated, with appropriate follow up, and therefore unlikely to recur for the duration of the study, in the opinion of the investigator
21. Has a known hypersensitivity to any of the ingredients or excipients of the IMP
22. At the time of signing the informed consent, is a user of illicit drugs or has had a recent history of drug or alcohol abuse or dependence
23. Has a known psychiatric or any other cognitive disorder that would, in the opinion of the investigator, interfere with the participant’s ability to cooperate with the requirements of the study
24. Is a WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study intervention. If the urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
25. Has used intravenous inotropes including, but not limited to levosimendan, dopamine, dobutamine, epinephrine, norepinephrine, noradrenaline or milrinone within 30 days prior to and over the duration of Screening
26. Has concomitant use of inhaled prostacyclin analogues, inhaled NO, or oral sGC modulators, or has used these medications within 90 days prior to and over the duration of Screening
27. Has participated in another investigational study within 4 weeks prior to the Screening. This window will be derived from the date
of the last dose of study medication taken in the previous study
28. For Phase 3 Cohort enrollment only: is currently participating in the MK-5475 Phase 2 Cohort or has completed the MK-5475 Phase 2 Cohort and has received the last study intervention dose within 90 days prior to Phase 3 Cohort Screening
29. Is or has an immediate family member who is investigational site or Sponsor staff directly involved with this study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Phase 2 Cohort: Change from Baseline in Pulmonary Vascular Resistance (PVR) at 12 Weeks
2. Phase 3 Cohort: Change from Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. At baseline and 12 weeks
2. At baseline and 12 weeks |
|
| E.5.2 | Secondary end point(s) |
1. Phase 2 Cohort: Change from Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks
2. Phase 2 Cohort: Change from Baseline in Mean Right Arterial Pressure (mRAP) at 12 Weeks
3. Phase 2 Cohort: Change from Baseline in Cardiac Index (CI) at 12 weeks
4. Phase 2 Cohort: Change from Baseline in Stroke Volume Index (SVI) at 12 weeks
5. Phase 3 Cohort: Change from Baseline in 6-Minute Walk Distance (6MWD) at 24 Weeks
6. Phase 3 Cohort: Change from Baseline in World Health Organization Functional Class (WHO-FC) at 12 Weeks
7. Phase 2 and 3 Cohorts: Number of Participants Who Experience an Adverse Event
8. Phase 2 and 3 Cohorts: Number of Participants Who Discontinue Study Drug Due to an Adverse Event |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At baseline and 12 weeks
2. At baseline and 12 weeks
3. At baseline and 12 weeks
4. At baseline and 12 weeks
5. At baseline and 24 weeks
6. At baseline and 12 weeks
7. Phase 2 Cohort: Up to 14 weeks, Phase 3 Cohort: Up to approximately 5.5 years
8. Phase 2 Cohort: Up to 14 weeks, Phase 3 Cohort: Up to approximately 5.5 years |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Adaptive Design; Phase 2: 4 groups, Phase 3: 2 groups |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Colombia |
| Israel |
| Mexico |
| New Zealand |
| Russian Federation |
| Turkey |
| United States |
| France |
| Germany |
| Greece |
| Italy |
| Poland |
| Sweden |
| United Kingdom |
| Argentina |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
