Phase 1
N=25
A Study of Single Doses of Frespaciguat (MK-5475) on Pulmonary Vascular Resistance (MK-5475-002)
Pulmonary Arterial Hypertension
Bottom Line
View on ClinicalTrials.gov: NCT03744637 ↗Enrolled (actual)
25
Serious AEs
0.0%
Results posted
Feb 2022
Primary outcome: Primary: Number of Participants Who Experienced at Least 1 Adverse Event (AE): All Parts — 2; 1; 3; 5 Participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 1
- Interventions
- Frespaciguat (Drug); Placebo (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Merck Sharp & Dohme LLC
- Primary completion
- Dec 2020
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Participants Who Experienced at Least 1 Adverse Event (AE): All Parts |
2; 1; 3; 5; 2; 4 | — |
| PRIMARY Number of Participants Who Discontinued From the Study Due to an AE: All Parts |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Percentage Change From Baseline in Minimum Pulmonary Vascular Resistance (PVR): Part 2 Right Heart Catheterization (RHC) Period |
-20.77; 13.01; -29.46; -29.25 | — |
| SECONDARY Change From Baseline in Heart Rate (HR) at 0.5 Hours Post-dose: Part 2 RHC Period |
74.75; 62.57; 68.75; 69.06; 3.56; 1.83 | — |
| SECONDARY Change From Baseline in Heart Rate (HR) at 4.5 Hours Post-dose: Part 2 RHC Period |
74.75; 62.57; 68.75; 69.06; -0.56; 3.20 | — |
| SECONDARY Change From Baseline in Heart Rate (HR) at 24 Hours Post-dose: Part 2 RHC Period |
74.75; 62.57; 68.75; 69.06; 1.78; 7.43 | — |
| SECONDARY Change From Baseline in Systolic Blood Pressure (SBP) at 0.5 Hours Post-dose: Part 2 RHC Period |
123.25; 132.86; 128.50; 119.11; 25.33; 2.67 | — |
| SECONDARY Change From Baseline in Systolic Blood Pressure (SBP) at 4.5 Hours Post-dose: Part 2 RHC Period |
123.25; 132.86; 128.50; 119.11; 10.67; 4.93 | — |
| SECONDARY Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours Post-dose: Part 2 RHC Period |
123.25; 132.86; 128.50; 119.11; 6.22; -5.95 | — |
| SECONDARY Change From Baseline in Diastolic Blood Pressure (DBP) at 0.5 Hours Post-dose: Part 2 RHC Period |
69.75; 72.43; 77.00; 70.78; 4.00; 0.94 | — |
| SECONDARY Change From Baseline in Diastolic Blood Pressure (DBP) at 4.5 Hours Post-dose: Part 2 RHC Period |
69.75; 72.43; 77.00; 70.78; -0.22; 1.07 | — |
| SECONDARY Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours Post-dose: Part 2 RHC Period |
69.75; 72.43; 77.00; 70.78; -1.44; -2.76 | — |
| SECONDARY Area Under the Concentration-Time Curve From Hour 0 to Infinity (AUC0-inf) of MK-5475: All Parts |
1.00; 0.721; 1.25; 2.15; 1.66; 4.59 | — |
| SECONDARY Area Under the Concentration-Time Curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-5475: All Parts |
0.259; 0.613; 1.42; 2.35; 1.82; 4.53 | — |
| SECONDARY Maximum Concentration (Cmax) of MK-5475: All Parts |
0.0722; 0.139; 0.297; 0.543; 0.409; 0.981 | — |
| SECONDARY Concentration of MK-5475 at 24 Hours Postdose (C24): All Parts |
NA; NA; NA; NA; NA; 0.0113 | — |
| SECONDARY Time to Maximum Concentration (Tmax) of MK-5475: All Parts |
2.00; 1.00; 2.00; 1.50; 1.00; 1.00 | — |
| SECONDARY Apparent Terminal Half-life (t1/2) of MK-5475: All Parts |
1.73; 1.76; 1.87; 2.12; 2.18; 3.67 | — |
| SECONDARY Percentage Change From Baseline in Pulmonary Blood Volume (PBV) Over Time: Part 2 Functional Respiratory Imaging (FRI) Period |
-2; 2; 3; 2; 2; 9 | — |
Summary
This study of frespaciguat in participants with Group 1 pulmonary arterial hypertension (PAH) will assess the safety, tolerability and pharmacokinetics (PK) of inhaled frespaciguat. There is no formal hypothesis to be tested.
Eligibility Criteria
Inclusion Criteria
- Be or have suspected Group 1 pulmonary hypertension as defined by the Nice 2013 Clinical Classification, including: idiopathic PAH, heritable PAH, drug- or toxin-induced PAH, or PAH associated with connective tissue disease or congenital heart disease
- Have a Body Mass Index (BMI) ≤35 kg/m2,
- Female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: She is a woman of nonchildbearing potential (WONCBP) or is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of 3.0 m/s and or significant right heart enlargement and or reduced right heart function.
Exclusion Criteria
- Has pulmonary hypertension subtypes including the following according to Nice 2013 Clinical Classification: human immunodeficiency (HIV) infection, portal hypertension, schistosomiasis, chronic hemolytic anemia, pulmonary veno-occlusive disease (PVOD) and or pulmonary capillary hemangiomatosis (PCH), persistent pulmonary hypertension of the newborn (PPHN), pulmonary hypertension owing to left heart diseases, left ventricular systolic dysfunction, left ventricular diastolic dysfunction, valvular disease, congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies, pulmonary hypertension owing to lung diseases and/or hypoxia, Chronic obstructive pulmonary disease, Interstitial lung disease, other pulmonary diseases with mixed restrictive and obstructive pattern, sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, developmental abnormalities, pulmonary hypertension defined as chronic thromboembolic pulmonary hypertension [CTEPH]), pulmonary hypertension with unclear multifactorial mechanisms, hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy, systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis, metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders, others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental pulmonary hypertension
- Has a history of clinically significant endocrine (not including stable diabetes mellitus), gastrointestinal, cardiovascular, hematological, hepatic (not including chronic stable Hepatitis B and Hepatitis C), immunological, renal, respiratory, genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases
- Is mentally or legally incapacitated, has significant emotional problems
- History of cancer (malignancy) except nonmelanomatous skin carcinoma or carcinoma in situ of the cervix or other malignancies which have been successfully treated 10 years prior to screening
- History of significant multiple and/or severe allergies
- Known hypersensitivity to iodine or iodine containing products
- Positive for HIV
- Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks of screening
- Has persistent or permanent atrial fibrillation with an uncontrolled ventricular rate
- Has significantly impaired gas exchange
- Has an active respiratory infection (e.g. common cold, bronchitis, influenza, pneumonia) with lung function outside of the normal range
- Is currently on monotherapy calcium channel blockers as a specific treatment for pulmonary hypertension
- Has taken nitrates within 24 hours of anticipated dosing
- Has taken inhaled prostacyclin within 24 hours of anticipated dosing (iloprost or treprostinil)
- Has taken diltiazem immediate release taken within 24 hours or extended release taken within 48 hours of anticipated dosing
- Has taken sildenafil or vardenafil within 24 hours or tadalafil within 7 days of anticipated dosing
- Has taken soluble guanylate cyclase (sGC) activator for PAH within 24 hours of anticipated dosing
- Is unable to refrain from or anticipates the use of
Data sourced from ClinicalTrials.gov (NCT03744637). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.