A Study of Single Doses of Frespaciguat (MK-5475) on Pulmonary Vascular Resistance (MK-5475-002)

NCT03744637 | Completed Phase 1 Results

• 2 other identifiers: 5475-002MK-5475-002
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Pulmonary Arterial Hypertension

Outcome Measures

Primary Outcomes (3)

• Number of Participants Who Experienced at Least 1 Adverse Event (AE): All Parts

  An AE was defined as any untoward medical occurrence in a participant which may not necessarily have a causal relationship with the treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease that was temporally associated with use of a medicinal product, regardless of whether or not it was considered related to the medicinal product. The number of participants who experienced at least 1 AE was reported by dose separately for Part 1 plus Part 2 Period 1, for the RHC Period, and for the FRI Period.

  Up to ~14 days after last dose of treatment period (Up to ~32 weeks total)

• Number of Participants Who Discontinued From the Study Due to an AE: All Parts

  An AE was defined as any untoward medical occurrence in a participant which may not necessarily have a causal relationship with the treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease that was temporally associated with use of a medicinal product, regardless of whether or not it was considered related to the medicinal product. The number of participants who discontinued from the study due to an AE was reported by dose separately for Part 1 plus Part 2 Period 1, for the RHC Period, and for the FRI Period.

  Up to ~14 days after last dose of treatment period (Up to ~32 weeks total)

• Percentage Change From Baseline in Minimum Pulmonary Vascular Resistance (PVR): Part 2 Right Heart Catheterization (RHC) Period

  For each participant in the RHC Period, the percentage change from baseline for the minimum post-dose PVR value over the duration of the RHC procedure was calculated. The average of pre-dose measurements was set as the baseline. Mean (SD) percent change from baseline in PVR minimum were calculated and reported for each dose group that underwent RHC in Part 2. Per protocol, this outcome measure was only assessed during the Part 2 RHC Period for each panel and was not assessed during Part 1.

  Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and up to 4.5 hours post-dose

Secondary Outcomes (16)

• Change From Baseline in Heart Rate (HR) at 0.5 Hours Post-dose: Part 2 RHC Period

  Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 0.5 hours post-dose

• Change From Baseline in Heart Rate (HR) at 4.5 Hours Post-dose: Part 2 RHC Period

  Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 4.5 hours post-dose

• Change From Baseline in Heart Rate (HR) at 24 Hours Post-dose: Part 2 RHC Period

  Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 24 hours post-dose

• Change From Baseline in Systolic Blood Pressure (SBP) at 0.5 Hours Post-dose: Part 2 RHC Period

  Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 0.5 hours post-dose

• Change From Baseline in Systolic Blood Pressure (SBP) at 4.5 Hours Post-dose: Part 2 RHC Period

  Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 4.5 hours post-dose

Study Arms (5)

Panel A: Frespaciguat 120 ug/165 ug/240 ug/240 ug/240 ug (Parts 1 and 2)

EXPERIMENTAL

Participants in Panel A will receive a single inhaled dose of frespaciguat 120 ug in Period 1 of Part 1, followed by frespaciguat 165 ug in Period 2, followed by frespaciguat 240 ug in Period 3. Each dose will be separated by at least a 7-day washout. In Part 2 Period 2, participants will receive a single inhaled dose of frespaciguat 240 ug and undergo a right heart catheterization (RHC). In Part 2 Period 3, participants will receive a single inhaled dose of frespaciguat 240 ug and undergo a functional respiratory imaging (FRI).

Drug: Frespaciguat

Panel B: 300 ug/360 ug/360 ug (Part 2)

EXPERIMENTAL

Participants in Panel B will receive a single inhaled dose of frespaciguat 300 ug in Period 1 of Part 2. In Period 2 of Part 2, participants will receive a single inhaled dose of frespaciguat 360 ug and undergo FRI. In Period 3 of Part 2, participants receive a single inhaled dose of frespaciguat 360 ug and undergo RHC. Each dose will be separated by at least a 7-day washout.

Drug: Frespaciguat

Panel C: 300 ug/360 ug/360 ug (Part 2, Expansion)

EXPERIMENTAL

Participants in Panel C will receive a single inhaled dose of frespaciguat 300 ug in Period 1 of Part 2. In Period 2 of Part 2, participants will receive a single inhaled dose of frespaciguat 360 ug and undergo FRI. In Period 3 of Part 2, participants receive a single inhaled dose of frespaciguat 360 ug and undergo RHC. Each dose will be separated by at least a 7-day washout.

Drug: Frespaciguat

Panel D: 480 ug/120 ug/120 ug (Part 2)

EXPERIMENTAL

Participants in Panel D will receive a single inhaled dose of frespaciguat 480 ug in Period 1 of Part 2. In Period 2 of Part 2, participants will receive a single inhaled dose of frespaciguat 120 ug and undergo FRI. In Period 3 of Part 2, participants receive a single inhaled dose of frespaciguat 120 ug and undergo RHC. Each dose will be separated by at least a 7-day washout.

Drug: Frespaciguat

Placebo (Part 1)

PLACEBO COMPARATOR

Participants will receive a single inhaled dose of matching placebo in Part 1.

Drug: Placebo

Interventions

Frespaciguat DRUG

Single inhaled dose of frespaciguat 120, 165, 240, 300, 360, or 480 ug depending upon randomization

Also known as: MK-5475

Panel A: Frespaciguat 120 ug/165 ug/240 ug/240 ug/240 ug (Parts 1 and 2); Panel B: 300 ug/360 ug/360 ug (Part 2); Panel C: 300 ug/360 ug/360 ug (Part 2, Expansion); Panel D: 480 ug/120 ug/120 ug (Part 2)

Placebo DRUG

Single inhaled dose of placebo to match frespaciguat

Placebo (Part 1)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 \<1% per year), with low user dependency or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis)
• Male participants are eligible to participate if they agree to the following during the intervention period and for at least 14 days, corresponding to time needed to eliminate study intervention(s) after the last dose of study intervention: Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent or must agree to use contraception unless confirmed to be azoospermic (Vasectomized) or secondary to medical cause.
• Have a clinical indication for right heart catheterization (RHC) as part of initial work-up or ongoing medical management
• Panel A: Have history of RHC within 3 years of starting study medication demonstrating mean pulmonary artery pressure of ≥ 27 mmHg and pulmonary vascular resistance (PVR) of ≥ 300 dynes/sec/cm5
• Panels B/C/D: Have history of RHC within 3 years of starting study medication demonstrating mean pulmonary artery pressure of ≥ 27 mmHg and PVR of ≥ 300 dynes/sec/cm5 OR have an echocardiogram performed by the investigator at screening or within 1 year of screening demonstrating pulmonary artery systolic pressure ≥ 50 mmHg in conjunction with 1 or more of the following: tricuspid regurgitation velocity \> 3.0 m/s and or significant right heart enlargement and or reduced right heart function.

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (1)

Republican Clinical Hospital of Moldova ( Site 0001)

Chisinau, 2025, Moldova

Location

Related Publications (1)

• Bajwa EK, Cislak D, Palcza J, Feng HP, Messina EJ, Reynders T, Denef JF, Corcea V, Lai E, Stoch SA. Effects of an inhaled soluble guanylate cyclase (sGC) stimulator MK-5475 in pulmonary arterial hypertension (PAH). Respir Med. 2023 Jan;206:107065. doi: 10.1016/j.rmed.2022.107065. Epub 2022 Nov 29.

  PMID: 36521262 RESULT

MeSH Terms

Conditions

Pulmonary Arterial Hypertension

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: In Part 1 (Panel A) of this study, a double-blinding technique will be used. Frespaciguat and placebo will be packaged identically so that blind is maintained. The participant, the investigator, and Sponsor personnel or delegate(s) who are involved in the study intervention administration or clinical evaluation of the participants are unaware of the intervention assignments. Part 2 of this study is conducted as open label; therefore, the Sponsor, investigator, and participant will know the intervention administered.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Part 1 of the study will evaluate safety, tolerability, and pharmacokinetics in this population using a sequential study design. Review of available safety data up to 24 hours post dose of at least the first 4 participants must occur prior to escalating to the next dose level. A break to review PK data from Periods 1 and 2 will occur after completion of Period 2. Review of safety will occur after completion of Period 3 in all participants from Panel A, prior to initiation of Part 2. An optional break to review rolling PK data from Panel A Period 3 will be dependent upon exposures observed in Periods 1 and 2.

Study Record Dates

• First Submitted: November 13, 2018
• First Posted: November 16, 2018
• Study Start: January 18, 2019
• Primary Completion: December 11, 2020
• Study Completion: December 11, 2020
• Last Updated: June 4, 2025
• Results First Posted: February 23, 2022

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share

Locations

MO (1)