Pulmonary HypertensionPhase 1NCT04370873
Frespaciguat (MK-5475) in Participants With Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease (PH-COPD) (MK-5475-006)
A Phase 1 study testing Frespaciguat in people with Pulmonary Hypertension, run by Merck Sharp & Dohme LLC at 9 sites in 3 countries.
Trial summary
The primary objectives of this study are to assess the safety/tolerability and efficacy (by evaluating changes in pulmonary vascular resistance [PVR] and pulmonary blood volume [PBV]) of frespaciguat in participants with pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD). Read more about this study
- Who is it for?
- Ages 40 to 80 years
- Conditions the study is for
- Pulmonary Hypertension
- What is being tested?
- Frespaciguat
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 22 participants
- Where
- 9 sitesin 3 countries
- Study dates
- 5 Jun 2020to 12 Jan 2022
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 40 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Is male or female, from 40 to 80 years of age inclusive at the time of signing informed consent.
- Be judged to have no untreated, clinically significant health issue from other comorbidities based on medical history, physical examination, vital signs and electrocardiograms performed at the screening visit(s)
- Be judged to have no untreated, clinically significant health issue from other comorbidities based on laboratory safety tests performed at the screening visit(s)
- 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) (eg, 5 terminal half-lives) plus an additional 90 days (a spermatogenesis cycle) 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 agrees to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause
- A 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)
- Have been diagnosed with mild to severe Chronic Obstructive Pulmonary Disease (COPD) according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) diagnostic criteria (postbronchodilator forced expiratory volume in 1 second (FEV1)/ forced vital capacity (FVC) ratio < 0.7)
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- Has Modified Medical Research Council (MMRC) Dyspnea Score in the range of 1 through 3 at screening
- Be deemed clinically stable by the investigator
- Be or have suspected Pulmonary Hypertension Group 3 in particular: COPD
- Have a history of right heart catheterization (RHC) within 3 years of starting study medication demonstrating mean pulmonary artery pressure (mPAP) ≥ 25mmHg and pulmonary vascular resistance (PVR) ≥ 3.75 Woods units or 300 dynes/sec/cm or have an echocardiogram performed by the investigator (or appropriate designee) at screening or within 1 year of screening demonstrating pulmonary artery systolic pressure ≥ 38 mmHg (Part 1 only) or ≥ 50 mmHg (Part 2 only) in conjunction with one or more of the following: tricuspid regurgitation velocity >3 m/s or significant right heart enlargement and or reduced right heart function
Who cannot join
- Has pulmonary hypertension subtypes including the following according to Nice 2013 Clinical classification. This includes Group 1 Pulmonary arterial hypertension (PAH): Idiopathic PAH, Heritable PAH including Bone morphogenetic protein receptor type II (BMPR2), Activin A receptor type II-like kinase-1 (ALK1), endoglin, Sterile alpha motif domain-containing protein 9 (SMAD9), caveolin 1 (CAV1), potassium two-pore-domain channel subfamily K member 3 (KCNK3) and unknown, Drug and toxin-induced PAH, PAH associated with Connective tissue disease, HIV infection, Portal hypertension, Congenital heart disease (unrepaired and not requiring repair or repaired simple cardiac defects at least 1year status post corrective surgery, with no clinically significant residual shunt), Schistosomiasis, Chronic hemolytic anemia, Persistent pulmonary hypertension of the newborn (PPHN), and Pulmonary veno-occlusive disease (PVOD) and or pulmonary capillary hemangiomatosis (PCH); Group 2 Pulmonary hypertension owing to left heart diseases including Left ventricular Systolic dysfunction, Left ventricular Diastolic dysfunction, Valvular disease, Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies; Group 3 Pulmonary hypertension owing to lung diseases or hypoxia not associated with COPD including Interstitial lung disease, Other pulmonary diseases with mixed restrictive and obstructive pattern, Sleep-disordered breathing (mild obstructive sleep apnea (OSA) may be permitted with sponsor consultation), Alveolar hypoventilation disorders. Chronic exposure to high altitude, Developmental abnormalities; Group 4 Pulmonary hypertension defined as Chronic thromboembolic pulmonary hypertension [CTEPH]); and Group 5 Pulmonary Hypertension with unclear multifactorial mechanisms including Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, Splenectomy, Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleimyomatosis, neurofibromatosis, vasculitis, Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders, and Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental pulmonary hypertension.
- Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic (not including chronic stable Hep B and C), immunological, renal, respiratory (not including PH-COPD), genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases
- Is mentally or legally incapacitated, has significant emotional problems at the time of pre-study (screening) visit or expected during the conduct of the study or has a history of clinically significant psychiatric disorder of the last 5 years. Participants who have had situational depression may be enrolled in the study at the discretion of the investigator
- Has a history of cancer (malignancy) except adequately treated nonmelanomatous skin carcinoma or carcinoma in situ of the cervix or 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 and with agreement of the Sponsor
- Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (ie, systemic allergic reaction) to prescription or non-prescription drugs or food
- Is positive for hepatitis B surface antigen (HBsAg) [acute infection] or HIV (participants with positive HBsAG that demonstrate low viral load (chronic stable infection) are permitted.
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- Part 2 only: Has known sensitivity to iodine or iodine containing products
- Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the prestudy (screening) visit.
- Has persistent or permanent atrial fibrillation with uncontrolled ventricular rate (participants with paroxysmal atrial fibrillation or controlled atrial fibrillation with no clinically significant arrhythmia may be allowed per the judgement of the investigator)
- Has history of combined pulmonary fibrosis and emphysema (CPFE) or severe bullous emphysema. If no history, a confirmed negative high-resolution computerized tomography scan (HRCT) for these conditions needs to have been performed within last 2 ears.
- Has an active respiratory infection (common cold, influenza, pneumonia, acute bronchitis) with lung function values (FEV1 and/or FEV1/FVC ratio) that do not meet eligibility range
- Has a physical limitation that will inhibit the participant to effectively perform low intensity exercise testing (e.g. severe arthritis of the hip or knee)
- Is unable to refrain from or anticipates the use of any medication, including prescription and nonprescription drugs or herbal remedies beginning approximately 2 weeks (or 5 half-lives) prior to administration of the initial dose of study drug, throughout the study (including washout intervals between treatment periods), until the poststudy visit. There may be certain medications that are permitted
- Is currently on monotherapy calcium channel blockers as a specific treatment for pulmonary hypertension
- Is currently taking nitrates, inhaled prostacyclin, immediate or extended release diltiazem, phosphodiesterase 5 (PDE5) inhibitors or soluble guanylate cyclase (sGC) or activators for the treatment of pulmonary hypertension. Participants previously using medications to treat pulmonary arterial hypertension may be enrolled provided they have been off therapy for at least 2 weeks prior to the start of the screening period
- Has participated in another investigational study within 4 weeks (or 5 half-lives, whichever is greater) prior to the prestudy (screening) visit. The window will be derived from the date of the last visit in the previous study
- Has FEV1 < 30% predicted based on Pulmonary Function Tests (PFTs) at screening
- Part 2 only: Does not meet RHC criteria at baseline
- Participant has an estimated creatinine clearance of < 60 mL/min based on the Cockcroft Gault equation at screening
- Suffers from claustrophobia and is unable to undergo a computerized tomography (CT) scan
- Has participated in a positron emission tomography (PET) research study or other research study involving administration of a radioactive substance or ionizing radiation within 12 months prior to the screening visit or has undergone or plans to have extensive radiological examination within the period with a radiation burden over 10 millisievert (mSv)
- Does not agree to follow the smoking restrictions as defined by the clinical research unit (CRU)
- Consumes greater than 3 glasses of alcoholic beverages
- Consumes excessive amounts, defined as greater than 6 servings of coffee, tea, cola, energy drinks, or other caffeinated beverages per day
- Is a regular user of cannabis, any illicit drugs or has a history of drug (including alcohol) abuse within approximately 12 months. Participants must have a negative urine drug screen (UDS) prior to randomization
Trial locations and contacts
9 sites in 3 countries.
9 sites in 3 countries
United States6 sites
Johns Hopkins - University ( Site 0003)
Baltimore, Maryland, 21205
Massachusetts General Hospital ( Site 0005)
Boston, Massachusetts, 02114
Brigham & Women's Hospital ( Site 0001)
Boston, Massachusetts, 02115
Medical Universtiy of South Carolina ( Site 0011)
Charleston, South Carolina, 29425
Lexington VA- Health Care System ( Site 0034)
Lexington, Kentucky, 40502
University of Rochester Medical Center ( Site 0012)
Rochester, New York, 14642
Israel2 sites
Rambam Medical Center ( Site 0037)
Haifa, 3109601
Rabin Medical Center ( Site 0035)
Petah Tikva, 4941492
Moldova1 site
Republican Clinical Hospital of Moldova ( Site 0013)
Chisinau, 2025
About this study
Official title: A Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Dose MK-5475 in Participants With Pulmonary Hypertension Associated With COPD
The primary objectives of this study are to assess the safety/tolerability and efficacy (by evaluating changes in pulmonary vascular resistance [PVR] and pulmonary blood volume [PBV]) of frespaciguat in participants with pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD). The primary hypothesis is that 28 days of frespaciguat treatment is superior to placebo treatment in reduction of PVR.
Read the detailed description
Part 1 of this study will assess safety, tolerability, and PK of frespaciguat compared to placebo. Part 2 will assess safety, tolerability, PK, and changes in PVR and PBV of frespaciguat compared to placebo.
- Conditions
- Pulmonary Hypertension
- Being tested
- Frespaciguat, Placebo
- Medical subject headings
- Hypertension, Pulmonary
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
FrespaciguatDrug
Also called MK-5475
Frespaciguat 32 µg, 100 µg, 195 µg, 360 µg or 380 µg administered as dry powder inhalation according to randomization. Following review of pharmacokinetic (PK) and safety data, a second 7 days of dosing may be initiated. A dose of up to 360 μg up to twice a day may be administered based on PK data. Dosage may be adjusted downwards in Part 2, if indicated by PK results in Part 1.
PlaceboDrug
Placebo administered as dry powder inhalation according to randomization
| Study group | Role | What they receive |
|---|---|---|
| Part 1: Frespaciguat | Experimental | Participants receive frespaciguat 360 μg once daily (QD) via inhalation from Days 1-7. Following review of pharmacokinetic (PK) and safety data, a second 7 days of dosing may be initiated. A dose of up to 360 μg up to twice a day may be administered based on PK data in these participants. Receives: Drug: Frespaciguat |
| Part 1: Placebo | Placebo comparator | Participants receive placebo QD via inhalation from Days 1-7. Receives: Drug: Placebo |
| Part 2: Frespaciguat | Experimental | Participants receive frespaciguat 32 µg, 100 µg, 195 µg or 380 μg QD via inhalation from Days 1-28. Receives: Drug: Frespaciguat |
| Part 2: Placebo | Placebo comparator | Participants receive placebo QD via inhalation from Days 1-28. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of Participants Who Experienced at Least 1 Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who experienced an AE was assessed.
Measured: Up to approximately 139 days
Percentage of Participants Who Discontinued Study Drug Due to an AE
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued treatment due to an AE was assessed.
Measured: Up to approximately 32 days
Percentage Change From Baseline to Day 28 in Pulmonary Vascular Resistance (PVR): Part 2
PVR was calculated in participants after MK-5475 dosing at baseline and Day 28. Based on the variables obtained by right heart catheterization (RHC), the fold change from baseline individual PVR was calculated. The difference from baseline was assessed on the log scale and then back-transformed for reporting (percent change from baseline). Per protocol, this outcome measure was only assessed during the Part 2 and was not assessed during part 1.
Measured: Baseline (between Day -5 and Day -1) and Day 28
Secondary outcomes (18)
Plasma Area Under the Concentration Time-Curve From 0 to Infinity (AUC0-inf) of MK-5475: Part 1
Blood samples were taken predose and at specified times postdose to determine the AUC0-inf of MK-5475. Plasma AUC0-inf was defined as the area under the concentration vs. time curve for MK-5475 from 0 to infinite hours.
Measured: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
Plasma Area Under the Concentration Time-Curve From 0 to 24 Hours (AUC0-24) of MK-5475: Part 1
Blood samples were taken predose and at specified times postdose on Day 7 to determine the AUC0-24 of MK-5475. AUC0-24 values for Day 1 correspond to extrapolated values since collection on Day 1 stopped at 8 hours.
Measured: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
Maximum Observed Plasma Concentration (Cmax) of MK-5475: Part 1
Plasma concentration of MK-5475 was quantified for each arm to determine Cmax.
Measured: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
Plasma Concentration 24 Hours Postdose (C24) of MK-5475: Part 1
Blood samples were taken to determine the C24 of MK-5475. Data are reported as Mean with Standard Deviation. Concentration values below the lower limit of quantification were treated as having a value of 0.
Measured: 24 hours postdose on Day 7
Time to Maximum Concentration (Tmax) of MK-5475: Part 1
Blood samples were taken at predose and at specified time points postdose to determine the Tmax of MK-5475. Tmax was defined as the time to maximum concentration of MK-5475.
Measured: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
Plasma Apparent Terminal Half-Life (t½) of MK-5475: Part 1
Blood samples were taken at predose and at specified time points postdose to determine the t½ of MK-5475.
Measured: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
Cmax Accumulation Ratio of MK-5475: Part 1
Blood samples were taken predose and at specified times postdose to determine the Cmax accumulation ratio of MK-5475. Accumulation ratio is the ratio of the Day 7 Cmax to the Day 1 Cmax.
Measured: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
AUC0-24 Accumulation Ratio of MK-5475: Part 1
Blood samples were taken predose and at specified times postdose to determine the AUC0-24 accumulation ratio of MK-5475. Accumulation ratio is the ratio of the Day 7 AUC0-24 to the Day 1 AUC0-24.
Measured: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
AUC0-inf Accumulation Ratio of MK-5475: Part 1
Blood samples were taken predose and at specified times postdose on Days 1-7 to determine the AUC0-inf accumulation ratio of MK-5475. Accumulation ratio is the ratio of the Day 7 AUC0-inf to the Day 1 AUC0-inf.
Measured: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
AUC0-inf of MK-5475: Part 2
Blood samples were taken pre-dose and at specified times post-dose to determine the AUC0-inf of MK-5475. Concentrations for samples collected pre-RHC in a time window of 6-8 hours postdose on Day 28 were used to derive PK parameter values on Day 28. A nominal elapsed time of 6.01 hours postdose was used in the calculation.
Measured: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
AUC0-24 of MK-5475: Part 2
Blood samples were taken predose and at specified times postdose on Day 28 to determine the AUC0-24 of MK-5475. Concentrations for samples collected pre-RHC in a time window of 6-8 hours postdose on Day 28 were used to derive PK parameter values on Day 28. A nominal elapsed time of 6.01 hours postdose was used in the calculation. AUC0-24 was calculated using extrapolated concentration at 24 hours postdose.
Measured: Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
Cmax of MK-5475: Part 2
Blood samples were taken predose and at specified times postdose to determine the Cmax of MK-5475.
Measured: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
Plasma Concentration 24 Hours Postdose (C24) of MK-5475: Part 2
Blood samples were taken to determine the C24 of MK-5475. Data are reported as Mean with Coefficient of Variation, but due to data entry limitations the table below labels them as Geometric Mean and Geometric Coefficient of Variation. Concentration values below the lower limit of quantification were treated as having a value of 0.
Measured: 24 hours postdose on Day 7
Tmax of MK-5475: Part 2
Blood samples were taken predose and at specified times postdose to determine the Tmax of MK-5475.
Measured: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
t½ of MK-5475: Part 2
Blood samples were taken predose and at specified times postdose to determine the t½ of MK-5475.
Measured: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
AUC0-3 Accumulation Ratio of MK-5475: Part 2
Blood samples were taken predose and at specified times postdose on to determine the AUC0-3 accumulation ratio of MK-5475. Accumulation ratio is the ratio of the Day 7 AUC0-3 to the Day 1 AUC0-3.
Measured: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
Cmax Accumulation Ratio of MK-5475: Part 2
Blood samples were taken predose and at specified times postdose to determine the Cmax accumulation ratio of MK-5475. Cmax accumulation ratio is the ratio of the Day 7 Cmax to the Day 1 Cmax.
Measured: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 15: 1 hour postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
Percent Change From Baseline in Pulmonary Blood Volume (PBV) at Day 28: Part 2
Participants underwent a series of computed tomography (CT) scans with an intravenous (IV) iodinated contrast agent to facilitate assessment of PBV at baseline and at several times points after MK-5475 dosing. Percentage change from baseline (CFB) in PBV was calculated and reported for each dose group that underwent FRI in Part 2. As pre-specified, central tendency for PBV percentage CFB was provided as numerical values rounded to whole numbers. Per protocol, this outcome measure was only assessed during the Part 2 FRI Period for each panel and was not assessed during part 1 and part 3.
Measured: Baseline (between Day -5 and Day -1) and Day 28
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 May 2020
- Study start5 Jun 2020
- Primary completion12 Jan 2022
- Study completion12 Jan 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Pulmonary HypertensionStudies of the same condition, open and under way.
- More trials run by Merck Sharp & Dohme LLCThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Model description
- Part 1 enrolled immediately. Part 2 enrolled following review of Part 1 pharmacokinetic data. A third part was planned but did not enroll because Part 2 yielded sufficient data and Part 3 was optional per protocol.
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- Merck Sharp & Dohme LLC
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Director, Study director, Merck Sharp & Dohme LLC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04370873
- Sponsor's protocol ID
- 5475-006
- Other IDs
- MK-5475-006, 2020-000488-22
- Status last verified
- May 2025
- First submitted
- 29 Apr 2020
- Last updated
- 28 May 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf
Publications
Bajwa EK, Cislak D, Kumar A, Li D, Messina EJ, Reynders T, Denef JF, Corcea V, Buch KP, Lai E, Stoch SA. Phase 1 Study of MK-5475, an Inhaled Soluble Guanylate Cyclase Stimulator, in Participants with Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease. Int J Chron Obstruct Pulmon Dis. 2024 May 23;19:1105-1121. doi: 10.2147/COPD.S454905. eCollection 2024.
PubMed 38803412
Study at a glance
From the registry record, last updated by the sponsor on 28 May 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Dose MK-5475 in Participants With Pulmonary Hypertension Associated With COPD
- ClinicalTrials.gov ID
- NCT04370873
- Acronym / sponsor ID
- 5475-006
- Conditions
- Pulmonary Hypertension
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 22 participants (actual)
- Lead sponsor
- Merck Sharp & Dohme LLCIndustry (pharma, biotech, devices)
- Study start
- 5 Jun 2020 (actual)
- Primary completion
- 12 Jan 2022 (actual)
- Study completion
- 12 Jan 2022 (actual)
- First posted
- 1 May 2020 (actual)
- Results
- Posted 26 Apr 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The primary objectives of this study are to assess the safety/tolerability and efficacy (by evaluating changes in pulmonary vascular resistance [PVR] and pulmonary blood volume [PBV]) of frespaciguat in participants with pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD). The primary hypothesis is that 28 days of frespaciguat treatment is superior to placebo treatment in reduction of PVR.
Detailed description
Part 1 of this study will assess safety, tolerability, and PK of frespaciguat compared to placebo. Part 2 will assess safety, tolerability, PK, and changes in PVR and PBV of frespaciguat compared to placebo.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- Double blind (participant, investigator)
- Number of arms
- 4
- Model description
- Part 1 enrolled immediately. Part 2 enrolled following review of Part 1 pharmacokinetic data. A third part was planned but did not enroll because Part 2 yielded sufficient data and Part 3 was optional per protocol.
| Arm | Type | Receives |
|---|---|---|
| Part 1: Frespaciguat | Experimental | Drug: FrespaciguatParticipants receive frespaciguat 360 μg once daily (QD) via inhalation from Days 1-7. Following review of pharmacokinetic (PK) and safety data, a second 7 days of dosing may be initiated. A dose of up to 360 μg up to twice a day may be administered based on PK data in these participants. |
| Part 1: Placebo | Placebo comparator | Drug: PlaceboParticipants receive placebo QD via inhalation from Days 1-7. |
| Part 2: Frespaciguat | Experimental | Drug: FrespaciguatParticipants receive frespaciguat 32 µg, 100 µg, 195 µg or 380 μg QD via inhalation from Days 1-28. |
| Part 2: Placebo | Placebo comparator | Drug: PlaceboParticipants receive placebo QD via inhalation from Days 1-28. |
Who may qualify
- Ages
- 40 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Is male or female, from 40 to 80 years of age inclusive at the time of signing informed consent.
- Be judged to have no untreated, clinically significant health issue from other comorbidities based on medical history, physical examination, vital signs and electrocardiograms performed at the screening visit(s)
- Be judged to have no untreated, clinically significant health issue from other comorbidities based on laboratory safety tests performed at the screening visit(s)
- 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) (eg, 5 terminal half-lives) plus an additional 90 days (a spermatogenesis cycle) 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 agrees to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause
- A 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)
Key exclusion criteria (25 listed)
- Has pulmonary hypertension subtypes including the following according to Nice 2013 Clinical classification. This includes Group 1 Pulmonary arterial hypertension (PAH): Idiopathic PAH, Heritable PAH including Bone morphogenetic protein receptor type II (BMPR2), Activin A receptor type II-like kinase-1 (ALK1), endoglin, Sterile alpha motif domain-containing protein 9 (SMAD9), caveolin 1 (CAV1), potassium two-pore-domain channel subfamily K member 3 (KCNK3) and unknown, Drug and toxin-induced PAH, PAH associated with Connective tissue disease, HIV infection, Portal hypertension, Congenital heart disease (unrepaired and not requiring repair or repaired simple cardiac defects at least 1year status post corrective surgery, with no clinically significant residual shunt), Schistosomiasis, Chronic hemolytic anemia, Persistent pulmonary hypertension of the newborn (PPHN), and Pulmonary veno-occlusive disease (PVOD) and or pulmonary capillary hemangiomatosis (PCH); Group 2 Pulmonary hypertension owing to left heart diseases including Left ventricular Systolic dysfunction, Left ventricular Diastolic dysfunction, Valvular disease, Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies; Group 3 Pulmonary hypertension owing to lung diseases or hypoxia not associated with COPD including Interstitial lung disease, Other pulmonary diseases with mixed restrictive and obstructive pattern, Sleep-disordered breathing (mild obstructive sleep apnea (OSA) may be permitted with sponsor consultation), Alveolar hypoventilation disorders. Chronic exposure to high altitude, Developmental abnormalities; Group 4 Pulmonary hypertension defined as Chronic thromboembolic pulmonary hypertension [CTEPH]); and Group 5 Pulmonary Hypertension with unclear multifactorial mechanisms including Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, Splenectomy, Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleimyomatosis, neurofibromatosis, vasculitis, Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders, and Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental pulmonary hypertension.
- Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic (not including chronic stable Hep B and C), immunological, renal, respiratory (not including PH-COPD), genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases
- Is mentally or legally incapacitated, has significant emotional problems at the time of pre-study (screening) visit or expected during the conduct of the study or has a history of clinically significant psychiatric disorder of the last 5 years. Participants who have had situational depression may be enrolled in the study at the discretion of the investigator
- Has a history of cancer (malignancy) except adequately treated nonmelanomatous skin carcinoma or carcinoma in situ of the cervix or 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 and with agreement of the Sponsor
- Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (ie, systemic allergic reaction) to prescription or non-prescription drugs or food
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| FrespaciguatAlso: MK-5475Frespaciguat 32 µg, 100 µg, 195 µg, 360 µg or 380 µg administered as dry powder inhalation according to randomization. Following review of pharmacokinetic (PK) and safety data, a second 7 days of dosing may be initiated. A dose of up to 360 μg up to twice a day may be administered based on PK data. Dosage may be adjusted downwards in Part 2, if indicated by PK results in Part 1. | Drug | Part 1: Frespaciguat, Part 2: Frespaciguat |
| PlaceboPlacebo administered as dry powder inhalation according to randomization | Drug | Part 1: Placebo, Part 2: Placebo |
Primary outcome
Percentage of Participants Who Experienced at Least 1 Adverse Event (AE)
Time frame: Up to approximately 139 days
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who experienced an AE was assessed.
Percentage of Participants Who Discontinued Study Drug Due to an AE
Time frame: Up to approximately 32 days
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued treatment due to an AE was assessed.
Percentage Change From Baseline to Day 28 in Pulmonary Vascular Resistance (PVR): Part 2
Time frame: Baseline (between Day -5 and Day -1) and Day 28
PVR was calculated in participants after MK-5475 dosing at baseline and Day 28. Based on the variables obtained by right heart catheterization (RHC), the fold change from baseline individual PVR was calculated. The difference from baseline was assessed on the log scale and then back-transformed for reporting (percent change from baseline). Per protocol, this outcome measure was only assessed during the Part 2 and was not assessed during part 1.
18 secondary outcomes
Plasma Area Under the Concentration Time-Curve From 0 to Infinity (AUC0-inf) of MK-5475: Part 1
Time frame: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
Plasma Area Under the Concentration Time-Curve From 0 to 24 Hours (AUC0-24) of MK-5475: Part 1
Time frame: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
Maximum Observed Plasma Concentration (Cmax) of MK-5475: Part 1
Time frame: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
Plasma Concentration 24 Hours Postdose (C24) of MK-5475: Part 1
Time frame: 24 hours postdose on Day 7
Time to Maximum Concentration (Tmax) of MK-5475: Part 1
Time frame: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
Plasma Apparent Terminal Half-Life (t½) of MK-5475: Part 1
Time frame: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
Cmax Accumulation Ratio of MK-5475: Part 1
Time frame: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
AUC0-24 Accumulation Ratio of MK-5475: Part 1
Time frame: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
AUC0-inf Accumulation Ratio of MK-5475: Part 1
Time frame: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
AUC0-inf of MK-5475: Part 2
Time frame: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
AUC0-24 of MK-5475: Part 2
Time frame: Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
Cmax of MK-5475: Part 2
Time frame: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
Plasma Concentration 24 Hours Postdose (C24) of MK-5475: Part 2
Time frame: 24 hours postdose on Day 7
Tmax of MK-5475: Part 2
Time frame: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
t½ of MK-5475: Part 2
Time frame: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
AUC0-3 Accumulation Ratio of MK-5475: Part 2
Time frame: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
Cmax Accumulation Ratio of MK-5475: Part 2
Time frame: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 15: 1 hour postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
Percent Change From Baseline in Pulmonary Blood Volume (PBV) at Day 28: Part 2
Time frame: Baseline (between Day -5 and Day -1) and Day 28
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 May 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 38803412Bajwa EK, Cislak D, Kumar A, Li D, Messina EJ, Reynders T, Denef JF, Corcea V, Buch KP, Lai E, Stoch SA. Phase 1 Study of MK-5475, an Inhaled Soluble Guanylate Cyclase Stimulator, in Participants with Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease. Int J Chron Obstruct Pulmon Dis. 2024 May 23;19:1105-1121. doi: 10.2147/COPD.S454905. eCollection 2024.
- Individual participant dataSharing planned: Yes. https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Director study director
Merck Sharp & Dohme LLC
9 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Frespaciguat in people with Pulmonary Hypertension, run by Merck Sharp & Dohme LLC at 9 sites in 3 countries.
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 10 inclusion and 25 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: finished, as of the sponsor's last update on 28 May 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 9 sites in United States, Israel, Moldova. 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this 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.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 26 Apr 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Percentage of Participants Who Experienced at Least 1 Adverse Event (AE) (time frame: Up to approximately 139 days). The study lists 3 primary outcomes in all. 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 NCT04370873, 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 28 May 2025.