Frespaciguat (MK-5475) in Participants With Pulmonary Hyp... | NCT04370873

NCT04370873

ID	Type	Description	Link
MK-5475-006	Other Identifier	MSD
2020-000488-22	EudraCT Number

Status Module

Sponsor/Collaborators Module

Oversight Module

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
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.	Drug: Frespaciguat
Part 1: Placebo	Placebo Comparator	Participants receive placebo QD via inhalation from Days 1-7.	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.	Drug: Frespaciguat
Part 2: Placebo	Placebo Comparator	Participants receive placebo QD via inhalation from Days 1-28.	Drug: Placebo

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Frespaciguat	Drug	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.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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.	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.	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.	Baseline (between Day -5 and Day -1) and Day 28

Secondary Outcomes

Measure	Description	Time Frame
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.	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

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

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)
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

Exclusion Criteria:

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.
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

Contacts/Locations Module

Name	Affiliation	Role
Medical Director	Merck Sharp & Dohme LLC	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Lexington VA- Health Care System ( Site 0034)		Lexington	Kentucky	40502	United States
Johns Hopkins - University ( Site 0003)

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
38803412	Result	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.

IPD Sharing Statement Module

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Part 1: MK-5475 360 μg	Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.
FG001	Part 1: Placebo	Participants received placebo QD via inhalation from Days 1-7.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Uploaded Document Information

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Sep 24, 2021

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

No data available

No data is available for this block.

Masking Info

One participant in Part 1 also participated in Part 2. That participant is counted only in Part 1 for baseline characteristics.

Arm/Group Information

ID	Title	Description
BG000	Part 1: MK-5475 360 μg	Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.
BG001	Part 1: Placebo	Participants received placebo QD via inhalation from Days 1-7.
BG002	Part 2: MK-5475 380 μg	Participants received MK-5475 380 μg QD via inhalation from Days 1-28.
BG003	Part 2: Placebo	Participants received placebo QD via inhalation from Days 1-28.
BG004	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

Years

Title	Denominators	Categories
	ParticipantsBG0006 ParticipantsBG0013 ParticipantsBG0028 ParticipantsBG003

Sex: Female, Male

Count of Participants

Participants

Title	Denominators	Categories
	ParticipantsBG0006 ParticipantsBG0013 ParticipantsBG002

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title	Denominators	Categories
	ParticipantsBG0006 ParticipantsBG0013 ParticipantsBG002

Race (NIH/OMB)

Count of Participants

Participants

Title	Denominators	Categories
	ParticipantsBG0006 ParticipantsBG0013 ParticipantsBG002

Pulmonary Vascular Resistance (PVR): Part 2

PVR was calculated in participants at baseline in participants who underwent right heart catheterization (RHC) via thermodilution.

The analysis population consisted of all participants in part 2 who received at least one dose of MK-5475 380 μg and complied with the protocol without major protocol deviations.

Mean

Standard Deviation

dynes*s*cm^-5

Title	Denominators	Categories
	ParticipantsBG0000 ParticipantsBG0010 Participants

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

All participants who received ≥1 dose of investigational treatment were analyzed according to treatment received.

Posted

Number

Percentage of Participants

Up to approximately 139 days

ID	Title	Description
OG000	Part 1: MK-5475 360 μg	Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.
OG001	Part 1: Placebo	Participants received placebo QD via inhalation from Days 1-7.
OG002	Part 2: MK-5475 380 μg	Participants received MK-5475 380 μg QD via inhalation from Days 1-28.
OG003	Part 2: Placebo	Participants received placebo QD via inhalation from Days 1-28.

Units	Counts
Participants	OG0006 OG0013 OG0029 OG003

Title

Denominators

Categories

Title	Measurements
	OG00033.3 OG00133.3 OG00233.3 OG003

Primary

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.

All participants who received ≥1 dose of investigational treatment were analyzed according to treatment received.

Posted

Number

Percentage of Participants

Up to approximately 32 days

ID	Title	Description
OG000	Part 1: MK-5475 360 μg	Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.
OG001	Part 1: Placebo	Participants received placebo QD via inhalation from Days 1-7.
OG002	Part 2: MK-5475 380 μg	Participants received MK-5475 380 μg QD via inhalation from Days 1-28.
OG003

Primary

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.

All Part 2 participants who complied with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model, and who had available data at baseline and Day 28.

Posted

Mean

Standard Deviation

Percentage change

Baseline (between Day -5 and Day -1) and Day 28

ID	Title	Description
OG000	Part 2: MK-5475 380 μg	Participants received MK-5475 380 μg QD via inhalation from Days 1-28.
OG001	Part 2: Placebo	Participants received placebo QD via inhalation from Days 1-28.

Units	Counts
Participants

Secondary

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.

The analysis population consisted of all participants in part 1 who received at least one dose of MK-5475 360 μg and who contributed blood samples for analysis of AUC0-inf. Per protocol, AUC0-inf was calculated for the participants who had concentration values.

Posted

Geometric Mean

Geometric Coefficient of Variation

hr*nM

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

ID	Title	Description
OG000	Part 1: MK-5475 360 μg	Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population consisted of all participants in part 1 who received at least one dose of MK-5475 360 μg and who contributed blood samples for analysis of AUC0-24. Per protocol, AUC0-24 was calculated for the participants who had concentration values.

Posted

Geometric Mean

Geometric Coefficient of Variation

hr*nM

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

ID	Title	Description
OG000	Part 1: MK-5475 360 μg	Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.

Units	Counts
Participants	OG000

Secondary

Maximum Observed Plasma Concentration (Cmax) of MK-5475: Part 1

Plasma concentration of MK-5475 was quantified for each arm to determine Cmax.

The analysis population consisted of all participants in part 1 who received at least one dose of MK-5475 360 μg and who contributed blood samples for analysis of Cmax. Per protocol, Cmax was calculated for the participants who had concentration values.

Posted

Geometric Mean

Geometric Coefficient of Variation

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

ID	Title	Description
OG000	Part 1: MK-5475 360 μg	Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population consisted of all participants in part 1 who received at least one dose of MK-5475 360 μg and who contributed blood samples for analysis of C24. Per protocol, C24 was calculated for the participants who had concentration.

Posted

Mean

Standard Deviation

24 hours postdose on Day 7

ID	Title	Description
OG000	Part 1: MK-5475 360 μg	Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population consisted of all participants in part 1 who received at least one dose of MK-5475 360 μg and who contributed blood samples for analysis of Tmax. Per protocol, Tmax was calculated for the participants who had concentration values.

Posted

Median

Full Range

Hours

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

ID	Title	Description
OG000	Part 1: MK-5475 360 μg	Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population consisted of all participants in part 1 who received at least one dose of MK-5475 360 μg and who contributed blood samples for analysis of t½. Per protocol, t½ was calculated for the participants who had concentration values.

Posted

Geometric Mean

Geometric Coefficient of Variation

Hours

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

ID	Title	Description
OG000	Part 1: MK-5475 360 μg	Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population consisted of all participants in part 1 who received at least one dose of MK-5475 360 μg and who contributed blood samples for analysis of Cmax accumulation ratio. Per protocol, Cmax accumulation ratio was calculated for the participants who had concentration values.

Posted

Geometric Mean

Geometric Coefficient of Variation

Ratio

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

ID	Title	Description
OG000	Part 1: MK-5475 360 μg	Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population consisted of all participants in part 1 who received at least one dose of MK-5475 360 μg and who contributed blood samples for analysis of AUC0-24 accumulation ratio. Per protocol, AUC0-24 accumulation ratio was calculated for the participants who had concentration values.

Posted

Geometric Mean

Geometric Coefficient of Variation

Ratio

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

ID	Title	Description
OG000	Part 1: MK-5475 360 μg	Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population consisted of all participants in part 1 who received at least one dose of MK-5475 360 μg and who contributed blood samples for analysis of AUC0-inf accumulation ratio. Per protocol, AUC0-inf accumulation ratio was calculated for the participants who had concentration values.

Posted

Geometric Mean

Geometric Coefficient of Variation

Ratio

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

ID	Title	Description
OG000	Part 1: MK-5475 360 μg	Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population consisted of all participants in part 2 who received at least one dose of MK-5475 380 μg and who contributed blood samples for analysis of AUC0-inf. Per protocol, AUC0-inf was calculated for the participants who had concentration values.

Posted

Geometric Mean

Geometric Coefficient of Variation

hr*nM

Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose

ID	Title	Description
OG000	Part 2: MK-5475 380 μg	Participants received MK-5475 380 μg QD via inhalation from Days 1-28.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population consisted of all participants in part 2 who received at least one dose of MK-5475 380 μg and who contributed blood samples for analysis of AUC0-24. Per protocol, AUC0-24 was calculated for the participants who had concentration values.

Posted

Geometric Mean

Geometric Coefficient of Variation

hr*nM

Day 28: Predose, 0.5, 1, 2 and 3 hours postdose

ID	Title	Description
OG000	Part 2: MK-5475 380 μg	Participants received MK-5475 380 μg QD via inhalation from Days 1-28.

Units	Counts
Participants	OG000

Secondary

Cmax of MK-5475: Part 2

Blood samples were taken predose and at specified times postdose to determine the Cmax of MK-5475.

The analysis population consisted of all participants in part 2 who received at least one dose of MK-5475 380 μg and who contributed blood samples for analysis of Cmax. Per protocol, Cmax was calculated for the participants who had concentration values.

Posted

Geometric Mean

Geometric Coefficient of Variation

Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose

ID	Title	Description
OG000	Part 2: MK-5475 380 μg	Participants received MK-5475 380 μg QD via inhalation from Days 1-28.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population consisted of all participants in part 2 who received at least one dose of MK-5475 380 μg and who contributed blood samples for analysis of C24. Per protocol, 24 hours samples were not collected. Therefore, no participants were analyzed.

Posted

24 hours postdose on Day 7

ID	Title	Description
OG000	Part 2: MK-5475 380 μg	Participants received MK-5475 380 μg QD via inhalation from Days 1-28.

Units	Counts
Participants	OG000

Secondary

Tmax of MK-5475: Part 2

Blood samples were taken predose and at specified times postdose to determine the Tmax of MK-5475.

The analysis population consisted of all participants in part 2 who received at least one dose of MK-5475 380 μg and who contributed blood samples for analysis of Tmax. Per protocol, Tmax was calculated for the participants who had concentration values.

Posted

Median

Full Range

Hours

Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose

ID	Title	Description
OG000	Part 2: MK-5475 380 μg	Participants received MK-5475 380 μg QD via inhalation from Days 1-28.

Units	Counts
Participants	OG000

Secondary

t½ of MK-5475: Part 2

Blood samples were taken predose and at specified times postdose to determine the t½ of MK-5475.

The analysis population consisted of all participants in part 2 who received at least one dose of MK-5475 380 μg and who contributed blood samples for analysis of t½. Per protocol, t½ was calculated for the participants who had concentration values.

Posted

Geometric Mean

Geometric Coefficient of Variation

Hours

Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose

ID	Title	Description
OG000	Part 2: MK-5475 380 μg	Participants received MK-5475 380 μg QD via inhalation from Days 1-28.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population consisted of all participants who received at least 1 treatment and who contributed blood samples for analysis of accumulation. Per protocol, accumulation was calculated for the participants who had concentration values.

Posted

Geometric Mean

Geometric Coefficient of Variation

Ratio

Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose

ID	Title	Description
OG000	Part 2: MK-5475 380 μg	Participants received MK-5475 380 μg QD via inhalation from Days 1-28.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population consisted of all participants in part 2 who received at least one dose of MK-5475 380 μg and who contributed blood samples for analysis of Cmax accumulation ratio. Per protocol, Cmax accumulation ratio was calculated for the participants who had concentration values.

Posted

Geometric Mean

Geometric Coefficient of Variation

Ratio

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

ID	Title	Description
OG000	Part 2: MK-5475 380 μg	Participants received MK-5475 380 μg QD via inhalation from Days 1-28.

Units	Counts
Participants	OG000

Secondary

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.

Posted

Mean

Standard Deviation

Percentage Change

Baseline (between Day -5 and Day -1) and Day 28

ID	Title	Description
OG000	Part 2: MK-5475 380 μg	Participants received MK-5475 380 μg QD via inhalation from Days 1-28.
OG001	Part 2: Placebo	Participants received placebo QD via inhalation from Days 1-28.

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	MK-5475 360 µg (Part 1)	Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	6	0	6	2	6
EG001	Placebo (Part 1)	Participants received placebo QD via inhalation from Days 1-7.	3	0	3	1	3
EG002	MK-5475 380 µg (Part 2)	Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	9	1	9	2	9
EG003	Placebo (Part 2)	Participants received placebo QD via inhalation from Days 1-28.	5	1	5	4	5

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Cardiac failure	Cardiac disorders	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected6 at risk EG0010 events0 affected3 at risk EG0020 events0 affected9 at risk EG0031 events1 affected5 at risk
COVID-19	Infections and infestations	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected6 at risk EG0010 events0 affected3 at risk EG0021 events1 affected9 at risk EG003
COVID-19 pneumonia	Infections and infestations	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected6 at risk EG0010 events0 affected3 at risk EG0021 events1 affected9 at risk EG003
Encephalopathy	Nervous system disorders	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected6 at risk EG0010 events0 affected3 at risk EG0021 events1 affected9 at risk EG003
Acute respiratory distress syndrome	Respiratory, thoracic and mediastinal disorders	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected6 at risk EG0010 events0 affected3 at risk EG0021 events1 affected9 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Lacrimation increased	Eye disorders	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected6 at risk EG0010 events0 affected3 at risk EG0020 events0 affected9 at risk EG0031 events1 affected5 at risk
Infusion site extravasation	General disorders	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected6 at risk EG0010 events0 affected3 at risk EG0021 events1 affected9 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected6 at risk EG0010 events0 affected3 at risk EG0020 events0 affected9 at risk EG003
Accidental overdose	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected6 at risk EG0010 events0 affected3 at risk EG0020 events0 affected9 at risk EG003
Blood creatinine increased	Investigations	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected6 at risk EG0010 events0 affected3 at risk EG0020 events0 affected9 at risk EG003
Dizziness	Nervous system disorders	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected6 at risk EG0010 events0 affected3 at risk EG0020 events0 affected9 at risk EG003
Headache	Nervous system disorders	MedDRA 25.0	Systematic Assessment	EG0002 events2 affected6 at risk EG0011 events1 affected3 at risk EG0020 events0 affected9 at risk EG003
Agitation	Psychiatric disorders	MedDRA 25.0	Systematic Assessment	EG0000 events0 affected6 at risk EG0010 events0 affected3 at risk EG0021 events1 affected9 at risk EG003

ID	Term
D006976	Hypertension, Pulmonary

ID	Term
D008171	Lung Diseases
D012140	Respiratory Tract Diseases
D006973	Hypertension
D014652	Vascular Diseases
D002318	Cardiovascular Diseases