MK-5475 in Participants With Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease (PH-COPD) (MK-5475-006)

Pulmonary Hypertension Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04370873
• Other study ID #: 5475-006
• Secondary ID: MK-5475-0062020-
• Status: Completed
• Phase: Phase 1
• Start date: June 5, 2020
• Est. completion date: January 12, 2022

Study information

• Verified date: November 2023
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 MK-5475 in participants with pulmonary hypotension associated with chronic obstructive pulmonary disease (PH-COPD). The primary hypothesis is that 28 days of MK-5475 treatment is superior to placebo treatment in reduction of PVR.

Description:

Part 1 of this study will assess safety, tolerability, and PK of MK-5475 compared to placebo. Part 2 will assess safety, tolerability, PK, and changes in PVR and PBV of MK-5475 compared to placebo.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 22
• Est. completion date: January 12, 2022
• Est. primary completion date: January 12, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Hypertension
• Hypertension, Pulmonary
• Pulmonary Hypertension

Intervention

Drug:
• MK-5475
MK-5475 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.
• Placebo
Placebo administered as dry powder inhalation according to randomization

Locations

Country	Name	City	State
Israel	Rambam Medical Center ( Site 0037)	Haifa
Israel	Rabin Medical Center ( Site 0035)	Petah Tikva
Moldova, Republic of	Republican Clinical Hospital of Moldova ( Site 0013)	Chisinau
United States	Johns Hopkins - University ( Site 0003)	Baltimore	Maryland
United States	Brigham & Women's Hospital ( Site 0001)	Boston	Massachusetts
United States	Massachusetts General Hospital ( Site 0005)	Boston	Massachusetts
United States	Medical Universtiy of South Carolina ( Site 0011)	Charleston	South Carolina
United States	Lexington VA- Health Care System ( Site 0034)	Lexington	Kentucky
United States	University of Rochester Medical Center ( Site 0012)	Rochester	New York

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Israel,  Moldova, Republic of, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Up to approximately 139 days
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.	Up to approximately 32 days
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.	Baseline (between Day -5 and Day -1) and Day 28
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.	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
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.	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
Secondary	Maximum Observed Plasma Concentration (Cmax) of MK-5475: Part 1	Plasma concentration of MK-5475 was quantified for each arm to determine Cmax.	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
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.	24 hours postdose on Day 7
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.	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
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.	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
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.	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
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.	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
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.	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
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.	Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
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.	Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
Secondary	Cmax of MK-5475: Part 2	Blood samples were taken predose and at specified times postdose to determine the Cmax of MK-5475.	Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
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.	24 hours postdose on Day 7
Secondary	Tmax of MK-5475: Part 2	Blood samples were taken predose and at specified times postdose to determine the Tmax of MK-5475.	Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
Secondary	t½ of MK-5475: Part 2	Blood samples were taken predose and at specified times postdose to determine the t½ of MK-5475.	Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
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.	Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
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.	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
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.	Baseline (between Day -5 and Day -1) and Day 28