Clinical trial NCT03744637: A Study of Single Doses of Frespaciguat (MK-5475) on Pulmonary Vascular Resistance (MK-5475-002)
Official title: A Study to Assess the Effect of Single Doses of MK-5475 on Pulmonary Vascular Resistance in Patients With Moderate to Severe Pulmonary Arterial Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pulmonary Arterial Hypertension
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2018-11-16
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Part 1 of the study will evaluate safety, tolerability, and pharmacokinetics in this population using a sequential study design. Review of available safety data up to 24 hours post dose of at least the first 4 participants must occur prior to escalating to the next dose level. A break to review PK data from Periods 1 and 2 will occur after completion of Period 2. Review of safety will occur after completion of Period 3 in all participants from Panel A, prior to initiation of Part 2. An optional break to review rolling PK data from Panel A Period 3 will be dependent upon exposures observed in Periods 1 and 2.
Primary purpose: TREATMENT

Brief summary: This study of frespaciguat in participants with Group 1 pulmonary arterial hypertension (PAH) will assess the safety, tolerability and pharmacokinetics (PK) of inhaled frespaciguat. There is no formal hypothesis to be tested.

Detailed description: In Part 1, one panel (Panel A) of up to 8 participants will dose in up to 3 dosing periods, with a minimum washout of 7 days between dosing periods. In each dosing period, 6 participants will receive frespaciguat and 2 will receive placebo, with 2 different participants receiving placebo in each of the dosing periods. Review of available safety data will occur prior to escalating to the next dose level.

Participants from Part 1 may continue into Part 2, which will assess safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single-dose inhaled frespaciguat. Three additional panels of participants (Panels B, C and D) will be enrolled into Part 2. Participants in Panel A will participate in 2 open-label dosing periods to assess PD measures associated with right heart catherization (RHC) \[Period 2\] and functional respiratory imaging (FRI) \[Period 3\]. Participants in Panels B, C, and D will participate in 3 dosing periods: Period 1 (open-label assessment of safety/tolerability and PK), Period 2 (FRI period) and Period 3 (RHC period).

Eligibility criteria: Inclusion Criteria:

* Be or have suspected Group 1 pulmonary hypertension as defined by the Nice 2013 Clinical Classification, including: idiopathic PAH, heritable PAH, drug- or toxin-induced PAH, or PAH associated with connective tissue disease or congenital heart disease
* Have a Body Mass Index (BMI) ≤35 kg/m2,
* Female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: She is a woman of nonchildbearing potential (WONCBP) or is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of \<1% per year), with low user dependency or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis)
* Male participants are eligible to participate if they agree to the following during the intervention period and for at least 14 days, corresponding to time needed to eliminate study intervention(s) after the last dose of study intervention: Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent or must agree to use contraception unless confirmed to be azoospermic (Vasectomized) or secondary to medical cause.
* Have a clinical indication for right heart catheterization (RHC) as part of initial work-up or ongoing medical management
* Panel A: Have history of RHC within 3 years of starting study medication demonstrating mean pulmonary artery pressure of ≥ 27 mmHg and pulmonary vascular resistance (PVR) of ≥ 300 dynes/sec/cm5
* Panels B/C/D: Have history of RHC within 3 years of starting study medication demonstrating mean pulmonary artery pressure of ≥ 27 mmHg and PVR of ≥ 300 dynes/sec/cm5 OR have an echocardiogram performed by the investigator at screening or within 1 year of screening demonstrating pulmonary artery systolic pressure ≥ 50 mmHg in conjunction with 1 or more of the following: tricuspid regurgitation velocity \> 3.0 m/s and or significant right heart enlargement and or reduced right heart function.

Exclusion Criteria:

* Has pulmonary hypertension subtypes including the following according to Nice 2013 Clinical Classification: human immunodeficiency (HIV) infection, portal hypertension, schistosomiasis, chronic hemolytic anemia, pulmonary veno-occlusive disease (PVOD) and or pulmonary capillary hemangiomatosis (PCH), persistent pulmonary hypertension of the newborn (PPHN), pulmonary hypertension owing to left heart diseases, left ventricular systolic dysfunction, left ventricular diastolic dysfunction, valvular disease, congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies, pulmonary hypertension owing to lung diseases and/or hypoxia, Chronic obstructive pulmonary disease, Interstitial lung disease, other pulmonary diseases with mixed restrictive and obstructive pattern, sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, developmental abnormalities, pulmonary hypertension defined as chronic thromboembolic pulmonary hypertension \[CTEPH\]), pulmonary hypertension with unclear multifactorial mechanisms, hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy, systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis, metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders, others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental pulmonary hypertension
* Has a history of clinically significant endocrine (not including stable diabetes mellitus), gastrointestinal, cardiovascular, hematological, hepatic (not including chronic stable Hepatitis B and Hepatitis C), immunological, renal, respiratory, genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases
* Is mentally or legally incapacitated, has significant emotional problems
* History of cancer (malignancy) except nonmelanomatous skin carcinoma or carcinoma in situ of the cervix or other malignancies which have been successfully treated 10 years prior to screening
* History of significant multiple and/or severe allergies
* Known hypersensitivity to iodine or iodine containing products
* Positive for HIV
* Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks of screening
* Has persistent or permanent atrial fibrillation with an uncontrolled ventricular rate
* Has significantly impaired gas exchange
* Has an active respiratory infection (e.g. common cold, bronchitis, influenza, pneumonia) with lung function outside of the normal range
* Is currently on monotherapy calcium channel blockers as a specific treatment for pulmonary hypertension
* Has taken nitrates within 24 hours of anticipated dosing
* Has taken inhaled prostacyclin within 24 hours of anticipated dosing (iloprost or treprostinil)
* Has taken diltiazem immediate release taken within 24 hours or extended release taken within 48 hours of anticipated dosing
* Has taken sildenafil or vardenafil within 24 hours or tadalafil within 7 days of anticipated dosing
* Has taken soluble guanylate cyclase (sGC) activator for PAH within 24 hours of anticipated dosing
* Is unable to refrain from or anticipates the use of 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
* Has participated in another investigational study within 4 weeks
* Does not agree to follow the smoking restrictions
* Part 2 only: Suffers from claustrophobia and would be unable to undergo computerized tomography (CT) scan
* Part 2 only: Has participated in a positron-emission tomography (PET) research study or other 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 this period
* Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately equivalent to: beer \[354 mL/12 ounces\], wine \[118 mL/4 ounces\], or distilled spirits \[29.5 mL/1 ounce\]) per day
* Consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) 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

Primary outcomes:
measure: Number of Participants Who Experienced at Least 1 Adverse Event (AE): All Parts
timeFrame: Up to ~14 days after last dose of treatment period (Up to ~32 weeks total)
measure: Number of Participants Who Discontinued From the Study Due to an AE: All Parts
timeFrame: Up to ~14 days after last dose of treatment period (Up to ~32 weeks total)
measure: Percentage Change From Baseline in Minimum Pulmonary Vascular Resistance (PVR): Part 2 Right Heart Catheterization (RHC) Period
timeFrame: Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and up to 4.5 hours post-dose
Secondary outcomes:
measure: Change From Baseline in Heart Rate (HR) at 0.5 Hours Post-dose: Part 2 RHC Period
timeFrame: Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 0.5 hours post-dose
measure: Change From Baseline in Heart Rate (HR) at 4.5 Hours Post-dose: Part 2 RHC Period
timeFrame: Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 4.5 hours post-dose
measure: Change From Baseline in Heart Rate (HR) at 24 Hours Post-dose: Part 2 RHC Period
timeFrame: Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 24 hours post-dose
measure: Change From Baseline in Systolic Blood Pressure (SBP) at 0.5 Hours Post-dose: Part 2 RHC Period
timeFrame: Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 0.5 hours post-dose
measure: Change From Baseline in Systolic Blood Pressure (SBP) at 4.5 Hours Post-dose: Part 2 RHC Period
timeFrame: Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 4.5 hours post-dose
measure: Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours Post-dose: Part 2 RHC Period
timeFrame: Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 24 hours post-dose
measure: Change From Baseline in Diastolic Blood Pressure (DBP) at 0.5 Hours Post-dose: Part 2 RHC Period
timeFrame: Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 0.5 hours post-dose
measure: Change From Baseline in Diastolic Blood Pressure (DBP) at 4.5 Hours Post-dose: Part 2 RHC Period
timeFrame: Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 4.5 hours post-dose
measure: Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours Post-dose: Part 2 RHC Period
timeFrame: Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 24 hours post-dose
measure: Area Under the Concentration-Time Curve From Hour 0 to Infinity (AUC0-inf) of MK-5475: All Parts
timeFrame: Part 1 and Part 2 Period 1: Predose and 0.1, 0.25, 0.5, 1, 2, 3, 4, 8, and 24 hours post-dose; RHC Period: predose and 0.25, 0.5, 1, 2, 3, 4, and 4.5 hours; FRI Period: predose and 1, 3, 8, and 24 hours postdose (Panel D also 0.25, 0.5, 2, 4 hours)
measure: Area Under the Concentration-Time Curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-5475: All Parts
timeFrame: Part 1 and Part 2 Period 1: Predose and 0.1, 0.25, 0.5, 1, 2, 3, 4, 8, and 24 hours post-dose; RHC Period: predose and 0.25, 0.5, 1, 2, 3, 4, and 4.5 hours; FRI Period: predose and 1, 3, 8, and 24 hours postdose (Panel D also 0.25, 0.5, 2, 4 hours)
measure: Maximum Concentration (Cmax) of MK-5475: All Parts
timeFrame: Part 1 and Part 2 Period 1: Predose and 0.1, 0.25, 0.5, 1, 2, 3, 4, 8, and 24 hours post-dose; RHC Period: predose and 0.25, 0.5, 1, 2, 3, 4, and 4.5 hours; FRI Period: predose and 1, 3, 8, and 24 hours postdose (Panel D also 0.25, 0.5, 2, 4 hours)
measure: Concentration of MK-5475 at 24 Hours Postdose (C24): All Parts
timeFrame: 24 hours postdose
measure: Time to Maximum Concentration (Tmax) of MK-5475: All Parts
timeFrame: Part 1 and Part 2 Period 1: Predose and 0.1, 0.25, 0.5, 1, 2, 3, 4, 8, and 24 hours post-dose; RHC Period: predose and 0.25, 0.5, 1, 2, 3, 4, and 4.5 hours; FRI Period: predose and 1, 3, 8, and 24 hours postdose (Panel D also 0.25, 0.5, 2, 4 hours)
measure: Apparent Terminal Half-life (t1/2) of MK-5475: All Parts
timeFrame: Part 1 and Part 2 Period 1: Predose and 0.1, 0.25, 0.5, 1, 2, 3, 4, 8, and 24 hours post-dose; RHC Period: predose and 0.25, 0.5, 1, 2, 3, 4, and 4.5 hours; FRI Period: predose and 1, 3, 8, and 24 hours postdose (Panel D also 0.25, 0.5, 2, 4 hours)
measure: Percentage Change From Baseline in Pulmonary Blood Volume (PBV) Over Time: Part 2 Functional Respiratory Imaging (FRI) Period
timeFrame: Baseline: Pre-dose on Day 1 of FRI Period (up to 227 days) and 1, 3, 8, and 24 hours post-dose
Other outcomes:
Locations:
city: Chisinau
country: Moldova, Republic of
facility: Republican Clinical Hospital of Moldova ( Site 0001)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Bajwa EK, Cislak D, Palcza J, Feng HP, Messina EJ, Reynders T, Denef JF, Corcea V, Lai E, Stoch SA. Effects of an inhaled soluble guanylate cyclase (sGC) stimulator MK-5475 in pulmonary arterial hypertension (PAH). Respir Med. 2023 Jan;206:107065. doi: 10.1016/j.rmed.2022.107065. Epub 2022 Nov 29.