Safety and Tolerability of Gefapixant (MK-7264) in Participants With Obstructive Sleep Apnea (MK-7264-039)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03882801
• Collaborator: (none)
• Enrollment: 24
• Locations: 5
• Arms: 2
• Actual Duration (Months): 6.4
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the safety and tolerability of multiple dose administration of gefapixant (MK-7264) in participants with moderate to severe obstructive sleep apnea (OSA). The primary hypothesis is that multiple dose administration of gefapixant (MK-7264) in participants with moderate to severe OSA reduces the Apnea Hypopnea Index (AHI) relative to placebo.

Condition or Disease	Intervention/Treatment	Phase
Obstructive Sleep Apnea (OSA)	Drug: Gefapixant; Drug: Placebo	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized Double Blind Clinical Trial to Evaluate the Effects of MK-7264 in Participants With Obstructive Sleep Apnea
• Actual Study Start Date: Apr 10, 2019
• Actual Primary Completion Date: Oct 22, 2019
• Actual Study Completion Date: Oct 22, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sequence 1: Placebo -> Gefapixant In Period 1, participants receive a single oral dose of placebo matching gefapixant (MK-7264) every night at bedtime (QHS), for 7 days. In Period 2, participants receive a single oral dose of gefapixant (MK-7264) QHS, for 7 days. The two 7-day dosing periods are separated by a 7-day washout period.	Drug: Gefapixant; In Periods 1 and 2 (7 days each) participants receive 4 tablets (180 mg) of gefapixant (MK-7264) QHS.; Other Names: MK-7264 ; Drug: Placebo; In Periods 1 and 2 (7 days each) participants receive 4 tablets of placebo QHS.
Experimental: Sequence 2: Gefapixant -> Placebo In Period 1, participants receive a single oral dose of gefapixant (MK-7264) QHS for 7 days. In Period 2, participants receive a single oral dose of placebo matching gefapixant (MK-7264) QHS, for 7 days. The two 7-day dosing periods are separated by a 7-day washout period.	Drug: Gefapixant; In Periods 1 and 2 (7 days each) participants receive 4 tablets (180 mg) of gefapixant (MK-7264) QHS.; Other Names: MK-7264 ; Drug: Placebo; In Periods 1 and 2 (7 days each) participants receive 4 tablets of placebo QHS.

Outcome Measures

Primary Outcome Measures

1. Apnea-Hypopnea Index (AHI) Change From Baseline as Calculated From Polysonagraphy (PSG) [Day-1 at Baseline and Day 7 of each treatment period]

   The apnea-hypopnea index (AHI) is the sum of the apnea and hypopnea indices for each participant. The apnea index for each participant is calculated as the number of apneas divided by the total sleep time. The hypopnea index for each participant is calculated as the number of hypopneas divided by the total sleep time. These measurements are collected from polysonagraphs (PSGs), which are diagnostic sleep studies that collect electroencephalogram (EEG), electrooculograph (EOG), electromyogram (EMG), electrocardiogram (ECG), airflow, respiratory effort, oximetry, and sleep position data. Baseline AHI measurements in each period are obtained on Day -1. Individual AHI fold-change from baseline in each treatment period are calculated as the ratio of on-treatment AHI to baseline AHI.

Secondary Outcome Measures

1. Number of Participants Who Experienced an Adverse Event (AE) During the Study [Up to 14 days after last dose of study drug (Up to 35 days)]

   An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the product, is also an AE.

2. Number of Participants Who Discontinued Study Drug Due to an AE [Up to 21 days]

   An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the product, is also an AE.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• International Classification of Sleep Disorders (ICSD-3) diagnosis of OSA, based on investigator's assessment of the obstructive sleep apnea (OSA) history and diagnostic interview which must include: Documented sleep study in the past that confirmed the OSA diagnosis without significant prior medical intervention.

• Apnea-Hypopnea Index (AHI) ≥ 20 events/hour at screening.

• No use of a positive airway pressure (PAP) device within the preceding 1 month or a dental appliance within the preceding 7 days prior to screening and is not allowed to use PAP or a dental appliance throughout the study (including washout intervals between treatment periods) and until the post-study visit.

• A baseline oxygen saturation via pulse oximetry (SpO2) ≥ 94% at screening to ensure that carotid body response to hyperoxia is not impaired.

• A body mass index (BMI) ≤ 35 kg/m^2 at the pre-study (Screening 1) visit.

• Judged to be in good health based on medical history, physical examination, vital sign measurements, and laboratory safety tests.

• No clinically significant abnormality on electrocardiogram (ECG)

• Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

• A female participant is eligible to participate if she is not pregnant or breastfeeding, and is not a woman of childbearing potential (WOCBP) OR is a WOCBP and using an acceptable contraceptive method.

• A WOCBP must have a negative highly sensitive pregnancy test (urine as required by local regulations) within 72 hours before the first dose of study intervention.

• If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required.

• The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.

• A consistent sleep-wake schedule that is not subject to any other unusual changes in sleeping routine (i.e., bedtimes and wake times do not vary more than 1-2 hours except on rare occasions).

• Able to maintain sleep for at least 4 consecutive hours based on self-report.

Exclusion Criteria:

• Other than OSA, has evidence of another clinically significant, active pulmonary disorder such as bronchiectasis, emphysema, or asthma documented by history, physical examination, or chest x-ray.

• A history within the past 6 months prior to the pre-study visit or current evidence of an unstable or clinically significant cardiovascular disorder, including but not limited to: acute coronary syndrome, unstable angina, congestive heart failure, cardiogenic syncope, cardiomyopathy, any symptomatic arrhythmia, orthostatic hypotension, uncontrolled hypertension, chronic kidney disease, kidney transplant

• Abnormal pre-randomization laboratory values for alanine transaminase > 1.5 x the upper limit of normal (x ULN), aspartate transaminase > 1.5 x ULN, direct bilirubin > 1.5 x ULN, serum creatinine of > 2 mg/dL

• A history or diagnosis of any of the following conditions, in the opinion of the investigator: narcolepsy (with or without cataplexy) or Idiopathic hypersomnia, circadian rhythm sleep disorder, parasomnia including nightmare disorder, sleep terror disorder, sleepwalking disorder, and rapid eye movement (REM) behavior disorder, periodic limb movement (PLM) disorder, restless legs syndrome, chronic insomnia

• A WOCBP who has a positive urine or serum pregnancy test within 24 hours before the baseline 1 of study intervention.

• A history of clinically significant or poorly-controlled endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases.

• Mentally or legally incapacitated, or has significant emotional problems at the time of pre-study screening

• A history or current evidence of any condition, therapy, lab or ECG abnormality or other circumstances that might confound the results of the study, or interfere with the participant's participation for the full duration of the study.

• Any history of a neurological disorder, including but not limited to seizure disorder (other than single episodes of childhood febrile seizures), stroke, transient ischemic attack, multiple sclerosis, cognitive impairment, or significant head trauma with sustained loss of consciousness within the last 10 years.

• A history of significant multiple and/or severe allergies (e.g., food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (i.e., systemic allergic reaction) to prescription or non-prescription drugs or food.

• A history of anaphylaxis or cutaneous adverse drug reaction (with or without systemic symptoms) to sulfonamide antibiotics or other sulfonamide-containing drugs.

• Positive for hepatitis B surface antigen, hepatitis C antibodies or HIV.

• A history of cancer (malignancy) with some exceptions including adequately treated non-melanomatous skin carcinoma or carcinoma in situ of the cervix or; and other malignancies that 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 (e.g., malignancies that have been successfully treated ≥ 10 years prior to the pre-study [screening] visit).

• An estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m^2 based on the Cockcroft-Gault (CG) Equation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	MD Clinical ( Site 0004)	Hallandale Beach	Florida	United States	33009
2	Research Centers of America, LLC ( Site 0002)	Hollywood	Florida	United States	33024
3	Neurotrials Research, Inc. ( Site 0001)	Atlanta	Georgia	United States	30342
4	Clinilabs, Inc. ( Site 0005)	New York	New York	United States	10019
5	Universitair Ziekenhuis Gent ( Site 0012)	Gent		Belgium	9000

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 2, 2019

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT03882801
• Other Study ID Numbers: 7264-039; 2018-004099-37; MK-7264-039
• First Posted: Mar 20, 2019
• Last Update Posted: Nov 19, 2020
• Last Verified: Nov 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Apnea; Sleep Apnea Syndromes; Sleep Apnea, Obstructive

Study Results

Participant Flow

Recruitment Details	Participants were enrolled from 3 centers in a single country
Pre-assignment Detail	24 participants were randomized and enrolled, 23 were administered with at least one dose of study drug, 1 participant was never dosed.

Arm/Group Title	Placebo Then Gefapixant 180 mg	Gefapixant 180 mg Then Placebo
Arm/Group Description	Placebo once daily at bedtime (QHS) oral for 7 days in Period 1 followed by a 7-day washout period and then Gefapixant, 180 mg, QHS, oral for 7 days in Period 2.	Gefapixant, 180 mg, QHS, oral for 7 days in Period 1 followed by a 7-day washout period and then placebo, QHS, oral for 7 days in Period 2.
Period Title: Period 1
STARTED	12	12
Treated	11	12
COMPLETED	10	10
NOT COMPLETED	2	2
Period Title: Period 1
STARTED	10	10
COMPLETED	10	9
NOT COMPLETED	0	1
Period Title: Period 1
STARTED	10	9
COMPLETED	10	8
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Placebo Then Gefapixant 180 mg	Gefapixant 180 mg Then Placebo	Total
Arm/Group Description	Placebo once daily at bedtime (QHS) oral for 7 days in Period 1 followed by a 7-day washout period and then Gefapixant, 180 mg, QHS, oral for 7 days in Period 2.	Gefapixant, 180 mg, QHS, oral for 7 days in Period 1 followed by a 7-day washout period and then placebo, QHS, oral for 7 days in Period 2.	Total of all reporting groups
Overall Participants	12	12	24
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	53.7 (7.0)	56.4 (7.9)	55.0 (7.5)
Sex: Female, Male (Count of Participants)
Female	6 50%	4 33.3%	10 41.7%
Male	6 50%	8 66.7%	14 58.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	8 66.7%	8 66.7%	16 66.7%
Not Hispanic or Latino	4 33.3%	4 33.3%	8 33.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 8.3%	0 0%	1 4.2%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 16.7%	4 33.3%	6 25%
White	9 75%	8 66.7%	17 70.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Apnea-Hypopnea Index (AHI) Change From Baseline as Calculated From Polysonagraphy (PSG)
Description	The apnea-hypopnea index (AHI) is the sum of the apnea and hypopnea indices for each participant. The apnea index for each participant is calculated as the number of apneas divided by the total sleep time. The hypopnea index for each participant is calculated as the number of hypopneas divided by the total sleep time. These measurements are collected from polysonagraphs (PSGs), which are diagnostic sleep studies that collect electroencephalogram (EEG), electrooculograph (EOG), electromyogram (EMG), electrocardiogram (ECG), airflow, respiratory effort, oximetry, and sleep position data. Baseline AHI measurements in each period are obtained on Day -1. Individual AHI fold-change from baseline in each treatment period are calculated as the ratio of on-treatment AHI to baseline AHI.
Time Frame	Day-1 at Baseline and Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

Analysis population consisted of all randomized participants who received at least 1 dose of study drug, were compliant with the study procedure and had available data.

Arm/Group Title	Placebo	Gefapixant 180 mg
Arm/Group Description	Placebo once daily at bedtime (QHS) taken orally for 7 days	Gefapixant, 180 mg, QHS, taken orally for 7 days
Measure Participants	18	19
Least Squares Mean (95% Confidence Interval) [ratio]	0.86	0.97

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Gefapixant 180 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Geometric Means Ratio
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 90%; 0.73 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	Back transformed least squares mean and confidence interval from linear mixed effects model performed on natural log-transformed values.

2. Secondary Outcome

Title	Number of Participants Who Experienced an Adverse Event (AE) During the Study
Description	An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the product, is also an AE.
Time Frame	Up to 14 days after last dose of study drug (Up to 35 days)

Outcome Measure Data

Analysis Population Description

Any participant who received at least one dose of study drug.

Arm/Group Title	Placebo	Gefapixant 180 mg
Arm/Group Description	Placebo once daily at bedtime (QHS) taken orally for 7 days	Gefapixant, 180 mg, QHS, taken orally for 7 days
Measure Participants	20	22
Count of Participants [Participants]	2 16.7%	13 108.3%

3. Secondary Outcome

Title	Number of Participants Who Discontinued Study Drug Due to an AE
Description	An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the product, is also an AE.
Time Frame	Up to 21 days

Outcome Measure Data

Analysis Population Description

Any participant who received at least 1 dose of study drug

Arm/Group Title	Placebo	Gefapixant 180 mg
Arm/Group Description	Placebo once daily at bedtime (QHS) taken orally for 7 days	Gefapixant, 180 mg, QHS, taken orally for 7 days
Measure Participants	20	22
Count of Participants [Participants]	0 0%	1 8.3%

Adverse Events

Time Frame	Up to 14 days after last dose of study drug (Up to 35 days)
Adverse Event Reporting Description	An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated, and/or related with the study drug. Any worsening of a preexisting condition which is temporally associated with the study drug, is also an AE. All-Cause Mortality table includes all randomized participants. Serious Adverse Events and Other Adverse Events tables include all randomized participants who received ≥1 dose of study drug.
Arm/Group Title	Screening		Gefapixant		Placebo		Post Trial
Arm/Group Description	Screening		Gefapixant 180 mg QHS taken orally for 7 days		Placebo once daily at bedtime (QHS) taken orally for 7 days		Post trial
All Cause Mortality
	Screening		Gefapixant		Placebo		Post Trial
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/22 (0%)		0/20 (0%)		0/24 (0%)
Serious Adverse Events
	Screening		Gefapixant		Placebo		Post Trial
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/22 (0%)		0/20 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	Screening		Gefapixant		Placebo		Post Trial
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/24 (8.3%)		13/22 (59.1%)		2/20 (10%)		1/24 (4.2%)
Cardiac disorders
Arrhythmia	0/24 (0%)	0	0/22 (0%)	0	1/20 (5%)	1	0/24 (0%)	0
Gastrointestinal disorders
Dry mouth	0/24 (0%)	0	1/22 (4.5%)	1	0/20 (0%)	0	0/24 (0%)	0
Dyspepsia	0/24 (0%)	0	1/22 (4.5%)	1	0/20 (0%)	0	0/24 (0%)	0
Hypoaesthesia oral	0/24 (0%)	0	2/22 (9.1%)	3	1/20 (5%)	1	0/24 (0%)	0
Nausea	0/24 (0%)	0	3/22 (13.6%)	3	0/20 (0%)	0	0/24 (0%)	0
Salivary hypersecretion	0/24 (0%)	0	1/22 (4.5%)	1	0/20 (0%)	0	0/24 (0%)	0
General disorders
Fatigue	0/24 (0%)	0	1/22 (4.5%)	1	0/20 (0%)	0	0/24 (0%)	0
Thirst	0/24 (0%)	0	0/22 (0%)	0	1/20 (5%)	1	0/24 (0%)	0
Feeling abnormal	1/24 (4.2%)	1	0/22 (0%)	0	0/20 (0%)	0	0/24 (0%)	0
Infections and infestations
Upper respiratory tract infection	1/24 (4.2%)	1	1/22 (4.5%)	1	0/20 (0%)	0	0/24 (0%)	0
Injury, poisoning and procedural complications
Accidental overdose	0/24 (0%)	0	1/22 (4.5%)	1	0/20 (0%)	0	0/24 (0%)	0
Investigations
Heart rate increased	0/24 (0%)	0	1/22 (4.5%)	1	0/20 (0%)	0	0/24 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	1/24 (4.2%)	1	0/22 (0%)	0	0/20 (0%)	0	0/24 (0%)	0
Nervous system disorders
Ageusia	0/24 (0%)	0	4/22 (18.2%)	4	2/20 (10%)	2	0/24 (0%)	0
Amnesia	0/24 (0%)	0	1/22 (4.5%)	1	0/20 (0%)	0	0/24 (0%)	0
Dizziness	0/24 (0%)	0	1/22 (4.5%)	1	0/20 (0%)	0	0/24 (0%)	0
Dysgeusia	0/24 (0%)	0	5/22 (22.7%)	5	0/20 (0%)	0	0/24 (0%)	0
Headache	0/24 (0%)	0	3/22 (13.6%)	3	1/20 (5%)	1	0/24 (0%)	0
Somnolence	0/24 (0%)	0	2/22 (9.1%)	2	0/20 (0%)	0	0/24 (0%)	0
Taste disorder	0/24 (0%)	0	2/22 (9.1%)	2	0/20 (0%)	0	0/24 (0%)	0
Psychiatric disorders
Agitation	0/24 (0%)	0	1/22 (4.5%)	1	0/20 (0%)	0	0/24 (0%)	0
Anxiety	0/24 (0%)	0	0/22 (0%)	0	1/20 (5%)	1	1/24 (4.2%)	1
Dysphoria	0/24 (0%)	0	1/22 (4.5%)	1	0/20 (0%)	0	0/24 (0%)	0
Social circumstances
Physical assault	0/24 (0%)	0	1/22 (4.5%)	1	0/20 (0%)	0	0/24 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

In accordance with standard editorial and ethical practice, the Sponsor will generally support publication of multicenter studies only in their entirety and not as individual site data. In this case, a coordinating investigator will be designated by mutual agreement. If publication activity is not directed by the Sponsor, the investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission.