A Study to Evaluate the Effect of Gefapixant (AF-219/MK-7... | NCT01993329

NCT01993329

ID	Type	Description
AF219-009	Other Identifier	Afferent Pharmaceuticals
2013-003566-13	EudraCT Number
MK-7264-009	Other Identifier	Merck

Status Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Gefapixant 50/ Gefapixant 300/ Placebo	Experimental	Gefapixant 50 mg and placebo (for gefapixant 300 mg) twice daily for 3.5 days during Period 1, gefapixant 300 mg and placebo (for gefapixant 50 mg) twice daily for 3.5 days during Period 2, placebo to match gefapixant 50 mg and placebo to match gefapixant 300 mg twice daily for 3.5 days during Period 3. Each period is separated by at least a 7-day wash-out period.	Drug: Gefapixant 50 mg Drug: Gefapixant 300 mg Drug: Placebo to mimic 50 mg tablets Drug: Placebo to mimic 300 mg tablets
Gefapixant 50/ Placebo/ Gefapixant 300	Experimental	Gefapixant 50 mg and placebo (for gefapixant 300 mg) twice daily for 3.5 days during Period 1, placebo to match gefapixant 50 mg and placebo to match gefapixant 300 mg twice daily for 3.5 days during Period 2, gefapixant 300 mg and placebo (for gefapixant 50 mg) twice daily for 3.5 days during Period 3. Each period is separated by at least a 7-day wash-out period.	Drug: Gefapixant 50 mg Drug: Gefapixant 300 mg Drug: Placebo to mimic 50 mg tablets Drug: Placebo to mimic 300 mg tablets
Gefapixant 300/ Gefapixant 50/ Placebo	Experimental	Gefapixant 300 mg and placebo (for gefapixant 50 mg) twice daily for 3.5 days during Period 1, gefapixant 50 mg and placebo (for gefapixant 300 mg) twice daily for 3.5 days during Period 2, placebo to match gefapixant 50 mg and placebo to match gefapixant 300 mg twice daily for 3.5 days during Period 3. Each period is separated by at least a 7-day wash-out period.	Drug: Gefapixant 50 mg Drug: Gefapixant 300 mg Drug: Placebo to mimic 50 mg tablets Drug: Placebo to mimic 300 mg tablets

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Gefapixant 50 mg	Drug	Gefapixant 50 mg tablet administered orally	Gefapixant 300/ Gefapixant 50/ Placebo Gefapixant 300/ Placebo/ Gefapixant 50 Gefapixant 50/ Gefapixant 300/ Placebo

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Provocative Concentration (PC20) After Methacholine Challenge	The provocative concentration (PC) of inhaled methacholine required to reduce forced expiratory volume in 1 second (FEV1) by 20% (PC20) was calculated from the methacholine challenge at screening and 2 hours (+15 minutes) post dose on Day 3 of each Treatment Period using a five-breath dosimeter method. The primary endpoint was the methacholine PC20 value normalized by means of a log (base 2) transformation, at 2 dose levels compared with placebo in participants with asthma following provocation with methacholine.	Screening (Day -21 to Day -1) and Day 3

Secondary Outcomes

Measure	Description	Time Frame
Highest FEV1 After Methacholine Challenge	Serial FEV1 was measured post inhalation of methacholine challenges for 90 minutes. The highest FEV1 at 5, 15, 30, 45, 60, and 90 minutes following methacholine challenge were evaluated for each subject. The minimum highest FEV1 was derived using the first three available measures that cover the first 30 minutes after the challenge.	Screening (Day -21 to Day -1) and Day 3

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Women of child-bearing potential (WOCBP) (i.e., women who are not surgically sterile, not having had hysterectomy, bilateral tubal occlusion or bilateral oophorectomy, or are not postmenopausal) must have a negative pregnancy test at Screening and prior to randomization. WOCBP must be using 2 forms of acceptable birth control method from Screening through the Follow-Up Visit. Acceptable birth control methods include (of which 2 must be used):
- Established use of oral, injected or implanted hormonal methods of contraception
- Intrauterine device (IUD) or intrauterine system (IUS)
- Condom with spermicide
- Diaphragm with spermicide
- Double-barrier method (diaphragm for female participant and condom for male partner with spermicidal) satisfies the requirement for 2 forms of acceptable birth control. When in line with the preferred lifestyle of the participant, true and complete abstinence (not periodic abstinence) is acceptable.
- Male participants with partners WOCBP (as defined in Inclusion No. 2) must use 2 methods of acceptable birth control with their partner, 1 of which must be a barrier method. Contraception must start from screening and continue until 3 months after last dose of study drug.
Non-smokers or former smokers, who stopped smoking 6 months prior to screening. Former smokers should not have a smoking history of more than 5 pack years (1 pack of 20 cigarettes per day over 5 years).
Physician documented history or diagnosis of asthma for at least 6 months prior to screening according to the Global Initiative in Asthma guidelines (GINA, 2012).
Requires the use of Short acting β2-agonist therapy only (≤ 8 puffs per day) for at least 4 weeks prior to screening and prior to randomization.

Exclusion Criteria:

Has been hospitalized or attended the emergency department for an asthma attack in the 12 months prior to screening.
Exacerbation of asthma or lower respiratory tract infection during the 4 weeks before screening or prior to randomization.
Upper respiratory tract infection during the 4 weeks before screening or prior to randomization requiring treatment with antibiotics.
Inhaled or systemic corticosteroids (oral, intravenous, intramuscular) within 4 weeks prior to screening or prior to randomization.
Short-acting or long-acting antihistamines within 48hrs or 7 days, respectively, prior to screening.
Body mass index (BMI) <18 kg/m2 or ≥ 35 kg/m2 at screening.
History of kidney/bladder stones (nephro/uro-lithiasis) within 5 years of screening.
History of conditions or disorders that predispose to nephrolithiasis, such as Type 1 renal tubular acidosis, cystinuria, gout, hyperparathyroidism, inflammatory bowel disease (i.e., ulcerative colitis and Crohn's disease), short bowel syndrome, or bariatric surgery.
History of concurrent malignancy or recurrence of malignancy within 2 years prior to Screening (not including participants with basal cell carcinomas or cervical carcinoma in situ that has been successfully treated surgically).
Personal or family history of congenital long QT Interval on ECG (QT) syndrome.
Presence of a cardiac pacemaker.
History of a diagnosis of drug or alcohol dependency or abuse within approximately the last 3 years.
Diagnosis of depression, psychosis, bipolar disorder, or schizoaffective disorder.
Participants with diabetes Type I or uncontrolled diabetes Type II or Glycosylated Hemoglobin (HbA1c) > 8.0% at screening.
Any condition possibly affecting drug absorption e.g., gastrectomy, gastroplasty, any type of bariatric surgery, vagotomy, or bowel resection.
History of cutaneous adverse drug reaction to sulphonamides or signs or symptoms suggestive of anaphylaxis to sulphonamides.
Requiring concomitant therapy with prohibited medications at screening or prior to randomization.
Pregnant or breastfeeding woman.
Donation of sperm from Screening until 3 months after the last dose of study drug.
Male participants with pregnant female partners.
Treatment with an investigational drug within 30 days or five half-lives preceding the first dose of study medication or plans to take another investigational drug within 30 days of study completion.
Donation or loss of 400 mL or more of blood or donations of plasma within eight (8) weeks prior to initial dosing or longer if required by local regulation.

Name	Affiliation	Role
Medical Director	Afferent Pharmaceuticals, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)	Study Director

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Gefapixant 50 mg>Gefapixant 300 mg>Placebo	Gefapixant 50 mg twice daily (BID) on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2 followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Arm/Group Information

ID	Title	Description
BG000	Gefapixant 50 mg>Gefapixant 300 mg>Placebo	Gefapixant 50 mg twice daily (BID) on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2 followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3
BG001	Gefapixant 50 mg>Placebo>Gefapixant 300 mg	Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
BG002	Gefapixant 300 mg>Gefapixant 50 mg>Placebo	Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3
BG003	Gefapixant 300 mg>Placebo>Gefapixant 50 mg	Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
BG004	Placebo> Gefapixant 50 mg>Gefapixant 300 mg	Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
BG005	Placebo> Gefapixant 300 mg>Gefapixant 50 mg	Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
BG006	Total	Total of all reporting groups

Units	Counts
Participants	BG0003 BG0014 BG0023 BG0033 BG0043 BG0054 BG00620

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

Provocative Concentration (PC20) After Methacholine Challenge

The provocative concentration (PC) of inhaled methacholine required to reduce forced expiratory volume in 1 second (FEV1) by 20% (PC20) was calculated from the methacholine challenge at screening and 2 hours (+15 minutes) post dose on Day 3 of each Treatment Period using a five-breath dosimeter method. The primary endpoint was the methacholine PC20 value normalized by means of a log (base 2) transformation, at 2 dose levels compared with placebo in participants with asthma following provocation with methacholine.

Analysis population included all randomized participants who received at least 1 dose of study medication and had any post-dose efficacy evaluations for a given Treatment Period and who completed all 3 Treatment Periods.

Posted

Geometric Mean

Geometric Coefficient of Variation

log [mg/mL]

Screening (Day -21 to Day -1) and Day 3

ID	Title	Description
OG000	Gefapixant 50	Participants received gefapixant 50 mg twice daily for 3.5 days during one period of the study
OG001	Gefapixant 300	Participants received gefapixant 300 mg twice daily for 3.5 days during one period of the study
OG002	Placebo	Participants received placebo twice daily for 3.5 days during each period of the study

Units	Counts
Participants	OG00018 OG00118 OG00218

Title

Denominators

Categories

Title	Measurements
	OG0000.91± 214.4 OG0010.84± 181.0 OG0020.82± 260.1

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002		ANOVA		0.616		Geometric means ratio	1.108			2-Sided	95	0.734	1.673			Analysis was based on an ANOVA model with log (base 2) PC20 methacholine challenge at each period as dependent variable, treatment and period as fixed effects and participant as random effect.		Superiority
OG001 OG002

Secondary

Highest FEV1 After Methacholine Challenge

Serial FEV1 was measured post inhalation of methacholine challenges for 90 minutes. The highest FEV1 at 5, 15, 30, 45, 60, and 90 minutes following methacholine challenge were evaluated for each subject. The minimum highest FEV1 was derived using the first three available measures that cover the first 30 minutes after the challenge.

Posted

Mean

Standard Deviation

Liters

Screening (Day -21 to Day -1) and Day 3

ID	Title	Description
OG000	Screening	Screening (Day -21 to Day -1)
OG001	Gefapixant 50	Participants received gefapixant 50 mg twice daily for 3.5 days during one period of the study
OG002	Gefapixant 300	Participants received gefapixant 300 mg twice daily for 3.5 days during one period of the study
OG003	Placebo

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Irritable bowel syndrome	Gastrointestinal disorders	MedDRA 16.1	Systematic Assessment	EG0001 events1 affected19 at risk EG0010 events0 affected19 at risk EG0020 events0 affected20 at risk
Nausea	Gastrointestinal disorders	MedDRA 16.1	Systematic Assessment	EG0000 events0 affected19 at risk EG0013 events3 affected19 at risk EG0021 events1 affected20 at risk
Thirst	General disorders	MedDRA 16.1	Systematic Assessment	EG0001 events1 affected19 at risk EG0011 events1 affected19 at risk EG0020 events0 affected20 at risk
Soft tissue injury	Injury, poisoning and procedural complications	MedDRA 16.1	Systematic Assessment	EG0001 events1 affected19 at risk EG0010 events0 affected19 at risk EG0020 events0 affected20 at risk
Musculoskeletal discomfort	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG0000 events0 affected19 at risk EG0011 events1 affected19 at risk EG0020 events0 affected20 at risk
Dysgeusia	Nervous system disorders	MedDRA 16.1	Systematic Assessment	EG00013 events13 affected19 at risk EG00118 events18 affected19 at risk EG0020 events0 affected20 at risk
Headache	Nervous system disorders	MedDRA 16.1	Systematic Assessment	EG0009 events8 affected19 at risk EG0016 events6 affected19 at risk EG0026 events6 affected20 at risk
Hypogeusia	Nervous system disorders	MedDRA 16.1	Systematic Assessment	EG0002 events2 affected19 at risk EG0011 events1 affected19 at risk EG0021 events1 affected20 at risk
Anxiety	Psychiatric disorders	MedDRA 16.1	Systematic Assessment	EG0000 events0 affected19 at risk EG0011 events1 affected19 at risk EG0020 events0 affected20 at risk
Nocturia	Renal and urinary disorders	MedDRA 16.1	Systematic Assessment	EG0001 events1 affected19 at risk EG0012 events2 affected19 at risk EG0020 events0 affected20 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 16.1	Systematic Assessment	EG0000 events0 affected19 at risk EG0012 events2 affected19 at risk EG0020 events0 affected20 at risk
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA 16.1	Systematic Assessment	EG0001 events1 affected19 at risk EG0011 events1 affected19 at risk EG0020 events0 affected20 at risk
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	MedDRA 16.1	Systematic Assessment	EG0001 events1 affected19 at risk EG0010 events0 affected19 at risk EG0020 events0 affected20 at risk
Eczema	Skin and subcutaneous tissue disorders	MedDRA 16.1	Systematic Assessment	EG0000 events0 affected19 at risk EG0011 events1 affected19 at risk EG0020 events0 affected20 at risk
Macule	Skin and subcutaneous tissue disorders	MedDRA 16.1	Systematic Assessment	EG0000 events0 affected19 at risk EG0011 events1 affected19 at risk EG0020 events0 affected20 at risk

ID	Term
D001982	Bronchial Diseases
D012140	Respiratory Tract Diseases
D008173	Lung Diseases, Obstructive
D008171	Lung Diseases
D012130	Respiratory Hypersensitivity
D006969	Hypersensitivity, Immediate
D006967	Hypersensitivity
D007154	Immune System Diseases

ID	Title	Description	Deaths (At Risk)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Gefapixant 50 mg	Participants received gefapixant 50 mg twice daily for 3.5 days during one period of the study	20	19	16	19
EG001	Gefapixant 300 mg	Participants received gefapixant 300 mg twice daily for 3.5 days during one period of the study	20	19	19	19
EG002	Placebo	Participants received placebo twice daily for 3.5 days during each period of the study	20	20	8	20