A Study to Evaluate the Effect of Gefapixant (AF-219/MK-7264) on Methacholine Hyper-reactivity in Participants With Asthma (MK-7264-009)

Study Overview
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Brief Summary
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This is a randomized, double-blind, double-dummy, placebo-controlled, three-way cross-over, single centre study in participants with asthma undergoing inhalation of methacholine and adenosine triphosphate (ATP) to assess the provocative concentration (PC20) response of two dose levels of gefapixant (AF-219) compared with placebo.

Official Title
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A Randomised, Double-Blind, Double-Dummy, Placebo-Controlled, Three-Way Cross-over Study to Evaluate the Effect of AF-219 on Methacholine Hyper-Reactivity in Subjects With Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Gefapixant 50 mg
* Drug: Gefapixant 300 mg
* Drug: Placebo to mimic 50 mg tablets
* Drug: Placebo to mimic 300 mg tablets


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gefapixant 50/ Gefapixant 300/ Placebo<br>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<br>* Gefapixant 50 mg tablet administered orally<br>* Other names: MK-7264;Drug: Gefapixant 300 mg<br>* Gefapixant 300 mg tablet administered orally<br>* Other names: MK-7264;Drug: Placebo to mimic 50 mg tablets<br>* Sugar pill manufactured to mimic gefapixant 50 mg tablets<br>Drug: Placebo to mimic 300 mg tablets<br>* Sugar pill manufactured to mimic gefapixant 300 mg tablets<br>|
| Experimental: Gefapixant 50/ Placebo/ Gefapixant 300<br>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<br>* Gefapixant 50 mg tablet administered orally<br>* Other names: MK-7264;Drug: Gefapixant 300 mg<br>* Gefapixant 300 mg tablet administered orally<br>* Other names: MK-7264;Drug: Placebo to mimic 50 mg tablets<br>* Sugar pill manufactured to mimic gefapixant 50 mg tablets<br>Drug: Placebo to mimic 300 mg tablets<br>* Sugar pill manufactured to mimic gefapixant 300 mg tablets<br>|
| Experimental: Gefapixant 300/ Gefapixant 50/ Placebo<br>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<br>* Gefapixant 50 mg tablet administered orally<br>* Other names: MK-7264;Drug: Gefapixant 300 mg<br>* Gefapixant 300 mg tablet administered orally<br>* Other names: MK-7264;Drug: Placebo to mimic 50 mg tablets<br>* Sugar pill manufactured to mimic gefapixant 50 mg tablets<br>Drug: Placebo to mimic 300 mg tablets<br>* Sugar pill manufactured to mimic gefapixant 300 mg tablets<br>|
| Experimental: Gefapixant 300/ Placebo/ Gefapixant 50<br>Gefapixant 300 mg and placebo (for gefapixant 50 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 50 mg and placebo (for 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<br>* Gefapixant 50 mg tablet administered orally<br>* Other names: MK-7264;Drug: Gefapixant 300 mg<br>* Gefapixant 300 mg tablet administered orally<br>* Other names: MK-7264;Drug: Placebo to mimic 50 mg tablets<br>* Sugar pill manufactured to mimic gefapixant 50 mg tablets<br>Drug: Placebo to mimic 300 mg tablets<br>* Sugar pill manufactured to mimic gefapixant 300 mg tablets<br>|
| Experimental: Placebo/ Gefapixant 50/ Gefapixant 300<br>Placebo to match gefapixant 50 mg and placebo to match gefapixant 300 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, 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<br>* Gefapixant 50 mg tablet administered orally<br>* Other names: MK-7264;Drug: Gefapixant 300 mg<br>* Gefapixant 300 mg tablet administered orally<br>* Other names: MK-7264;Drug: Placebo to mimic 50 mg tablets<br>* Sugar pill manufactured to mimic gefapixant 50 mg tablets<br>Drug: Placebo to mimic 300 mg tablets<br>* Sugar pill manufactured to mimic gefapixant 300 mg tablets<br>|
| Experimental: Placebo/ Gefapixant 300/ Gefapixant 50<br>Placebo to match gefapixant 50 mg and placebo to match 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, gefapixant 50 mg and placebo (for 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<br>* Gefapixant 50 mg tablet administered orally<br>* Other names: MK-7264;Drug: Gefapixant 300 mg<br>* Gefapixant 300 mg tablet administered orally<br>* Other names: MK-7264;Drug: Placebo to mimic 50 mg tablets<br>* Sugar pill manufactured to mimic gefapixant 50 mg tablets<br>Drug: Placebo to mimic 300 mg tablets<br>* Sugar pill manufactured to mimic gefapixant 300 mg tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 Outcome Measures

| Outcome Measure | 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 |