Asthma
Conditions
Brief summary
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.
Interventions
DRUGGefapixant 50 mg
Gefapixant 50 mg tablet administered orally
DRUGGefapixant 300 mg
Gefapixant 300 mg tablet administered orally
DRUGPlacebo to mimic 50 mg tablets
Sugar pill manufactured to mimic gefapixant 50 mg tablets
DRUGPlacebo to mimic 300 mg tablets
Sugar pill manufactured to mimic gefapixant 300 mg tablets
Sponsors
Afferent Pharmaceuticals, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Provocative Concentration (PC20) After Methacholine Challenge | Screening (Day -21 to Day -1) and Day 3 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Highest FEV1 After Methacholine Challenge | Screening (Day -21 to Day -1) and Day 3 | 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. |
Participant flow
Pre-assignment details
A Screening Phase of up to 21 days ensured that each participant met all the specified inclusion and none of the exclusion criteria. Screening procedures were performed over at least 2 days
Participants by arm
| Arm | Count |
|---|---|
| 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 | 3 |
| 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 | 4 |
| 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 | 3 |
| 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 | 3 |
| 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 | 3 |
| 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 | 4 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Period 2 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 |
| Wash-out | Personal reasons | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Gefapixant 50 mg>Gefapixant 300 mg>Placebo | Gefapixant 50 mg>Placebo>Gefapixant 300 mg | Gefapixant 300 mg>Gefapixant 50 mg>Placebo | Gefapixant 300 mg>Placebo>Gefapixant 50 mg | Placebo> Gefapixant 50 mg>Gefapixant 300 mg | Placebo> Gefapixant 300 mg>Gefapixant 50 mg | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 35.7 Years STANDARD_DEVIATION 7 | 27.5 Years STANDARD_DEVIATION 7.6 | 43.3 Years STANDARD_DEVIATION 7.6 | 31.3 Years STANDARD_DEVIATION 8 | 52.7 Years STANDARD_DEVIATION 8.1 | 40.0 Years STANDARD_DEVIATION 14.3 | 38.0 Years STANDARD_DEVIATION 11.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 4 Participants | 3 Participants | 3 Participants | 3 Participants | 4 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 4 Participants | 3 Participants | 3 Participants | 3 Participants | 4 Participants | 20 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 1 Participants | 3 Participants | 2 Participants | 2 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 16 / 19 | 19 / 19 | 8 / 20 |
| serious Total, serious adverse events | 0 / 19 | 0 / 19 | 0 / 20 |
Outcome results
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.
Time frame: Screening (Day -21 to Day -1) and Day 3
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Gefapixant 50 | Provocative Concentration (PC20) After Methacholine Challenge | 0.91 log [mg/mL] | Geometric Coefficient of Variation 214.4 |
| Gefapixant 300 | Provocative Concentration (PC20) After Methacholine Challenge | 0.84 log [mg/mL] | Geometric Coefficient of Variation 181 |
| Placebo | Provocative Concentration (PC20) After Methacholine Challenge | 0.82 log [mg/mL] | Geometric Coefficient of Variation 260.1 |
p-value: 0.61695% CI: [0.734, 1.673]ANOVA
p-value: 0.93995% CI: [0.673, 1.534]ANOVA
p-value: 0.67195% CI: [0.607, 1.384]ANOVA
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.
Time frame: Screening (Day -21 to Day -1) and Day 3
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gefapixant 50 | Highest FEV1 After Methacholine Challenge | +15 minutes | 2.69 Liters | Standard Deviation 0.75 |
| Gefapixant 50 | Highest FEV1 After Methacholine Challenge | +90 minutes | 3.10 Liters | Standard Deviation 0.88 |
| Gefapixant 50 | Highest FEV1 After Methacholine Challenge | +60 minutes | 2.99 Liters | Standard Deviation 0.84 |
| Gefapixant 50 | Highest FEV1 After Methacholine Challenge | Minimum Highest FEV1 | 2.44 Liters | Standard Deviation 0.66 |
| Gefapixant 50 | Highest FEV1 After Methacholine Challenge | +30 minutes | 2.86 Liters | Standard Deviation 0.82 |
| Gefapixant 50 | Highest FEV1 After Methacholine Challenge | + 5 minutes | 2.44 Liters | Standard Deviation 0.66 |
| Gefapixant 50 | Highest FEV1 After Methacholine Challenge | +45 minutes | 2.93 Liters | Standard Deviation 0.83 |
| Gefapixant 300 | Highest FEV1 After Methacholine Challenge | +45 minutes | 3.02 Liters | Standard Deviation 0.88 |
| Gefapixant 300 | Highest FEV1 After Methacholine Challenge | +90 minutes | 3.15 Liters | Standard Deviation 0.93 |
| Gefapixant 300 | Highest FEV1 After Methacholine Challenge | +30 minutes | 2.93 Liters | Standard Deviation 0.88 |
| Gefapixant 300 | Highest FEV1 After Methacholine Challenge | +60 minutes | 3.11 Liters | Standard Deviation 0.93 |
| Gefapixant 300 | Highest FEV1 After Methacholine Challenge | Minimum Highest FEV1 | 2.53 Liters | Standard Deviation 0.7 |
| Gefapixant 300 | Highest FEV1 After Methacholine Challenge | +15 minutes | 2.72 Liters | Standard Deviation 0.8 |
| Gefapixant 300 | Highest FEV1 After Methacholine Challenge | + 5 minutes | 2.53 Liters | Standard Deviation 0.7 |
| Placebo | Highest FEV1 After Methacholine Challenge | +45 minutes | 2.99 Liters | Standard Deviation 0.9 |
| Placebo | Highest FEV1 After Methacholine Challenge | + 5 minutes | 2.43 Liters | Standard Deviation 0.71 |
| Placebo | Highest FEV1 After Methacholine Challenge | +15 minutes | 2.67 Liters | Standard Deviation 0.83 |
| Placebo | Highest FEV1 After Methacholine Challenge | +30 minutes | 2.83 Liters | Standard Deviation 0.86 |
| Placebo | Highest FEV1 After Methacholine Challenge | +60 minutes | 3.06 Liters | Standard Deviation 0.91 |
| Placebo | Highest FEV1 After Methacholine Challenge | +90 minutes | 3.12 Liters | Standard Deviation 0.9 |
| Placebo | Highest FEV1 After Methacholine Challenge | Minimum Highest FEV1 | 2.43 Liters | Standard Deviation 0.71 |
| Placebo | Highest FEV1 After Methacholine Challenge | +30 minutes | 2.94 Liters | Standard Deviation 0.89 |
| Placebo | Highest FEV1 After Methacholine Challenge | Minimum Highest FEV1 | 2.54 Liters | Standard Deviation 0.75 |
| Placebo | Highest FEV1 After Methacholine Challenge | +90 minutes | 3.18 Liters | Standard Deviation 0.95 |
| Placebo | Highest FEV1 After Methacholine Challenge | +15 minutes | 2.77 Liters | Standard Deviation 0.84 |
| Placebo | Highest FEV1 After Methacholine Challenge | + 5 minutes | 2.54 Liters | Standard Deviation 0.75 |
| Placebo | Highest FEV1 After Methacholine Challenge | +60 minutes | 3.14 Liters | Standard Deviation 0.96 |
| Placebo | Highest FEV1 After Methacholine Challenge | +45 minutes | 3.03 Liters | Standard Deviation 0.93 |
p-value: 0.06695% CI: [-0.23, 0.008]ANOVA
p-value: 0.84395% CI: [-0.131, 0.107]ANOVA
p-value: 0.09895% CI: [-0.218, 0.02]ANOVA