Asthma
Conditions
Brief summary
This was a 2-part study in participants with allergen-induced asthma. It included a procedural pilot component (Part 1). Part 1 tested the key procedures and timing of Part 2; no study drug was administered during Part 1. Part 2 included a pre-randomization placebo run-in (Period 1) and 3 treatment periods (Periods 2, 3, and 4) during which participants were randomized to receive double-blind placebo, MK-1029 60 mg or MK-1029 500 mg in a crossover design. The treatment periods were followed by a minimum 21-day washout. Part 2 assessed allergen-induced sputum eosinophils and allergen-induced late asthmatic response (LAR) compared to placebo.
Interventions
DRUGMK-1029 10 mg
Six capsules once daily for 5 days in Period 2, 3, or 4 in a crossover design
DRUGMK-1029 100 mg
Five capsules once daily for 5 days in Period 2, 3, or 4 in a crossover design
DRUGPlacebo for MK-1029 10 mg
Six capsules once daily for 5 days in Period 1, and the same in Period 2, 3, or 4 in a crossover design.
DRUGPlacebo for MK-1029 100 mg
Five capsules once daily for 5 days in Period 2, 3, or 4 in a crossover design
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
Parts 1 and 2 * Is male or a female of non-childbearing potential * Has a history of allergen-induced asthma for at least 6 months * Is judged to be in good health (other than asthma) * Is able to perform reproducible pulmonary function testing * Has a positive methacholine challenge test on Day -1 * Has an allergic response to house dust mite allergen as defined by positive skin prick test * Is a nonsmoker and/ or has not used nicotine or nicotine-containing products for at least 12 months * Has body mass index (BMI) ≥17 kg/m\^2, but ≤33 kg/m\^2 Part 2 only * Must demonstrate a dual airway response to an allergen challenge in Period 1, decrease in FEV1 of at least 20% 0 to 2 hours after allergen challenge for early asthmatic response (EAR) and a positive late asthmatic response (LAR) to an inhaled allergen challenge as defined by a bronchoconstrictive response of at least 15% reduction in FEV1 3 to 8 hours after allergen challenge * Can tolerate sputum induction and produce adequate sputum
Exclusion criteria
Parts 1 and 2 * Has a history of any illness that, in the opinion of the study investigator, might confound the results of the study or poses additional risk to the participant * Has recent (4 weeks) or ongoing upper or lower respiratory tract infection * Is unable to refrain from or anticipates the use of any medication other than the ones permitted in this study * Has taken oral, intramuscular, intra-articular, high-potency topical or orally inhaled corticosteroids within 8 weeks * Has taken the following medications outside the washout margins: nasal corticosteroids and anti-leukotrienes within 3 weeks; inhaled long-acting β2-agonists, long-acting antihistamines (e.g., loratadine, sustained-release agents), intra-nasal anticholinergics over-the-counter decongestants within 1 week; short-acting oral decongestants, short-acting antihistamines (e.g., chlorpheniramine) within 48 hours * Consumes excessive amounts of alcohol or caffeinated beverages * Has had major surgery, donated or lost 1 unit of blood or participated in another investigational study within 3 months * Has a history of severe allergies, or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food * Is a nursing mother * Has a history of receiving anti-immunoglobulin E (IgE) or immunotherapy * Has a history of serious allergies to drugs or a history of hypersensitivity to mometasone furoate or any of its inactive ingredients such as lactose, or inhaled salbutamol, antihistamines, or any other potential asthma/anaphylaxis rescue medication Part 2 only \- Has a decline in FEV1 of 70% or greater from the post allergen diluent baseline and/or FEV1 \<1.0L or has symptomatic drop in FEV1 associated with shortness of breath unresolved with bronchodilators within a reasonable timeframe (60 minutes) after the allergen challenge study in Period 1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Percent (%) Eosinophils in Induced Sputum At 8 Hours Post Allergen | Baseline (Day -1) and Day 5 (8 hours after allergen challenge in each treatment period) | The effect of MK-1029 on the reduction of percent (%) sputum eosinophils following allergen challenge with standardized cat pelt or hair (CPH) allergen extract was assessed. Baseline % eosinophils were measured before treatment (and pre-allergen challenge) on Day -1. The change from baseline in allergen-induced % sputum eosinophils at 8 hr post allergen challenge testing on Day 5 was analyzed using a repeated measures linear mixed effects model with treatment, period, time, time-by-treatment interaction as fixed factors, and participant as a random factor. Outcome Measure 6 shows % eosinophil values at baseline. |
| Forced Expiratory Volume in One Second (FEV1) From 3 to 8 Hours Postdose (AUC3-8hr) During the Late Asthmatic Response (LAR) | From 3 to 8 hours after allergen challenge on Day 5 of each treatment period | The effect of MK-1029 on the FEV1 AUC(3-8hr) during LAR was assessed. The unit of measure for an FEV1 AUC value is L\*hr. The effect of treatment on LAR was assessed as the percent-fall in FEV1 AUC(3-8hr), evaluated by spirometry following allergen challenge on Day 5. The FEV1 AUC(3-8hr) during LAR was analyzed using a linear mixed effects model with treatment and period as fixed factors and participant as a random factor. |
| Number of Participants With an Adverse Event (AE) | Up to 26 days in each treatment period | The number of participants who had at least one adverse event (AE) during study treatment and follow-up was assessed. 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 SPONSOR's product, whether or not considered related to the use of the product. |
| Number of Participants Discontinuing Treatment Due to an AE | Up to 5 days in each treatment period | The number of participants who discontinued study treatment due to an AE was assessed. 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 SPONSOR's product, whether or not considered related to the use of the product. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Inhibition of the Expression of Cluster of Differentiation (CD)11b on Blood Eosinophils | Baseline (Day -1, predose), 24 hours after allergen challenge on Day 5 in each treatment period | The concentration of CD11b in whole blood samples was assessed. The percent-inhibition of CD11b (a cell-surface biomarker on activated eosinophils) was assessed following inhaled allergen challenge on Day 5. Inhibition of CD11b expression was assessed by analyzing the % inhibition of CD11b expression from baseline (Day -1) using a linear mixed-effects model with period, treatment, time, and treatment by time as fixed terms and subject as a random term. Outcome Measure 7 shows CD11b expression values at baseline. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Baseline Expression of Cluster of Differentiation (CD)11b on Blood Eosinophils | Day 1, predose | Baseline values for the antibody-specific expression of CD11b in whole blood samples, as obtained by flow cytometry, were obtained. The baseline CD11b values were obtained before treatment with MK-1029 60 mg, MK-1029 500 mg, or placebo, and were used to assess the effects of treatment. |
| Baseline (Pre-Treatment) Percent (%) Eosinophils | Baseline (Day -1), pre-antigen challenge | Baseline values of the percent (%) sputum eosinophils were measured pre-antigen challenge on Day -1. The baseline % eosinophil values were provided to assess the change from baseline after treatment. |
Participant flow
Pre-assignment details
This was a 2-part study. Part 1 was a procedural pilot, performed first and including placebo run-in (Period 1), with no study drug administration. Part 2 began with pre-randomization placebo run-in (Period 1), followed by 3 randomized, crossover treatment periods (Periods 2, 3, and 4). The Participant Flow applies only to randomized participants.
Participants by arm
| Arm | Count |
|---|---|
| Randomized Participants Crossover treatment with MK-1029 60 mg, MK-1029 500 mg, and matching placebo | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Second Treatment Period (Part 2) | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 |
| Second Washout (Part 2) | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Randomized Participants |
|---|---|
| Age, Continuous | 35.3 years STANDARD_DEVIATION 7.2 |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 16 | 0 / 16 |
| other Total, other adverse events | 11 / 14 | 10 / 16 | 11 / 16 |
| serious Total, serious adverse events | 0 / 14 | 0 / 16 | 0 / 16 |
Outcome results
Primary
Forced Expiratory Volume in One Second (FEV1) From 3 to 8 Hours Postdose (AUC3-8hr) During the Late Asthmatic Response (LAR)
The effect of MK-1029 on the FEV1 AUC(3-8hr) during LAR was assessed. The unit of measure for an FEV1 AUC value is L\*hr. The effect of treatment on LAR was assessed as the percent-fall in FEV1 AUC(3-8hr), evaluated by spirometry following allergen challenge on Day 5. The FEV1 AUC(3-8hr) during LAR was analyzed using a linear mixed effects model with treatment and period as fixed factors and participant as a random factor.
Time frame: From 3 to 8 hours after allergen challenge on Day 5 of each treatment period
Population: Participants who comply with the protocol sufficiently to ensure data obtained will be likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-1029 60 mg | Forced Expiratory Volume in One Second (FEV1) From 3 to 8 Hours Postdose (AUC3-8hr) During the Late Asthmatic Response (LAR) | 41.24 L*hr |
| MK-1029 500 mg | Forced Expiratory Volume in One Second (FEV1) From 3 to 8 Hours Postdose (AUC3-8hr) During the Late Asthmatic Response (LAR) | 49.76 L*hr |
| Placebo | Forced Expiratory Volume in One Second (FEV1) From 3 to 8 Hours Postdose (AUC3-8hr) During the Late Asthmatic Response (LAR) | 86.37 L*hr |
p-value: 0.00690% CI: [0.32, 0.72]Linear mixed effects model
p-value: 0.01290% CI: [0.41, 0.81]Linear mixed effects model
Primary
Number of Participants Discontinuing Treatment Due to an AE
The number of participants who discontinued study treatment due to an AE was assessed. 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 SPONSOR's product, whether or not considered related to the use of the product.
Time frame: Up to 5 days in each treatment period
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-1029 60 mg | Number of Participants Discontinuing Treatment Due to an AE | 0 Participants |
| MK-1029 500 mg | Number of Participants Discontinuing Treatment Due to an AE | 0 Participants |
| Placebo | Number of Participants Discontinuing Treatment Due to an AE | 1 Participants |
Primary
Number of Participants With an Adverse Event (AE)
The number of participants who had at least one adverse event (AE) during study treatment and follow-up was assessed. 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 SPONSOR's product, whether or not considered related to the use of the product.
Time frame: Up to 26 days in each treatment period
Population: All randomized participants who received at least one dose of study treatment and had follow-up.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-1029 60 mg | Number of Participants With an Adverse Event (AE) | 11 Participants |
| MK-1029 500 mg | Number of Participants With an Adverse Event (AE) | 10 Participants |
| Placebo | Number of Participants With an Adverse Event (AE) | 11 Participants |
Primary
Percent Change From Baseline in Percent (%) Eosinophils in Induced Sputum At 8 Hours Post Allergen
The effect of MK-1029 on the reduction of percent (%) sputum eosinophils following allergen challenge with standardized cat pelt or hair (CPH) allergen extract was assessed. Baseline % eosinophils were measured before treatment (and pre-allergen challenge) on Day -1. The change from baseline in allergen-induced % sputum eosinophils at 8 hr post allergen challenge testing on Day 5 was analyzed using a repeated measures linear mixed effects model with treatment, period, time, time-by-treatment interaction as fixed factors, and participant as a random factor. Outcome Measure 6 shows % eosinophil values at baseline.
Time frame: Baseline (Day -1) and Day 5 (8 hours after allergen challenge in each treatment period)
Population: Participants who comply with the protocol sufficiently to ensure data obtained will be likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-1029 60 mg | Percent Change From Baseline in Percent (%) Eosinophils in Induced Sputum At 8 Hours Post Allergen | -10.6 Percent change |
| MK-1029 500 mg | Percent Change From Baseline in Percent (%) Eosinophils in Induced Sputum At 8 Hours Post Allergen | -7.3 Percent change |
| Placebo | Percent Change From Baseline in Percent (%) Eosinophils in Induced Sputum At 8 Hours Post Allergen | 11.6 Percent change |
p-value: 0.01190% CI: [-35.7, -8.7]Linear mixed effects model
p-value: 0.02390% CI: [-32.1, -5.8]Linear mixed effects model
Secondary
Percent Inhibition of the Expression of Cluster of Differentiation (CD)11b on Blood Eosinophils
The concentration of CD11b in whole blood samples was assessed. The percent-inhibition of CD11b (a cell-surface biomarker on activated eosinophils) was assessed following inhaled allergen challenge on Day 5. Inhibition of CD11b expression was assessed by analyzing the % inhibition of CD11b expression from baseline (Day -1) using a linear mixed-effects model with period, treatment, time, and treatment by time as fixed terms and subject as a random term. Outcome Measure 7 shows CD11b expression values at baseline.
Time frame: Baseline (Day -1, predose), 24 hours after allergen challenge on Day 5 in each treatment period
Population: Participants who comply with the protocol sufficiently to ensure data obtained will be likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-1029 60 mg | Percent Inhibition of the Expression of Cluster of Differentiation (CD)11b on Blood Eosinophils | 89.9 Percentage of inhibition |
| MK-1029 500 mg | Percent Inhibition of the Expression of Cluster of Differentiation (CD)11b on Blood Eosinophils | 87.4 Percentage of inhibition |
| Placebo | Percent Inhibition of the Expression of Cluster of Differentiation (CD)11b on Blood Eosinophils | 4.1 Percentage of inhibition |
p-value: <0.00190% CI: [65.3, 106.4]Linear mixed effects model
p-value: <0.00190% CI: [63.9, 102.7]Linear mixed effects model
Other Pre-specified
Baseline Expression of Cluster of Differentiation (CD)11b on Blood Eosinophils
Baseline values for the antibody-specific expression of CD11b in whole blood samples, as obtained by flow cytometry, were obtained. The baseline CD11b values were obtained before treatment with MK-1029 60 mg, MK-1029 500 mg, or placebo, and were used to assess the effects of treatment.
Time frame: Day 1, predose
Population: Participants who were compliant with the protocol sufficiently to ensure their data would be likely to exhibit the effects of treatment were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-1029 60 mg | Baseline Expression of Cluster of Differentiation (CD)11b on Blood Eosinophils | 62619 Antibody fluorescence units | Standard Deviation 28790 |
| MK-1029 500 mg | Baseline Expression of Cluster of Differentiation (CD)11b on Blood Eosinophils | 62254 Antibody fluorescence units | Standard Deviation 13690 |
| Placebo | Baseline Expression of Cluster of Differentiation (CD)11b on Blood Eosinophils | 63398 Antibody fluorescence units | Standard Deviation 22022 |
Other Pre-specified
Baseline (Pre-Treatment) Percent (%) Eosinophils
Baseline values of the percent (%) sputum eosinophils were measured pre-antigen challenge on Day -1. The baseline % eosinophil values were provided to assess the change from baseline after treatment.
Time frame: Baseline (Day -1), pre-antigen challenge
Population: Participants who were compliant with the protocol sufficiently to ensure their data would be likely to exhibit the effects of treatment were included.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MK-1029 60 mg | Baseline (Pre-Treatment) Percent (%) Eosinophils | 18.42 % sputum eosinophils |
| MK-1029 500 mg | Baseline (Pre-Treatment) Percent (%) Eosinophils | 17.04 % sputum eosinophils |
| Placebo | Baseline (Pre-Treatment) Percent (%) Eosinophils | 11.99 % sputum eosinophils |