Neutrophilic Asthma
Conditions
Brief summary
4-Week Safety Study in Subjects with Neutrophilic Asthma
Detailed description
Effect of treatment with navarixin (MK-7123, SCH 527123) on sputum neutrophils and asthma symptoms
Interventions
DRUGNavarixin
Navarixin 30 mg capsule to be taken by mouth once daily in the morning for 4 weeks.
DRUGPlacebo
Placebo capsule to match navarixin to be taken by mouth once daily in the morning for 4 weeks.
DRUGRescue medication
Participant choice of short-acting beta-2 agonist (salbutamol/albuterol), anticholinergic, or combination medication as needed for asthma symptoms
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* 18 to \<=70 years of age, either sex, any race. * Induced sputum neutrophil count \>=40% of total white blood cells and \<10 million/mL at Screening. * Documented diagnosis of asthma (within past 5 years), determined by at least one of the following: \>=12% and 200 mL improvement in Forced Expiratory Volume in 1 second (FEV1) post-bronchodilator, and/or airway hyperresponsiveness (eg, positive methacholine challenge \<8 mg/mL). * Nonsmoker or previous smoker with cumulative smoking history less than 20 pack-years (pack-year = 20 cigarettes smoked daily for 1 year). Previous smokers may not have smoked within 1 year prior to Screening. * Must not have had an exacerbation of asthma for 4 weeks prior to Screening and must be on a stable medication regimen for asthma at least 4 weeks prior to Screening. * Must be receiving \>=800 mcg/day of beclomethasone dipropionate (BDP) or equivalent for at least 3 months prior to Screening (and on stable dose for at least 4 weeks prior to Screening). * Must be willing to give written informed consent to participate in the study * Must be capable of complying with the dosing regimen, adhere to the visit schedule, and participate in all treatment procedures, including sputum induction. * Female subject of childbearing potential must have a negative serum pregnancy test at Screening and must be using a medically acceptable, highly effective, adequate form of birth control (ie, failure rate \<1% per year when used consistently and correctly) prior to Screening and agree to continue using it while in the study (Screening and Treatment Periods). Medically acceptable, highly effective forms of birth control are hormonal implants, oral contraceptives, medically acceptable prescribed intrauterine devices (IUDs), and monogamous relationship with a male partner who has had a vasectomy. Female subject who is not of childbearing potential must have a medical record of being surgically sterile (eg, hysterectomy, tubal ligation), or be at least 1 year postmenopausal. Absence of menses for at least 1 year will indicate that a female is postmenopausal. A female subject should be encouraged to continue using a highly effective method of birth control for 30 days following the end of treatment. * Male subject must agree to use an adequate form of contraception for the duration of the study and agree to have sexual relations only with women who use a highly effective birth control method.
Exclusion criteria
* Chronic Obstructive Pulmonary Disease (COPD)/other relevant lung disease (other than asthma). * 4 weeks prior to/or Screening: upper/lower respiratory tract infection. * Prohibited medications received more recently than indicated washout prior to Screening * Screening: Inadequate amount or difficulty producing sputum. * Screening: Sputum neutrophil count over 10 million/mL. * Screening: peripheral blood neutrophil (PBN) count \<3000/µL. * Post-bronchodilator FEV1 \<1L. * Clinically significant chronic infectious disease(s) (eg, Human Immunodeficiency Virus \[HIV\], hepatitis B or C). * Allergy/sensitivity to study drug/excipients. * Breast-feeding, pregnant/intends to become pregnant during study. * Requiring mechanical ventilation for respiratory event within 6 months of Screening. * Medical condition(s) (eg, hematologic, cardiovascular, renal, hepatic, neurologic, or metabolic) or medication that may interfere with effect of study medication. * Within 30 days of Screening: any other investigational drug. * Participation in any other clinical study. * Part of the staff personnel involved with the study. * Family member of investigational study staff.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Maintained an Absolute Peripheral Blood Neutrophil Count >=1500/µL | Up to 4 weeks | Peripheral blood neutrophil counts were performed on Day 2 and Weeks 1, 2, 3, and 4 of the treatment period |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Total Asthma Symptom Score | Baseline and Weeks 1, 2, 3, and 4 | Total Asthma Symptom Score is the sum of individual symptoms of wheezing, coughing, and dyspnea assessed twice daily (morning and evening) and is recorded on a comment diary card. Each of the symptoms receives a daily score from 0 (none) to 3 (severe), averaged over the two daily assessments. The total score ranges from 0 to 9, with a lower score indicating less severe asthma symptoms. |
| Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in One Second (FEV1) | Baseline and up to 4 weeks | Spirometry was used to measure post-bronchodilator FEV1 at Baseline and before study drug administration at Weeks 1, 2, 3, and 4. Participants received 4 puffs of bronchodilator (salbutamol hydrofluoroalkane or equivalent) at 30-second intervals and spirometry was performed 30 minutes later. The mean change from baseline is based on the average change over all post-baseline assessments. |
| Change From Baseline in Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ[S]) | Baseline and up to 4 weeks | The AQLQ\[S\] was administered at Baseline and at Weeks 2 and 4. The assessment consists of a 32-item questionnaire covering 4 domains: symptoms, emotional functioning, impact of environmental stimuli, and activity limitation. Each item receives a score from 1 (worst, or most affected) to 7 (not at all affected). The score is the mean across all items, and ranges from 1 to 7. The mean change from baseline is based on the average change over all post-baseline assessments. |
| Number of Participants With an Adverse Event (AE) | Up to 5 weeks | An AE is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. AEs may include the onset of new illness and the exacerbation of pre-existing conditions. |
| Mean Change From Baseline in Sputum Absolute Neutrophil Count | Baseline and while on study drug (up to 4 weeks) | Induced sputum samples were obtained at Baseline and at Weeks 2 and 4 of the treatment period. Samples were collected before study drug administration using the nebulizer method and sent to a central laboratory for analysis. An average was taken over all post-baseline samples collected no later than one day after the last dose of study drug. |
| Number of Participants With a Laboratory Adverse Event | Up to 5 weeks | The endpoint measured was any laboratory (hematology, blood chemistry, or urinalysis) abnormality that was reported as an AE. An AE is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. AEs may include the onset of new illness and the exacerbation of pre-existing conditions. |
| Number of Participants Who Discontinued the Study Because of an Adverse Event | Up to 5 weeks | An AE is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. AEs may include the onset of new illness and the exacerbation of pre-existing conditions. |
| Number of Participants Who Discontinued Treatment Because of an Adverse Event or a Protocol-defined Clinical Event | Up to 4 weeks | An AE is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. AEs may include the onset of new illness and the exacerbation of pre-existing conditions. A protocol-defined clinical event is an asthma exacerbation requiring addition of or increase in systemic steroids, as determined by the investigator. |
| Maximum Plasma Concentration of Navarixin (Cmax) | Week 1, 2, 3, and 4 | Plasma samples were to be collected at baseline and up to 24 hours after dosing with navarixin at Weeks 1, 2, 3, and 4 |
| Number of Participants With an Electrocardiogram Adverse Event | Week 4 | The endpoint measured was any electrocardiogram abnormality that was reported as an AE. An AE is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. AEs may include the onset of new illness and the exacerbation of pre-existing conditions. |
Participant flow
Pre-assignment details
Participants were considered to complete the study if they completed the follow-up visit, whether or not they completed treatment.
Participants by arm
| Arm | Count |
|---|---|
| Navarixin Navarixin 30 mg capsule to be taken by mouth once daily for 4 weeks | 22 |
| Placebo Placebo capsule to be taken by mouth once daily for 4 weeks | 12 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Randomized not treated | 3 | 0 |
Baseline characteristics
| Characteristic | Navarixin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 48.7 Years STANDARD_DEVIATION 10.6 | 53.9 Years STANDARD_DEVIATION 6.8 | 50.6 Years STANDARD_DEVIATION 9.6 |
| Sex: Female, Male Female | 13 Participants | 7 Participants | 20 Participants |
| Sex: Female, Male Male | 9 Participants | 5 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 22 | 8 / 12 |
| serious Total, serious adverse events | 0 / 22 | 0 / 12 |
Outcome results
Primary
Number of Participants Who Maintained an Absolute Peripheral Blood Neutrophil Count >=1500/µL
Peripheral blood neutrophil counts were performed on Day 2 and Weeks 1, 2, 3, and 4 of the treatment period
Time frame: Up to 4 weeks
Population: The analysis population included all participants who received at least one dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Navarixin | Number of Participants Who Maintained an Absolute Peripheral Blood Neutrophil Count >=1500/µL | 20 Number of participants |
| Placebo | Number of Participants Who Maintained an Absolute Peripheral Blood Neutrophil Count >=1500/µL | 12 Number of participants |
Secondary
Change From Baseline in Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ[S])
The AQLQ\[S\] was administered at Baseline and at Weeks 2 and 4. The assessment consists of a 32-item questionnaire covering 4 domains: symptoms, emotional functioning, impact of environmental stimuli, and activity limitation. Each item receives a score from 1 (worst, or most affected) to 7 (not at all affected). The score is the mean across all items, and ranges from 1 to 7. The mean change from baseline is based on the average change over all post-baseline assessments.
Time frame: Baseline and up to 4 weeks
Population: The analysis population included all randomized participants who received at least one dose of study drug and had endpoint evaluation at Baseline or at any post-baseline visit
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Navarixin | Change From Baseline in Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ[S]) | Baseline AQLQ[S] Score | 4.822 Score on a scale | Standard Deviation 1.568 |
| Navarixin | Change From Baseline in Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ[S]) | Average change from baseline at up to 4 weeks | 0.165 Score on a scale | Standard Deviation 0.901 |
| Placebo | Change From Baseline in Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ[S]) | Baseline AQLQ[S] Score | 4.897 Score on a scale | Standard Deviation 1.128 |
| Placebo | Change From Baseline in Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ[S]) | Average change from baseline at up to 4 weeks | 0.119 Score on a scale | Standard Deviation 0.936 |
Secondary
Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in One Second (FEV1)
Spirometry was used to measure post-bronchodilator FEV1 at Baseline and before study drug administration at Weeks 1, 2, 3, and 4. Participants received 4 puffs of bronchodilator (salbutamol hydrofluoroalkane or equivalent) at 30-second intervals and spirometry was performed 30 minutes later. The mean change from baseline is based on the average change over all post-baseline assessments.
Time frame: Baseline and up to 4 weeks
Population: The analysis population included all randomized participants who received at least one dose of study drug and had endpoint assessment at Baseline or at any post-baseline visit
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Navarixin | Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in One Second (FEV1) | Baseline FEV1 | 2.197 Liters | Standard Deviation 0.948 |
| Navarixin | Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in One Second (FEV1) | Average change from baseline at up to 4 weeks | -0.099 Liters | Standard Deviation 0.315 |
| Placebo | Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in One Second (FEV1) | Baseline FEV1 | 1.851 Liters | Standard Deviation 0.469 |
| Placebo | Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in One Second (FEV1) | Average change from baseline at up to 4 weeks | -0.094 Liters | Standard Deviation 0.106 |
Secondary
Maximum Plasma Concentration of Navarixin (Cmax)
Plasma samples were to be collected at baseline and up to 24 hours after dosing with navarixin at Weeks 1, 2, 3, and 4
Time frame: Week 1, 2, 3, and 4
Population: The analysis population was to include all participants who received at least one dose of navarixin and had navarixin plasma concentrations available for endpoint evaluation. The planned outcome measure was not evaluated.
Secondary
Mean Change From Baseline in Sputum Absolute Neutrophil Count
Induced sputum samples were obtained at Baseline and at Weeks 2 and 4 of the treatment period. Samples were collected before study drug administration using the nebulizer method and sent to a central laboratory for analysis. An average was taken over all post-baseline samples collected no later than one day after the last dose of study drug.
Time frame: Baseline and while on study drug (up to 4 weeks)
Population: The analysis population included all randomized participants who received at least one dose of study drug and had sputum absolute neutrophil counts at Baseline or Week 4
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Navarixin | Mean Change From Baseline in Sputum Absolute Neutrophil Count | Baseline sputum absolute neutrophil count | 3.275 Neutrophil count X10^9/L | Standard Deviation 3.995 |
| Navarixin | Mean Change From Baseline in Sputum Absolute Neutrophil Count | Change from baseline at up to 4 weeks | -0.270 Neutrophil count X10^9/L | Standard Deviation 6.673 |
| Placebo | Mean Change From Baseline in Sputum Absolute Neutrophil Count | Baseline sputum absolute neutrophil count | 3.408 Neutrophil count X10^9/L | Standard Deviation 2.973 |
| Placebo | Mean Change From Baseline in Sputum Absolute Neutrophil Count | Change from baseline at up to 4 weeks | 0.680 Neutrophil count X10^9/L | Standard Deviation 2.249 |
Secondary
Mean Change From Baseline in Total Asthma Symptom Score
Total Asthma Symptom Score is the sum of individual symptoms of wheezing, coughing, and dyspnea assessed twice daily (morning and evening) and is recorded on a comment diary card. Each of the symptoms receives a daily score from 0 (none) to 3 (severe), averaged over the two daily assessments. The total score ranges from 0 to 9, with a lower score indicating less severe asthma symptoms.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Population: The analysis population included all randomized participants who received at least one dose of study drug and had Asthma Symptom Scores evaluated at the time points reported
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Navarixin | Mean Change From Baseline in Total Asthma Symptom Score | Change at 1 week (n=21, 12) | -0.07 Score on a scale | Standard Deviation 1.01 |
| Navarixin | Mean Change From Baseline in Total Asthma Symptom Score | Change at 3 weeks (n=19, 12) | -0.19 Score on a scale | Standard Deviation 1.56 |
| Navarixin | Mean Change From Baseline in Total Asthma Symptom Score | Change at 2 weeks (n=20, 12) | -0.25 Score on a scale | Standard Deviation 1.5 |
| Navarixin | Mean Change From Baseline in Total Asthma Symptom Score | Change at 4 weeks (n=18, 9) | -0.00 Score on a scale | Standard Deviation 1.62 |
| Navarixin | Mean Change From Baseline in Total Asthma Symptom Score | Baseline Total Asthma Symptom Score (n=21, 12) | 2.47 Score on a scale | Standard Deviation 1.83 |
| Placebo | Mean Change From Baseline in Total Asthma Symptom Score | Change at 4 weeks (n=18, 9) | -0.26 Score on a scale | Standard Deviation 2.06 |
| Placebo | Mean Change From Baseline in Total Asthma Symptom Score | Baseline Total Asthma Symptom Score (n=21, 12) | 2.40 Score on a scale | Standard Deviation 1.3 |
| Placebo | Mean Change From Baseline in Total Asthma Symptom Score | Change at 1 week (n=21, 12) | 0.05 Score on a scale | Standard Deviation 0.78 |
| Placebo | Mean Change From Baseline in Total Asthma Symptom Score | Change at 2 weeks (n=20, 12) | 0.19 Score on a scale | Standard Deviation 1.14 |
| Placebo | Mean Change From Baseline in Total Asthma Symptom Score | Change at 3 weeks (n=19, 12) | 0.04 Score on a scale | Standard Deviation 1.3 |
Secondary
Number of Participants Who Discontinued the Study Because of an Adverse Event
An AE is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. AEs may include the onset of new illness and the exacerbation of pre-existing conditions.
Time frame: Up to 5 weeks
Population: The analysis population included all participants who received at least one dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Navarixin | Number of Participants Who Discontinued the Study Because of an Adverse Event | 0 Participants |
| Placebo | Number of Participants Who Discontinued the Study Because of an Adverse Event | 1 Participants |
Secondary
Number of Participants Who Discontinued Treatment Because of an Adverse Event or a Protocol-defined Clinical Event
An AE is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. AEs may include the onset of new illness and the exacerbation of pre-existing conditions. A protocol-defined clinical event is an asthma exacerbation requiring addition of or increase in systemic steroids, as determined by the investigator.
Time frame: Up to 4 weeks
Population: The analysis population included all participants who received at least one dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Navarixin | Number of Participants Who Discontinued Treatment Because of an Adverse Event or a Protocol-defined Clinical Event | Protocol-defined clinical event | 1 Participants |
| Navarixin | Number of Participants Who Discontinued Treatment Because of an Adverse Event or a Protocol-defined Clinical Event | Adverse event | 2 Participants |
| Placebo | Number of Participants Who Discontinued Treatment Because of an Adverse Event or a Protocol-defined Clinical Event | Adverse event | 2 Participants |
| Placebo | Number of Participants Who Discontinued Treatment Because of an Adverse Event or a Protocol-defined Clinical Event | Protocol-defined clinical event | 1 Participants |
Secondary
Number of Participants With a Laboratory Adverse Event
The endpoint measured was any laboratory (hematology, blood chemistry, or urinalysis) abnormality that was reported as an AE. An AE is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. AEs may include the onset of new illness and the exacerbation of pre-existing conditions.
Time frame: Up to 5 weeks
Population: The analysis population included all participants who received at least one dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Navarixin | Number of Participants With a Laboratory Adverse Event | 2 Participants |
| Placebo | Number of Participants With a Laboratory Adverse Event | 0 Participants |
Secondary
Number of Participants With an Adverse Event (AE)
An AE is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. AEs may include the onset of new illness and the exacerbation of pre-existing conditions.
Time frame: Up to 5 weeks
Population: The analysis population included all participants who received at least one dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Navarixin | Number of Participants With an Adverse Event (AE) | 13 Participants |
| Placebo | Number of Participants With an Adverse Event (AE) | 8 Participants |
Secondary
Number of Participants With an Electrocardiogram Adverse Event
The endpoint measured was any electrocardiogram abnormality that was reported as an AE. An AE is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. AEs may include the onset of new illness and the exacerbation of pre-existing conditions.
Time frame: Week 4
Population: The analysis population included all participants who received at least one dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Navarixin | Number of Participants With an Electrocardiogram Adverse Event | 0 Participants |
| Placebo | Number of Participants With an Electrocardiogram Adverse Event | 0 Participants |