Efficacy and Safety of Navarixin (SCH 527123) in Participants With Allergen-Induced Asthma (P05363)

A Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Efficacy and Safety of SCH 527123 in Subjects With Allergen-Induced Asthma

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00688467

Enrollment

Registered

2008-06-03

Start date

2008-06-01

Completion date

2009-03-01

Last updated

2019-01-02

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Asthma

Keywords

Neutrophilic Asthma

Brief summary

Evaluation of treatment in participants with mild asthma.

Detailed description

To evaluate the effect of navarixin (MK-527123, SCH 527123) treatment on allergen-induced late asthmatic response (LAR) in participants with mild asthma.

Interventions

DRUGNavarixin

30 mg capsule to be taken once daily in the morning for 10 days during Treatment Period 1 or Treatment Period 2

DRUGPlacebo

Matching capsule to be taken once daily in the morning for 10 days during Treatment Period 1 or Treatment Period 2

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

Inclusion criteria

* Man or woman 18 to 65 years of age of any race. * Has mild, stable, allergic asthma as defined by American Thoracic Society criteria. * Has history of episodic wheezing and shortness of breath. * Has Forced Expiratory Volume in 1 second (FEV1) of at least 70% of predicted at Screening and within 10% of preallergen screening value at both baselines. * Has positive methacholine challenge at Screening. Methacholine challenges are considered positive if decreases of at least 20% in the FEV1 occur at a concentration of less than or equal to 16 mg/mL. * Baseline methacholine PC20 (concentration that initiated a 20% fall in FEV1) must be within 1 doubling concentration of the preallergen screening PC20 to enter treatment. * Has positive skin-prick test to common allergens (cat, dust mite, grass, pollen). * Has a positive Early Asthmatic Response of \>=20% fall in FEV1 measured from the FEV1 immediately prior to challenge, and Late Asthmatic Response of \>=15% fall in FEV1 from the FEV1 measured immediately prior to challenge during Screening period. * Has been free from asthma exacerbation for at least 4 weeks before Screening. An exacerbation is defined as an occurrence of any clinical deterioration of asthma that requires emergency treatment, hospitalization due to asthma, or treatment with additional medication, as judged by the clinical investigator. * Has been free from relevant seasonal allergen exposure for at least 4 weeks before the study and be able to remain so for the duration of the study. * Has a current nonsmoking status. If previous smokers, cumulative smoking history must be fewer than 10 pack-years (pack-year=20 cigarettes smoked daily for 1 year). Previous smokers must not have smoked within 1 year before Screening. * Is willing to give written informed consent to participate in the study. * Has the ability to comply with the dosing regimen, to adhere to the visit schedule, and to participate in all treatment procedures, including sputum induction. * Female participant of childbearing potential must have a negative serum pregnancy tests (human chorionic gonadotropin; hCG) at Screening and must use 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 agrees to continue using it while in the study (Screening and Treatment Periods). Medically acceptable, highly effective forms of birth control include hormonal implants, oral contraceptives, hormonal patches, intravaginal ring, medically acceptable prescribed intrauterine devices (IUDs), and a monogamous relationship with a male partner who has had a vasectomy. A female participant 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 participant should be encouraged to continue using a highly effective method of birth control for 30 days following the end of treatment. * Participants, if male and sexually active with women of childbearing potential, must agree to use an adequate form of contraception for the duration of the study and to have sexual relations with only those women who use a highly effective birth control method. * Clinical laboratory tests (complete blood count \[CBC\], blood chemistries, and urinalysis) must be within normal limits or clinically acceptable to the investigator/sponsor.

Exclusion criteria

* Has had a diagnosis of chronic obstructive pulmonary disease (COPD) or any other clinically relevant lung disease (eg, cystic fibrosis, pulmonary fibrosis, bronchiectasis) other than mild allergic asthma, or has a history of having been intubated. * Has had a worsening of a respiratory tract infection within 4 weeks before Screening. * Has had any clinically significant abnormality; history of clinically significant hypotensive episodes of fainting, dizziness, or lightheadedness; history or symptoms of cardiovascular disease; significant neurologic disease; or hematologic abnormality, including coagulopathy; or has a medication regimen or clinically relevant medical condition other than asthma that may interfere with the effect of study medication. * Had a peripheral blood neutrophil (PBN) count of \<3 × 10\^9/L at the Screening Visit. * Has an allergy/sensitivity to the study drug or its excipients. * Is pregnant, breast-feeding, or intends to become pregnant during the study. * Has used any investigational drug within 30 days or 5 half-lives of Screening. * Is presently participating in any other clinical study. * Is part of the staff personnel directly involved with this study * Is a family member of the investigational study staff. * Has received any treatment prohibited by the protocol (Table 3), or any medication that may interfere with the effect of the study medication more recently than the indicated washout period prior to Screening, or must continue to receive the prohibited treatment.

Design outcomes

Primary

Measure	Time frame	Description
Percent Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve From 3 to 7 Hours (AUC3-7hr) After Allergen Challenge Following 9 Days Pretreatment With Navarixin	Baseline and between 3 and 7 hours after allergen challenge	This is a measure of the Late Asthmatic Response (LAR) between 3 and 7 hours after allergen challenge. Allergen challenge was administered 1 hour after the ninth daily dose of study drug in each treatment period. Baseline FEV1 was defined as the prechallenge FEV1 in the treatment period. A percent change \>0 indicates a fall in FEV1 after allergen challenge. The reported standard deviations (SDs) are pooled across all treatment groups. The rationale for the use of an analysis of variance using pooled SD values is the assumption that the SDs are similar across treatment groups. The pooled SD values were used in the calculation of test statistics to assess treatment differences (p-value generation).

Secondary

Measure	Time frame	Description
Change in Concentration of Methacholine That Initiated a 20% Reduction in FEV1 From 24 Hours Before (Baseline) to 24 Hours After Allergen Challenge	Baseline and 24 hours after allergen challenge	This is a measure of allergen-induced changes in airway responsiveness to methacholine. The reported SDs are pooled across all treatment groups. The rationale for the use of an analysis of variance using pooled SD values is the assumption that the SDs are similar across treatment groups.
Percent Change From Baseline in FEV1 Area Under the Curve From 0 to 2 Hours (AUC0-2hr) After Allergen Challenge Following 9 Days Pretreatment With Navarixin	Baseline and between 0 to 2 hours after allergen challenge	This is a measure of Early Asthmatic Response (EAR) between 0 to 2 hours after allergen challenge. Allergen challenge was administered 1 hour after the ninth daily dose of study drug in each treatment period. A percent change \>0 indicates a reduction in FEV1 from before to after allergen challenge. The reported SDs are pooled across all treatment groups. The rationale for the use of an analysis of variance using pooled SD values is the assumption that the SDs are similar across treatment groups. The pooled SD values were used in the calculation of test statistics to assess treatment differences (p-value generation).
Maximum Percent Change From Baseline in FEV1 During the Early Asthmatic Response Following 9 Days of Pretreatment With Navarixin	Baseline and between 0 to 2 hours after allergen challenge	Allergen challenge was administered 1 hour after the ninth daily dose of study drug in each treatment period. The EAR was 0 to 2 hours after allergen challenge. The reported SDs are pooled across all treatment groups. The rationale for the use of an analysis of variance using pooled SD values is the assumption that the SDs are similar across treatment groups. The pooled SD values were used in the calculation of test statistics to assess treatment differences (p-value generation).
Change From Baseline in Sputum Neutrophils After Allergen Challenge Following 9 Days Pretreatment With Navarixin	Baseline and 7 and 24 hours after allergen challenge	Induced sputum samples were collected via the nebulized method. Baseline values were determined at 24 hours before allergen challenge in each treatment period. Sputum neutrophils were measured as percent of total white blood cells. The reported SDs are pooled across all treatment groups. The rationale for the use of an analysis of variance using pooled SD values is the assumption that the SDs are similar across treatment groups.
Change From Baseline in Peripheral Blood Eosinophil Count After Allergen Challenge Following 9 Days Pretreatment With Navarixin	Baseline and 7 and 24 hours after allergen challenge	Baseline values were determined at 24 hours before allergen challenge in each treatment period. The reported SDs are pooled across all treatment groups. The rationale for the use of an analysis of variance using pooled SD values is the assumption that the SDs are similar across treatment groups.
Maximum Change From Baseline in FEV1 During the LAR Following 9 Days of Pretreatment With Navarixin	Baseline and between 3 and 7 hours after allergen challenge	Allergen challenge was administered 1 hour after the ninth daily dose of study drug in each treatment period. Baseline FEV1 was defined as the prechallenge FEV1 in the treatment period. The LAR was 3 to 7 hours after allergen challenge. The reported SDs are pooled across all treatment groups. The rationale for the use of an analysis of variance using pooled SD values is the assumption that the SDs are similar across treatment groups. The pooled SD values were used in the calculation of test statistics to assess treatment differences (p-value generation).
Change From Baseline in Sputum Neutrophil Elastase After Allergen Challenge Following 9 Days Pretreatment With Navarixin	Baseline and 7 and 24 hours after allergen challenge	Induced sputum samples were to be collected via the nebulized method. Neutrophil elastase activity was measured in the sputum supernatant as milli units/mL (mU/mL). Baseline values were determined at 24 hours before allergen challenge in each treatment period. The reported SDs are pooled across all treatment groups. The rationale for the use of an analysis of variance using pooled SD values is the assumption that the SDs are similar across treatment groups.
Change From Baseline in Sputum Myeloperoxidase (MPO) Level After Allergen Challenge Following 9 Days Pretreatment With Navarixin	Baseline and 7 and 24 hours after allergen challenge	Induced sputum samples were to be collected via the nebulized method. MPO level was measured in the sputum supernatant.
Change From Baseline in Sputum Eosinophil Cationic Protein (ECP) Level After Allergen Challenge Following 9 Days Pretreatment With Navarixin	Baseline and 7 and 24 hours after allergen challenge	Induced sputum samples were to be collected via the nebulized method. ECP level was measured in the sputum supernatant.
Number of Participants With an Adverse Event (AE)	Up to 48 days	An AE is any unfavorable and unintended sign (eg, an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to study drug. AEs were reported based on the study drug taken at the time of the event.
Number of Participants Discontinued From the Study Because of an Adverse Event	Up to 48 days	An AE is any unfavorable and unintended sign (eg, an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to study drug. Discontinuations due to an AE are reported based on the study drug taken at the time of the event.
Change From Baseline in Sputum Interleukin 8 (IL-8) After Allergen Challenge Following 9 Days Pretreatment With Navarixin	Baseline and 7 and 24 hours after allergen challenge	Induced sputum samples were to be collected via the nebulized method. IL-8 level was measured in the sputum supernatant. Baseline values were determined at 24 hours before allergen challenge in each treatment period. The reported SDs are pooled across all treatment groups. The rationale for the use of an analysis of variance using pooled SD values is the assumption that the SDs are similar across treatment groups.

Participant flow

Participants by arm

Arm	Count
Navarixin → Placebo Navarixin 30 mg capsule to be taken once daily in the morning for 10 days in Treatment Period 1, followed by a 2-4 week washout period, followed by matching placebo capsule to be taken once daily in the morning for 10 days in Treatment Period 2	9
Placebo → Navarixin Matching placebo capsule to be taken once daily in the morning for 10 days in Treatment Period 1, followed by a 2-4 week washout period, followed by navarixin 30 mg capsule to be taken once daily in the morning for 10 days in Treatment Period 2	10
Total	19

Withdrawals & dropouts

Period	Reason	FG000	FG001
Treatment Period 1	Adverse Event	2	1
Treatment Period 1	Did not meet protocol eligibility	0	1
Treatment Period 2	Adverse Event	0	1
Treatment Period 2	Protocol Violation	0	1

Baseline characteristics

Characteristic	Navarixin → Placebo	Placebo → Navarixin	Total
Age, Continuous	34.3 Years STANDARD_DEVIATION 12	24.9 Years STANDARD_DEVIATION 4	29.4 Years STANDARD_DEVIATION 9.8
Sex: Female, Male Female	6 Participants	7 Participants	13 Participants
Sex: Female, Male Male	3 Participants	3 Participants	6 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	8 / 16	8 / 17
serious Total, serious adverse events	0 / 16	1 / 17

Outcome results

Primary

Percent Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve From 3 to 7 Hours (AUC3-7hr) After Allergen Challenge Following 9 Days Pretreatment With Navarixin

This is a measure of the Late Asthmatic Response (LAR) between 3 and 7 hours after allergen challenge. Allergen challenge was administered 1 hour after the ninth daily dose of study drug in each treatment period. Baseline FEV1 was defined as the prechallenge FEV1 in the treatment period. A percent change \>0 indicates a fall in FEV1 after allergen challenge. The reported standard deviations (SDs) are pooled across all treatment groups. The rationale for the use of an analysis of variance using pooled SD values is the assumption that the SDs are similar across treatment groups. The pooled SD values were used in the calculation of test statistics to assess treatment differences (p-value generation).

Time frame: Baseline and between 3 and 7 hours after allergen challenge

Population: The population analyzed included all participants who completed both treatment periods

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Navarixin	Percent Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve From 3 to 7 Hours (AUC3-7hr) After Allergen Challenge Following 9 Days Pretreatment With Navarixin	26.225 Percent change from baseline	Standard Deviation 27.377
Placebo	Percent Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve From 3 to 7 Hours (AUC3-7hr) After Allergen Challenge Following 9 Days Pretreatment With Navarixin	35.427 Percent change from baseline	Standard Deviation 27.377

p-value: 0.411ANOVA

Secondary

Change From Baseline in Peripheral Blood Eosinophil Count After Allergen Challenge Following 9 Days Pretreatment With Navarixin

Baseline values were determined at 24 hours before allergen challenge in each treatment period. The reported SDs are pooled across all treatment groups. The rationale for the use of an analysis of variance using pooled SD values is the assumption that the SDs are similar across treatment groups.