Study to Evaluate the Safety and Dose-Range of Navarixin (SCH 527123, MK-7123) in Participants With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) (MK-7123-012)

Study Overview
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Brief Summary
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This is a two-part study conducted at multiple centers, of navarixin (SCH 527123, MK-7123) in participants with moderate to severe chronic obstructive pulmonary disease (COPD). Part 1 of the study is a double-blind, placebo-controlled, randomized, rising-dose study consisting of four treatment groups enrolled in three cohorts. The duration of treatment, for each cohort, will be a 2-week run-in period, followed by a 12-week double-blind treatment period. Treatment initiation for each cohort was staggered by 4 weeks to allow for safety assessment prior to use of higher doses of navarixin. Part 2 of the study will be a double-blind, placebo-controlled, randomized, parallel group study consisting of four treatment groups enrolled as one cohort. The duration of treatment will consist of a 2-week run-in period, followed by a 12-week double-blind treatment period.

Official Title
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Safety and Dose-Ranging Study of the Effects of SCH 527123 in Subjects With Moderate to Severe COPD

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: Navarixin 1 mg
* Drug: Navarixin 10 mg
* Drug: Placebo to match navarixin
* Drug: Rescue medication


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of COPD based on the American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria. >40 to <=75 years of age, of either sex, and of any race. Current smoker with at least 10 pack-years of smoking history (eg, 10 pack-year history is equal to smoking 1 pack of cigarettes per day for 10 years or 2 packs per day for 5 years). Participant will be counseled on the risks of smoking and available smoking cessation programs prior to enrollment. Participant who elects to continue to smoke will be eligible for enrollment. Once enrolled, if a participant elects to discontinue smoking, or reduces cigarette consumption, he/she will be allowed to complete the study. History of daily sputum production for at least the past 3 months. Post-bronchodilator FEV1 must be >=800 mL, and >=40% to <=70% of predicted FEV1. Post-bronchodilator ratio of FEV1 to forced vital capacity (FVC) must be <=70%. Female participants of childbearing potential must be using a medically acceptable, highly effective, adequate form of birth control (ie, failure rate less than 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 participants should be encouraged to continue using a highly effective method of birth control 30 days following the end of treatment. Female participant of child-bearing potential who is not currently sexually active must agree to use a highly effective method of contraception should she become sexually active while participating in the study. Male participant must agree to use an adequate form of contraception for the duration of the study and agree to have sexual relations only with women using a highly effective birth control method according to the note for guidance on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals (CPMP/ICH/286/95 mod). A highly effective method of birth control is defined as that which results in a low failure rate (ie, less that 1% per year) when used consistently and correctly, such as hormonal implants, injectables, combined oral contraceptives, hormonal IUDs. 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. Capable of complying with the dosing regimen and visit schedules. Willing to give written informed consent to participate in the study. Exclusion Criteria: Diagnosed with asthma or other clinically relevant lung disease (other than COPD), eg, sarcoidosis, tuberculosis, pulmonary fibrosis, bronchiectasis, or lung cancer. History of previous lung surgery (eg, lobectomy, pneumonectomy, or lung volume reduction). Lower respiratory tract infection within 4 weeks prior to the Screening Visit. Receiving chronic antibiotic therapy. Exacerbation of COPD within the 4 weeks prior to the Screening Visit. >20% change at Screening in post-bronchodilator FEV1. Female participant who is breast-feeding, pregnant, or intends to become pregnant during the study. Clinically relevant medical conditions (eg, hematologic, cardiovascular, renal, hepatic, neurologic, or metabolic). Taken inhaled or systemic steroids within 4 weeks of Screening Visit (Visit 1). Received an investigational drug within the last 30 days. Produced an inadequate amount of sputum at the Screening Visit (Visit 1) or is known to have difficulty producing sputum. PBN count of <3000 cells/microliters at Screening Visit (Visit 1). Part of the staff personnel directly involved with this study. Family member of the investigational study staff. Received any study prohibited medication more recently than the indicated washout period, prior to (Screening), or who must continue to receive any prohibited treatment.

Ages Eligible for Study
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Minimum Age: 41 Years
Maximum Age: 75 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Navarixin 3 mg<br>Cohort 1: Participants receive navarixin 3 mg (three 1 mg capsules) once daily (QD) for up to 12 weeks | Drug: Navarixin 1 mg<br>* Navarixin 1 mg capsules<br>Drug: Rescue medication<br>* Salbutamol/albuterol - 2 puffs of salbutamol/albuterol approximately every 4 hours as needed for dyspnea relief<br>|
| Placebo Comparator: Part 1: Placebo to navarixin 3 mg<br>Cohort 1: Participants receive placebo to navarixin (three capsules) QD for up to 12 weeks | Drug: Placebo to match navarixin<br>* Placebo to navarixin capsules<br>Drug: Rescue medication<br>* Salbutamol/albuterol - 2 puffs of salbutamol/albuterol approximately every 4 hours as needed for dyspnea relief<br>|
| Experimental: Part 1: Navarixin 10 mg<br>Cohort 2: Participants receive navarixin 10 mg (one 10 mg capsule and two placebo capsules) QD for up to 12 weeks | Drug: Navarixin 10 mg<br>* Navarixin 10 mg capsules<br>Drug: Placebo to match navarixin<br>* Placebo to navarixin capsules<br>Drug: Rescue medication<br>* Salbutamol/albuterol - 2 puffs of salbutamol/albuterol approximately every 4 hours as needed for dyspnea relief<br>|
| Placebo Comparator: Part 1: Placebo to navarixin 10 mg<br>Cohort 2: Participants receive placebo to navarixin (three capsules) QD for up to 12 weeks | Drug: Placebo to match navarixin<br>* Placebo to navarixin capsules<br>Drug: Rescue medication<br>* Salbutamol/albuterol - 2 puffs of salbutamol/albuterol approximately every 4 hours as needed for dyspnea relief<br>|
| Experimental: Part 1: Navarixin 30 mg<br>Cohort 3: Participants receive navarixin 30 mg (three 10 mg capsules) QD for up to 12 weeks | Drug: Navarixin 10 mg<br>* Navarixin 10 mg capsules<br>Drug: Rescue medication<br>* Salbutamol/albuterol - 2 puffs of salbutamol/albuterol approximately every 4 hours as needed for dyspnea relief<br>|
| Placebo Comparator: Part 1: Placebo to navarixin 30 mg<br>Cohort 3: Participants receive placebo to navarixin (three capsules) QD for up to 12 weeks | Drug: Placebo to match navarixin<br>* Placebo to navarixin capsules<br>Drug: Rescue medication<br>* Salbutamol/albuterol - 2 puffs of salbutamol/albuterol approximately every 4 hours as needed for dyspnea relief<br>|
| Experimental: Part 2: Navarixin 3 mg<br>Cohort 4: Participants receive navarixin 3 mg (three 1 mg capsules) QD for up to 12 weeks | Drug: Navarixin 1 mg<br>* Navarixin 1 mg capsules<br>Drug: Rescue medication<br>* Salbutamol/albuterol - 2 puffs of salbutamol/albuterol approximately every 4 hours as needed for dyspnea relief<br>|
| Experimental: Part 2: Navarixin 10 mg<br>Cohort 4: Participants receive navarixin 10 mg (one 10 mg capsule and two placebo capsules) QD for up to 12 weeks | Drug: Navarixin 10 mg<br>* Navarixin 10 mg capsules<br>Drug: Placebo to match navarixin<br>* Placebo to navarixin capsules<br>Drug: Rescue medication<br>* Salbutamol/albuterol - 2 puffs of salbutamol/albuterol approximately every 4 hours as needed for dyspnea relief<br>|
| Experimental: Part 2: Navarixin 30 mg<br>Cohort 4: Participants receive navarixin 30 mg (three 10 mg capsules) QD for up to 12 weeks | Drug: Navarixin 10 mg<br>* Navarixin 10 mg capsules<br>Drug: Rescue medication<br>* Salbutamol/albuterol - 2 puffs of salbutamol/albuterol approximately every 4 hours as needed for dyspnea relief<br>|
| Placebo Comparator: Part 2: Placebo to navarixin<br>Cohort 4: Participants receive placebo to navarixin (three capsules) QD for up to 12 weeks | Drug: Placebo to match navarixin<br>* Placebo to navarixin capsules<br>Drug: Rescue medication<br>* Salbutamol/albuterol - 2 puffs of salbutamol/albuterol approximately every 4 hours as needed for dyspnea relief<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants Who Experience at Least One Adverse Event (AE) | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, biologic (at any dose), or medical device, 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. The number of participants who experienced an AE, regardless of causality or severity, was summarized. | Up to 12 weeks | 
| Part 1: Number of Participants Who Discontinue Study Drug Due to an AE | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, biologic (at any dose), or medical device, 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. The number of participants who discontinued study drug, whether permanently or temporarily, due to an AE was summarized. | Up to 12 weeks | 
| Part 1: Change From Baseline in Absolute Peripheral Blood Neutrophil (PBN) Count | Participants were assessed for absolute PBN counts at Baseline and Week 12. The reported standard deviations (SDs) are pooled across all treatment groups. The rationale for the use of an analysis of variance (ANOVA) method using pooled SD values is the assumption that the SDs are similar across treatment groups. | Baseline and Week 12 | 
| Part 2: Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) | FEV1, as measured in liters via spirometry, is a measure of the amount of air expired in 1 second. Participants were to be assessed for pre-bronchodilator FEV1 immediately before dosing with bronchodilator (albuterol sulfate or equivalent) at Baseline and at Week 12. Pre-bronchodilator FEV1 data were to be averaged weekly over the 12-week treatment period for analysis. | Baseline and the Average over 12 weeks | 
| Part 2: Change From Baseline in Daily Morning/Nighttime Sputum Production, Cough, and Dyspnea (SCDS) Score | Participants were to assess their morning (AM) and nighttime (PM) COPD symptoms (sputum production, cough, and dyspnea) on a daily basis in their e-Diaries. Baseline SCDS was defined as the average of AM and PM values over the week prior to and including Day 1 (AM) prior to the first dose of study drug. SCDS data were to be averaged weekly over the 12-week treatment period for analysis. | Baseline and the Average over 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Change From Baseline in Percent PBN Count | Participants were to be assessed for percent PBN counts at Baseline and at Week 12. | Baseline and Week 12 | 
| Part 1: Change From Baseline in Sputum Absolute Neutrophil Count (Induced Sputum) | Participants were assessed for induced sputum absolute neutrophil counts via the nebulized method at Baseline and at Week 12. The reported SDs are pooled across all treatment groups. The rationale for the use of an ANOVA method using pooled SD values is the assumption that the SDs are similar across treatment groups. | Baseline and Week 12 | 
| Part 1: Change From Baseline in Sputum Percent Neutrophil Count (Induced Sputum) | Sputum neutrophils were to be measured as percent of total white blood cells. Participants were to be assessed for induced sputum percent neutrophil counts via the nebulized method at Baseline and at Week 12. | Baseline and Week 12 | 
| Part 2: Change From Baseline in Post-Bronchodilator FEV1 | FEV1, as measured in liters via spirometry, is a measure of the amount of air expired in 1 second. Participants were to be assessed for post-bronchodilator FEV1 30 minutes after dosing with bronchodilator (albuterol sulfate or equivalent) (reversibility test) at Baseline and Week 12. Post-bronchodilator data were to be averaged weekly over the 12-week treatment period for analysis. | Baseline and the Average over 12 weeks | 
| Part 2: Change From Baseline in Forced Expiratory Flow During Middle Half of Forced Vital Capacity (FVC) (FEF25%-75%) | Mid-Breath Forced Expiratory Flow (FEF25%-75%), as measured in liters/minute via spirometry, is the rate at which participants breathe out air from 25 percent of their breath to 75 percent of their breath. Participants were to be assessed for FEF25%-75% at Baseline and Week 12. | Baseline and Week 12 | 
| Part 2: Change From Baseline in FVC | FVC, as measured in liters via spirometry, is the amount of air forcibly exhaled from the lungs after taking the deepest breath possible. Post-bronchodilator FVC was to be assessed 30 minutes after bronchodilator administration at Baseline and Week 12. | Baseline and Week 12 | 
| Part 2: Change From Baseline in Functional Residual Capacity (FRC) | FRC, as measured in liters via body plethysmography, is the volume of air present in the lungs, specifically the parenchyma tissues, at the end of passive expiration. Participants were to be assessed for FRC at Baseline and Week 12. | Baseline and Week 12 | 
| Part 2: Number of Participants Who Experience a COPD Exacerbation | COPD exacerbation is defined as any change in symptoms or functional status that leads to administration of systemic corticosteroids, antibiotics, an emergency room visit or a hospitalization. The number of participants who experienced a COPD exacerbation was to be summarized. | Up to Week 12 | 
| Part 2: Change From Baseline in Peak Expiratory Flow (PEF) | PEF, as measured in liters/minute via peak flow meter, is the maximum speed of expiration. Participants were to measure their PEF in triplicate every morning before taking study drug and again every evening. | Baseline and Week 12 | 
| Part 2: Change From Baseline in Induced Sputum Absolute Neutrophil Count | Participants were to be assessed for induced sputum absolute neutrophil counts via the nebulized method at Baseline and at Week 12. | Baseline and Week 12 | 
| Part 2: Change From Baseline in Induced Sputum Percent Neutrophil Count | Sputum neutrophils were to be measured as percent of total white blood cells. Participants were to be assessed for induced sputum percent neutrophil counts via the nebulized method at Baseline and at Week 12. | Baseline and Week 12 | 
| Part 2: Change From Baseline in Individual Symptom Scores | Participants were to be assessed for individual symptom scores at Baseline and Week 12 using the following scales: Sputum Production (0=none, unaware of any sputum production to 4=severe, an almost constant problem), Cough (0=none, unaware of coughing to 4=severe, never free of cough or need to cough), and Dyspnea (0=none, unaware of any difficulty to 4=severe, almost constant: present even when resting). | Baseline and Week 12 | 
| Part 2: Change From Baseline in St George's Respiratory Questionnaire (SGRQ) Individual/Total Domains | SGRQ consists of 76 items aggregated into 3 domain scores: Symptoms (frequency/severity), Activity (cause or limited by breathlessness), Impact (social functioning, psychological disturbances from airway disease), and total score. Participants were to assess their symptoms, activity and impact at Baseline and Week 12. | Baseline and Week 12 |