A Pilot Study of Danirixin for Disease Progression in Chronic Obstructive Pulmonary Disease (COPD)

NCT03170232 | Terminated Phase 2 Results FDA Drug FDA Device

• 1 other identifier: 205864
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 11

Brief Summary

This is a pilot study to investigate the effect of danirixin hydrobromide 35 milligram (mg) tablets on lung function and health related quality of life (HRQoL) in subjects with mild to moderate airflow obstruction and a demonstrated history of decline in forced expiratory volume in one second (FEV1). Specifically, this study aims to assess whether or not danirixin has the potential to impact disease progression in subjects with a COPD progression score indicating they are likely to decline based on 5 year data from a COPDGene study and support the conduct of a larger Phase III study for disease progression. Subjects will receive either placebo or danirixin 35 mg tablets (as hydrobromide hemihydrate salt) twice daily for 52 weeks (12months). Study subjects will continue with their standard of care inhaled medications (i.e. long acting bronchodilators with or without inhaled corticosteroids) while receiving study treatment. This study will be an ancillary study within the COPDGene study investigating the enrichment strategy for assessing disease progression. Potential subjects most likely to decline from the well established COPDGene cohort, will be based on data collected over the initial 5 year period. With the use of an enriched population, it is anticipated that one year of treatment will be sufficient to detect a trend in altering disease progression. Approximately 130 subjects will be screened to enroll 100 subjects in this study. The data from this study will provide useful information in determining whether to progress to a Phase III study to explore an indication for slowing disease progression.

Conditions

Pulmonary Disease, Chronic Obstructive

Keywords

HRQoL; Disease Progression; Danirixin; COPD

Outcome Measures

Primary Outcomes (2)

• Rate of Decline in Forced Expiratory Volume in One Second (FEV1)

  FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. The effect of treatment on decline of post bronchodilator FEV1 recorded during the treatment period was analyzed using a repeated measures random coefficients model with covariates of treatment group, age, sex, smoking status, baseline FEV1, body mass index (BMI), study day and the treatment group by study day interaction. The adjusted mean and standard error for rate of decline in FEV1 have been presented.

  Up to Week 52

• Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score (Derived From SGRQ-Chronic Obstructive Pulmonary Disease Specific Tool [SGRQ-C])

  The SGRQ-C is a disease-specific questionnaire designed to measure the impact of respiratory disease and its treatment on a COPD participant's health-related quality of life (HRQoL). SGRQ-C total score was converted to SGRQ total score according to manual. The SGRQ Questionnaire is a well-established, self-completed tool, with 50 questions comprising three domains; Symptoms, Activity, and Impacts scores (each ranging from 0 to 100). SGRQ total score was calculated by summing weights from all positive items, divided by sum of weights for all items in SGRQ questionnaire and multiplying by 100. The SGRQ total score ranges from 0 to 100, with 0 implying the best possible health status and 100 implying worst possible health status. Baseline was defined as the score recorded prior to dosing on Day 1. Change from Baseline was calculated by subtracting Baseline value from the post dose visit value.

  Baseline (Day 1 pre-dose), Weeks 12, 24 and 32

Secondary Outcomes (18)

• Number of Participants With Adverse Events (AEs) and Serious Adverse Event (SAEs)

  Up to Week 52

• Number of Participants With Worst Case Hematology Results by Potential Clinical Importance (PCI) Criteria

  Up to Week 52

• Number of Participants With Worst Case Clinical Chemistry Results by PCI Criteria

  Up to Week 52

• Number of Participants With Worst Case Liver Function Tests Results by PCI Criteria

  Up to Week 52

• Number of Participants With Abnormalities in Urinalysis Data

  Up to Week 52

Study Arms (2)

Subjects receiving danirixin

EXPERIMENTAL

Following screening and assessment of rescue medication use, subjects will receive one tablet of danirixin 35 mg (as hydrobromide hemihydrate salt) orally twice daily with food for 52 weeks during treatment period. Study treatment will be dispensed to subjects at the study visits.

Drug: Danirixin 35 mg tablets; Device: Metered dose inhaler (MDI) sensor device; Drug: Rescue medication

Subjects receiving placebo

PLACEBO COMPARATOR

Following screening and assessment of rescue medication use, subjects will receive one tablet of placebo 35 mg orally twice daily with food for 52 weeks during treatment period. Placebo will be dispensed to subjects at the study visits.

Drug: Placebo; Device: Metered dose inhaler (MDI) sensor device; Drug: Rescue medication

Interventions

Danirixin 35 mg tablets DRUG

Danirixin 35 mg (as hydrobromide hemihydrate salt) is a white film coated oval shaped tablet. It will be provided in a labeled high-density polyethylene (HDPE) bottle with desiccant.

Subjects receiving danirixin

Placebo DRUG

Placebo is a white film coated oval shaped tablet. It will be provided in a labeled HDPE bottle with desiccant.

Subjects receiving placebo

Metered dose inhaler (MDI) sensor device DEVICE

MDI sensor devices will be fitted onto rescue medication MDI devices to electronically record rescue medication usage.

Subjects receiving danirixin; Subjects receiving placebo

Rescue medication DRUG

Subjects may continue to use rescue medication(s) via their usual route. Allowed medications are: short acting beta agonists (SABA) (e.g., albuterol/salbutamol); short acting muscarinic antagonists (SAMA) (e.g., ipratropium); short acting combination (SABA/SAMA) bronchodilators, (e.g. Duoneb, Combivent)

Subjects receiving danirixin; Subjects receiving placebo

Eligibility Criteria

• Age: 40 Years - 76 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject must be 40 to 76 years of age inclusive, at the time of signing the informed consent.
• At the screening visit, the subject must have an FEV1 \>40 percent of the predicted normal.
• Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD.
• Body weight \>=45 kilogram (kg).
• A male subject must agree to use contraception during the treatment period and for at least 60 hours after the last dose of study treatment, corresponding to approximately 6 half-lives (which is the time needed to eliminate any teratogenic study treatment) and to refrain from donating sperm during this period.
• A female subject is eligible to participate if she is not pregnant, not breastfeeding, and not a woman of childbearing potential (WOCBP).
• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions for this study.

You may not qualify if:

• Diagnosis of other clinically relevant lung disease (other than COPD), e.g. sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer.
• COPD due to alpha-1-antitrypsin deficiency.
• Pulse oximetry \<88 percent at rest at screening. Subjects should be tested while breathing room air. However, subjects living at high altitudes (above 5000 feet or 1500 meters above sea level) who are receiving supplemental oxygen can be included provided they are receiving the equivalent of \< 4Liter/minute and screening oximetry is measured while on their usual settings.
• Less than 14 days have elapsed from completion of a course of antibiotics or oral corticosteroids for a recent COPD exacerbation.
• Subjects with a peripheral blood neutrophil count \<1 x 10\^9/Liter.
• Diagnosis of pneumonia (chest X-ray or computerized tomography \[CT\] confirmed) within the 3 months prior to screening.
• Chest X-ray (posterior with lateral) or CT scan reveals evidence of a clinically significant abnormality not believed to be due to the presence of COPD (historic data up to 1 year may be used).
• History or current evidence of clinically significant renal disease, diabetes mellitus/metabolic syndrome, hypertension, or any other clinically significant cardiovascular, neurological, immunological, endocrine, or hematological abnormality that is uncontrolled on permitted therapies. Significant is defined as any disease that, in the opinion of the Investigator, would put the safety of the subjects at risk through study participation, or which would affect the safety analysis or other analysis if the disease/condition exacerbated during the study.
• History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator of GlaxoSmithKline (GSK) medical monitor, contraindicates their participation.
• Current of chronic history of liver disease, or know hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Abnormal and clinically significant 12-lead ECG finding. The investigator will determine the clinical significance of each abnormal ECG finding in relation to the subject's medical history and exclude subjects who would be at undue risk by participating in the trial. An abnormal and clinically significant finding that would preclude a subject from entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following:
• Atrial fibrillation (AF) with rapid ventricular rate \>120 beats per minute (bpm), Sustained or non-sustained ventricular tachycardia (VT), Second-degree heat block Mobitz type II and third degree heart block (unless pacemaker or defibrillator has been implanted, or; QT interval corrected for heart rate per Friderica formula (QTcF) \>=500 milliseconds (msec) in subjects with QRS \<120 msec and QTcF \>=530 msec in subjects with QRS \>=120 msec.
• Previous lung surgery (e.g. lobectomy, pneumonectomy) or lung volume reduction procedure.
• Current or expected chronic use of macrolide antibiotics during the study period for the prevention of COPD exacerbations. Examples of chronic use include, but are not limited to, daily or two to three times per week use for at least 3 months.
• Oral or injectable cytochrome P450 3A4 (CYP3A4) or breast cancer resistance protein (BRCP) substrates with a narrow therapeutic index (CYP3A4 substrates include, but are not limited to, alfenatil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, and theophylline; BCRP substrates include, but are not limited to, topotecan) The Investigator should consult with the medical monitor if necessary.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (11)

GSK Investigational Site

Birmingham, Alabama, 35294, United States

Location

GSK Investigational Site

San Diego, California, 92103-8415, United States

Location

GSK Investigational Site

Torrance, California, 90502, United States

Location

GSK Investigational Site

Denver, Colorado, 80206, United States

Location

GSK Investigational Site

Iowa City, Iowa, 52243, United States

Location

GSK Investigational Site

Baltimore, Maryland, 21224, United States

Location

GSK Investigational Site

Ann Arbor, Michigan, 48109-5360, United States

Location

GSK Investigational Site

Saint Paul, Minnesota, 55101, United States

Location

GSK Investigational Site

Philadelphia, Pennsylvania, 19140, United States

Location

GSK Investigational Site

Pittsburgh, Pennsylvania, 15213, United States

Location

GSK Investigational Site

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive; Disease Progression

Interventions

danirixin; Metered Dose Inhalers

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Nebulizers and Vaporizers; Equipment and Supplies

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 18, 2017
• First Posted: May 30, 2017
• Study Start: October 16, 2017
• Primary Completion: November 15, 2018
• Study Completion: November 15, 2018
• Last Updated: July 31, 2020
• Results First Posted: February 5, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

US (11)