A 4-week Study to Test Different Doses of BI 1265162 in Adolescents and Adults With Cystic Fibrosis Using the Respimat® Inhaler - BALANCE - CF™1

Study Overview
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Brief Summary
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The primary objective of this trial is to assess the efficacy, safety and pharmacokinetics of twice daily inhaled doses of BI 1265162 delivered by Respimat® inhaler versus placebo in adolescents and adult patients with cystic fibrosis.

Official Title
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A Randomised, Double-blind, Placebo-controlled and Parallel Group Trial to Evaluate Efficacy and Safety of Twice Daily Inhaled Doses of BI 1265162 Delivered by Respimat® Inhaler as add-on Therapy to Standard of Care Over 4 Weeks in Patients With Cystic Fibrosis - BALANCE - CF™ 1

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: BI 1265162
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients, 12 years of age or older at screening; Documented diagnosis of cystic fibrosis including: positive sweat chloride ≥ 60 mEq/L, by pilocarpine iontophoresis OR genotype with 2 identifiable mutations consistent with cystic fibrosis accompanied by one or more clinical features with cystic fibrosis phenotype; Patients able to perform acceptable spirometric manoeuvres according to American Thoracic Society (ATS) standards; FEV1 ≥ 40% and ≤ 90% of predicted values at screening and predose at Visit 2; Women of childbearing potential (WOCBP) must be willing and able to use highly effective methods of birth control per ICH M3 (R2) that result in a failure rate of less than1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient (or patient's legal guardian) information; Signed and dated written informed consent and assent in accordance with ICH Harmonized Guideline for Good Clinical Practice (GCP) and local legislation prior to admission in the trial. Exclusion Criteria: Evidence of acute upper or lower respiratory tract infection within 4 weeks prior to randomization based on investigator's judgement; Pulmonary exacerbation requiring use of i.v./oral/inhaled antibiotics or oral corticosteroids within 4 weeks prior to randomisation; Patients with history of Acute Tubular Necrosis (ATN); Any documented active or suspected malignancy or history of malignancy within 5 years prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix; Patients unable to inhale trial drug in an appropriate manner from the Respimat® inhaler based on investigator's judgement; Patients who have started a new chronic medication for CF within 4 weeks of randomisation; Patients who have previously received a lung transplant or patients who are currently on a waiting list to receive a lung transplant; Patients with a significant history of allergy/hypersensitivity (including medication allergy) which is deemed relevant to the trial as judged by the investigator or with a known hypersensitivity to trial drug or its components. Significance in this context refers to any increased risk of hypersensitivity reaction to trial medication; Any clinically significant laboratory abnormalities at screening as judged by the investigator, or any of the following: Potassium > upper limit of normal (ULN) in non-haemolysed blood Abnormal renal function defined as estimated Glomerular Filtration Rate (eGFR) < 60ml/min/1.73m² Abnormal liver function, defined by serum level of either alanine transaminase (ALT), aspartate transaminase (AST) or total bilirubine ≥ 3 x upper limit of normal (ULN) Clinically significant disease or medical condition other than CF or CF-related conditions that, in the opinion of the investigator, would compromise the safety of the patient or the data quality. This includes significant haematological, hepatic, renal, cardiovascular and neurologic disease. Patients with diabetes may participate if their disease is under good control prior to screening; Patients not expected to comply with the protocol requirements or not expected to complete the trial as scheduled; Previous randomisation in this trial; Currently enrolled in another investigational device or drug trial, or less than 30 days or six half-lives (whichever is greater) since ending another investigational device or drug trial(s), or receiving other investigational treatment(s); Chronic alcohol or drug abuse or any condition that, in the investigator's opinion, makes them an unreliable trial patient or unlikely to complete the trial; Women who are pregnant, nursing, or who plan to become pregnant while in the trial.

Ages Eligible for Study
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Minimum Age: 12 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 |
| --- | --- |
| Placebo Comparator: Placebo<br>2 puffs ofmatching placebowere inhaledorally via theRespimat®inhaler twice dailyfor a treatmentperiod of 4 weeksin patients withcystic fibrosis. | Drug: Placebo<br>* Inhalation solution<br>|
| Experimental: BI 1265162 50 μg b.i.d.<br>2 puffs of 25micrograms (μg)BI 1265162(Total: 50μg)were inhaledorally via theRespimat®inhaler twice daily(b.i.d., daily dose:100μg) for atreatment periodof 4 weeks inpatients withcystic fibrosis. | Drug: BI 1265162<br>* Inhalation solution<br>|
| Experimental: BI 1265162 100 μg b.i.d.<br>2 puffs of 50micrograms (μg)BI 1265162(Total: 100μg)were inhaledorally via theRespimat®inhaler twice daily(b.i.d., daily dose:200μg) for atreatment periodof 4 weeks inpatients withcystic fibrosis. | Drug: BI 1265162<br>* Inhalation solution<br>|
| Experimental: BI 1265162 200 μg b.i.d.<br>2 puffs of 100micrograms (μg)BI 1265162(Total: 200μg)were inhaledorally via theRespimat®inhaler twice daily(b.i.d., daily dose:400μg) for atreatment periodof 4 weeks inpatients withcystic fibrosis. | Drug: BI 1265162<br>* Inhalation solution<br>|
| Experimental: BI 1265162 20 μg b.i.d.<br>2 puffs of 10micrograms (μg)BI 1265162(Total: 20μg)were inhaledorally via theRespimat®inhaler twice daily(b.i.d., daily dose:40μg) for atreatment periodof 4 weeks inpatients withcystic fibrosis. | Drug: BI 1265162<br>* Inhalation solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Percent Predicted Trough Forced Expiratory Volume in 1 Second (FEV1) After 4 Weeks of Treatment | Trough FEV1 was measured within 30 minutes prior to dosing of study medication. | At 30 minutes prior to dosing in Day 1 (baseline) and Day 29 (end of 4-week treatment period). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Lung Clearance Index (LCI) Assessed by N2 Multiple Breath Washout (N2MBW) Procedure After 4 Weeks of Treatment | Change from baseline in Lung Clearance Index (LCI) assessed by N2 Multiple Breath Washout (N2MBW) procedure after 4 weeks of treatment was reported. LCI was calculated as the ratio of cumulative expired volume (CEV) to functional residual capacity (FRC), which was LCI = CEV (milliliter/kilogram) / FRC (milliliter/kilogram) and hence, LCI was Unitless. The change from baseline after 4 weeks of treatment in LCI was then calculated as the LCI value measured after 4 weeks of treatment at Day 29 minus the LCI value measured at baseline on Day 1. | At pre-dose in Day 1 (baseline) and Day 29 (end of 4-week treatment period). | 
| Change From Baseline in Cystic Fibrosis Questionnaire Revised (CFQ-R) Total Score After 4 Weeks of Treatment | The adult/adolescent format of the CFQ-R consists of 50 questions (qts) dividing into 12 domains: Physical functioning(8 qts), role limitations(4 qts), vitality(4 qts), emotional functioning(5 qts), social functioning(6 qts), body image(3 qts), eating disturbance(3 qts), treatment burden(3 qts), health perceptions(3 qts), weight(1 qts), respiratory symptoms(7 qts), and digestive system(3 qts). The score of some qts is first reversed if reversed coded, so that the score for each of the 50 qts ranges from 1 to 4 points (less symptoms). Then, a domain score for a domain with N qts is calculated as (sum of the scores of the N qts - N)/(N ✕ 4 - N) ✕ 100. Each domain score ranges from 0 to 100 (better health). The CFQ-R total score is summing up the domain scores and ranges from 0 to 1200 (better quality of life). The change from baseline in Cystic Fibrosis Questionnaire Revised (CFQ-R) total score after 4 weeks of treatment was reported. | At Day 1 (baseline) and Day 29 (end of 4-week treatment period). | 
| Change From Baseline in Cough and Sputum Assessment Questionnaire (CASA-Q) (4 Separate Sub-scores) After 4 Weeks of Treatment | The 20-item Sputum Assessment Questionnaire (CASA-Q) consisted of 4 domains: Cough Symptoms Domain (3 items), Cough Impact Domain (8 items), Sputum Symptoms Domain (3 items), and Sputum Impact Domain (6 items). Score of each item has been reversed such that better responses have higher score, which ranges from 1 (worse) to 5 (better health). For each domain, the domain score was calculated by summing up the scores of the respective items and scaling to a value ranging from 0 to 100, with higher score associated with fewer symptoms/less impact due to cough or sputum. The 4 domain scores (sub-scores) were reported. | At Day 1 (baseline) and Day 29 (end of 4-week treatment period). | 
| Percentage of Patients With Treatment-emergent Adverse Events (AE) up to Day 36 | Percentage of patients with any treatment-emergent Adverse Events (AE) up to day 36 was reported. | From Day 1 (baseline) until end of 4 weeks of treatment period (Day 29) plus 7 days of follow-up, up to 36 days. | 
| Concentration of BI 1265162 in Plasma at 0.083 Hour at Steady State Following Dose 15 (C0.083,ss,15) | Concentration of BI 1265162 in plasma at 0.083 hour at steady state following dose 15 (C0.083,ss,15) was reported. | At 5 minutes (around 0.083 hours) post dosing at steady state on Day 8 for dose 15 (morning dose on Day 8). | 
| Concentration of BI 1265162 in Plasma at 0.083 Hour at Steady State Following Dose 57 (C0.083,ss,57) | Concentration of BI 1265162 in plasma at 0.083 hour at steady state following dose 57 (C0.083,ss,57) was reported. | At 5 minutes (around 0.083 hours) post dosing at steady state on Day 29 for dose 57 (morning dose on Day 29). | 
| Pre-dose Concentration Measured of BI 1265162 in Plasma at Steady State After Dose 15 (Cpre,ss, 15) | Pre-dose concentration measured of BI 1265162 in plasma at steady state after dose 15 (Cpre,ss, 15) was reported. | At pre-dose (taken within 60 minutes prior to dosing) at steady state on Day 8 for dose 15 (morning dose on Day 8). | 
| Pre-dose Concentration Measured of BI 1265162 in Plasma at Steady State After Dose 57 (Cpre,ss, 57) | Pre-dose concentration measured of BI 1265162 in plasma at steady state after dose 57 (Cpre,ss, 57) was reported. | At pre-dose (taken within 60 minutes prior to dosing) at steady state on Day 29 for dose 57 (morning dose on Day 29). | 
| Area Under the Concentration-time Curve of BI 1265162 in Plasma From 0 to 4 Hours at Steady State After Dose 15 (AUC0-4,ss,15) | Area under the concentration-time curve of BI 1265162 in plasma from 0 to 4 hours at steady state after dose 15 (AUC0-4,ss,15) was reported. | At pre-dose (taken within 60 minutes prior to dosing) and 5 minutes (min), 30 min, 1 hour, and 4 hours post dosing at steady state on Day 8 for dose 15 (morning dose on Day 8). |