Dose-range Finding Efficacy and Safety Study for QBW251 in COPD Patients
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| ClinicalTrials.gov Identifier: NCT04072887 |
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Recruitment Status :
Completed
First Posted : August 28, 2019
Last Update Posted : July 29, 2022
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Pulmonary Disease, Chronic Obstructive | Drug: QBW251 Drug: Placebo Drug: COPD maintenance background therapy | Phase 2 |
This study used a 6 treatment arm, parallel-group, randomized, double-blind study design. 974 male and female COPD patients were randomized into the trial. The study consisted of four distinct study periods:
- Screening (Weeks -3 to -2): Participants underwent a screening period of 1 week where were assessed for eligibility and tapered off disallowed medications.
- Run-in (Days -14 to 1): Subsequently, participants entered the run-in period of up to 2 weeks to establish baseline values for symptom assessments, to standardize the COPD background therapy (triple combination LABA/LAMA/ICS), and to complete eligibility assessments.
- Treatment (Day 1 to Week 24): Eligible participants moved into the Day 1 visit where they were stratified according to their smoking status (current or ex-smoker) and severity of airflow limitation (FEV1 ≥ 30% to < 50% and ≥ 50% to < 80%) and then randomized into 1 of 6 treatment arms with a randomization ratio of 2:2:1:1:1:2 (450 mg b.i.d., 300 mg b.i.d., 150 mg b.i.d., 75 mg b.i.d., 25 mg b.i.d., placebo). The treatment period consisted of 24 weeks, during which the participant returned to the site for regular visits (Day 1 - Week 24).
- Follow-up (Weeks 25-28): Upon completion of the treatment period, participants were followed up for safety assessments for 30 days.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 974 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Triple (Participant, Care Provider, Investigator) |
| Primary Purpose: | Treatment |
| Official Title: | A 24-week Multi-center, Double-blind, Placebo Controlled Dose-range Finding Study to Investigate the Efficacy and Safety of Oral QBW251 in COPD Patients on Triple Inhaled Therapy (LABA / LAMA / ICS) |
| Actual Study Start Date : | September 12, 2019 |
| Actual Primary Completion Date : | October 8, 2021 |
| Actual Study Completion Date : | February 1, 2022 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: QBW251 450 mg
QBW251 was orally administered 450 mg b.i.d for 24 weeks
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Drug: QBW251
QBW251 oral capsules (450, 300, 150, 75 and 25 mg) of identical appearance to ensure blinding administered twice a day (b.i.d) for 24 weeks Drug: COPD maintenance background therapy Combination of fluticasone furoate, vilanterol and umeclidinium |
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Experimental: QBW251 300 mg
QBW251 was orally administered 300 mg b.i.d for 24 weeks
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Drug: QBW251
QBW251 oral capsules (450, 300, 150, 75 and 25 mg) of identical appearance to ensure blinding administered twice a day (b.i.d) for 24 weeks Drug: COPD maintenance background therapy Combination of fluticasone furoate, vilanterol and umeclidinium |
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Experimental: QBW251 150 mg
QBW251 was orally administered 150 mg b.i.d for 24 weeks
|
Drug: QBW251
QBW251 oral capsules (450, 300, 150, 75 and 25 mg) of identical appearance to ensure blinding administered twice a day (b.i.d) for 24 weeks Drug: COPD maintenance background therapy Combination of fluticasone furoate, vilanterol and umeclidinium |
|
Experimental: QBW251 75 mg
QBW251 was orally administered 75 mg b.i.d for 24 weeks
|
Drug: QBW251
QBW251 oral capsules (450, 300, 150, 75 and 25 mg) of identical appearance to ensure blinding administered twice a day (b.i.d) for 24 weeks Drug: COPD maintenance background therapy Combination of fluticasone furoate, vilanterol and umeclidinium |
|
Experimental: QBW251 25 mg
QBW251 was orally administered 25 mg b.i.d for 24 weeks
|
Drug: QBW251
QBW251 oral capsules (450, 300, 150, 75 and 25 mg) of identical appearance to ensure blinding administered twice a day (b.i.d) for 24 weeks Drug: COPD maintenance background therapy Combination of fluticasone furoate, vilanterol and umeclidinium |
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Placebo Comparator: Placebo
Placebo was orally administered b.i.d for 24 weeks
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Drug: Placebo
Placebo oral capsules administered twice a day for 24 weeks Drug: COPD maintenance background therapy Combination of fluticasone furoate, vilanterol and umeclidinium |
- Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at week 12 [ Time Frame: Baseline and Week 12 ]
The primary efficacy analysis assessed the effect of QBW251 on the absolute change from baseline in trough FEV1 in liters on Week 12. Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline measurement was defined as the baseline visit pre-bronchodilator spirometry assessment. A positive trend for change from baseline in FEV1 across the dose range is considered a favorable outcome.
Change from baseline in the FEV1 mean scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in FEV1 + airflow limitation severity + region + time interval + treatment*time interval interaction + baseline score*time interval interaction.
- Change From Baseline in Forced Expiratory Volume in One Second (FEV1) [ Time Frame: Baseline, weeks 4, 8, 16, 20 and 24 ]
The primary efficacy analysis assessed the effect of QBW251 on the absolute change from baseline in trough FEV1 in liters compared to placebo on Weeks 4, 8, 16, 20 and 24. Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline measurement was defined as the baseline visit pre-bronchodilator spirometry assessment. A positive trend for change from baseline in FEV1 across the dose range is considered a favorable outcome.
Change from baseline in the FEV1 mean scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in FEV1 + airflow limitation severity + region + time interval + treatment*time interval interaction + baseline score*time interval interaction.
- Change from baseline in Evaluating Respiratory Symptoms (E-RS); Total score [ Time Frame: Baseline, weeks 12 and 24 ]
The E-RS assesses overall daily respiratory COPD symptoms (Total score) and it is derived as the sum of 11 severity items; a higher scores indicate more severe symptoms.
Change from baseline in the E-RS Total weekly mean scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in E-RS + airflow limitation severity + region + time interval + treatment*time interval interaction + baseline score*time interval interaction.
The mean baseline E-RS Total score was the average of the corresponding daily scores from the run-in period. Lower scores in the change from baseline correspond to lower symptom severity.
- Change from baseline in Evaluating Respiratory Symptoms (E-RS); Cough and Sputum score [ Time Frame: Baseline, weeks 12 and 24 ]
The E-RS assesses both overall daily respiratory COPD symptoms (Total score) and specific respiratory symptoms using 3 subscales (Breathlessness, Cough & Sputum, and Chest Symptoms). The E-RS comprises 11 severity items and higher scores indicate more severe symptoms. The Cough and Sputum subscale score was derived as the sum of items 2 - 4.
Change from baseline in the E-RS Cough and Sputum weekly mean scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in E-RS + airflow limitation severity + region + time interval + treatment*time interval interaction + baseline score*time interval interaction.
The mean baseline E-RS Cough & Sputum subscale score was the average of the corresponding daily scores from the run-in period. Lower scores in the change from baseline correspond to lower symptom severity.
- Number of Participants with a "Better" change in the Patient Global Impression of Severity (PGI-S) from baseline [ Time Frame: Baseline, weeks 12 and 24 ]The PGI-S questionnaire is a patient-reported outcomes score that rates the severity of the respiratory symptoms and of cough and mucus. The change in severity scores (Better, No change and Worse) from baseline were reported at weeks 12 and 24. Thus, the number of participants with a Better change in the severity score are reported in the table below.
- Change from baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) [ Time Frame: Baseline, weeks 12 and 24 ]
The CASA-Q is a validated questionnaire instrument used to measure cough and sputum production, and their impact in patients COPD and/or chronic bronchitis. It contains a total of 20 items on a 5-step scale distributed in 4 domains: Cough symptoms, Cough impact, Sputum symptoms and Sputum impact. All items are rescored from 1-5 to 0-4 and then reverse scored such that better responses have higher scores. The four domains are ranged from 0-100 where higher scores associated with fewer symptoms/less impact due to cough or sputum. Within each domain, items are summed and rescaled: CASA-Q domain scores= (sum of rescored items) / (range of rescored items) ×100
Change from baseline in the CASA-Q cough and symptoms scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in E-RS + airflow limitation severity + region + time interval + treatment*time interval interaction + baseline score*time interval interaction.
- Change from baseline in St. George's Respiratory Questionnaire (SGRQ) [ Time Frame: Baseline, weeks 12 and 24 ]
SGRQ measures health impairment and contains 50 items divided into three components: Symptoms, Activity and Impacts. A score was calculated for each component and a "Total" score was also calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of quality of life.
Change from baseline in the SGRQ scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + baseline SGRQ score + airflow limitation severity + region + time interval + treatment*time interval interaction + baseline score*time interval interaction.
- Minimum plasma concentration (Cmin) for QBW251 [ Time Frame: Days 15, 29, 57, 85, 113, 141 and 169 ]Venous whole blood samples were collected for pharmacokinetics characterization. Cmin was calculated from plasma concentration data using non-compartmental methods and summarized using descriptive statistics. Cmin was measured pre dose at all visits. All concentration below the lower limit of quantification (LLOQ) was treated as zero.
- Maximum plasma concentration (Cmax) for QBW251 [ Time Frame: Days 1, 15 and 169 ]Venous whole blood samples were collected for pharmacokinetics characterization. Cmax was calculated from plasma concentration data using non-compartmental methods and summarized using descriptive statistics. Cmax was estimated using the 3hr concentration for participants not in the Serial PK set. For participants in the Serial PK set, the calculated Cmax is presented only for Day 1 and Day 15. All concentration below the lower limit of quantification (LLOQ) was treated as zero.
- Maximum plasma concentration (Cmax) for QBW251 in Serial PK set [ Time Frame: Days 1 and 15 ]Venous whole blood samples were collected for pharmacokinetics characterization. Cmax was calculated from plasma concentration data using non-compartmental methods and summarized using descriptive statistics. All concentration below the lower limit of quantification (LLOQ) was treated as zero.
- Area under de curve from time 0 to 24 hours (AUC0-24h) of QBW251 in Serial PK set [ Time Frame: Days 1 and 15 ]Venous whole blood samples were collected for pharmacokinetics characterization. AUC0-24h was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics. AUC0-24h was estimated as 2 x AUC0-12h. All concentration below the lower limit of quantification (LLOQ) was treated as zero.
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| Ages Eligible for Study: | 40 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Male and female COPD patients aged ≥40 years, who have signed an Informed Consent Form prior to initiation of any study-related procedure.
- Current or ex-smokers who have a smoking history of at least 10 pack years.
- Patients who have been treated with a triple combination of LABA/LAMA/ICS for the last 3 months prior to screening.
- Patients featuring chronic bronchitis
Exclusion Criteria:
- Patients who have had a COPD exacerbation that required treatment with antibiotics and/or oral corticosteroids and/or hospitalization, or a respiratory tract infection in the 4 weeks prior to screening, or between screening and randomization.
- Patients with any documented history of asthma, or with an onset of chronic respiratory symptoms, including a COPD diagnosis, prior to age 40 years.
- Patients with a body mass index (BMI) of more than 40 kg/m2.
- Use of other investigational drugs (approved or unapproved) within 30 days or 5 half-lives prior to screening, or until the expected pharmacodynamic effect has returned to baseline (e.g., biologics), whichever is longer; or longer if required by local regulations.
- Pregnant or nursing (lactating) women, and women of childbearing potential not willing to use acceptable effective methods of contraception during study participation.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04072887
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| Responsible Party: | Novartis Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT04072887 |
| Other Study ID Numbers: |
CQBW251B2201 2018-003197-28 ( EudraCT Number ) |
| First Posted: | August 28, 2019 Key Record Dates |
| Last Update Posted: | July 29, 2022 |
| Last Verified: | July 2022 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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COPD |
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Pulmonary Disease, Chronic Obstructive Lung Diseases Respiratory Tract Diseases Lung Diseases, Obstructive |