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AMPLIFY - D6571C00001 Duaklir USA Phase III Study

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02796677
Recruitment Status : Completed
First Posted : June 13, 2016
Results First Posted : November 9, 2018
Last Update Posted : November 9, 2018
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE May 31, 2016
First Posted Date  ICMJE June 13, 2016
Results First Submitted Date  ICMJE June 8, 2018
Results First Posted Date  ICMJE November 9, 2018
Last Update Posted Date November 9, 2018
Actual Study Start Date  ICMJE July 5, 2016
Actual Primary Completion Date June 8, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 7, 2018)
  • Change From Baseline in 1-hour Morning Post-dose Dose Forced Expiratory Volume in 1 Second (FEV1) of AB/FF 400/12 μg Compared to AB 400 μg at Week 24 [ Time Frame: At baseline 1-hour postdose and Week 24 ]
    To assess the bronchodilatory effect by evaluating the mean changes from baseline in FEV1 at 1 hour post-dose of AB/FF 400/12 µg compared to AB 400 μg after administration of oral inhalation powder BID via DIP to participants with COPD. Baseline was defined as the average of the two FEV1 values measured just prior to the administration of the first dose of investigational product (IP) at randomization Visit. If one of the two was missing, then the available one would be used as baseline value.
  • Change From Baseline in Morning Predose (Trough) FEV1 of AB/FF 400/12 μg Compared to FF 12 μg at Week 24 [ Time Frame: At baseline morning predose and Week 24 ]
    To assess the bronchodilatory effect by evaluating the mean changes from baseline in FEV1 in morning pre-dose (trough) of AB/FF 400/12 µg compared to FF 12 μg after administration of oral inhalation powder BID via DPI to participants with COPD. Morning pre-dose (trough) FEV1 was defined as the average of the corresponding -30 minute and 0 minute before the morning study medication at Week 24. If one time-point was missing then the available one would be used as morning pre-dose.
  • Change From Baseline in Morning Predose (Trough) FEV1 at Week 24 Comparing AB 400 μg Versus TIO 18 μg to Demonstrate Non-inferiority [ Time Frame: At baseline morning predose and Week 24 ]
    To assess the non-inferior bronchodilatory effect by evaluating the mean changes from baseline in FEV1 in morning pre-dose (trough)of AB 400 µg compared to TIO 18 μg after administration of oral inhalation powder BID via DPI to participants with COPD.
Original Primary Outcome Measures  ICMJE
 (submitted: June 7, 2016)
  • Change from baseline in 1-hour morning post-dose dose FEV1 of AB/FF 400/12 μg compared to AB 400 μg at week 24. [ Time Frame: Baseline 1-hour Postdose and Week 24 ]
    Mean changes from baseline in FEV1 at 1 hour post-dose when compared between AB/FF 400/12 μg and AB 400 μg.
  • Change From Baseline in Morning Predose (Trough) FEV1 of AB/FF 400/12 μg Compared to FF 12 μg at Week 24 [ Time Frame: Baseline Morning Predose and Week 24 ]
    Morning pre-dose (trough) FEV1 is defined as the average of the corresponding -30 and 0 minute time points values before the morning study medication at Week 24. If one time-point is missing then the available one will used as morning pre-dose. Baseline for both variables is defined as the average of the two FEV1 values measured just prior to the administration of the first dose of study medication at Visit 2. If one of the two is missing, then the available one will be used as baseline value.
  • Change from baseline in morning predose (trough) FEV1 at week 24 comparing AB 400 μg versus TIO 18 μg to demonstrate non-inferiority. [ Time Frame: Baseline Morning Predose and Week 24 ]
    Morning pre-dose (trough) FEV1 is defined as the average of the corresponding -30 and 0 minute time points values before the morning study medication at Week 24. If one time-point is missing then the available one will used as morning pre-dose. Baseline for both variables is defined as the average of the two FEV1 values measured just prior to the administration of the first dose of study medication at Visit 2. If one of the two is missing, then the available one will be used as baseline value.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 7, 2018)
  • Change From Baseline in Normalized Area Under Curve 3hours Post-dose (nAUC0-3/3h) FEV1 of AB/FF 400/12 μg Compared to AB 400 μg and and FF 12 μg at Week 24 [ Time Frame: At Day 1 and Day 169 ]
    To assess the bronchodilatory effect by evaluating the mean changes from baseline in nAUC0-3/3h FEV1 of AB/FF 400/12 µg compared to AB 400 μg and and FF 12 μg after administration of oral inhalation powder BID via DPI to participants with COPD.
  • Responder (Number of Participants) Analysis of St. George's Respiratory Questionnaire (SGRQ) Total Score With AB/FF 400/12 μg Versus AB 400 μg and FF 12 μg. [ Time Frame: At baseline and Week 24 ]
    SGRQ was a A standardized self-completed tool used to measure impaired health and perceived well-being ("quality of life") in respiratory diseases. The questionnaire contained 50 items divided into 3 (symptoms, activity and impacts) dimensions. Each of the three dimensions of the questionnaire is scored separately in the range from 0 to 100%, zero score indicating no impairment of life quality. A summary score utilizing responses to all items is the total SGRQ score which also ranges from 0 to 100%. The SGRQ scores are calculated using weights attached to each item of the questionnaire which provides an estimate of the distress associated with the symptoms or state described in each item. Higher scores indicate poorer health. A decrease of at least 4 units in the SGRQ total score has been established as the criterion for minimal meaningful improvement. SGRQ responders will be those with a decrease in SGRQ total score of at least 4 units from baseline.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 7, 2016)
  • Change from baseline in normalized AUC0-3/3h FEV1 of AB/FF 400/12 μg compared to AB 400 μg at Week 24. [ Time Frame: Baseline and Week 24 ]
    Change from baseline in normalized AUC0-3/3h FEV1 of AB/FF 400/12 μg at week 24 compared to AB 400 μg.
  • Change from baseline in normalized AUC0-3/3h FEV1 of AB/FF 400/12 μg compared to FF 12 μg at Week 24. [ Time Frame: Baseline and Week 24 ]
    Change from baseline in normalized AUC0-3/3h FEV1 of AB/FF 400/12 μg at week 24 compared to FF 12 μg.
  • Responder analysis of St. George's Respiratory Questionnaire (SGRQ) total score with AB/FF 400/12 μg versus AB 400 μg. [ Time Frame: Baseline and Week 24 ]
    The SGRQ is a self-administered instrument to evaluate the disease-specific health status. The questionnaire contains 50 items divided into three dimensions: Symptoms, Activity and Impacts. Each of the three dimensions of the questionnaire is scored separately in the range from 0 to 100%, zero score indicating no impairment of life quality. A summary score utilizing responses to all items is the total SGRQ score which also ranges from 0 to 100%. The SGRQ scores are calculated using weights attached to each item of the questionnaire which provides an estimate of the distress associated with the symptoms or state described in each item. Higher scores indicate poorer health. A decrease of at least 4 units in the SGRQ total score has been established as the criterion for minimal meaningful improvement. SGRQ responders were those with a decrease in SGRQ total score of at least 4 units from baseline.
  • Responder analysis of SGRQ total score with AB/FF 400/12 μg versus FF 12 μg. [ Time Frame: Baseline and Week 24 ]
    The SGRQ is a self-administered instrument to evaluate the disease-specific health status. The questionnaire contains 50 items divided into three dimensions: Symptoms, Activity and Impacts. Each of the three dimensions of the questionnaire is scored separately in the range from 0 to 100%, zero score indicating no impairment of life quality. A summary score utilizing responses to all items is the total SGRQ score which also ranges from 0 to 100%. The SGRQ scores are calculated using weights attached to each item of the questionnaire which provides an estimate of the distress associated with the symptoms or state described in each item. Higher scores indicate poorer health. A decrease of at least 4 units in the SGRQ total score has been established as the criterion for minimal meaningful improvement. SGRQ responders were those with a decrease in SGRQ total score of at least 4 units from baseline.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE AMPLIFY - D6571C00001 Duaklir USA Phase III Study
Official Title  ICMJE A 24 Week Treatment, Multicenter, Randomized, Double Blinded, Double Dummy, Parallel-group, Clinical Trial Evaluating the Efficacy and Safety of Aclidinium Bromide 400 μg/Formoterol Fumarate 12 μg Fixed-dose Combination BID Compared With Each Monotherapy (Aclidinium Bromide 400 μg BID and Formoterol Fumarate 12 μg BID) and Tiotropium 18 μg QD When Administered to Patients With Stable Chronic Obstructive Pulmonary Disease.
Brief Summary This is a multiple dose, randomized, parallel, double-blind, double-dummy, multicenter and multinational Phase III study to determine the efficacy and safety of Aclidinium bromide 400μg/Formoterol Fumarate (AB/FF) 12 μg compared to individual components and TIO (Tiotropium) 18 μg when administered to patients with stable chronic obstructive pulmonary disease (COPD).
Detailed Description This study was conducted to assess the bronchodilator efficacy and safety as well as effect on health related quality of life of AB/FF 400/12 μg compared to the individual components (AB 400 μg and FF 12 μg) in COPD patients. The trial duration of 24 weeks allows the assessment of the effect on symptoms improvement of the combined treatments versus individual components as well as the long term bronchodilation comparison between AB 400 μg and TIO 18 μg in minimizing the risk of COPD exacerbations in current or former smokers, aged ≥40 in symptomatic COPD patients.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Chronic Obstructive Pulmonary Disease
Intervention  ICMJE
  • Drug: Aclidinium bromide 400 μg/Formoterol Fumarate 12 μg (AB/FF 400/12 μg)
    Inhalation powder
    Other Name: Oral Inhalation (by Pressair®/Genuair® Dry Powder Inhaler)
  • Drug: Aclidinium bromide 400 μg (AB 400 μg)
    Inhalation powder
    Other Name: Oral Inhalation (by Pressair®/Genuair® Dry Powder Inhaler)
  • Drug: Formoterol fumarate 12 μg (FF 12 μg)
    Inhalation powder
    Other Name: Oral Inhalation (by Pressair®/Genuair® Dry Powder Inhaler)
  • Other: Placebo to AB/FF 400/12 μg, AB 400 μg and FF 12 μg
    Inhalation powder
    Other Name: Oral Inhalation (by Pressair®/Genuair® Dry Powder Inhaler)
  • Drug: Tiotropium 18 μg (TIO 18 μg)
    Powder in capsules for oral inhalation
    Other Name: Oral Inhalation (by Handihaler® Dry Powder Inhaler, DPI)
  • Other: Placebo to TIO 18 μg
    Powder in capsules for oral inhalation
    Other Name: Oral Inhalation (by Handihaler® Dry Powder Inhaler, DPI)
Study Arms  ICMJE
  • Experimental: AB/FF 400/12 μg BID
    Participants were administered AB/FF 400/12 μg via Pressair®/Genuair® inhaler twice daily for 24 weeks of treatment.
    Interventions:
    • Drug: Aclidinium bromide 400 μg/Formoterol Fumarate 12 μg (AB/FF 400/12 μg)
    • Other: Placebo to AB/FF 400/12 μg, AB 400 μg and FF 12 μg
  • Experimental: AB 400 μg BID
    Participants were administered AB 400 μg via Pressair®/Genuair® inhaler twice daily for 24 weeks of treatment.
    Interventions:
    • Drug: Aclidinium bromide 400 μg (AB 400 μg)
    • Other: Placebo to AB/FF 400/12 μg, AB 400 μg and FF 12 μg
  • Experimental: FF 12 μg BID
    Participants were administered FF 12 μg via Pressair®/Genuair® inhaler twice daily for 24 weeks of treatment.
    Interventions:
    • Drug: Formoterol fumarate 12 μg (FF 12 μg)
    • Other: Placebo to AB/FF 400/12 μg, AB 400 μg and FF 12 μg
  • Experimental: TIO 18 μg QD
    Participants were administered TIO 18 μg via Handihaler® inhale once daily for 24 weeks of treatment.
    Interventions:
    • Drug: Tiotropium 18 μg (TIO 18 μg)
    • Other: Placebo to TIO 18 μg
Publications * Sethi S, Kerwin E, Watz H, Ferguson GT, Mroz RM, Segarra R, Molins E, Jarreta D, Garcia Gil E. AMPLIFY: a randomized, Phase III study evaluating the efficacy and safety of aclidinium/formoterol vs monocomponents and tiotropium in patients with moderate-to-very severe symptomatic COPD. Int J Chron Obstruct Pulmon Dis. 2019 Mar 22;14:667-682. doi: 10.2147/COPD.S189138. eCollection 2019.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 4, 2017)
1595
Original Estimated Enrollment  ICMJE
 (submitted: June 7, 2016)
1500
Actual Study Completion Date  ICMJE June 8, 2017
Actual Primary Completion Date June 8, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Adult male or non-pregnant, non-lactating female patients aged ≥40.
  • Patients with diagnosis of moderate to very severe stable COPD: post-bronchodilator FEV1 < 80% of the predicted normal and post-bronchodilator FEV1/FVC < 70% at Screening Visit.
  • Symptomatic patients with a CAT score ≥10 at Screening and Randomization visit (Visits 1 and 2).
  • Current or former-smokers, with a smoking history of ≥ 10 pack-years.
  • Patients able to perform acceptable and repeatable pulmonary function testing for FEV1 according to the American Thoracic Society (ATS)/European Respiratory Society (ERS) 2005 criteria at Visit 1.
  • Patients eligible and able to participate in the study and who had signed an Informed Consent Form prior to initiation of any study-related procedures.

Exclusion Criteria:

  • Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff and/or site staff), or patients employed by or relatives of the employees of the site or sponsor.
  • Previous randomization in the present study D6571C00001.
  • Patients with predominant asthma.
  • Any respiratory tract infection (including the upper respiratory tract) or COPD exacerbation (including the mild COPD exacerbation) within 6 weeks prior to screening or during the run-in period.
  • Patients hospitalized for a COPD exacerbation (an emergency room visit for longer than 24 hours is considered a hospitalization) within 3 months prior to Screening Visit.
  • Clinically significant respiratory conditions other than COPD.
  • Patients who in the Investigator's opinion may need to start a pulmonary rehabilitation program during the study and/or patients who started/finished it within 3 months prior to Screening.
  • Use of long-term oxygen therapy (≥ 15 hours/day).
  • Patients who do not maintain regular day/night, waking/sleeping cycles including night shift workers.
  • Clinically significant cardiovascular conditions.
  • Patients with uncontrolled Type I or Type II diabetes, uncontrolled hypo-or hyperthyroidism, hypokalaemia, or hyperadrenergic state, uncontrolled hypertension.
  • Patients with history of long QT syndrome or whose QTc (calculated according to Fridericia's Formula QTc=QT/RR1/3) > 470 ms as indicated in the centralised reading report assessed at Screening.
  • Patients with clinically significant abnormalities in the laboratory tests, ECG parameters (other than QTc) or in the physical examination at Screening Visit that might comprise patient safety.
  • Patient with known non-controlled history of infection with human immunodeficiency virus and/or active hepatitis.
  • Patient with a history of hypersensitivity reaction to inhaled medication or any component thereof, including paradoxical bronchospasm.
  • Patients with known narrow-angle glaucoma, symptomatic bladder neck obstruction, acute urinary retention or symptomatic non-stable prostate hypertrophy.
  • History of malignancy of any organ system (including lung cancer), treated or untreated, within the past 5 years other than basal or squamous cell skin cancer.
  • Patients with any other serious or uncontrolled physical or mental dysfunction.
  • Patients with a history (within 2 years prior to screening) of drug and/or alcohol abuse that may prevent study compliance based on the Investigator judgment.
  • Patients unlikely to be cooperative or that cannot comply with the study procedures.
  • Patients treated with any investigational drug within 30 days (or 6 half-lives, whichever is longer) prior to Screening.
  • Patients who intended to use any concomitant medication not permitted by this protocol or who had not undergone the required washout period for a particular prohibited medication.
  • Patients unable to give consent, or patients of consenting age but under guardianship, or vulnerable patients. Patients who demonstrate < 80% compliance with the electronic diary during the run-in period.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 130 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Bulgaria,   Czechia,   Germany,   Hungary,   Israel,   Poland,   Spain,   Ukraine,   United Kingdom,   United States
Removed Location Countries Czech Republic,   Romania,   Russian Federation,   South Africa
 
Administrative Information
NCT Number  ICMJE NCT02796677
Other Study ID Numbers  ICMJE D6571C00001
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Sanjay Sethi 3495 Bailey Ave , Buffalo NY14215, USA
PRS Account AstraZeneca
Verification Date November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP