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A Study Comparing Efficacy, Safety and Tolerability of the Fixed Dose Triple Combination CHF 5993 With the Fixed Dose Dual Combination CHF 1535 in Subjects With COPD (TRITON)

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04320342
Recruitment Status : Recruiting
First Posted : March 25, 2020
Last Update Posted : February 9, 2023
Sponsor:
Information provided by (Responsible Party):
Chiesi Farmaceutici S.p.A.

Study Description
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Brief Summary:
The purpose of this study is to compare CHF 5993 with CHF 1535 in improving lung function, reducing moderate and severe COPD exacerbations, and other clinical efficacy and safety outcomes in the target subject population.

Condition or disease Intervention/treatment Phase
COPD COPD Exacerbation Drug: Beclomethasone Dipropionate Drug: Glycopyrronium Bromide Drug: Formoterol Fumarate Phase 3

Detailed Description:

This is a phase III, multinational, multicenter, randomized, double-blind active controlled 2-arm parallel group study to compare efficacy, safety, and tolerability of CHF 5993 pMDI with CHF 1535 pMDI with respect to lung function, incidence of moderate and severe COPD exacerbations, and other clinical efficacy and safety outcomes.

After screening, eligible subjects will enter 2-week run-in period using their regular COPD maintenance therapies after which they will be randomized to one of 2 study treatment groups. Following randomization, subjects will be assessed after 4 weeks then at 6-week intervals thereafter for a period of 52 weeks. A follow-up safety phone call will be performed a week after the last clinic visit. A subset of subjects consenting to participate in the pharmacokinetic substudy will undergo additional assessments (totaling 3 visits) during the scheduled study visits.

During the study, daily symptoms, rescue medication use and compliance with the study drug will be recorded via a subject electronic diary. Subject concomitant medications, adverse events, and healthcare resource utilization will be assessed and recorded throughout the study. At intermittent study visits, subjects will undergo vital signs examinations including weight, spirometry measurements, and 12-lead ECG. Symptoms and COPD health status will be assessed through disease specific questionnaires. Routine hematology, blood chemistry, and serum pregnancy testing will be performed before enrollment and at end of study.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 2934 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase III, 52-week, Multinational, Multicenter, Randomized, Double-blind, 2-arm Parallel Group Study Comparing Efficacy, Safety and Tolerability of the Fixed Dose Triple Combination of Beclomethasone Dipropionate Plus Formoterol Fumarate Plus Glycopyrronium Bromide (CHF 5993) With the Fixed Dose Dual Combination of Beclomethasone Dipropionate Plus Formoterol Fumarate (CHF 1535), Both Administered Via pMDI in Subjects With Chronic Obstructive Pulmonary Disease (COPD)
Actual Study Start Date : April 28, 2022
Estimated Primary Completion Date : July 2024
Estimated Study Completion Date : July 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: BDP/FF/GB - CHF 5993
Two inhalations twice daily of BDP/FF/GB (100/6/12.5μg) for a period of 52 weeks via pressurized metered dose inhaler
 Drug: Beclomethasone Dipropionate
Available in pressurized inhalation solution BDP/FF/GB 100/6/12.5μg and BDP/FF 100/6μg
Other Name: BDP

Drug: Glycopyrronium Bromide
Available in pressurized inhalation solution BDP/FF/GB 100/6/12.5μg
Other Names:
  • glycopyrrolate
  • GB

Drug: Formoterol Fumarate
Available in pressurized inhalation solution BDP/FF/GB 100/6/12.5μg and BDP/FF 100/6μg
Other Name: FF
Active Comparator: BDP/FF - CHF 1535
Two inhalations twice daily of BDP/FF (100/6μg) for a period of 52 weeks via pressurized metered dose inhaler
 Drug: Beclomethasone Dipropionate
Available in pressurized inhalation solution BDP/FF/GB 100/6/12.5μg and BDP/FF 100/6μg
Other Name: BDP

Drug: Formoterol Fumarate
Available in pressurized inhalation solution BDP/FF/GB 100/6/12.5μg and BDP/FF 100/6μg
Other Name: FF


Outcome Measures
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Primary Outcome Measures :
  1. Change from baseline in pre-dose morning Forced Expiratory Volume in the 1st second (FEV1) at Week 28 [ Time Frame: Week 28 ]

Secondary Outcome Measures :
  1. Change from baseline in 2-hour post-dose morning FEV1 at Week 28 [ Time Frame: Week 28 ]
  2. Rate of moderate and severe COPD exacerbations over 52 weeks of treatment [ Time Frame: 52-week treatment period ]
    Annualized rate of moderate and severe COPD exacerbations as observed during the 52-week study treatment period.

  3. Change from baseline in pre-dose morning FEV1 at designated clinic visits [ Time Frame: Week 4, Week 10, Week 40, & Week 52 ]
  4. Change from baseline in 2-hour post-dose morning FEV1 designated clinic visits [ Time Frame: Day 1, Week 4, Week 10, Week 40, & Week 52 ]
  5. Change from pre-dose to 2-hour post-dose morning FEV1 at designated clinic visits [ Time Frame: Day 1, Week 4, Week 10, Week 28, Week 40, & Week 52 ]
  6. FEV1 response (change from baseline in pre-dose morning FEV1 ≥100ml) at designated clinic visits [ Time Frame: Day 1, Week 4, Week 10, Week 28, Week 40, & Week 52 ]
  7. Time to first moderate or severe COPD exacerbation [ Time Frame: 52-week treatment period ]
  8. Rate of severe COPD exacerbations over 52 weeks of treatment [ Time Frame: 52-week treatment period ]
    Annualized rate of severe COPD exacerbations as observed during 52-week treatment period

  9. Time to first severe COPD exacerbation [ Time Frame: 52-week treatment period ]
  10. Saint George's Respiratory Questionnaire (SGRQ) response (a decrease from baseline in total score ≥4) at designated clinic visits [ Time Frame: Week 4, Week 10, Week 28, Week 40, & Week 52 ]
  11. Change from baseline in the SGRQ total score and domain scores at each designated clinic visit [ Time Frame: Week 4, Week 10, Week 28, Week 40, & Week 52 ]
  12. Change from baseline to each inter-visit period in the percentage of days without intake of rescue medication [ Time Frame: Day 1-Week 4, Week 4-Week 10, Week 10-Week 28, Week 28-Week 40, Week 40-Week 52 ]
    Change from baseline (defined as the 2-week run-in period prior to randomization) to each inter-visit period (defined as the period of time between designated clinic visits) in percentage of days without rescue medication

  13. Change from baseline to each inter-visit period in the average use of rescue medication (number of puffs/day) [ Time Frame: Day 1-Week 4, Week 4-Week 10, Week 10-Week 28, Week 28-Week 40, Week 40-Week 52 ]
    Change from baseline (defined as the 2-week run-in period prior to randomization) in the average number of puffs per day of rescue medication for each inter-visit period (defined as the period of time between designated clinic visits).

  14. Change from baseline in pre-dose morning Forced Vital Capacity (FVC) at designated clinic visits [ Time Frame: Week 4, Week 10, Week 28, Week 40, & Week 52 ]
  15. Change from baseline in 2-hour post-dose morning FVC at designated clinic visits [ Time Frame: Day 1, Week 4, Week 10, Week 28, Week 40, & Week 52 ]
    Change from baseline (defined as the pre-dose value on Day 1) in 2-hour post-dose morning FVC at designated clinic visits

  16. Change from pre-dose to 2-hour post-dose morning FVC at designated clinic visits [ Time Frame: Day 1, Week 4, Week 10, Week 28, Week 40, & Week 52 ]
  17. Change from baseline to each inter-visit period in the average E-RS total score and domain scores [ Time Frame: Day 1-Week 4, Week 4-Week 10, Week 10-Week 28, Week 28-Week 40, Week 40-Week 52 ]
    Change from baseline (defined as the 2-week run-in period prior to randomization) in the average E-RS total score and E-RS domain scores for the period of time between designated clinic visits.

  18. Change from baseline in COPD Assessment Test (CAT) score at designated clinic visit [ Time Frame: Week 4, Week 10, Week 28, Week 40, & Week 52 ]
    The CAT is composed of 8 questions to measure the impact of COPD on daily life, which are scored from 0 to 5 with higher scores reflecting greater impact.

  19. CAT response (decrease from baseline ≥2 points) at designated clinic visits [ Time Frame: Week 4, Week 10, Week 28, Week 40, & Week 52 ]
  20. Modified Medical Research Council (mMRC) dyspnea scale at designated clinic visits [ Time Frame: Day 1, Week 4, Week 10, Week 28, Week 40, & Week 52 ]
    Descriptive statistics of the mMRC dyspnea scale score at designated clinic visits. The mMRC dyspnea scale is graded from 0 to 4, with higher grades reflecting greater severity.

  21. Change from baseline in health-related quality of life (decrease from baseline in total SGRQ score ≥4) over 52 weeks of treatment. [ Time Frame: 52-week treatment period ]

Eligibility Criteria
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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Signed and dated written informed consent must be obtained prior to initiating any study-related procedures
  • Outpatient
  • Male or female subjects aged ≥40 years
  • A female is eligible to participate in the study if she is of non-childbearing potential defined as physiologically incapable of becoming pregnant OR childbearing potential with negative serum and urine pregnancy tests at screening, and is willing to use highly effective birth control methods for the full duration of the study
  • COPD diagnosis for at least 12 months before the screening visit in accordance with the definition by the GOLD 2020 Report
  • Current or ex-smokers who quit smoking at least 6 months prior to screening with a smoking history of at least 10 pack-years [pack-years = (number of cigarettes per day x number of years)/20]
  • COPD Assessment Test (CAT) score ≥10
  • A pre- and post-bronchodilator FEV1/FVC ratio <0.70 at screening
  • A post-bronchodilator FEV1 <50% predicted normal at screening and a documented history of ≥1 moderate or severe COPD exacerbation in the previous 12 months OR a post-bronchodilator FEV1 ≥50% and <80% of predicted normal at screening and a documented history of ≥2 moderate COPD exacerbations or ≥1 severe COPD exacerbation in the previous 12 months
  • Subjects receiving daily inhaled maintenance therapy for their COPD, at a stable dose for at least 3 months prior to the screening and randomization visits
  • Documentation (including imagery and report) of chest x-ray (CXR) or CT scan performed within 6 months prior to the screening visit, without evidence of significant abnormalities (other than those related to the presence of COPD).
  • A cooperative attitude and ability to demonstrate correct use of the pMDI inhalers and eDiary.

Exclusion Criteria:

  • Female subjects who are pregnant (as evident by a positive urine hCG or serum β-hCG test) or lactating

  • Subjects using the following medications prior to the screening visit and during the run-in period:

    1. Systemic/oral/parenteral corticosteroids in the prior 4 weeks
    2. Use of antibiotics for a lower respiratory tract infection (e.g. pneumonia) or COPD exacerbation in the prior 4 weeks
    3. Any long-term chronic maintenance use of antibiotic treatment in the prior 4 weeks
    4. Oral xanthine derivatives (e.g. theophylline) in the prior 7 days
  • A moderate or severe COPD exacerbation or a respiratory tract infection (e.g., pneumonia) that has not resolved ≤14 days prior to the screening visit or during the run-in period
  • Current treatment with non-cardioselective β-blockers
  • Requirement of long term (> 15 hours daily) oxygen therapy
  • Known respiratory disorders other than COPD which may impact the efficacy of the study drug according to investigator's judgement.
  • Lung transplant surgery or lung volume reduction surgery (subjects with lung volume reduction surgery are excluded if the procedure was performed within 1 year before the Screening visit)
  • Medical diagnosis of narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that, in the opinion of the investigator, would prevent use of anticholinergic agents
  • History of hypersensitivity to M3 receptor antagonists, β2 agonists, corticosteroids or any of the excipients contained in any of the study drugs used in the trial which may raise contra-indications or impact the efficacy of the study drug according to the investigator's judgement
  • Subject has severe, acute or uncontrolled cardiovascular condition (such as but not limited to unstable ischemic heart disease, NYHA Class IV, left ventricular failure, acute myocardial infarction or unstable angina) in the last 6 months

  • An abnormal and clinically significant 12-lead ECG at either the screening or randomization visit. This is characterized as but not limited to any of the following findings:

    1. Atrial fibrillation (AF) with rapid ventricular response > 120 bpm
    2. Ventricular tachycardias (sustained, non-sustained [>3 up to 30 sec])
    3. Evidence of Mobitz Type II second degree or third-degree atrioventricular block
    4. Prolonged QTcF (>450ms for males, or >470ms for females). This criterion is not applicable for subjects with a pacemaker or permanent AF.
  • Clinically significant laboratory abnormalities indicating a significant or unstable concomitant disease which may impact the efficacy or the safety of the study drug according to investigator's judgement
  • Unstable or uncontrolled concurrent disease which may impact the efficacy or safety of the study drug or the subject's participation in the study according to investigator's judgment
  • Malignancy that has not been in complete remission for at least 1 year or any untreated localized carcinomas
  • History of alcohol abuse and/or substance/drug abuse (including marijuana inhaled and oral) within 12 months prior to the screening visit
  • Receipt of any other investigational drug within 1 month or 5 half-lives (whichever is greater) prior to the screening visit or have been previously randomized in this trial, or are currently participating in another clinical trial
  • Currently in the acute phase of a pulmonary rehabilitation program within 4 weeks before the screening visit or planning to enroll in the acute phase of such a program during the study. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded
  • Mentally or legally incapacitated, or subjects incarcerated as a result of an official or judicial order
  • Major surgery in the 3 months prior to the screening visit or have a planned surgery during the trial
  • Non-satisfactory compliance with the eDiary (<65% or >135%) during the run-in period
  • Subjects requiring the use of spacer device or nebulizer for administration of maintenance COPD therapies.
  • Veins unsuitable for repeat venipuncture
  • Blood donation or blood loss (≥450mL) in the 4 weeks before randomization
Contacts and Locations
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Information from the National Library of Medicine

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): NCT04320342


Contacts
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Contact: Chiesi Clinical Trial Info +39 0521 2791 clinicaltrials_info@chiesi.com

Locations
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Sponsors and Collaborators
Chiesi Farmaceutici S.p.A.
Investigators
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Principal Investigator: Gregory M Feldman, MD Vitalink Research - Spartanburg
More Information
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Additional Information:

Publications:
Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Barker-Collo S, Bartels DH, Bell ML, Benjamin EJ, Bennett D, Bhalla K, Bikbov B, Bin Abdulhak A, Birbeck G, Blyth F, Bolliger I, Boufous S, Bucello C, Burch M, Burney P, Carapetis J, Chen H, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahodwala N, De Leo D, Degenhardt L, Delossantos A, Denenberg J, Des Jarlais DC, Dharmaratne SD, Dorsey ER, Driscoll T, Duber H, Ebel B, Erwin PJ, Espindola P, Ezzati M, Feigin V, Flaxman AD, Forouzanfar MH, Fowkes FG, Franklin R, Fransen M, Freeman MK, Gabriel SE, Gakidou E, Gaspari F, Gillum RF, Gonzalez-Medina D, Halasa YA, Haring D, Harrison JE, Havmoeller R, Hay RJ, Hoen B, Hotez PJ, Hoy D, Jacobsen KH, James SL, Jasrasaria R, Jayaraman S, Johns N, Karthikeyan G, Kassebaum N, Keren A, Khoo JP, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Lipnick M, Lipshultz SE, Ohno SL, Mabweijano J, MacIntyre MF, Mallinger L, March L, Marks GB, Marks R, Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM, McGrath J, Mensah GA, Merriman TR, Michaud C, Miller M, Miller TR, Mock C, Mocumbi AO, Mokdad AA, Moran A, Mulholland K, Nair MN, Naldi L, Narayan KM, Nasseri K, Norman P, O'Donnell M, Omer SB, Ortblad K, Osborne R, Ozgediz D, Pahari B, Pandian JD, Rivero AP, Padilla RP, Perez-Ruiz F, Perico N, Phillips D, Pierce K, Pope CA 3rd, Porrini E, Pourmalek F, Raju M, Ranganathan D, Rehm JT, Rein DB, Remuzzi G, Rivara FP, Roberts T, De Leon FR, Rosenfeld LC, Rushton L, Sacco RL, Salomon JA, Sampson U, Sanman E, Schwebel DC, Segui-Gomez M, Shepard DS, Singh D, Singleton J, Sliwa K, Smith E, Steer A, Taylor JA, Thomas B, Tleyjeh IM, Towbin JA, Truelsen T, Undurraga EA, Venketasubramanian N, Vijayakumar L, Vos T, Wagner GR, Wang M, Wang W, Watt K, Weinstock MA, Weintraub R, Wilkinson JD, Woolf AD, Wulf S, Yeh PH, Yip P, Zabetian A, Zheng ZJ, Lopez AD, Murray CJ, AlMazroa MA, Memish ZA. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012 Dec 15;380(9859):2095-128. doi: 10.1016/S0140-6736(12)61728-0. Erratum In: Lancet. 2013 Feb 23;381(9867):628. AlMazroa, Mohammad A [added]; Memish, Ziad A [added].

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Responsible Party: Chiesi Farmaceutici S.p.A.
ClinicalTrials.gov Identifier: NCT04320342    
Other Study ID Numbers: CLI-05993AA3-06
2020-002389-16 ( EudraCT Number )
First Posted: March 25, 2020    Key Record Dates
Last Update Posted: February 9, 2023
Last Verified: February 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Chiesi Farmaceutici S.p.A.:
Lung Function
Safety Profile
Beclomethasone Dipropionate
Glycopyrronium Bromide
Formoterol Fumarate
Additional relevant MeSH terms:
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Pulmonary Disease, Chronic Obstructive
Lung Diseases, Obstructive
Lung Diseases
Respiratory Tract Diseases
Chronic Disease
Disease Attributes
Pathologic Processes
Beclomethasone
Glycopyrrolate
Bromides
Formoterol Fumarate
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
 Anti-Asthmatic Agents
Respiratory System Agents
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anticonvulsants
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Adjuvants, Anesthesia
Muscarinic Antagonists