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A Dose Ranging Study of CHF 1531 in Asthmatic Subjects (FLASH)

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ClinicalTrials.gov Identifier: NCT03086460
Recruitment Status : Completed
First Posted : March 22, 2017
Last Update Posted : July 29, 2019
Sponsor:
Information provided by (Responsible Party):
Chiesi Farmaceutici S.p.A.

Brief Summary:
The purpose of this study is to evaluate the dose-response of different doses of CHF 1531 on lung function and other clinical outcomes, to identify the optimal dose(s) in terms of benefit/ risk ratio for further development in the target subject population.

Condition or disease Intervention/treatment Phase
Asthma Drug: CHF 1531 Drug: Formoterol Inhalation Solution Drug: Placebo Phase 2

Detailed Description:

This is a phase II, randomized, double-blind, placebo and active controlled dose-ranging, 6 arm incomplete block cross-over study to identify the optimal dose of CHF 1531 with respect to lung function and other clinical efficacy and safety outcomes.

After a 2 week run-in period under rescue albuterol as needed and background inhaled corticosteroid (ICS), qualifying subjects will be required to complete 4 treatment periods of 2 weeks each separated by a 2 week wash-out intervals. During each treatment period, the subject will be randomly assigned to take one of 5 double-blind study treatments twice daily (one of 4 doses of CHF 1531 or a matching placebo) or the open-label active control treatment also twice daily. All subjects will concomitantly receive ICS treatment with QVAR® inhaler (beclomethasone dipropionate 40 or 80 µg /actuation) twice daily at a dose that matches their pre-enrollment ICS, and an albuterol inhaler to use as needed as asthma rescue medication, during the entire study. The subjects will visit the study center every 2 weeks to undergo study procedures, and will receive a safety follow-up phone call one week after their last visit. In total, the study will last 18 weeks and will require 10 visits to the study center.

During the study, daily asthma symptoms, peak expiratory flow, rescue and background medication use, and compliance with the study medication will be recorded via subject diary. Treatment-Emergent Adverse Events (TEAEs) will be assessed and recorded throughout the study. A full physical exam, routine hematology, blood chemistry, spirometry, vital signs measurement, 12-lead ECG and pregnancy testing will be performed before enrollment and at end of study. Furthermore on Day 1 and 14 of each treatment period, serial spirometry, 12-lead ECGs, BP, and serum potassium and glucose will also be measured at the study center up to 12 hours post-dosing.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 67 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Other
Official Title: A Randomized, Double-blind, Placebo and Active-controlled, Incomplete Block Cross-over, Dose Ranging Study to Evaluate the Efficacy and Safety of 4 Doses of CHF 1531 pMDI (Formoterol Fumarate) in Asthmatic Subjects
Actual Study Start Date : September 8, 2017
Actual Primary Completion Date : July 23, 2018
Actual Study Completion Date : July 28, 2018


Arm Intervention/treatment
Experimental: Treatment A
CHF 1531 pMDI Dose 1
Drug: CHF 1531
Dose Response: Test one of five different doses of CHF 1531
Other Name: Dose Finding

Experimental: Treatment B
CHF 1531 pMDI Dose 2
Drug: CHF 1531
Dose Response: Test one of five different doses of CHF 1531
Other Name: Dose Finding

Experimental: Treatment C
CHF 1531 pMDI Dose 3
Drug: CHF 1531
Dose Response: Test one of five different doses of CHF 1531
Other Name: Dose Finding

Experimental: Treatment D
CHF 1531 pMDI Dose 4
Drug: CHF 1531
Dose Response: Test one of five different doses of CHF 1531
Other Name: Dose Finding

Experimental: Treatment E
Matched placebo
Drug: Placebo
Matched Placebo

Active Comparator: Treatment F
Formoterol fumarate inhalation solution, 20μg
Drug: Formoterol Inhalation Solution
Active Control
Other Name: PERFOROMIST® 20μg/ 2mL vial, 1 vial bid




Primary Outcome Measures :
  1. Change from baseline in FEV1 AUC0-12h normalized by time at Day 14 [ Time Frame: 14 Days ]

Secondary Outcome Measures :
  1. Change from baseline in FEV1 AUC0-12h normalized by time at Day 1 [ Time Frame: 1 Day ]
  2. Change from baseline in FEV1 AUC0-4h normalized by time and in FEV1 peak0-4h at Day 1 and Day 14 [ Time Frame: 1 Day & 14 Days ]
  3. Change from baseline in FVC AUC0-12h normalized by time, in FVC AUC0-4h normalized by time and in FVC peak0-4h at Day 1 and at Day 14 [ Time Frame: 1 Day & 14 Days ]
  4. Change from baseline in pre-dose morning FEV1 at Day 14 [ Time Frame: 14 Days ]
  5. Change from baseline in pre-dose morning FVC at Day 14 [ Time Frame: 14 Days ]
  6. Time to onset of action (change from baseline in post-dose FEV1 ≥ 12% and ≥ 200mL) at Day 1 [ Time Frame: 1 Day ]
  7. Adverse Events (AEs) [ Time Frame: 14 Days ]
  8. Adverse Drug Reactions (ADRs) [ Time Frame: 14 Days ]
  9. Vital signs (systolic and diastolic blood pressure) [ Time Frame: 14 Days ]
  10. 12-lead ECG parameters (HR, QTcF, QRS, PR) [ Time Frame: 14 Days ]
  11. HR AUC0-4h normalized by time and HR peak0-4h [ Time Frame: 14 Days ]
  12. Serum potassium and blood glucose [ Time Frame: 14 Days ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female subjects aged ≥18 and ≤75 years who have signed an Informed Consent Form prior to initiation of any study-related procedure.
  • A diagnosis of asthma as defined in the GINA Report, 2016, documented for at least 1 year prior to screening.
  • Poorly controlled or uncontrolled asthma evidenced by a score ≥1.5 on the Asthma Control Questionnaire 7 © (ACQ-7)
  • A pre-bronchodilator FEV1 ≥60% and <85% of their predicted normal value, after appropriate washout from bronchodilators, at the screening and randomization visits
  • Subjects with a positive response to a reversibility test at screening, defined as ΔFEV1 ≥12% and ≥200mL over baseline within 30 minutes after inhaling 4 puffs of albuterol HFA 90µg/actuation.
  • Use of ICS (low/medium dose according to GINA Report, 2016) with or without a LABD for 3 months (at a stable dose in the last 4 weeks) before screening visit.
  • A cooperative attitude and ability to demonstrate correct use of the diary, peak flow meter and pMDI inhaler.

Exclusion Criteria:

  • Pregnant or lactating women and all women physiologically capable of becoming pregnant UNLESS they are willing to use a highly effective birth control methods
  • Subjects who suffer from COPD as defined by the GOLD Report, 2017, or are suspected of having Asthma COPD Overlap Syndrome (ACOS) as described in the GINA Report, 2016.
  • Inability to carry out pulmonary function testing, to comply with study procedures or with study drug intake.
  • Current smokers or ex-smokers (tobacco, vapor cigarettes, marijuana) with a smoking history of >10 pack-years or having stopped smoking one year or less prior to screening visit.
  • History of life-threatening asthma, clinically significant uncontrolled disease or respiratory infection.
  • An asthma exacerbation requiring oral/intravenous corticosteroids ≤ 30 days, intramuscular depot corticosteroid ≤3 months or hospitalization within 6 months prior to screening.
  • Subjects with unresolved bacterial or viral respiratory tract, sinus, or middle ear infection affecting asthma status within 2 weeks prior to screening.
  • Subjects who received a vaccination within 2 weeks prior to screening or during the run-in.
  • Subjects with oral candidiasis at screening and at randomization.
  • Subjects with any clinically significant, uncontrolled condition.
  • Subjects with serum potassium levels <3.5 mEq/L (or 3.5 mmol/L) at screening.
  • Subjects who have clinically significant cardiovascular condition.
  • Subjects who have a clinically significant abnormal 12-lead ECG that results in active medical problem which may impact the safety of the patient according to Investigator's judgment.
  • Subjects whose 12-lead ECG shows Fridericia's corrected QT interval (QTcF) >450ms for males or QTcF >470ms for females at screening or randomization visits.
  • Subjects with known intolerance/hypersensitivity or contra-indication to treatment with inhaled β2-adrenergic receptor agonists, corticosteroids or propellant gases/excipients.
  • Subjects with concomitant immunosuppressive therapy, use of oral or injected corticosteroids, anti-IgE, anti-IL5 or other monoclonal or polyclonal antibodies within 12 weeks prior to screening.
  • Use of potent cytochrome P450 3A4 inhibitors and inducers within 4 weeks prior to screening.
  • History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening.
  • Subjects who have received an investigational drug within 1 month or 5 half-lives (whichever is greater) prior to screening visit, or have been previously randomized in this trial, or are currently participating in another clinical trial.
  • Subjects who are mentally or legally incapacitated or subjects accommodated in an establishment as a result of an official or judicial order.
  • Subjects who have undergone major surgery in the 3 months prior to screening visit or have a planned surgery during the trial.

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): NCT03086460


Locations
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United States, Arizona
Chiesi Investigational Site
Tucson, Arizona, United States, 85710
United States, California
Chiesi Investigational Site
Los Angeles, California, United States, 90048
United States, Maryland
Chiesi Investigational Site
Lutherville, Maryland, United States, 21093
United States, Missouri
Chiesi Investigational Site
Saint Louis, Missouri, United States, 63141
United States, North Carolina
Chiesi Investigational Site
Raleigh, North Carolina, United States, 27607
United States, South Carolina
Chiesi Investigational Site
Greenville, South Carolina, United States, 29615
Chiesi Investigational Site
Orangeburg, South Carolina, United States, 29118
Chiesi Investigational Site
Spartanburg, South Carolina, United States, 29303
United States, Tennessee
Chiesi Investigational Site
Knoxville, Tennessee, United States, 37909
United States, Washington
Chiesi Investigational Site
Richland, Washington, United States, 99352
Sponsors and Collaborators
Chiesi Farmaceutici S.p.A.
Investigators
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Principal Investigator: Richard Sterling Sterling ENT, PA
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 León 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].
Novartis Pharma. FORADIL®AEROLIZER® US Prescribing Information. Whitehouse Station, New Jersey; 2012 Sep.
Chiesi Farmaceutici S.p.A. A randomized, double blind, double dummy, single dose, crossover trial comparing the efficacy and safety of a single dose administered via 1 puff of 6 μg or 2 puffs of 6 μg of formoterol-HFA (pMDI) versus a single dose of 12 μg of formoterol- DPI (Foradil®Aerolizer®) and of placebo (pMDI or Aerolizer®) in moderate to severe asthmatic patients. RA/PR/3301/009/03.
Mylan Specialty L.P. PERFOROMIST® US Prescribing Information. Morgantown, West Virginia; 2013 Mar.
Chiesi Farmaceutici S.p.A. CHF 1535 HFA : BDP + formoterol 100/6 μg pressurized inhalation solution : Common Technical Document. Module 2.5: 8.
Center for Drug Evaluation and Research Medical Review. Clinical Team Leader Memorandum: Formoterol fumarate inhalation solution 20mcg/2mL; NDA # 22-007: 2007 Mar 15.

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Responsible Party: Chiesi Farmaceutici S.p.A.
ClinicalTrials.gov Identifier: NCT03086460    
Other Study ID Numbers: CCD-05993AA3-03
First Posted: March 22, 2017    Key Record Dates
Last Update Posted: July 29, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Asthma
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
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