Formoterol-beclomethasone in Patients With Bronchiectasis: a Randomized Controlled Trial (FORZA)

Randomized, double-blind, placebo-controlled study comparing formoterol-beclometason 12/200 mcg BID versus placebo to evaluate the clinical effect on coughing in patients with non-cystic fibrosis (non-CF) bronchiectasis, native to inhaled corticosteroid (ICS) therapy and no history of asthma or chronic obstructive pulmonary disease (COPD)

Study Overview

• Status: Terminated
• Conditions: Bronchiectasis
• Intervention / Treatment: Drug: Formoterol-beclomethasone; Drug: Placebo

Detailed Description

In the management of non-CF bronchiectasis, bronchodilator treatment (LABA)and use of inhaled corticosteroids (ICS) is still a matter of debate. Previous studies have claimed beneficial effects of ICS (with or without bronchodilator), such as improvement of the HRQL, a reduction in daily sputum volume and/or exacerbation frequency. However, in all previous studies there was no clear exclusion of patients with asthma or COPD, or no use of placebo. The current study will be the first study evaluating the effect of ICS/LABA treatment in non-CF bronchiectasis excluding patients with asthma and COPD.

This is a prospective double-blind randomized controlled trial comparing Formoterol-beclomethasone 12/200 mcg BID versus placebo to evaluate the reduction in cough measured by the Leicester cough questionnaire. Secondary objectives are the improvement of health-related quality of life and symptoms, reduction in sputum production, pulmonary function (FEV1) and the frequency of exacerbation. Furthemore, we will assess the inflammatory response in serum and sputum.

After a wash-out period of 1 month, eligible subjects will be randomized to treatment with formoterol-beclomethasone or matching placebo. All subjects will be treated with the regimen of medication for 3 months. An end-of-study (EOS) visit will be performed after completion of the follow-up period.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Den Haag, Netherlands
    • Hagaziekenhuis
  • Rotterdam, Netherlands
    • Franciscus Gasthuis & Vlietland
  • Rotterdam, Netherlands, 3015GD
    • Tjeerd van der Veer

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Symptomatic patient (wheezing, cough and dyspnoea);
• Proven and documented diagnosis of BE by high resolution computed tomography ;
• Stable pulmonary status as indicated by FEV1 (percent of predicted) ≥30%
• Stable clinically phase (ie, subjects free from acute exacerbation for at least 6 weeks prior to the start of the study);
• Stable regimen of standard treatment as chronic treatment for BE, at least for the past 4 weeks prior to screening. And/or macrolides if used as chronic treatment for BE at least for the past 6 months prior to screening;
• Coughing on the majority of days for more than 8 weeks;
• Ability to follow the inhaler device instructions;
• Ability to complete questionnaires;
• Written informed consent.

Exclusion Criteria:

• Possible asthma according to the definition of the Global Initiative for Asthma (GINA);
• Positive histamine provocation test
• Known intolerance for ICS or LABA;
• Women who are pregnant, lactating, or in whom pregnancy cannot be excluded;
• Expected to die within 72 hours after enrolment;
• Cigarette smoking history of > 10 pack-years or current smokers;
• Other cardiopulmonary conditions (other than bronchiectasis) that could modify spirometric values.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Formoterol-beclomethasone; Formoterol (fumarate dehydrate) 12 microg - beclomethasone (dipropionate) 200 microg administered BID, per inhalation using '100/6' Metered Dose Inhaler.	Drug: Formoterol-beclomethasone; formoterol (fumarate dihydrate) 12 microg - beclomethasone (dipropionate) 200 microg administered BID, per inhalation using '100/6' Metered Dose Inhaler
Placebo Comparator: Placebo; Matching placebo (identically package) administered BID	Drug: Placebo; Matching placebo (identically package) administered BID

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical effect on coughing	Using the Leicester Cough Questionnaire (LCQ) at baseline and 3 months. The LCQ is a valid, repeatable 19 item self-completed quality of life measure of chronic cough which is responsive to change. Score range: 19-133 (Higher values represent a better outcome.)	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of life in patient with bronchiectasis	Mean Change From Baseline in Patient Reported Outcome Quality of Life Questionnaire for Bronchiectasis (QoL-B) Respiratory Symptoms Domain Score (measured at baseline and 3 months). The QoL-B was a disease-specific questionnaire developed for non-Cystic fibrosis Bronchiectasis. It covers 8 dimensions: physical functioning, role functioning, emotional functioning, social functioning, vitality, treatment burden, health perceptions, and respiratory symptoms. Each dimension was scored separately on a scale of 0 to 100, and higher scores represent better outcomes. For this outcome measure, the respiratory symptoms domain score was reported.	3 months
Pulmonary function	Spirometry: FEV1	3 months
Exacerbation frequency	The frequency of exacerbation requiring an intervention with systemic antibiotics (oral/intravenous [i.v.])	3 months
Sputum production	in mL	3 months
Dyspnea score	mMRC (Modified Medical Research Council) Dyspnea Scale. This stratifies severity of dyspnea in respiratory diseases. Grading from 0 to 4, respectively from 'no dyspnea' to 'very severe dyspnea'.	3 months
Incidence of Adverse Events [Safety and Tolerability]).	Incidence of Adverse Events [Safety and Tolerability]).	3 months
Sputum culture	Micro organisms isolated during study	3 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inflammatory response in serum: C-reactive protein	Measuring high-sensitivity C-reactive protein (mg/L) at baseline and 3 months	3 months
Inflammatory response in serum: erythrocyte sedimentation rate	Measuring the erythrocyte sedimentation rate (mm/h) at baseline and 3 months	3 months
Inflammatory response in serum: WBC	Measuring the white blood cell (WBC) count including polymorphonuclear leukocytes (10^9/L), neutrophils (10^9/L) and eosinophils (10^9/L) at baseline and 3 months	3 months
Inflammatory response in serum: pulmonary type 2 innate lymphoid cells	Measuring pulmonary type 2 innate lymphoid cells including IL-4, IL-5 and IL-13 (all in pg/ml) at baseline and 3 months	3 months
Inflammatory response in sputum	Measuring the numbers of pulmonary type 2 innate lymphoid cells (ILC2) per ml sputum, observing any change from baseline to 3 months.	3 months

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: Chiesi Farmaceutici S.p.A.
• Investigators: Principal Investigator: Menno M Van der Eerden, Erasmus Medical Center; Principal Investigator: Tjeerd Van der Veer, Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2019
• Primary Completion (Actual): July 5, 2022
• Study Completion (Actual): July 5, 2022

Study Registration Dates

• First Submitted: February 14, 2019
• First Submitted That Met QC Criteria: February 18, 2019
• First Posted (Actual): February 19, 2019

Study Record Updates

• Last Update Posted (Actual): March 1, 2023
• Last Update Submitted That Met QC Criteria: February 28, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Cough; Placebo; Inhaled corticosteroids
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Bronchial Diseases; Bronchiectasis; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Beclomethasone; Formoterol Fumarate
• Other Study ID Numbers: NL61630.078.18

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: 36 months after publication
• IPD Sharing Access Criteria: Data can be requested immediately following publication up to 36 months, after which the data will be filed in the Erasmus MC respiratory medicine department archives without further research support. Data requests are to be addressed to: research.longziekten@erasmusmc.nl
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No