Effects of roflumilast in COPD patients receiving inhaled corticosteroid/long-acting β₂-agonist fixed-dose combination: RE²SPOND rationale and study design

Figures & data

Table 1 Comparison of the REACT^18,27 and RE²SPOND trials

	REACT	RE^2SPOND
Study design	Double-blind, placebo-controlled, parallel group, multicenter, Phase IV	Double-blind, placebo-controlled, parallel group, multicenter, Phase IV
Trial length	4-week single-blind run-in +52-week DB treatment	2-week single-blind run-in +52-week DB treatment
Number of participants	1,945	2,300 (expected)
Trial sites	203 sites across 21 countries	380 sites across 17 countries
Eligible participants	Diagnosis of severe to very severe COPD with chronic bronchitis and a history of COPD exacerbations	Diagnosis of severe to very severe COPD with chronic bronchitis and a history of COPD exacerbations
Randomization	1:1	1:1, stratified by LAMA use
Treatment	500 μg roflumilast or placebo + FDC ICS/LABAa (+70% of participants were on LAMAb treatment)	500 μg roflumilast or placebo + FDC ICS/LABAc (+ up to 60% of participants allowed LAMA treatment)
Roflumilast formulation	Film-coated tablets (information on file)	Uncoated tablets
Allowed concomitanttreatments	Salbutamol, corticosteroids, antibioticsd	Salbutamol/albuterol, corticosteroids, H1- antihistamines, antibiotics,d SAMAe
Follow-up	4 weeks (safety) and 12 weeks	4 weeks (safety) or up to the scheduled Week 52 visit for early terminated participants
Primary outcome	Rate of moderate or severe COPD exacerbations per participant per yearf	Rate of moderate or severe COPD exacerbations per participant per yearf
Primary outcomeanalyses	Poisson regression model with overdispersion correction and negative binomial regression model	Negative binomial regression model and sensitivity analysis
Secondary outcomes	Change in postbronchodilator FEV1, rate of severe COPD exacerbations, rate of moderate to severe or antibiotic-treated COPD exacerbations, spirometry	Change in prebronchodilator FEV1; rate of severe COPD exacerbations; and rate of moderate, severe, or antibiotic-treated exacerbations
Additional/safetyoutcomes	Electronic rescue medication diary, CAT, major adverse cardiac events, mortality	Spirometry, electronic rescue medication diary, CAT, EXACT-PRO, major adverse cardiac events, C-SSRS
Pharmacokinetics	Sparse sampling (n=986)	Sparse sampling (n=420), serial sampling (n=40)

Notes:

a Participants were allowed to use any commercially available fixed ICS/LABA combination at the maximum dosage approved in each country (not sponsor provided).

b Participants were classified as receiving concomitant treatment with a LAMA if they used this therapy during baseline and at least 80% of the duration of the treatment period.

c Sponsor provided fluticasone 250 μg/salmeterol 50 μg (one inhalation twice daily) or budesonide 160 μg/formoterol 4.5 μg (two inhalations twice daily).

d For treatment of purulent sputum or suspected bacterial infection.

e If not on a LAMA.

f Moderate COPD exacerbations are defined as those requiring corticosteroid treatment; severe COPD exacerbations are those that require hospitalization and/or lead to death.

Abbreviations: CAT, COPD assessment test; C-SSRS, Columbia Suicide Severity Rating Scale; DB, double-blind; EXACT-PRO, exacerbation of chronic pulmonary disease tool – patient reported outcomes; FDC, fixed-dose combination; FEV₁, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; REACT, Roflumilast and Exacerbations in patients receiving Appropriate Combination Therapy; SAMA, short-acting muscarinic antagonist.

Figure 1 RE²SPOND trial design.

Note: ^aFollow-up was conducted 4 weeks after Visit 8 (last visit) or after early termination visit, as applicable.
Abbreviations: ET/LV, early termination or last visit; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; qd, once daily; R, randomization; S, screening; TC, telephone contact.

Table 2 Baseline demographics and characteristics (safety population)

Characteristics	Total (N=2,352)
Age, mean (SD), years	64.5 (8.6)
Male, n (%)	1,615 (68.7)
White, n (%)	1,879 (79.9)
Weight, mean (SD), kg	73.1 (19.1)
BMI, mean (SD), kg/m^2	25.9 (5.8)
Current smoker, n (%)	926 (39.4)
Years smoking, mean (SD)	40.7 (10.5)a
COPD severity, n (%)
Moderate	1 (<1)
Severe	1,417 (62.2)
Very severe	920 (39.1)
Prebronchodilator FEV1% predicted, mean (SD), %	29.9 (8.9)b
Number of COPD exacerbations in 12 months prior to screening, n (%)
1	23 (1.0)
2–5	2,290 (97.4)
6+	39 (1.7)
Stable LAMA use, n (%)	1,094 (46.5)
Suicidal ideation or behavior, n (%)	195 (8.3)c

Notes:

a N=2,349.

b N=2,341.

c N=2,348.

Abbreviations: BMI, body mass index; FEV₁, forced expiratory volume in 1 second; LAMA, long-acting muscarinic antagonist; SD, standard deviation.

Figure 2 Timeline of participant enrollments and discontinuations.

MartinezFJCalverleyPMAGoehringU-MBroseMFabbriLMRabeKFEffect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trialLancet2015385997185786625684586

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