Objectives

To determine the efficacy and tolerability of roflumilast for obese individuals with poorly controlled asthma.

Background

Obesity is a risk factor for the development of asthma. Patients with obesity often have poorly controlled asthma and do not respond well to conventional controller therapy when compared to lean people with asthma.

Roflumilast, a phosphodiesterase 4 inhibitor approved for use for people with chronic obstructive pulmonary disease (COPD), showed improvement of asthma in mouse model trials as well as beneficial metabolic effects in patients with metabolic syndrome. Previous studies have shown that a weight loss of 5% or more improves asthma control in people with obesity.

The primary objective was to assess the potential efficacy of roflumilast for the treatment of asthma in obese individuals; however, the study also compared outcomes between those who did and did not lose at least 5% of their baseline weight (regardless of treatment assignment).

Participants

A total of 291 participants were screened by the TRIM study. Of these, 41 participants entered the run-in period, and 38 participants were randomized. In total, 22 participants were randomized to the treatment arm and 16 participants were randomized to the placebo arm.

Eligible participants were obese adults (BMI > 30kg/m2) with a history of physician-diagnosed asthma who were prescribed regular controller therapy for the 3 months prior. Poorly controlled asthma was defined by the study as an Asthma Control Test (ACT) score of less than 20. Participants were excluded from randomization for liver cirrhosis, major psychiatric disorders, other comorbidities, smoking history, history of bariatric surgery, current/recent participation in another investigational study, use of drugs metabolized by P450, and COPD.

Design

The TRIM study was a 24-week, randomized, double-masked, placebo-controlled pilot study. After an eligibility assessment, participants underwent a 1-week-run-in period during which an asthma control diary was completed. Participants with a completed diary who maintained eligibility were randomly assigned to receive 500 mcg roflumilast or a placebo. Participants randomized to the treatment arm received 500 mcg every other day for the first two weeks and then 500 mcg daily for the remainder of the study. Follow-up visits were conducted at week 2, week 6, week 12, week 18, and week 24.

Diary cards were completed by participants and used to assess episodes of poor asthma control. Spirometry and methacholine challenge tests were performed at in-person clinic visits before March 2020 and were not conducted after that date due to COVID-19. Participants completed the following questionnaires: ASUI (Asthma Symptom Utility Index), MAQLQ (Marks Asthma Quality of Life Questionnaire), a general health Short Form (36) Health Survey, GSRS (Gastrointestinal Symptom Rating Scale), PHQ-9 (Patient Health Questionnaire), and GAD-7 (Generalized Anxiety Disorder).

The primary outcome was a change in ACT score from baseline to week 24. A secondary analysis was conducted to evaluate the effect of weight loss on asthma control regardless of treatment arm.

Conclusions

Roflumilast had no effect on asthma control and was associated with a 3.5-fold increase in the risk of asthma exacerbations in participants receiving roflumilast compared to participants in the placebo arm. Participants with a weight loss of at least 5% experienced a clinically and statistically significant improvement in asthma control.

Dixon AE, Que LG, Kalhan R, et al. Roflumilast May Increase Risk of Exacerbations When Used to Treat Poorly Controlled Asthma in People with Obesity. Ann Am Thorac Soc. 2023;20(2):206-214. doi:10.1513/AnnalsATS.202204-368OC

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