A Total Diet Replacement Weight Management Program for Difficult-to-Treat Asthma Associated With Obesity

Background Obesity is often associated with uncontrolled, difficult-to-treat asthma and increased morbidity and mortality. Previous studies suggest that weight loss may improve asthma outcomes, but with heterogenous asthma populations studied and unclear consensus on the optimal method of weight management. The Counterweight-Plus Programme (CWP) for weight management is an evidence-based, dietitian-led total diet replacement (TDR) program. Research Question Can use of the CWP compared with usual care (UC) improve asthma control and quality of life in patients with difficult-to-treat asthma and obesity? Study Design and Methods We conducted a 1:1 (CWP to UC) randomized, controlled single-center trial in adults with difficult-to-treat asthma and BMI of ≥ 30 kg/m2. The CWP was a 12-week TDR phase (800 kcal/d low-energy formula) followed by stepwise food reintroduction and weight loss maintenance for up to 1 year. The primary outcome was the change in Asthma Control Questionnaire 6 (ACQ6) score over 16 weeks. The secondary outcome was change in Asthma Quality of Life Questionnaire (AQLQ) score. Results Thirty-five participants were randomized (36 screened) and 33 attended the 16-week follow-up (n = 17 in the CWP group, n = 16 in the UC group). Overall, mean ACQ6 score at baseline was 2.8 (95% CI, 2.4-3.1). Weight loss was greater in the CWP than UC group (mean difference, –12.1 kg; 95% CI, –16.9 to –7.4; P < .001). ACQ6 score improved more in the CWP than UC group (mean difference, –0.69; 95% CI, –1.37 to –0.01; P = .048). A larger proportion of participants achieved the minimal clinically important difference in ACQ6 score with CWP than with UC (53% vs 19%; P = .041; Number needed to treat, 3 [95% CI, 1.5-26.9]). AQLQ score improvement was greater in the CWP than UC group (mean difference, 0.76; 95% CI, 0.18-1.34; P = .013). Interpretation Using a structured weight management program results in clinically important improvements in asthma control and quality of life over 16 weeks compared with UC in adults with difficult-to-treat asthma and obesity. This generalizable program is easy to deliver for this challenging phenotype. Longer-term outcomes continue to be studied. Trial Registry ClinicalTrials.gov; No.: NCT03858608; URL: www.clinicaltrials.gov

Approximately 17% of people living with asthma have difficult-to-treat disease because of factors including poor inhaler technique, treatment nonadherence, and comorbidities such as obesity. 1,2sthma associated with obesity is less steroid responsive; is linked with poorer control, quality of life, and increased morbidity and mortality; and has limited treatment options. 3,4The pathophysiologic effects of obesity on asthma are multifactorial.
1][12] A Cochrane review 13 of four studies (N ¼ 197) suggested that weight loss may improve asthma control, but the quality of the evidence was poor and further well-constructed randomized controlled trials were recommended.
In the United Kingdom, the Counterweight-Plus Programme (CWP) for weight management is a commercially available dietitian-supported regimen of total diet replacement (TDR), stepwise food reintroduction, and weight loss maintenance.It has shown efficacy in obesity (mean weight loss, 10 kg; approximately one-third achieving loss of $ 15 kg) and type 2 diabetes mellitus (remission in 46% of patients). 14,15Its effects on asthma have not been evaluated, and we hypothesized that use of the CWP would result in improvements in asthma control and asthma-related quality of life.To test this hypothesis, we performed a randomized, controlled, proof-of-concept feasibility trial of CWP in patients with obesity and difficult-to-treat asthma.Herein, we report the primary outcome results for the first 16 weeks of treatment after completion of the first phase of the intervention program.

Study Design and Methods
In this randomized, controlled, open-label, parallel study of a TDR weight loss program compared with usual care (UC) in individuals with difficult-to-treat asthma and obesity, participants were randomized 1:1 using a password-protected, online, third-party randomization service to CWP or UC. 16Study visits were scheduled at baseline and 16 weeks, with further visits planned for the 1-year and 2-year follow-up.The trial was approved by the West of Scotland Regional Ethics Committee (Identifier: 18/WS/ 0216), was sponsored and funded by an NHS Greater Glasgow and Clyde Endowment Fund, and is registered at ClinicalTrials.gov(Identifier: NCT03858608), where trial protocol is described. 17The funder and contributors to the fund had no input in study design or the trial outcomes.Because of the COVID-19 pandemic, face-toface follow-up study visits were replaced with telephone consultations where necessary to optimize data collection.Recruitment and randomization was undertaken by the clinical research fellow.Study visits and data collection were performed by the clinical research fellow and clinical research nursing team at the Glasgow Royal Infirmary Clinical Research Facility.

Participants
Eligible participants 18 to 75 years of age with BMI of $ 30.0 kg/m 2 , a diagnosis of asthma according to Global Initiative for Asthma guidelines, 18 and difficult-to-treat disease according to Scottish Intercollegiate Guidelines Network/British Thoracic Society guidelines 19 were identified from secondary and tertiary asthma clinics and ward admissions across NHS Greater Glasgow and Clyde (e-Appendix 1).Asthma clinicians and asthma specialist nurses referred patients to the clinical research fellow for screening after a brief explanation of the program.Asthma clinicians were aware of participation in the trial (consent forms were uploaded to electronic patient health-care records), but were not involved in recruitment, study visits, or data analysis.Eligible participants were provided with written information and were invited to attend the Glasgow Royal Infirmary Clinical Research Facility, where written informed consent was obtained before randomization and baseline data collection (visit 1).Participants were enrolled and randomized by the clinical research fellow.

Take-home Points
Study Question: Can use of the Counterweight-Plus Programme (CWP) for weight management improve asthma control and quality of life in patients with difficult-to-treat asthma and obesity, compared with those receiving usual care (UC)?Results: Over 16 weeks, the CWP resulted in clinically relevant improvements in both asthma control and quality-of-life indexes, with substantial weight loss, as compared with UC.Interpretation: Initial results using the CWP are encouraging, and adherence to the program was better than expected, although longer-term outcomes are awaited to assess sustainability of the benefits seen.

Measurements
Baseline demographics, asthma and other medical history, and medication information were obtained at visit 1.At all visits, the Asthma Control Questionnaire 6 (ACQ6) and Asthma Quality of Life Questionnaire (AQLQ) scores were recorded.The ACQ6 is a validated asthma control score comprising six questions, 20 a score of $ 1.5 reflecting poor disease control, and with a minimal clinically important difference (MCID) of 0.5.The AQLQ is a validated score comprising 32 questions covering several domains (symptoms, activity limitation, emotional function, and environmental stimuli) assessing quality of life in asthma. 21A higher score reflects better quality of life and the MCID is 0.5.At all visits, other data collected included anthropomorphic measures, health-care use, Medical Research Council dyspnea scale score, Hospital Anxiety Depression scale score, blood sampling, spirometry (Vitalograph ALPHA spirometer) as per European Respiratory Society/American Thoracic Society standards, 22 peak expiratory flow rate, fractional exhaled nitric oxide (FENO; NIOX VERO; Aerocrine AB) according to American Thoracic Society guidelines, 23 6-min walk test according to European Respiratory Society/American Thoracic Society standards, 24 and accelerometery (e-Appendix 1).

Counterweight-Plus Program
The CWP consisted of three phases: TDR (0-12 weeks), food reintroduction (13-18 weeks), and weight loss maintenance (19-52 weeks) and was delivered by experienced dietitians with CWP training (e-Appendix 1).The TDR phase comprised a low-energy liquid diet consisting of 825 to 853 kcal/d (approximately 59% carbohydrate, 13% fat, 26% protein, and 2% fiber) administered via sachets of dried soups and shakes in a variety of flavors made up with water by the participant.The dietitian team reviewed participants at 1 week and then fortnightly.To allow flexibility for participants, acknowledging other commitments or logistical limitations, this phase was extended to 20 weeks if participants did not lose > 15 kg by week 12.Conversely, if a participant's BMI fell to < 23.0 kg/m 2 , then food reintroduction was introduced earlier.The food reintroduction phase involved a reducing formula diet and stepwise reintroduction of calorie-controlled meals (with fortnightly dietitian review continuing).Flexible periods of 2 to 8 weeks were used for this phase based on participant confidence with weight loss management.In the weight loss maintenance phase, dietitians provided individually tailored calorie prescription for weight stabilization and to prevent weight regain, with monthly reviews.All program phases were underpinned by recognized behavior change strategies. 25,26Dietitian-led relapse treatments to correct weight regain were available. 27ual Care Standard asthma care was continued in all participants in all groups.This included continuation of previously initiated asthma medication, but also modification of asthma treatment based on clinical need; those with worsening asthma received treatment escalation, whereas those with improving disease or lack of treatment efficacy underwent medication removal.All participants continued to be reviewed at their original secondary asthma clinic as part of standard care.All participants had the opportunity for weight management advice (ie, healthy eating and promoting exercise if in the UC group), inhaler technique, and asthma education as needed at each study visit.

Primary Outcome
The primary outcome was difference in change in ACQ6 score from baseline (visit 1) to 16 weeks (visit 2) between the CWP and UC groups.

Secondary Outcomes
Secondary measures included difference in change in AQLQ score from baseline to 16 weeks between CWP and UC groups, overall and in each AQLQ domain (symptoms, activity, emotional, and environmental), and the difference in proportion of participants with $ 0.5 change (MCID in ACQ6 20 and AQLQ 21 ) between groups at 16 weeks.For other outcomes, see e-Appendix 1.

Sample Size
To demonstrate a difference of 0.5 between mean changes in ACQ6 score in CWP and UC groups from baseline to 16 weeks, based on an SD of 0.5 from a similar population, 28 a sample size of 30 (15 per group) was required, assuming an a values of 0.05, a b values of 0.2, and power of 0.8.A target of 40 participants was chosen to allow for a 25% dropout rate.

Statistical Analysis
Participants attending visits 1 and 2 were included for intention-to-treat analysis.Continuous variables were described as mean (95% CI) or median (interquartile range [IQR]) based on distribution and compared using independent t tests or Mann-Whitney U tests, respectively.Change in continuous variables over time was analyzed using analysis of covariance with the baseline variable as a covariate and comparing change in variables using t tests or Mann-Whitney U tests, depending on distribution.Categorical variables were described as number (percentage) and were compared using Pearson c 2 test or the Fisher exact test as appropriate.Analyses were performed using IBM SPSS Statistics for Mac version 28 (IBM Corp.); graphs were produced using GraphPad Prism for Mac version 9.3.1 (GraphPad Software).A P value of # .05 was significant.All data analysis was performed by the clinical research fellow using anonymized data.

Participation and Baseline Characteristics
Participants were recruited from August 2019 through August 2021, with 2-year follow-up scheduled to finish in August 2023.Sixteen-week follow-up visits continued until December 2021.Of 36 participants screened, one was ineligible (e-Appendix 1) and 35 were randomized.Two patients were lost to follow-up and 33 patients attended visit 2 to be included in the intention-to-treat analysis (n ¼ 17 in the CWP group, n ¼ 16 in the UC group; Fig 1).Recruitment was halted before the target of 40 because of a lower than expected dropout rate.
Individuals in the CWP group were slightly older, had lower baseline peak expiratory flow rate and FEV 1 , and were more sedentary, with accelerometery data demonstrating more inactive time and less time spent in light to moderate vigorous physical activity compared with the UC group.No other between-group differences were observed.

Adverse Events
No unexpected serious adverse events or interventionrelated adverse events occurred during the trial.Overall, five participants were hospitalized during the 16-week period: three participants in the UC group (one participant with a ward level exacerbation of asthma, one participant with exacerbation of asthma requiring high dependency monitoring, one participant with COVID-19 pneumonitis) and two participants in the CWP group (one participant with COVID-19 gastroenteritis and one participant with migraine).

Discussion
In this pragmatic open-label, randomized, controlled trial, we showed that delivery of a supported low-calorie total diet replacement program (Counterweight-Plus) to patients with difficult-to-treat asthma and obesity was safe and led to significant improvements in asthma  This trial has several possible limitations.This proofof-concept feasibility study was sufficient to detect significant effects, but a larger study is needed to chestjournal.orggenerate definitive results.Small differences were observed between groups at baseline (age, peak expiratory flow rate, FEV 1 , and accelerometery), although because of randomization, these were unlikely to impact the primary and secondary outcomes we obtained.Baseline asthma control and quality-of-life measures (which are affected by factors such as lung function and activity levels) were similar in both groups, suggesting that potential clinical gains would be similar in both groups.National lockdowns during the COVID-19 pandemic limited data collection (39% complete datasets) for variables requiring physical attendance (specifically, blood tests, FENO, spirometry, 6-min walk test, and accelerometery), although data for primary and key secondary outcomes were complete (e-Appendix 1).With a higher proportion of complete datasets, it would be possible to assess differences in other key outcomes (eg, lung function and inflammation).As with all weight management studies, this was an openlabel trial potentially subject to biases that may affect treatment effect estimates.This trial was conducted in a real-life clinical setting where asthma clinicians could be aware of the substantial effects on body weight from the intervention, and as such, masking would not have been feasible.It is feasible that participants pleased with weight loss in the intervention group, might have been included more often to minimize asthma symptoms, and thus would generate a more positive response to the intervention than their physiologic features might reveal.However, this still constitutes a positive beneficial outcome from both patient and health-care perspectives.Certain variables (eg, number of exacerbations) were reliant on participant recollection, and thus are subject to recall bias.Participants willing to take part in a weight loss trial are more likely to be motivated to lose weight, leading to potential selection bias, although this would not detract from clinical value.Key strengths of the trial include the pragmatic and realworld applicability of the intervention.Randomization led to broadly comparable CWP and UC groups, which adds confidence to reported results.The population studied is one with difficult-to-treat asthma with frequent exacerbations, an at-risk group with disease that is troublesome to manage.
Longer-term follow-up is required to determine whether weight loss is maintained and whether asthma-related benefits persist.Additionally, a future trial with a greater sample size is justified to generate definitive results.Further research should explore the factors associated with successful treatment outcome and efficacy in the overweight (BMI, 25.0-29.9kg/m 2 ) population with difficult-to-treat asthma.

Interpretation
Compared with UC, use of the CWP weight management program with dietitian support improved asthma control and quality of life as well as dyspnea and anthropomorphic measures over 16 weeks in individuals with difficult-to-treat asthma and obesity.Further research is needed to confirm the longer-term outcomes and to identify predictors of treatment response.

Funding/Support
This study was funded by an NHS Greater Glasgow and Clyde Endowment fund.

(
V. S., H. C. R., A. G., F. S., M E. J. L., and D. C. C.), Glasgow Royal Infirmary, the Division of Sport and Exercise (D. S. B.), School of Health and Life Sciences, University of the West of Scotland, Glasgow, Scotland; and Counterweight, Ltd. (N.B.), London, England.Presented as an abstract at the European Respiratory Society International Congress, September 5, 2022 and the British Thoracic Society Winter Meeting, November 25, 2022.
Care (n = 17) Lost to follow-up (n = 1): Did not attend follow-up Lost to follow-up (n = 1): Did not attend follow-up Intention-to-treat analysis (n = 17) Intention-to-treat analysis (n = 16) Figure 1 -Consolidated Standards of Reporting Trials flow chart.

Figure 2 -
Figure 2 -A-F, Graphs showing change in ACQ6 score (A), AQLQ overall score (B), AQLQ symptom domain score (C), AQLQ activity domain score (D), AQLQ emotional domain score (E), and AQLQ environmental domain score (F) between the CWP group and UC group at baseline (V1) and 16 weeks (V2).P value compares change in variable between CWP and UC groups with independent t test.ACQ6 ¼ Asthma Control Questionnaire 6; AQLQ ¼ Asthma Quality of Life Questionnaire; CWP ¼ Counterweight-Plus Program; UC ¼ usual care.

Figure 3 -
Figure 3 -Bar graph showing the proportion of participants achieving minimal clinically important difference in ACQ6 and AQLQ scores in the Counterweight-Plus Program group and usual care group over 16 weeks.Compared using c 2 or Fisher exact test.a Significant result.ACQ6 ¼ Asthma Control Questionnaire 6; AQLQ ¼ Asthma Quality of Life Questionnaire; ns ¼ not significant.

TABLE 2 ]
Intention-to-Treat Comparison of Asthma Control and Quality-of-Life Outcomes Between CWP and UC Data are presented as mean (95% CI).ACQ6 ¼ Asthma Control Questionnaire 6; AQLQ ¼ Asthma Quality of Life Questionnaire; CWP ¼ Counterweight-Plus Programme; UC ¼ usual care.a Comparison of mean difference using analysis of covariance with baseline variable as covariate.

TABLE 3 ]
Intention-to-Treat Comparison of Other Outcomes Between CWP and UC Groups Data are presented as mean (95% CI) for parametric data or median (interquartile range) for nonparametric data (the latter denoted by *).Annualized health-care use variables compare change from baseline data (No. of events in prior 12 mo) to 16 wk ([No. of events Â 365] / No. of d between visits).6MWD ¼ 6-min walk distance; BD ¼ bronchodilator; CWP ¼ Counterweight-Plus Programme; FENO ¼ fractional exhaled nitric oxide; GP ¼ general practitioner; HAD ¼ Hospital Anxiety and Depression; MRC ¼ Medical Research Council; N/A ¼ not available; PEF ¼ peak expiratory flow; ppb ¼ parts per billion; UC ¼ usual care.a Comparison using independent t test for parametric data or Mann-Whitney U test for nonparametric data.[P ¼ .049];e-Table

TABLE 4 ]
Post Hoc Comparison of Asthma Control and Quality of Life With CWP by Percentage Weight Loss a Comparison of mean difference using analysis of variance.