Confirmatory psychometric evaluations of the Impact of Weight on Quality of Life–Lite Clinical Trials Version (IWQOL‐Lite‐CT)

Summary The Impact of Weight on Quality of Life–Lite Clinical Trials Version (IWQOL‐Lite‐CT) was developed to assess weight‐related physical and psychosocial functioning in the context of clinical trials. Data from two pivotal trials of once‐weekly subcutaneous semaglutide for the purpose of weight management (NCT03548935 and NCT03552757) were analysed to confirm the structure, reliability, validity, and responsiveness of the IWQOL‐Lite‐CT and evaluate the magnitude of meaningful within‐patient change in patients with overweight or obesity, with and without type 2 diabetes. Factor analyses and inter‐item correlations confirmed the IWQOL‐Lite‐CT structure and scoring algorithm. Each composite score (physical, physical function, psychosocial, and total) demonstrated excellent internal consistency (Cronbach's alphas ≥ 0.82) and test–retest reliability (intraclass correlation coefficients ≥ 0.85) in both trials. Patterns of cross‐sectional and longitudinal construct validity correlations were generally consistent with hypotheses. Each of the IWQOL‐Lite‐CT composites was able to discriminate between known groups. Effect sizes and paired t tests comparing IWQOL‐Lite‐CT scores at baseline and Week 68 were statistically significant for all composites in both trials (P < 0.0001), providing strong support for the ability to detect change. Results of anchor‐based analyses supported responder thresholds ranging from 13.5 to 16.6 across composite scores. The IWQOL‐Lite‐CT, a comprehensive assessment of weight‐related functioning from the patient perspective, is appropriate for use in clinical trials evaluating the efficacy of new treatments for weight management.

• While changes in patient-reported outcomes (PROs), including patient functioning, are commonly key outcomes in weight management trials, they are rarely mentioned in product labelling, particularly in the United States (US).
• The Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT) is a PRO measure of weight-related functioning, developed in accordance with recommendations published by the US Food and Drug Administration (FDA) for measures used to support labelling, based on information gleaned from the obesity literature, qualitative research conducted with patients, clinical experts, and consultation with the FDA.
What this study adds?
• Results of the psychometric analyses presented here confirm the reliability, validity, and responsiveness and provide estimates of meaningful within-patient change on the final 20-item version of the IWQOL-Lite-CT, further contributing to the body of evidence supporting the IWQOL-Lite-CT.
• The IWQOL-Lite-CT is appropriate for assessing weight-related physical and psychosocial functioning in populations commonly targeted for weight management clinical trials.

| INTRODUCTION
Obesity is a chronic disease with adverse health, social, psychological, and economic consequences. 1,2 In their patient-centred disease model, for example, Fastenau and colleagues 3 describe negative impacts of obesity on physical functioning, social/leisure functioning, emotional functioning, psychological functioning, sexual functioning, and work productivity, as well as comorbid conditions and other aspects of the patient's life. Among individuals with obesity, weight reduction is commonly accompanied by improvements in health-related quality of life (HRQOL), with subsequent changes in HRQOL generally matching long-term patterns of weight loss, gain, and stability. 4 Because treatment has the potential to improve various aspects of functioning and HRQOL among patients with obesity, these concepts are important outcomes in evaluations of weight-loss and weight-management interventions, including behavioural, psychological, surgical, and pharmaceutical treatments. [4][5][6][7][8][9][10] In their review of patient-reported outcome (PRO) measures used to assess HRQOL in the context of obesity, Wadden and Phelan (2002) describe several generic measures, including the Short Form Health Survey (SF-36), the Nottingham Health Profile (NHP), and the Sickness Impact Profile (SIP), which have demonstrated the ability to capture improvements associated with weight loss. 11 While recommending use of the SF-36 among the generic measures of HRQOL, the authors note that by capturing impacts most salient to patients, disease-specific measures tend to be more sensitive to change than generic measures. At least four obesity-specific measures of HRQOL are available. The 31-item Impact of Weight on Quality of Life-Lite (IWQOL-Lite) was developed to evaluate the impact of obesity on HRQOL and functioning in individuals with obesity in a variety of settings. 12 The 17-item Obesity and Weight-Loss Quality-of-Life (OWLQOL) was developed to evaluate HRQOL in individuals with obesity or who are trying to lose weight, 13 whereas the 6-item Moorehead-Ardelt Quality of Life is a measure of HRQOL specifically developed for a postoperative population. 14 In addition, a 140-item battery constructed for use in the Swedish Obesity Study (SOS), which evaluated surgically treated individuals with severe obesity compared with a conventionally treated control group, included an 8-item obesity-related problems scale used to measure the impact of obesity on psychosocial functioning. 4 In a systematic review of research examining the effects of obesity and weight loss on HRQOL (based on the results of 12 previously published reviews), Kolotkin and Andersen 15 found that the IWQOL-Lite 12 was used more commonly than any other obesity-specific measure and consistently demonstrated an association between obesity and reduced HRQOL.
Although the IWQOL-Lite has also performed well in numerous evaluations of pharmacological, 16,17 surgical, 18,19 and dietary 20 interventions for obesity, the content of this questionnaire was largely based on the input of individuals receiving residential treatment for obesity. 12 As such, this measure may not be ideal for demonstrating treatment benefit among populations participating in clinical trials of pharmacological interventions, which typically include individuals with lesser degrees of obesity and fewer comorbid conditions than those who seek such intensive treatment. Furthermore, this measure was developed prior to the publication of the US Food and Drug Administration's (FDA's) Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims (PRO Guidance), 21 which may also limit its acceptance by the FDA and possibly other regulatory authorities to support product labelling claims.  guidance documents pertaining to PRO measures used to support   product labeling 21,24 based on information gleaned from the obesity   literature, qualitative research conducted with patients, clinical experts, and consultation with the FDA. 22 Development also aligned with current standards described by professional organizations such as the International Society for Quality of Life Research (ISOQOL). 25 Furthermore, developmental versions of the IWQOL-Lite-CT have been shown to be reliable, valid, and responsive measures of weightrelated functioning in the populations commonly targeted for clinical trials of new weight-management medications. 23 The objectives of this study were to supplement the evidence supporting the IWQOL-Lite-CT by confirming the reliability, validity, and responsiveness and providing estimates of meaningful withinpatient change on the final 20-item version of this measure, using data from pharmacological trials for weight management.

| Study population
Confirmatory psychometric evaluations of the IWQOL-Lite-CT were conducted with the use of data from two multinational phase 3a clinical trials of semaglutide for weight management, STEP 1 (NCT03548935) and STEP 2 (NCT03552757). [26][27][28] Both trials were designed to compare the efficacy and safety of once-weekly semaglutide (2.4 mg administered subcutaneously for 68 weeks) with placebo, as an adjunct to a reduced calorie diet and increased physical activity. STEP 1 included nondiabetic patients with overweight (body mass index [BMI] ≥ 27 kg/m 2 to <30 kg/m 2 ) in the presence of at least one weight-related comorbidity or obesity (BMI ≥ 30.0 kg/m 2 ). STEP 2 included patients with type 2 diabetes (T2D) in addition to overweight or obesity (BMI ≥ 27.0 kg/m 2 ). Psychometric analyses were conducted using all randomized patients in the full analysis set who completed the baseline IWQOL-Lite-CT assessment (n = 1945 in STEP 1; n = 1186 in STEP 2).

| Measures
The IWQOL-Lite-CT is a 20-item patient-reported outcome (PRO) measure designed to assess the impact of changes in weight on patients' physical and psychosocial functioning. Each item employs a 5-point graded response scale (never, rarely, sometimes, usually, always; or not at all true, a little true, moderately true, mostly true, completely true). In addition to yielding a Total score, the final 20-item IWQOL-Lite-CT includes two primary domains: Physical (7 items) and Psychosocial (13 items). Based on feedback from the FDA and to facilitate labelling in the United States (US), a 5-item subset of the Physical domain, the Physical Function composite, has also been evaluated and supported. 23 A conceptual framework for the IWQOL-Lite-CT is depicted in Figure 1.
The IWQOL-Lite-CT is generally scored according to the rules of the IWQOL-Lite 29 to yield composite scores and a Total score ranging from 0 to 100, with higher scores reflecting better levels of functioning.
In addition to weight, BMI, and the IWQOL-Lite-CT, the psychometric evaluation utilized data from the Short Form Health Survey-   Table 1 summarizes these measures in further detail.

| Analytic methods
Each of the following analyses were conducted separately with the use of data from STEP 1 and STEP 2 to evaluate and support the measurement properties of the IWQOL-Lite-CT for use in patients with overweight and obesity, with and without T2D.
• Standard descriptive statistics were computed to characterize the sample, and item-level response frequency distributions were examined for floor and ceiling effects for each IWQOL-Lite-CT item.
• To confirm the two-domain structure (physical and psychosocial composites) supported by the previous psychometric evaluations and qualitative research, longitudinal confirmatory factor analyses (CFAs) were conducted with the use of baseline, Week 20,and Week 68 data.
• Two models were tested with the use of data from each clinical trial, yielding a total of four models. Scale invariance was imposed within each model such that the unstandardized factor loadings and intercepts were constrained to equality across time points, and the residuals of each item were also allowed to be correlated across time points. In the first 2-factor model tested within each trial, the IWQOL-Lite-CT items were allowed to load only on the factor with which they were grouped for scoring purposes. The second 2-factor model was based on the residual correlations and the modification indices from the first CFA model as well as the results of previous IWQOL-Lite-CT factor analyses. Goodness-of-fit indices were also evaluated. • To evaluate test-retest reliability, intraclass correlation coefficients (ICCs) for the IWQOL-Lite-CT composite scores using subsets of stable patients defined by body weight and PGI-S ratings. "Test" and "retest" data were IWQOL-Lite-CT scores obtained at Week 16 and Week 20, respectively, from patients with 5% or less change in body weight and who rated themselves the same on the corresponding PGI-S items at both time points.
• To evaluate cross-sectional construct validity, correlations were computed between IWQOL-Lite-CT composite scores and scores on the SF-36v2 (subscale, physical component   21,24 were also applied to provide support for the anchor-based responder thresholds.

| Participant characteristics
The analysis population included trial participants who completed a baseline IWQOL-Lite-CT assessment (n = 1945 in STEP 1; n = 1186 in STEP 2). Table 2 presents key baseline characteristics of the analysis population. Patients participating in STEP 1 ranged in age from 18 to 86 years, with a mean age of 46.5 years. The majority of patients were female (n = 1440, 74.0%) and the majority were white  The analysis population included only STEP 1 and STEP 2 participants who completed a baseline IWQOL-Lite-CT assessment.
T A B L E 3 Summary of key measurement properties of IWQOL-Lite-CT composites    Table S2, the CFA results based on the data from STEP 2 were very consistent with those based on the STEP 1 data, further confirming and supporting the structure and scoring of the IWQOL-Lite-CT.

| Reliability
As shown in Table 3, internal consistency results were strong for all composite scores at all-time points in both STEP 1 and STEP 2 (alpha ≥ 0.82), further supporting the IWQOL-Lite-CT scoring algorithm.
Additionally, substantial test-retest agreement was observed among stable subjects, with ICCs ≥ 0.85 for all composite scores in both studies (Table 3). Specific to the Physical Function composite, ICCs were 0.86 in STEP 1 and 0.85 in STEP 2.

| Construct validity
Observed patterns and magnitudes of construct validity correlations (both cross-sectional and longitudinal) were generally consistent with hypotheses. In cross-sectional analyses (Table 3) In longitudinal analyses (Table 3), changes in IWQOL-Lite-CT Physical and Physical Function scores were moderately to strongly

| Discriminating ability
Known-groups analyses of variance confirmed the ability of the   points for the IWQOL-Lite-CT Total score (Table 4). All supportive estimates, including those computed based on data from STEP 2, were somewhat smaller in magnitude (see Table 4). As such, the thresholds based on the primary anchor are recommended for use in future clinical studies to identify patients with meaningful responses to treatment.

| DISCUSSION
The IWQOL-Lite-CT has been rigorously developed to assess weight- The results of these analyses should be interpreted in the context of several strengths and limitations. A key strength of the study is its use of data from two large, multinational phase 3 trials. Nonetheless, the psychometric evidence supporting the IWQOL-Lite-CT has primarily been generated through analysis of data from pharmaceutical clinical trials for weight management. As such, it is unknown whether the results could be generalized to other contexts of use or influenced by the type of weight-loss intervention.

| CONCLUSIONS
The IWQOL-Lite-CT is appropriate for assessing weight-related physi-