Patient-reported outcomes in transition from high-dose U-100 insulin to human regular U-500 insulin in severely insulin-resistant patients with type 2 diabetes: analysis of a randomized clinical trial

The detailed trial design, including a description of the study population, has been previously reported but is discussed here briefly [3]. Baseline demographic and clinical characteristics of the TID and BID patients are provided in Table 1. For the overall study population, baseline body mass index was 41.9 ± 7.5 kg/m², HbA1c was 8.7 % ± 1.0 %, median number of daily injections was 5 (range 2–10), and total daily dose (TDD) was 287.5 ± 80.5 units/day (2.4 ± 0.8 units/kg/day) [3]. Baseline insulin therapies included basal bolus (69.6 % [96.5 % analog insulins]), premixed insulin (12.3 %), basal only (6.2 %), and other (12.0 %) [3]. All patients were prior U-100 insulin users who were placed on a 4-week lead-in period, during which U-100 doses were verified and adjusted per investigators’ judgment. Patients were then randomized to receive subcutaneous U-500R TID (n = 162) or BID (n = 163) [3]. The syringes provided for administration were 6-mm, 31-gauge U-100 insulin syringes (Becton, Dickinson and Company) and dosing was recommended 30 min before meals for both treatment groups. Patient-reported outcome measures, including the TRIM-D [8], EQ-5D-5L [9, 10], and VAS-ISP [11], were used to compare changes in diabetes treatment-related impact measures, quality of life, and injection site pain from baseline to endpoint between and within the BID and TID treatment groups. The TRIM-D and EQ-5D-5L assessments were performed at visit 1 (screening, -4 weeks), visit 3 (baseline/randomization, 0 weeks), and visit 16 (endpoint, 24 weeks) or early termination (if patients did not reach 24 weeks of study). The VAS-ISP was completed at visit 3 (baseline/randomization), visit 12 (12 weeks), and visit 16 (endpoint). Descriptive statistics by treatment and injection method were also provided as part of this analysis. The ethics review boards provided written approval of the study protocol and the informed consent form. The study was conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki and all patients provided written informed consent.

The TRIM-D is a validated, patient-reported outcome measure that assesses treatment-related impact on participants with type 1 or type 2 diabetes [8, 12, 13]. The instrument consists of 28 items that are measured on a 5-point Likert scale, with higher scores indicating a better health state. TRIM-D items make up the following five domains: treatment burden (six items), daily life (five items), diabetes management (five items), compliance (four items), and psychological health (eight items). For example, items on the compliance domain depict how often a medication is missed, delayed, or postponed on a response scale ranging from never/almost never to almost always/always. Transformed scale scores range from 0 to 100, with higher scores indicating a better health state (less negative impact). The reliability and validity for TRIM-D has been previously assessed [12].

The EQ-5D-5L is a generic, well-validated, patient-reported outcome measure consisting of the descriptive system and Visual Analog Scale (EQ-5D VAS) [9, 10]. The descriptive system captures 5 dimensions (mobility, self-care, usual activity, pain/discomfort, and anxiety/depression), and each dimension has 5 levels (no problems, slight problems, moderate problems, severe problems, and extreme problems). The respondents were asked to indicate their health status by checking item boxes on the questionnaire that fit the way they felt about their health on that day. The EQ-5D VAS measures the respondent’s self-rated health on a 20-cm vertical VAS numbered from 0 to 100, with 0 representing the worst health and 100 the best health imaginable. The EQ-5D-5L has been validated in a diverse patient population in 6 countries and many different chronic disease states, including diabetes, for all dimensions and all levels [10]. Reliability and responsiveness remain to be assessed for the EQ-5D-5L [10].

The VAS-ISP assesses injection site pain over the past 24 h using a 100-mm horizontal VAS with anchors from “no pain” to “as severe as I can imagine” derived from Huskisson [11]. Early in the study, the VAS-ISP version of the questionnaire administered in this trial was modified from pain intensity ‘now’ to a corrected version of the VAS-ISP questionnaire with the time frame of the ‘past 24 h’. Results from both instruments were analyzed and found to be comparable. The reliability and responsiveness of the VAS-ISP has not been assessed.

Baseline measurements for continuous variables were evaluated using analysis of variance. The EQ-5D-5L US Index and EQ-5D VAS values were calculated using the crosswalk method [10]. The TRIM-D, EQ-5D-5L, and VAS-ISP scores were compared between treatment groups at screening and baseline using analysis of covariance (ANCOVA). Change from baseline to endpoint scores were compared between treatment groups using the ANCOVA model with treatment as factor, baseline HbA1c, baseline TDD, investigator site, and baseline score as covariates. Comparisons of within-treatment group scores were conducted using mixed-effect model repeated measures (MMRM) with treatment, visit, interaction between treatment and visit, baseline HbA1c, TDD, investigator site, and baseline score as covariates using an unstructured covariance matrix.

The study population was categorized based on reduction of per-day insulin injections in the transition from U-100 to U-500 (0–2, 3–4, >4 per day). TRIM-D and EQ-5D-5L scores for subgroups were compared between treatment groups using an ANCOVA model. Based on the conventional definition of 80 % compliance being clinically meaningful for adherence to diabetes medications, an arbitrary cutoff of TRIM-D compliance score ≥80 (the lowest and highest possible raw scores are 28 and 140, and after transformation, the lowest and highest possible score is 0–100) was used to compare the percentage achieving scores of ≥80 versus <80 between the two treatment groups [14, 15]. Logistic regression was used with treatment, baseline score, and baseline stratification variables (baseline HbA1c ≤8 % or >8 %, baseline TDD ≤300 or >300 units) as independent variables. The dependent variable was patients achieving a TRIM-D score ≥80.

The sample size calculation was based on the primary outcome: change in HbA1c from randomization to week 24 [3]. It was estimated that 260 completers would provide at least 80 % probability to determine non-inferiority of BID to TID, or vice versa, for the primary endpoint (non-inferiority margin 0.4 %). Patient-reported outcomes were exploratory. The p-values < .05 were considered statistically significant. All analyses were performed using SAS version 9.2 or higher (SAS Institute, Inc., Cary, NC) and were based on the full analysis set.