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Introduction

As of 2012 it was estimated that there were 2.5 million people with a confirmed diagnosis of diabetes in the UK, responsible for 10% of the NHS budget.222_{Type 1 diabetes is responsible for 10% of this}

diabetic population.222

A structured education programme is‘a planned and graded programme that is comprehensive in scope, flexible in content, responsive to an individual’s clinical and psychological needs, and adaptable to his or her educational and cultural background’.223_{The DAFNE course is a 5-day outpatient course aiming to}

teach individuals about CP counting and insulin dose adjustments.

However, it is not always convenient for individuals to attend an intensive 5-day programme because of work and other committments. Given that many relevant structured education courses are delivered on a 1 day a week basis for up to 8 weeks,98_{and the possible biases associated with using observational data}

from the original DAFNE trial,7_{a separate RCT was undertaken.}

This study aimed to estimate the cost-effectiveness of two alternative delivery strategies for the DAFNE programme by using data from the 5 × 1-day DAFNE RCT for within-trial analyses (short term) and modelling analyses (long term). Full details of all analyses conducted are intended for publication. Methods

Within-trial analyses

The within-trial analyses were based on individual-level data collected during the 1-year follow-up after the completion of the trial. The within-trial resource use covered insulin, admissions, NHS contacts, other medication and the intervention. This information was collected from RCT participants using designated questionnaires.

Long-term modelling

Longer-term cost-effectiveness was assessed using version 1.2 of the Sheffield Type 1 Diabetes Policy Model (seeDevelopment of the Sheffield Type 1 Diabetes Policy Model).183_{The model was used to}

estimate the long-term cost-effectiveness of the two arms in the DAFNE 5 × 1-day RCT.

Long-term cost-effectiveness was evaluated from the perspective of the NHS. The outcomes of the model were lifetime costs and QALYs. The within-trial costs were based on insulin, admissions, NHS contacts, other medication and the intervention whereas the long-term model costs were based on the cost of developing a particular diabetes-related complication. Both costs and QALYs were discounted at a rate

of 3.5% in line with recommendations from NICE and the UK Treasury.168,224_{For each annual cycle, patient}

progression to a more severe health state was modelled using the Monte Carlo simulation technique, which allowed the development of multiple complications for a single patient. A total of 5000 patients were simulated based on a lifetime horizon, and 500 PSA runs were undertaken in line with the internal capacity of the Simul8 software program used.

Statistical analysis

The participants were individually randomised using a random block size, stratified by centre, and a web-based remote randomisation system to either a 1-week course or a 5-week course.101

The missing observations in the cost and utility data were completed using the multiple imputation approach. The predictive mean matching method was used to estimate the imputed utility values as this method is suitable for predicting variables that are bounded, continuous and distributed non-normally, such as the left-skewed EQ-5D data.225

Treatment effectiveness in terms of changes in glycated haemoglobin for the 5 × 1-day randomised controlled trial

The 5 × 1-day DAFNE RCT results were examined to develop a regression model predicting HbA1clevel at

12 months conditional on baseline HbA1cand arm of the trial, that is, 1-week DAFNE education compared

with 5-week DAFNE education (Table 47). Results

Within-trial results

Table 48provides a summary of the within-trial analysis undertaken for the DAFNE 5 × 1-day RCT. The costing analysis based on the within-trial data shows that the mean cluster-adjusted cost per individual was £9.94 more expensive for the 5-week arm than for the 1-week arm during the 12-month trial period.

TABLE 48 Within-trial analysis summary for the DAFNE 5 × 1-day RCT

Arm Complete-case QALYs (SD) Baseline QALYs (SD) Adjusted difference (SD)a Complete-case cost (SD) (£) Adjusted differencea (SD) (£) Adjusted bootstrapped ICER (£) (cost-effectiveness probability, %b₎ 1 week 0.8529 (0.2129) 0.8561 (0.2225) 0.0252 (0.0180) 1102 (468) 9.94 (63.90) 786 (91.2) 5 weeks 0.8532 (0.2130) 0.8238 (0.2364) 1112 (368)

a Refers to the within-cluster correlation adjustment undertaken by the xtgee command in Stata 12 (StataCorp LP, College Station, TX, USA) and the regression-based adjustment for the baseline.

b Refers to the probability that the 5-week arm is cost-effective at a £20,000 per QALY threshold.

TABLE 47 Regression for 12-month HbA1ctreatment effect from the 5 × 1-day RCT: 1-week and 5-week arms

Coefficient Standard error 95% CI

Intercept 1.6440 0.4899 0.6634 to 2.6246

5-week arm 0.1278 0.1301 _–0.1327 to 0.3883

Baseline HbA1c 0.7884 0.0609 0.6665 to 0.9103

12-month HbA1c=intercept+coeff × baseline HbA1c+coeff × treatment arm (1=5-week arm, 0=1-week arm)+error.

Using the regression-based approach to adjust for baseline values, the utility difference between the two arms was 0.0252 for the complete-case data. Similar to the cost difference, the utility difference between the two arms was not statistically significant at the conventional significance levels.

Although the cost and utility values were very similar for the two arms, there was considerable uncertainty around the within-trial utility values.

Long-term modelling results

Table 49provides the results of the economic evaluation of 1-week compared with 5-week DAFNE training using evidence from the DAFNE 5 × 1-day RCT. Using the data on complete cases, the modelled lifetime cost for the 1-week arm was £44,911 and for the 5-week arm was £45,687, a difference of £776. The costs calculated for each arm are the sum of the insulin costs, the long-term complication and adverse event costs that were modelled for a lifetime and discounted back to the present and the observed within-trial costs used to replace the first-year costs in the long-term model.

TABLE 49 Economic evaluation of 1-week vs. 5-week DAFNE education using evidence from the DAFNE 5 × 1-day RCT Diabetes-related complications Control: 1-week DAFNE education (n₌5000) Intervention: 5-week DAFNE education (n₌5000) Increment

Clinical results (total incidence in whole cohort over a lifetime horizon)

Microalbuminuria 2589 2602 13

Macroalbuminuria 1847 1864 17

ESRD 1569 1585 16

Death from ESRD 889 901 12

Background retinopathy 1237 1260 23 Proliferative retinopathy 725 741 16 Macular oedema 932 939 7 Blindness 90 91 1 Clinical neuropathy 1606 1626 20 Amputation 513 520 7 Non-fatal MI 1664 1656 _–8 Fatal MI 1693 1689 –4 Non-fatal stroke 342 341 _–1 Fatal stroke 98 97 –1

Non-fatal heart failure 727 723 _–4

Fatal heart failure 45 45 0

Angina 1843 1832 _–11

Severe hypoglycaemia 18,606 18,488 –118

DKA 717 740 23

Number of patient-years 156,077 155,752 –325

Life-years per patient 31.22 31.15 _–0.07

The model estimated the long-term QALY difference as 0.0352 in favour of the 1-week arm, which corresponds to 12.86 days per person in perfect health.

Using the PSA samples (Figure 12), the long-term model reported higher uncertainty than the within-trial analysis because of the long-term complications and adverse events observed within the lifetime (maximum 100 years) of each individual. For the full cohort the probability of the 5-week arm being cost-effective at a £20,000 per QALY threshold was 20% (Figure 13).

Discussion and conclusions

In addition to the within-trial analyses, this study used a long-term simulation model to assess the cost-effectiveness of the 1-week and 5-week arms in the DAFNE 5 × 1-day RCT, namely the Sheffield Type 1 Diabetes Policy Model, which improved on the previous economic evaluation of the DAFNE programme by incorporating macrovascular complications, allowing for a heterogeneous HbA1cresponse

to DAFNE, extending the time horizon and conducting PSA analyses.

Based on both the within-trial analyses and the long-term model, it has been shown that the mean utility values in the 1-week and 5-week arms are similar. Given the small differences in mean cost per patient between the two arms, the results suggested that both the 1-week training method and the 5-week training method could be used by the NHS to deliver structured education programmes to individuals with type 1 diabetes. The within-trial analyses showed that the probability that the 5-week arm was cost-effective was 95.2%. By simulating the long-term complications based on the full cohort data from the trial and by acknowledging the effect of these complications on costs and utilities, the health economic analyses undertaken using the Sheffield Type 1 Diabetes Policy Model showed that the

TABLE 49 Economic evaluation of 1-week vs. 5-week DAFNE education using evidence from the DAFNE 5 × 1-day RCT (continued)

Diabetes-related complications Control: 1-week DAFNE education (n=5000) Intervention: 5-week DAFNE education (n=5000) Increment

Cost-effectiveness results (per patient over a lifetime horizon)

DAFNE intervention cost (£) 359 371 12

Discounted insulin cost (£) 6884 6973 89

Discounted cost of long-term complications (£) 37,222 37,894 671 Discounted cost of adverse events (£) 446 449 3 Combined total average discounted cost (£) 44,911 45,687 776 Mean discounted QALYs lived if no complications 15.0350 15.0102 _–0.0248 Discounted QALYs lost because of long-term complications –0.8906 –0.9010 0.0104 Discounted QALYs lost because of adverse events _–0.0036 _–0.0037 _–0.0001 Combined total average discounted QALYs 14.1407 14.1055 –0.0352

ICER (unadjusted) (£) _{– – –}21,677

ICER (jackknife) (£) – – –21,541

Net monetary benefit at threshold of £20,000 per QALYa_{(£) – – –1466}

Probability that DAFNE education is cost-effective at £20,000 per QALY threshold (%)

– – 20

a Net monetary benefit_=ΔQALYs × threshold_–Δcosts.

–6 –4 –2 0 2 4 6 – 0.3 – 0.2 – 0.1 0.0 0.1 0.2 0.3 Incremental disc ounted costs (£000)

Incremental discounted QALYs

Base-case PSA samples

Base-case PSA mean ICER = £20,000 per QALY

FIGURE 12 The cost-effectiveness of 1-week vs. 5-week DAFNE training using evidence from the DAFNE 5 × 1-day RCT on the cost-effectiveness plane.

0 10 20 30 40 50 60 70 80 90 100 0 5 10 15 20 25 30 35 40 45 50 Pr o b ab ility co st-effective (%) Willingness-to-pay threshold (_λ; £000) 5-week arm 1-week arm NICE threshold

FIGURE 13 Cost-effectiveness acceptability curve: the probability that the DAFNE 1-week arm is cost-effective compared with the DAFNE 5-week arm in the DAFNE 5 × 1-day RCT population at different willingness-to-pay thresholds.

The generalisability of the results of this study is limited to cohorts with similar characteristics, such as cohorts of adults (aged≥18 years) for whom UK-based costs are used to analyse resource use. However, the development of the Sheffield Type 1 Diabetes Policy Model is important not only for the original DAFNE and DAFNE 5 × 1-day RCTs but also for RCTs of other interventions for people with type 1 diabetes, as long-term analyses of ongoing trials in other type 1 diabetes populations will be undertaken by adapting the Sheffield Type 1 Diabetes Policy Model.

In conclusion, the results of this study suggest that the 5-week delivery method for DAFNE structured education programmes is likely to be slightly more cost-effective than the 1-week delivery method in the short-term (1 year) within-trial analysis but that the lifetime analysis marginally favours the 1-week arm over the 5-week arm. The small differences in projected utilities, costs and incidence rates between the two arms suggest that both delivery methods could be used by the NHS. This conclusion appears robust to sensitivity analyses of baseline HbA1clevels and the persistence of the HbA1ceffect after completion of

the programme.

Modelling patient psychology and behaviour alongside