15 th Annual DAFNE collaborative meeting Tuesday 28 th June 2016

Transcription

1 15 th Annual DAFNE collaborative meeting Tuesday 28 th June 2016 Sponsored by: Abbott Diabetes Care and Lilly Diabetes

2 The REPOSE Trial (Relative Effectiveness of Pumps over Structured Education)

3 Background The limitations of conventional insulin therapy (MDI) results in many people keeping blood glucose at higher than recommended levels Pump therapy may deliver a more stable blood glucose, less hypoglycaemia and an enhanced quality of life In the UK it is estimated around 6% of adults with T1DM use pumps compared with 40% in the USA Proponents of pumps suggest that far more people should be offered pump therapy in the UK

4 Meta-analysis of MDI analogue trials vs CSII Bolli et al, Diabetes Care 2009; Bruttomesso et al, Diabet Med 2008; Thomas et al Diabetes Care, 2007.

5 The evidence base for CSII 21 trials of CSII versus MDI Only four of analogue MDI Longest duration 24 weeks Largest trial against MDI had only 4 weeks on CSII Of 17 non-analogue trials, only five lasted 12 months or more

6 Rationale and study aims A limitation of existing evidence is that people allocated to pumps may receive more training and attention compared with MDI Few trials have compared pump vs MDI with comparable training in insulin adjustment, so the benefit of pump technology is unclear We hypothesised that much benefit of pumps is from training in insulin use Main aim - to assess the effectiveness of pump compared to optimised MDI therapy for people with T1DM, with both groups receiving the same high quality structured training

7 REPOSE Study Design Adults with type 1 diabetes 8 UK diabetes centres recruiting 40 adults to 3 pump and 3 MDI courses (5-8 on each course) DAFNE course DAFNE course Inclusion criteria MDI CSII Baselin T1DM 12 months, e >18y 6 Months 12 Months Exclusion criteria Outcomes 24 months Willing to undertake Clinical indication for flexible intensive insulin pumps therapy MDI with SMBG and (eg hypoglycaemia CHO counting Background, bd insulin problems) detemir need for structured Bolus, pre-meal insulin No spoken aspart English education to improve Accu-Chek Aviva Expert Bolus Advisor System (Roche) diabetes Pumps self-management Medtronic Paradigm Veo insulin pump (Model X54) no strong preference for Insulin aspart pump therapy or clinical indication

8 Outcomes HbA1c measured centrally (1 o outcome HbA1c at 24 months in those 7.5% (58mmol/mol)). Moderate and severe hypoglycaemia, insulin dose, and body weight. Psychosocial outcomes, quality of life (both generic and diabetes specific), fear of hypoglycaemia, treatment satisfaction and emotional wellbeing. Health economics and qualitative sub-study

9 Consort Diagram (1) Invited (N=1278) Non-responders=393 (31%) Responders 885 (69%) Not interested=523 (59%) Interested 362 (41%) Eligible 334 (92%) Ineligible=19(5%) Not screened=9(2%) Eligible & consented 321 (96%) Not consented= 13 (4%) Dropped out before randomisation (n=4) Randomised (N=317)

10 Consort Diagram (2) Randomised (N=317) CSII (n=156) MDI (n=161) Dropped out before baseline (n=17) Dropped out before DAFNE (n=7) Baseline data (n=139) Baseline data (n=138) Dropped out before baseline (n=23) Dropped out before DAFNE (n=3) Courses (n=23) Course attendees (n=132) Baseline questionnaires completed (n=132) Courses (n=23) Course attendees (n=135) Baseline questionnaires completed (n=132) Lost to follow up n=6; withdrawn n=1 Lost to follow up n=1; withdrawn n=1 6 month FU data (n=132) 12 month FU data (n=126) (4 continuing in study, missing HbA1c) 6 month FU data (n=123) (5 continuing in study, missing HbA1c) Lost to follow up n=3 12 month FU data (n=120) (5 continuing in study, missing HbA1c) Lost to follow up n=2 Lost to follow up n=5 24 month FU data (n=128) 24 month FU data (n=120)

11 Baseline characteristics CSII (N=132) MDI (N=135) Age (y) Median, (range) 40.7(18.5 to 77.6) 41.0(18.5 to 73.1) Sex Male, No (%) 78(59.1%) 82(60.7%) Ethnicity (White British) 95% 88% Duration diabetes (y) med (range) 16.5(1 to 57) 14.9(1 to 52) Mean BMI (SD) 27.4 (5.0) 27.0 (5.0) HbA1c (mmol/l) mean (SD) 77.9(21.0) 74.8(15.6) HbA1c (%) mean (SD) 9.3 (1.9) 9.0 (1.4) Participants with 1 episode severe hypoglycaemia in previous year 16(12.1%) 15(11.1%) Any microvascular complication (%) 68 (52) 79 (59)

12 HbA1c Change in HbA1c (%) from baseline to 24 month follow up, treatment groups combined HbA1c (%) n Mean change (95% CI) All participants with 24 month data % (-0.69 to -0.38) Participants with baseline HbA1c 7.5% and complete 24 month data % (-0.80 to -0.48)

13 HbA1c Mean HbA1c over time in participants with baseline HbA1c 7.5% (those with data at all four visits, n=208) Mean change in the CSII group -0.85% Mean change in MDI group was -0.42% After adjusting for centre, DAFNE course and baseline HbA1c, mean difference in HbA1c change from baseline -0.24% (95% CI to 0.05) ( P=0.098)

14 HbA1c Mean difference in change in HbA1c at 6 and 12 months in participants whose baseline HbA1c was at or above 7.5% Treatment group CSII MDI Outcome HbA1c (%) n Mean change n Mean change Difference* 95% CI p-value 6 months to months to *adjusted for baseline HbA1c, Centre and DAFNE course using a mixed effects regression model.

15 Sensitivity analysis Forest plot of mean difference in change from baseline in HbA1c (%) at 24 months between groups for the sensitivity analysis samples Mean Clinically Important Difference

16 Implications of per protocol analysis Excluded participants who switched from MDI to pumps (and vice versa) 11 switched from pumps to MDI Change in HbA1c (baseline to 24 months, 10.4 to 9.7%) 7 from MDI to pumps Change in HbA1c (baseline to 24 months, 10.3 to 8.3%) Per protocol analysis CSII MDI N(mean change) N(mean change) Difference* (95% CI) p-value 108 (-0.85%) 109 (-0.31%) (-0.36% ) (-0.64 to -0.07) 0.015

17 HbA1c Proportion of participants with HbA1c 7.5% at 24 months (including all participants regardless of HbA1c at baseline) Treatment group CSII MDI Outcome n(%) n(%) Odds ratio* (95% CI) p-value HbA1c 7.5% 6 months 26/132 (20.5%) 26/123 (21.1%) 1.03 (0.51 to 2.10) months 29/126 (23.0%) 27/120 (22.5%) 1.32 (0.62 to 2.80) months 32/128 (25.0%) 28/120 (23.3%) 1.22 (0.62 to 2.39) *adjusted for baseline HbA1c, Centre and DAFNE course using a mixed effects logistic regression model.

18 Severe Hypoglycaemia Severe Hypoglycaemic episodes per patient year in study (n=267, all participants with baseline data and who attended a DAFNE course) When combined: the average number of episodes per patient year reduced from 0.17 before baseline to 0.10 during follow up. 13 (0.18) 7 (0.10) 20 (0.14) The incidence rate ratio for the number of severe hypoglycaemic 8 (0.13) episodes 5 (0.19) over 1324 (0.11) months, compared 4 (0.03) to the 12 year (0.11) before 16 (0.07) baseline is 0.46 (0.24 to 0.89, p=0.021). No of events, events per year (incidence rate ratio) Time period CSII (n=132) MDI (n=135) Total (n=267) Before baseline 24 (0.18) 21 (0.16) 45 (0.17) Between baseline and 6 month follow up Between 6 and 12 months follow up Between 12 and 24 months follow up Overall (post baseline) 25 (0.10) 24 (0.10) 49 (0.10) Excluding first 6 months 12 (0.06) 17 (0.10) 29 (0.08) Incidence ratio (95% CI)*: 1.13 (0.51 to 2.51) p-value = *Incidence rate ratio calculated using negative binomial random effects regression adjusted for centre, DAFNE course, baseline HBA1c and presence of at least one severe hypoglycaemic episode before baseline. Incidence rate ratio was calculated on the ITT set only (n=260).

19 Severe hypoglycaemic episodes over time per participant with at least one episode post baseline, by treatment group (CSII: n=14, MDI n=11) Each dot represents a severe hypoglycaemic episode. Dots connected by a line represent severe hypoglycaemic episodes experienced by the same person

20 Psychological outcomes High rate of questionnaire completion (around 90% at each time point) Overall improvement in DSQOL total score, WHOQOL-BREF psychological and environment. Hypoglycaemia Fear Scale (HFS) behaviour and worry, HADS anxiety and depression, and DTSQ treatment satisfaction No differences between groups for total DSQOL, SF12, EQ5D, WHOQOL- BREF, HADS, HFS DSQOL diet restrictions evidence of better improvement in pump arm (24 month adjusted mean difference in change from baseline; -5.1 (95% CI -8.6 to -1.6), p=0.004) The pump group had better improvement in DSQOL daily hassle or functions at 24 months the score had decreased by 10 points in CSII group, compared to 4 points in MDI group, (adjusted mean difference; -6.3 (95% CI to -1.8), p=0.006) Pump group had better improvement in DTSQ treatment satisfaction (p=0.067 at 6 months, p<0.001 at both 12 and 24 months)

21 Serious Adverse Events Number (%) participants with >=1 SAE CSII MDI Total (n=132) (n=135) (n=267) DKA Events Any SAE 31 (23.5%) 26 (19.3%) 57 (21.3%) Greater DKA number of episodes 17 of (12.9%) DKA 5 on (3.7%) pump 22 (8.2%) vs MDI Myocardial infarction 2 (1.5%) 0 (0.0%) 2 (0.7%) More patients on pumps had multiple episodes, 5 vs 2 Severe hypoglycaemia 0 (0.0%) 1 (0.7%) 1 (0.4%) Difference confined to the 1 st year, 4 vs 4 in year 2 Foot ulcer 1 (0.8%) 0 (0.0%) 1 (0.4%) 3 Renal episodes disease in 2 patients switching 1 (0.8%) to 0 (0.0%) CSII, 1 (0.4%) and Abdominal 1 Pain someone switching 1 to (0.8%) MDI 2 (1.5%) 3 (1.1%) Pregnancy* 4 (3.0%) 3 (2.2%) 7 (2.6%) Most DKAs due to infections. In pump patients 18% due Hyperglycaemia 3 (2.3%) 4 (3.0%) 7 (2.6%) to set failure Migraine 0 (0.0%) 1 (0.7%) 1 (0.4%) Only Overdose/suicide 5 episodes attempt occurred when 1 (0.8%) all sick 1 (0.7%) day 2 rules (0.7%) were Chest pain 2 (1.5%) 1 (0.7%) 3 (1.1%) implemented Infection 2 (1.5%) 2 (1.5%) 4 (1.5%) Other 5 (3.8%) 12 (8.9%) 17 (6.4%) *Pregnancy is included where there was a hospital admission

22 Health economic analysis (summary) The ICER for pump+dafne would be < 30,000 per QALY gained if all individuals on pump+dafne achieved additional HbA1c reduction of 0.8% compared to MDI < 20,000 per QALY gained if all individuals receiving pump+dafne achieved an additional HbA1c reduction of 1.2 % compared to MDI+DAFNE If pump+dafne is to be cost-effective, the true treatment effect must be higher than HbA1c of 0.5% Findings consistent with the current care pathway for adults, who should undertake structured education with MDI ideally around 12 months after diagnosis Reserve pumps as alternative therapy for people with particular indications

23 Summary The primary outcome improved in both groups at 24 months with significant and sustained reductions in HbA1c of around 0.6% (7mmol/l ) No significant differences in HbA1c change from baseline to 24 months between the groups (-0.24% in favour of CSII) Severe hypoglycaemia rate fell overall with no differences between groups HbA1c remained well above recommended national and international targets Some consistent improvements in isolated QoL measures A small but significant improvement of HbA1c in favour of pumps (-0.36%) between groups in the per-protocol analysis

24 Strengths Robust, multi-site design, compared to previous trials: Much larger numbers Longer follow-up analogue insulins and bolus calculators Study conducted in experienced secondary care centres involved an established structured training course of proven benefit 1 0 outcome measured centrally Comprehensive psychological evaluation High levels of data completeness A pragmatic design with good external validity Training led to sustained improvements in glycaemic control and reduced rates of severe hypoglycaemia

25 Limitations Open trial since insulin delivery systems are fundamentally different but HbA1c was objectively assessed centrally Those randomised to pumps treatment may be insufficiently motivated (emphasised by high HbA1c at baseline)to exploit technological benefits without a strong wish to use pumps (many potential recruits were not keen on pumps) Newer pumps offer additional features and some are more convenient

26 Conclusion These results support a care pathway for adults with T1DM that starts with initial structured training using MDI, with pumps offered later to those in whom the limitations of MDI interfere with effective self-management Structured training reduces the risk of severe hypoglycaemia and leads to modest but long-lasting benefits in HbA1c and should be delivered widely Further work is needed to develop effective approaches to support people in achieving tighter glucose targets

27 Acknowledgements The people with diabetes who participated The clinical, research and administrative staff at each NHS Hospital Researchers at the Universities of Warwick and Edinburgh University of Sheffield Clinical Trials Research Unit Medtronic Ltd, UK Our funders, the NIHR Health Technology Assessment (HTA) Programme ( ) The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health.

28 Update of DAFNE Plus Programme Developing and trialling the DAFNEplus (Dose Adjustment for Normal Eating) intervention. A lifelong approach to promote effective self-management in adults with type 1 diabetes.

29 Berger and Mühlhauser A systematic attempt to modernise Type 1 diabetes treatment Patients need skills to manage Type 1 diabetes Used Therapeutic Education to develop a Diabetes Teaching Training Programme (DTTP): - separation of meal and basal insulin - doses adjusted on basis of SMBG and pre-meal glucose - flexible diet with no forbidden foods

30 Previous DAFNE PGfAR Psychosocial DAFNE HART Economi cs Databa se 5x1 Pump pilot Heller et al, Improving management of type 1 diabetes in the UK: the Dose Adjustment For Normal Eating (DAFNE) programme as a research test-bed. NIHR Journals Library, Southampton, 2014

31 Aims and Objectives In adults with T1D, will modifying the existing DAFNE curriculum and developing structured professional input, using learning from our recent research, behaviour change theory and new forms of technological support, produce: (a) improved and sustained diabetes self-management behaviours (b) better glucose control than currently achieved without compromising quality of life

32 DAFNEplus (years 1-3)!

33 DAFNEplus (years 3-6)

34 DAFNEplus (years 1-3) 3 work streams WS1 Revising the curriculum (Heller) Reviewing and updating the 5 week curriculum Incorporating new theories of behaviour change Addressing numeracy and consistent glucose targets Delivering the course over 5 weeks

35 DAFNEplus (years 1-3) WS2 Structured support (Hopkins) Revisiting motivation and knowledge Identifying and contacting those struggling Annual review Changing diabetes educators working practices

36 DAFNEplus (years 1-3) WS3 Utilising technology (Elliott) Incorporate use of wireless, mobile and internet technologies to support self-management Automated data entry into DAFNE diaries (Withcare+ and Glucollector App and website) Online behaviour change modules (adaptation of Lifeguide)

37 DAFNEplus progress to date WS1: Curriculum review Detailed review undertaken by clinicians and psychologists Identifying common themes WS2: Structured support Systematic review: scope agreed, searches and sifting Horizon scanning Innovator interviews Health economic analysis plan WS3: Technology Withcare+/Glucollector Prototype development Preliminary user testing - ethics application Lifeguide website Prototype development Preliminary user testing - ethics application Across project activity Project management PPI Group Dissemination planning Pilot planning

38 Conclusions Current DAFNE training fails in achieving tight glucose control in most graduates (in contrast to QoL and hypoglycaemia) We are now funded to develop DAFNE training to support patients in meeting tight glucose goals The project is challenging but the prize is great We need the support of the collaborative in finding 14 centres who will sign up enthusiastically to trial the intervention