Diagnostics guidance Published: 12 February 2016 nice.org.uk/guidance/dg21. NICE All rights reserved.

Integr Integrated ated sensor-augmented pump ther therap apyy systems for managing blood glucose le levvels in type 1 diabetes (the MiniMed P Par aradigm adigm V Veo eo system and the Vibe and G4 PLA PLATINUM TINUM CGM system) Diagnostics guidance Published: 12 February 2016 nice.org.uk/guidance/dg21

© NICE 2016. All rights reserved.

Integrated sensor-augmented pump therapy systems for managing blood glucose levels in type 1 diabetes (the MiniMed Paradigm Veo system and the Vibe and G4 PLATINUM CGM system) (DG21)

Contents 1 Recommendations ........................................................................................................................................................

4

2 The technologies............................................................................................................................................................

6

3 Clinical need and practice ..........................................................................................................................................

7

The problem addressed ...............................................................................................................................................................

7

The condition ...................................................................................................................................................................................

7

The diagnostic and care pathways ..........................................................................................................................................

8

4 The diagnostic tests...................................................................................................................................................... 10 The interventions........................................................................................................................................................................... 10 The comparators ............................................................................................................................................................................ 12

5 Outcomes ......................................................................................................................................................................... 13 How outcomes were assessed.................................................................................................................................................. 13 Clinical effectiveness in adults.................................................................................................................................................. 14 Clinical effectiveness in children ............................................................................................................................................. 18 Additional clinical-effectiveness analyses for the economic model.......................................................................... 20 Costs and cost effectiveness ..................................................................................................................................................... 20

6 Considerations................................................................................................................................................................ 31 Current practice ............................................................................................................................................................................. 31 Clinical evidence............................................................................................................................................................................. 32 Cost effectiveness ......................................................................................................................................................................... 35 Additional considerations........................................................................................................................................................... 38

7 Recommendations for further research............................................................................................................... 39 8 Implementation.............................................................................................................................................................. 40 9 Review................................................................................................................................................................................ 41 10 Diagnostics Advisory Committee members and NICE project team..................................................... 42 Diagnostics Advisory Committee............................................................................................................................................ 42 NICE project team ......................................................................................................................................................................... 44

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Integrated sensor-augmented pump therapy systems for managing blood glucose levels in type 1 diabetes (the MiniMed Paradigm Veo system and the Vibe and G4 PLATINUM CGM system) (DG21)

11 Sources of evidence considered by the Committee...................................................................................... 45 Registered stakeholders ............................................................................................................................................................. 45

Glossary ................................................................................................................................................................................ 47 Disabling hypoglycaemia ............................................................................................................................................................ 47

About this guidance.......................................................................................................................................................... 48

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Integrated sensor-augmented pump therapy systems for managing blood glucose levels in type 1 diabetes (the MiniMed Paradigm Veo system and the Vibe and G4 PLATINUM CGM system) (DG21)

1

Recommendations

1.1

The MiniMed Paradigm Veo system is recommended as an option for managing blood glucose levels in people with type 1 diabetes only if: they have episodes of disabling hypoglycaemia despite optimal management with continuous subcutaneous insulin infusion and the company arranges to collect, analyse and publish data on the use of the MiniMed Paradigm Veo system (see section 7.1).

1.2

The MiniMed Paradigm Veo system should be used under the supervision of a trained multidisciplinary team who are experienced in continuous subcutaneous insulin infusion and continuous glucose monitoring for managing type 1 diabetes only if the person or their carer: agrees to use the sensors for at least 70% of the time understands how to use it and is physically able to use the system and agrees to use the system while having a structured education programme on diet and lifestyle, and counselling.

1.3

People who start to use the MiniMed Paradigm Veo system should only continue to use it if they have a decrease in the number of hypoglycaemic episodes that is sustained. Appropriate targets for such improvements should be set.

1.4

The Vibe and G4 PLATINUM CGM system shows promise but there is currently insufficient evidence to support its routine adoption in the NHS for managing blood glucose levels in people with type 1 diabetes. Robust evidence is needed to show the clinical effectiveness of using the technology in practice.

1.5

People with type 1 diabetes who are currently provided with the MiniMed Paradigm Veo system or the Vibe and G4 PLATINUM CGM system by the NHS for clinical indications that are not recommended in this NICE guidance should be able to continue using them until they and their NHS clinician consider it appropriate to stop.

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Integrated sensor-augmented pump therapy systems for managing blood glucose levels in type 1 diabetes (the MiniMed Paradigm Veo system and the Vibe and G4 PLATINUM CGM system) (DG21) During the development of this guidance, NICE became aware that a new integrated sensor-augmented pump therapy system, the MiniMed 640G system (Medtronic), has become available. The evidence for the MiniMed 640G system has not been assessed in the guidance, and the recommendations, therefore, do not relate to its routine use in the NHS. For further information on the MiniMed 640G system please see the related NICE Medtech innovation briefing.

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Integrated sensor-augmented pump therapy systems for managing blood glucose levels in type 1 diabetes (the MiniMed Paradigm Veo system and the Vibe and G4 PLATINUM CGM system) (DG21)

2

The technologies

2.1

Two integrated sensor-augmented pump therapy systems were identified during scoping as relevant to the assessment (see section 4 for additional details).

2.2

The integrated sensor-augmented pump therapy systems, which combine continuous glucose monitoring with continuous subcutaneous insulin infusion, are intended to help people with type 1 diabetes manage their blood glucose levels. The systems are designed to continuously measure interstitial glucose levels (every few minutes) and allow immediate real-time adjustment of insulin therapy. The systems produce alerts if the glucose levels become too high or too low. The MiniMed Paradigm Veo system can also automatically suspend insulin delivery if there is no response to a low-glucose warning.

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Integrated sensor-augmented pump therapy systems for managing blood glucose levels in type 1 diabetes (the MiniMed Paradigm Veo system and the Vibe and G4 PLATINUM CGM system) (DG21)

3

Clinical need and pr practice actice

The problem addressed 3.1

The purpose of this assessment is to evaluate the clinical and cost effectiveness of the MiniMed Paradigm Veo system and the Vibe and G4 PLATINUM CGM system for managing blood glucose levels in people with type 1 diabetes.

3.2

Using these integrated sensor-augmented pump therapy systems may improve glucose control and consequently may reduce the number of diabetes-related complications and improve the quality of life for people with type 1 diabetes. They may also make it easier for people to adhere to treatment. The ability of the MiniMed Paradigm Veo system to automatically suspend insulin delivery may help to reduce the incidence of severe and nocturnal hypoglycaemia, and its associated anxiety. Both systems may also offer benefits to the NHS through cost and resource savings by reducing the number of hospital admissions and consultations for diabetes-related complications, and by achieving optimum blood glucose control more quickly.

The condition 3.3

Type 1 diabetes is a chronic metabolic disorder caused by the destruction of insulin-producing cells in the pancreas that leads to an absolute lack of the hormone and subsequent loss of blood glucose control. As a result, blood glucose levels become too high and lifelong treatment with insulin is needed. Type 1 diabetes typically develops in children and young adults. It is estimated that about 370,000 adults and 24,000 children and young people in the UK have type 1 diabetes.

3.4

Achieving good control of blood glucose levels with insulin can reduce the risk of developing both short- and long-term diabetes-related complications. Short-term complications of diabetes include diabetic ketoacidosis, a life-threatening acute metabolic emergency caused by high blood glucose levels (hyperglycaemia), and hypoglycaemia, which happens when blood sugar levels become too low as a result of insulin therapy.

3.5

Hypoglycaemia can be mild, which is corrected by eating or drinking sugar, or severe, which is defined by the need for help from another person for recovery.

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Integrated sensor-augmented pump therapy systems for managing blood glucose levels in type 1 diabetes (the MiniMed Paradigm Veo system and the Vibe and G4 PLATINUM CGM system) (DG21) The main symptoms of hypoglycaemia are blurred vision, dizziness, fatigue, hunger and sweating. More severe symptoms include confusion, convulsions, coma and death. Severe symptoms may be associated with disabling hypoglycaemia, which can happen often and without warning for some people with type 1 diabetes. In children, especially those younger than 5 years, severe hypoglycaemia can cause long-term cognitive impairment. Hypoglycaemia can also occur during sleep (nocturnal hypoglycaemia) and is particularly serious because the person cannot detect its symptoms while sleeping and may not awake during an episode. Although death from nocturnal hypoglycaemia is rare, it can occur in extreme cases. Repeated hypoglycaemia can also lead to an impaired awareness of hypoglycaemia, in which people with type 1 diabetes are often less able to notice when they have hypoglycaemia. Fear of recurrent hypoglycaemia not only decreases quality of life in the short-term but can also hinder treatment adherence and good glycaemic control. 3.6

Long-term complications of chronically elevated blood glucose levels include retinopathy and blindness, peripheral and autonomic nephropathy, renal failure, ischaemic heart disease, stroke, neuropathy, and foot ulceration.

3.7

Diabetes that complicates pregnancy is also becoming more common, and it is estimated that up to 5% of about 700,000 women who give birth in England and Wales each year have pre-existing or gestational diabetes. Maternal risks of pre-existing diabetes include recurrent hypoglycaemia, progression of retinopathy, nephropathy, and increased incidence of pre-eclampsia (especially in women with microvascular disease) and operative delivery. Fetal risks of pre-existing maternal diabetes include structural congenital abnormality and intrauterine death. Neonatal complications include excessive birth weight (macrosomia), premature delivery and associated complications, birth trauma resulting from conditions such as shoulder dystocia, hypoglycaemia, and neonatal death.

The diagnostic and care pathways 3.8

Treatment of type 1 diabetes is by insulin therapy to achieve blood glucose control. Blood glucose levels are monitored to determine the type and amount of insulin needed to regulate blood glucose levels. These interventions are described in more detail in sections 3.9, 3.10 and 3.11.

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Integrated sensor-augmented pump therapy systems for managing blood glucose levels in type 1 diabetes (the MiniMed Paradigm Veo system and the Vibe and G4 PLATINUM CGM system) (DG21)

Insulin ther therap apyy 3.9

There are various types of insulin, distinguished by their rate of onset and duration of action, that can be combined into different regimens depending on a person's individual needs. Insulin therapy can be delivered by multiple daily insulin injections or by continuous subcutaneous insulin infusion using an insulin pump. The care pathways for insulin therapy for adults and children are outlined in NICE's guidelines on type 1 diabetes in adults, diabetes in children and young people, and diabetes in pregnancy and in NICE's technology appraisal guidance on continuous subcutaneous insulin infusion.

Monitoring blood glucose 3.10

Blood glucose concentrations vary widely during a 24-hour period and from day to day in diabetes. Blood glucose measurements are taken after several hours of fasting, usually in the morning before breakfast (fasting blood glucose level), and before and after each meal to measure the change in glucose concentration (postprandial blood glucose level). Levels of blood glucose can be measured by testing a drop of blood using a glucose meter (capillary blood testing), or by a continuous glucose monitor that does frequent automated testing of interstitial tissue glucose and is calibrated to reflect blood glucose. The care pathways for measuring blood glucose for children and adults are outlined in NICE's guideline on type 1 diabetes in adults, diabetes in children and young people, and diabetes in pregnancy.

3.11

Long-term monitoring of blood glucose control is achieved by measuring glycated haemoglobin (HbA1c levels), which reflect average blood glucose levels over the preceding 3 months. People with type 1 diabetes should aim for a target HbA1c level of 48 mmol/mol (6.5%) or lower, as recommended in NICE guidelines on type 1 diabetes in adults and diabetes (type 1 and type 2) in children and young people. The assessment for this guidance was based on a target HbA1c value of 58.5 mmol/mol (7.5%) or less. This was informed by the NICE guideline on diagnosis and management of type 1 diabetes in children, young people and adults, which was current at the time of the assessment. For people with diabetes, the higher the HbA1c value, the greater the risk of developing diabetes-related complications. The care pathways for monitoring HbA1c levels for adults and children are outlined in NICE's guidelines on type 1 diabetes in adults, diabetes in children and young people, and diabetes in pregnancy.

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Integrated sensor-augmented pump therapy systems for managing blood glucose levels in type 1 diabetes (the MiniMed Paradigm Veo system and the Vibe and G4 PLATINUM CGM system) (DG21)

4

The diagnostic tests

The interventions MiniMed P Par aradigm adigm V Veo eo system 4.1

The MiniMed Paradigm Veo system (Medtronic) is an integrated sensor-augmented pump therapy system that has 3 components: An Enlite glucose sensor that is placed under the skin to continuously measure the glucose levels in interstitial fluid (the thin layer of fluid between blood capillaries and the body's cells). An insulin pump that delivers insulin continuously to the subcutaneous tissue through an infusion set. A MiniLink non-implanted transmitter that sends glucose-level readings wirelessly from the sensor to the pump.

4.2

The system produces an alarm sound if glucose levels become too high or low, if levels are rapidly changing, or if the system predicts that levels will be too high or too low in the near future. It has an automated low-glucose suspend function that works independently of user action and stops insulin delivery for 2 hours if there is no response to the alert.

4.3

The system is intended to be used with standard capillary blood glucose tests because the sensor measures interstitial glucose levels rather than capillary blood glucose levels. Because glucose moves from the capillaries to tissues, there is a lag between blood and interstitial glucose levels of at least 15 minutes and so a minimum of 2 capillary blood glucose tests per day are needed for calibration. The lag increases when blood glucose levels are changing rapidly, so although trends in interstitial glucose are representative of blood glucose changes, absolute interstitial glucose values do not always match blood glucose levels. Further capillary blood glucose tests may be needed to confirm the value displayed on the pump by the continuous glucose monitor, before making any adjustments to diabetes therapy.

4.4

The insulin pump in the system continuously delivers insulin from a storage reservoir through an infusion set, consisting of thin plastic tubing and a cannula

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Integrated sensor-augmented pump therapy systems for managing blood glucose levels in type 1 diabetes (the MiniMed Paradigm Veo system and the Vibe and G4 PLATINUM CGM system) (DG21) that is placed under the skin. The pump can be programmed to deliver a basal rate of insulin throughout the day, with higher infusion rates triggered by pushing a button on the pump at meal times. The higher infusion rate may be a bolus dose (that is a dose taken specifically at meal times to keep glucose levels under control after a meal) or periodic doses over a period of time. It can also deliver different basal rates of insulin at different times of the day and night. The company's instructions for use state that the infusion set and reservoir should be replaced every 2 to 3 days. 4.5

The MiniMed Paradigm Veo system is compatible with the CareLink software platform (Medtronic), which is designed to allow users to upload their data from the MiniMed Paradigm Veo system so that clinicians can evaluate the person's glycaemic control, notice any trends and adjust their therapy as appropriate.

Vibe and G4 PLA PLATINUM TINUM CGM system 4.6

The Vibe and G4 PLATINUM CGM system is an integrated sensor-augmented pump system that has 3 components: The Vibe CGM-enabled insulin pump (Animas) that delivers insulin continuously. The G4 PLATINUM sensor (Dexcom) that continuously monitors interstitial glucose levels. A non-implanted transmitter (Dexcom) that sends glucose-level readings wirelessly from the sensor to the pump.

4.7

The sensor is placed under the skin and measures interstitial glucose levels. It is approved for up to 7 days of use. The system produces glucose-level readings in real-time and glucose trend information. There is an alarm that alerts the user if the glucose levels become too high or too low, or if the levels are rapidly changing. The system also has a default low-glucose alarm that cannot be altered by the user. It does not have an automated low-glucose suspend function. There is a lag between blood and interstitial glucose levels of at least 15 minutes and so at least 2 capillary blood glucose tests per day are needed to calibrate the system, before making any adjustments to diabetes therapy.

4.8

The insulin pump in the Vibe and G4 PLATINUM CGM system delivers insulin continuously from a storage reservoir through a cannula placed under the skin.

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Integrated sensor-augmented pump therapy systems for managing blood glucose levels in type 1 diabetes (the MiniMed Paradigm Veo system and the Vibe and G4 PLATINUM CGM system) (DG21) The pump can be programmed to deliver a basal rate of insulin throughout the day, with the option of triggering higher infusion rates at meal times, either as a bolus dose or over a period of time. The pump can also be programmed for different basal rates of insulin at different times of the day and night. 4.9

The Vibe and G4 PLATINUM CGM system is compatible with Diasend, a software platform that allows users to upload data from their pump for interpretation, to adjust settings and to keep a food database. Users can share their data with healthcare professionals, who can then use it to assess glucose trends and inform changes in therapy.

The comparators 4.10

To reflect the combinations of technologies that may be used by people with type 1 diabetes to monitor blood glucose levels and administer insulin therapy in current practice, 4 comparators are included: capillary blood testing with continuous subcutaneous insulin infusion capillary blood testing with multiple daily insulin injections continuous glucose monitoring with continuous subcutaneous insulin infusion (non-integrated devices) continuous glucose monitoring with multiple daily insulin injections.

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Integrated sensor-augmented pump therapy systems for managing blood glucose levels in type 1 diabetes (the MiniMed Paradigm Veo system and the Vibe and G4 PLATINUM CGM system) (DG21)

5

Outcomes

The Diagnostics Advisory Committee (section 10) considered evidence from a number of sources (section 11). Full details of all the evidence are in the committee papers.

How outcomes were assessed 5.1

The assessment consisted of a systematic review of the clinical-effectiveness data for the MiniMed Paradigm Veo system, the Vibe and G4 PLATINUM CGM system and comparator technologies.

5.2

In total, 54 publications reporting the results of 19 studies met the inclusion criteria. These studies included either the intervention or comparator technologies in a treatment arm. Two studies included data for the MiniMed Paradigm Veo system, 1 of which compared the system with an integrated sensor-augmented pump therapy system without a low-glucose suspend function (included as a clinical proxy for the Vibe and G4 PLATINUM CGM system in the absence of any data for this technology), and a further 7 studies included data for the integrated sensor-augmented pump therapy system without a low-glucose suspend function. The remainder of the studies reported data for capillary blood testing with continuous subcutaneous insulin and capillary blood testing with multiple daily insulin injections. No studies reported data for either continuous glucose monitoring with continuous subcutaneous insulin infusion (non-integrated devices) or continuous glucose monitoring with multiple daily insulin injections. Of the 19 included studies: 10 included adults only 3 included children only 3 included a mixed population (adults and children) but did not report data for each group separately 2 included a mixed population and reported data for adults and children separately 1 included pregnant women only.

5.3

The 1 study that included pregnant women only reported data for capillary blood testing with continuous subcutaneous insulin infusion and capillary blood testing with multiple daily insulin injections. Because no comparative data were

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Integrated sensor-augmented pump therapy systems for managing blood glucose levels in type 1 diabetes (the MiniMed Paradigm Veo system and the Vibe and G4 PLATINUM CGM system) (DG21) found to assess the clinical effectiveness of the integrated sensor-augmented pump therapy systems in pregnant women, this study was not included in the analyses. 5.4

All the studies were randomised controlled trials. The methodological quality of each study was appraised using the Cochrane risk of bias tool. Eleven of the 19 studies were rated as a high risk of bias, primarily because the patients, clinicians and assessors were not blinded to the allocation of interventions and glycated haemoglobin (HbA1c) results were interpreted with knowledge of the treatment allocation. Of the remaining 8 studies, 4 were rated as unclear risk of bias and 4 were rated as low risk of bias.

5.5

There was substantial heterogeneity in the populations included in the studies. Nine studies included people who had not used an insulin pump before, and only 4 studies reported including people who had experienced hypoglycaemia before the trial.

5.6

The results of the studies were presented as a narrative synthesis and combined into network meta-analyses where possible. Direct head-to-head meta-analyses were done using a fixed-effect model unless significant heterogeneity was observed. Indirect meta-analyses were done according to the method devised by Bucher et al. (1997).

Clinical effectiveness in adults 5.7

Twelve studies reported data for adults: 10 studies done solely in adults and 2 studies reported subgroup data for adults.

MiniMed P Par aradigm adigm V Veo eo system 5.8

One study (ASPIRE in-home) compared the MiniMed Paradigm Veo system with an integrated sensor-augmented pump therapy system (no low-glucose suspend) at 3-month follow-up in adults with type 1 diabetes. This study included people who had experienced 2 or more nocturnal hypoglycaemic events during the study run-in phase, but excluded people who had experienced more than 1 episode of severe hypoglycaemia in the 6 months before study recruitment. The study reported that hypoglycaemic events occurred less often in the MiniMed Paradigm Veo system group (3.3±2.0 weekly events per patient

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Integrated sensor-augmented pump therapy systems for managing blood glucose levels in type 1 diabetes (the MiniMed Paradigm Veo system and the Vibe and G4 PLATINUM CGM system) (DG21) compared with 4.7±2.7 weekly events per patient; p