CAM 10130

Artificial Pancreas Device Systems

Category:Medicine   Last Reviewed:February 2020
Department(s):Medical Affairs   Next Review:February 2021
Original Date:February 2015    

Description 
Artificial pancreas device systems link a glucose monitor to an insulin infusion pump that automatically takes action (eg, suspends or adjusts insulin) based on the glucose monitor reading. These devices are proposed to improve glycemic control in patients with insulin-dependent diabetes, in particular, control of nocturnal hypoglycemia.

For individuals who have type 1 diabetes who receive an artificial pancreas device system with a low-glucose suspend feature, the evidence includes 2 randomized controlled trials (RCTs) conducted in-home settings. Relevant outcomes are symptoms, change in disease status, morbid events, resource utilization, and treatment-related morbidity. Primary eligibility criteria of the key RCT, the Automation to Simulate Pancreatic Insulin Response (ASPIRE) trial, were ages 16-to-70 years old, type 1 diabetes, glycated hemoglobin levels between 5.8% and 10.0%, and at least 2 nocturnal hypoglycemic events (≤65 mg/dL) lasting more than 20 minutes during a 2-week run-in phase. Both trials required at least 6 months of insulin pump use. Both RCTs reported significantly less hypoglycemia in the treatment group than in the control group. In both trials, primary outcomes were favorable for the group using an artificial pancreas system; however, 1 trial was limited by its nonstandard reporting of hypoglycemic episodes, and the other trial was no longer statistically significant when 2 outliers were excluded from analysis. The evidence is insufficient to determine that the technology results in a meaningful improvement in the net health outcome. 

For individuals who have type 1 diabetes who receive a hybrid closed-loop insulin delivery system, the evidence includes a single-arm study and a multicenter pivotal trial using a device cleared by the Food and Drug Administration and 3 crossover RCTs using a similar device approved outside the United States. Relevant outcomes are symptoms, change in disease status, morbid events, resource utilization, and treatment-related morbidity. The single-arm study analysis is part of an ongoing study; it was not designed to evaluate the impact of the device on glycemic control and did not include a comparison intervention. The pivotal trial, submitted with other materials for device approval, evaluated the safety of the device and was not designed to address efficacy. Published data are needed on the efficacy of the semiautomatic insulin adjustment feature of the new device compared with current standard care. Of the 3 crossover RCTs assessing a related device conducted outside the United States, two found significantly better outcomes (ie, time spent in nocturnal hypoglycemia and time spent in preferred glycemic range) with the new device than with standard care and the other had mixed findings (significant difference in time spent in nocturnal hypoglycemia and no significant difference in time spent in preferred glycemic range). The evidence is insufficient to determine the effects of the technology on health outcomes.  

Background   
DIABETES AND GLYCEMIC CONTROL
Tight glucose control in patients with diabetes hasbeen associatedwith improved health outcomes. The American Diabetes Association has recommended a glycated hemoglobin level below 7% for most patients. However, hypoglycemia, may place a limit on the ability to achieve tighter glycemic control. Hypoglycemic events in adults range from mild to severe based ona number offactors including the glucose nadir, thepresenceof symptoms, and whether the episode can be self-treated or requires help for recovery. Children and adolescents represent a population of type 1 diabetics who have challenges in controlling hyperglycemia and avoiding hypoglycemia. Hypoglycemia is the most common acute complication of type 1 diabetes (T1D).

Table 1 is a summary of selected clinical outcomes in T1D clinical management and research.

Table 1. Outcome Measures for Type 1 Diabetes

Measure

Definition

Guideline type

Organization

Date

Hypoglycemia

 

Stakeholder survey, expert opinion with evidence review

Type 1 Diabetes Outcome Programa1,

2017       

Level 1

Level 2

Level 3

Glucose <70mg/dl but≥54 mg/dl

Glucose <54 mg/dl

Event characterized by altered mental/physical status requiring assistance

     

Hypoglycemia

Same as Type 1 Diabetes Outcome Programa

Professional Practice Committee with systematic literature review

 

ADA2,

2019

Hypoglycemia

Clinical alert for evaluation and/or treatment

Clinically important or serious

Severe hypoglycemia

 

 Glucose <70mg/dl

Glucose <54 mg/dl

Severe cognitive impairment requiring external assistance by another person to take corrective action

Clinical Practice Consensus

ISPAD3,

2018

Hyperglycemia

Level 1

Level 2

 

 Glucose >180 mg/dL and≤250 mg/dL

 Glucose >250 mg/dL

 

 

Type 1 Diabetes Outcome Programa1

2017

Time in Rangeb

Percentage of glucose readings in the range of 70–180 mg/dL per unit of time

 

 

 

Type 1 Diabetes Outcome Programa

2017

Diabetic ketoacidosis (DKA)

Elevated serum or urine ketones > ULN

Serum bicarbonate <15 mEq/L

Blood pH <7.3

 

Type 1 Diabetes Outcome Programa3

2017

ADA: American Diabetes Association, ISPAD: International Society for Pediatric and Adolescent Diabetes; ULN: upper limit of normal.
Steering Committee: representatives from American Association of Clinical Endocrinologists (AACE), American Association Diabetes Educators, the American Diabetes Association (ADA), the Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, T1D Exchange.
Time in range: has also been adopted by researchers evaluating the precision and effectiveness of emerging glucose monitoring and automated insulin delivery technologies.

Treatment
Type 1 diabetes is caused by the destruction of the pancreatic beta cells which produce insulin, and the necessary mainstay of treatment isinsulin injections. Multiple studies have shown that intensive insulin treatment, aimed at tightly controlling blood glucose, reduces the risk of long-term complications of diabetes, such as retinopathy and renal disease. Optimal glycemic control, as assessed by glycated hemoglobin, and avoidance of hyper- and hypoglycemic excursions have been shown to prevent diabetes-related complications.Currently, insulin treatment strategies include either multiple daily insulin injections or continuous subcutaneous insulin infusion with an insulin pump.

The use of the continuous glucose monitoring (CGM) component of diabetes self-management is specifically addressed in evidence review 1.01.20.

Restoration of pancreatic function is potentially available through islet cell or allogeneic pancreas transplantation. Evidence reviews of these interventions are 7.03.12 and 7.03.02, respectively.

Regulatory Status
The Food and Drug Administration (FDA) describes the basic design of an artificial pancreas device system (APDS) as a CGM linked to an insulin pump with the capability to automatically stop, reduce, or increase insulin infusion based on specified thresholds of measured interstitial glucose.4,

The APDS components are designed to communicate with each other to automate the process of maintaining blood glucose concentrations at or near a specified range or target and to minimize the incidence and severity of hypoglycemic and hyperglycemic events. An APDS control algorithm is embedded in software in an external processor or controller that receives information from the CGM and performs a series of mathematical calculations. Based on these calculations, the controller sends dosing instructions to the infusion pump.

Different APDS types are currently available for clinical use. Sensor augmented pump therapy (SAPT) with low glucose suspend (LGS) (suspend on low) may reduce the likelihood or severity of a hypoglycemic event by suspending insulin delivery temporarily when the sensor value reaches (reactive) a predetermined lower threshold of measured interstitial glucose. Low glucose suspension (LGS) automatically suspends basal insulin delivery for up to two hours in response to sensor-detected hypoglycemia.

A sensor augmented pump therapy with predictive low glucose management (PLGM) (suspend before low) suspends basal insulin infusion with the prediction of hypoglycemia. Basal insulin infusion is suspended when sensor glucose is at or within 70 mg/dL above the patient-set low limit, and is predicted to be 20 mg/dL above this low limit in 30 minutes. In the absence of a patient response, the insulin infusion resumes after a maximum suspend period of two hours. In certain circumstances, auto-resumption parameters may be used.

When a sensor value is above or predicted to remain above the threshold, the infusion pump will not take any action based on CGM readings. Patients using this system still need to monitor their blood glucose concentration, set appropriate basal rates for their insulin pump, and give premeal bolus insulin to control their glucose levels.

A control-to-range system reduces the likelihood or severity of a hypoglycemic or hyperglycemic event by adjusting insulin dosing only if a person's glucose levels reach or approach predetermined higher and lower thresholds. When a patient's glucose concentration is within the specified range, the infusion pump will not take any action based upon CGM readings. Patients using this system still need to monitor their blood glucose concentration, set appropriate basal rates for their insulin pump, and give premeal bolus insulin to control their glucose levels.

A control-to-target system sets target glucose levels and tries to maintain these levels at all times. This system is fully automated and requires no interaction from the user (except for calibration of the CGM). There are two subtypes of control-to-target systems: insulin-only and bihormonal (eg, glucagon). There are no systems administering glucagon marketed in the United States.

An APDS may also be referred to as a “closed-loop” system. A closed-loop system has automated insulin delivery and continuous glucose sensing and insulin delivery without patient intervention. The systems utilize a control algorithm that autonomously and continually increases and decreases the subcutaneous insulin delivery based on real-time sensor glucose levels. There are no completely closed-loop insulin delivery systems marketed in the United States.

A hybrid closed-loop system also uses automated insulin delivery with continuous basal insulin delivery adjustments. However, at mealtime, the patient enters thenumberof carbohydrates they are eating in order for the insulin pump to determine the bolus meal dose of insulin. A hybrid system option with thepatientadministration of a premeal or partial premeal insulin bolus can be used in either control-to-range or control-to-targetsystems.

These systems are regulated by the FDA as class III device systems.

Table 2 summarizes the FDA-approved automated insulin delivery systems.

Table 2. FDA-Approved Automated Insulin Delivery Systems (Artificial Pancreas Device Systems)

Device

Age Indication

Manufacturer

Date Approved

PMA No./
Device Code

MiniMed 530G Systema(open-loop, LGS)

≥16 y

Medtronic

Jul 2013

P120010/OZO

MiniMed 630G System with SmartGuard™b(open-loop, LGS)

≥16 y

≥14 y

Medtronic

Aug 2016

Jun 2017

P150001/OZO

P150001/S008

MiniMed 670GSystemc(hybrid closed-loop, LGS or PLGM)

≥14 y

≥7-13 y

Medtronic

Sep 2016

Jul 2018

P160017/OZP

P160017/S031

FDA: Food and Drug Administration; LGS: low glucosesuspend; OZO: Artificial Pancreas Device System, threshold suspend; OZP: Automated Insulin Dosing Device System, Single Hormonal Control; PMA: premarket approval; PLGM: predictive low glucose management.
MiniMed 530G System consists of the following devices that can be used in combination or individually: MiniMed 530G Insulin Pump, Enlite™ Sensor, Enlite™Serter, the MiniLink Real-Time System, the Bayer Contour NextLink glucose meter, CareLink® Professional Therapy Management Software for Diabetes, and CareLink® Personal Therapy Management Software for Diabetes (at time of approval).
MiniMed 630G System with SmartGuard™ consists of the following devices: MiniMed 630G Insulin Pump, Enlite® Sensor, One-Press Serter, Guardian® Link Transmitter System, CareLink® USB, Bayer’s CONTOUR ® NEXT LINK 2.4 Wireless Meter, and Bayer’s CONTOUR® NEXT Test Strips (at time of approval).
MiniMed 670G System consists of the following devices: MiniMed 670G Pump, the Guardian Link (3) Transmitter, the Guardian Sensor (3), One-Press Serter, and the Contour NEXT Link 2.4 Glucose Meter (at time of approval).

The MiniMed® 530G System includes a threshold suspend or LGS feature.5,The thresholdsuspendtool temporarily suspends insulin delivery when the sensor glucose level is at or below a preset threshold within the 60- to 90-mg/dL range. When the glucose value reaches this threshold, an alarm sounds. If patients respond to the alarm, they can choose to continue or cancel the insulin suspend feature. If patients fail to respond, the pump automatically suspends action for two hours, and then insulin therapy resumes.

The MiniMed® 630G System with SmartGuard™, which is similar to the 530G, includes updates to the system components including waterproofing.6,The threshold suspend feature can be programmed to temporarily suspend delivery of insulin for up to two hours when the sensor glucose value falls below a predefined threshold value. The MiniMed 630G System with SmartGuard™ is not intended to be used directly for making therapy adjustments, but rather to provide an indication of when a finger stick may be required. All therapy adjustments should be based on measurements obtained using a home glucose monitor and not on thevaluesprovided by the MiniMed 630G system. The device is not intended to be used directly for preventing or treating hypoglycemia but to suspend insulin delivery when the user is unable to respond to the SmartGuard™ Suspend onLowalarm to take measures to prevent or treat hypoglycemia themselves.

The MiniMed® 670G System is a hybrid closed-loop insulin delivery system consisting of an insulin pump, a glucose meter, and a transmitter, linked by a proprietary algorithm and the SmartGuard Hybrid Closed Loop.7,The system includes an LGS feature that suspends insulin delivery; this feature either suspends delivery on low-glucose levels or suspends delivery before low-glucose levels, and has an optional alarm (manual mode). Additionally, the system allows semiautomatic basal insulin-level adjustment (decrease or increase) to preset targets (automatic mode). As a hybrid system; basal insulin levels are automatically adjusted, but the patient needs to administer premeal insulin boluses. The CGM component of the MiniMed 670G System is not intended to be used directly for making manual insulin therapy adjustments; rather it is to provide an indication of when a glucose measurement should be taken.

The most recent supplemental approval for the MiniMed® 670G System in July 2018 followed the granting a designation of breakthrough device status.

On June 21, 2018, the FDA approved the t:slim X2 Insulin Pump with Basal-IQ Technology (PMA P180008) for individuals who are 6 years of age and older. The System consists of the t:slim X2 Insulin Pump paired with the Dexcom G5 Mobile CGM (Continuous Glucose Monitor), as well as the Basal-IQ Technology. The t:slim X2 Insulin Pump is intended for the subcutaneous delivery of insulin, at set and variable rates, for the management of diabetes mellitus in persons requiring insulin. The t:slim X2 Insulin Pump can be used solely for continuous insulin delivery and as part of the System as the receiver for a therapeutic CGM. The t:slim X2 Insulin Pump running the Basal-IQ Technology can be used to suspend insulin delivery based on CGM sensor readings. Introduction into clinical care is planned for summer 2019.

Related Policies
10120  Continuous or Intermittent Monitoring of Glucose in Interstitial Fluid

Policy 
Use of an FDA-approved artificial pancreas device system with a low glucose suspend feature may be considered MEDICALLY NECESSARYin patients with type 1 diabetes who meet all of the following criteria:

  • Age 16 and older
  • Type 1 diabetes
  • Glycated hemoglobin value between 5.8% and 10.0%
  • Used insulin pump therapy for more than 6 months
  • At least 2 documented nocturnal hypoglycemic events (see Policy Guidelines) in a 2 week period.

Use of an artificial pancreas device system is considered investigational and/ or unproven and therefore considered NOT MEDICALLY NECESSARYin all other situations. 

Use of hybrid closed loop insulin delivery system (including the Food and Drug Administration approved device for age 14 and older) as an artificial pancreas device system is considered investigational and/or unproven and is therefore considered NOT MEDICALLY NECESSARY.

Policy Guidelines 
The definition of a hypoglycemic episode is not standardized. In the pivotal ASPIRE randomized controlled trial, a hypoglycemic episode was defined as a sensor glucose value of 65 mg per deciliter or less between 10 P.M. and 8 A.M. for more than 20 consecutive minutes in the absence of a pump interaction within 20 minutes.

Effective in July 2014, there are HCPCS codes specific to the “artificial pancreas” system –

S1034: Artificial pancreas device system (eg, low glucose suspend [LGS] feature) including continuous glucose monitor, blood glucose device, insulin pump and computer algorithm that communicates with all of the devices 
S1035: Sensor; invasive (eg, subcutaneous), disposable, for use with artificial pancreas device system, 1 unit = 1 day supply 
S1036: Transmitter; external, for use with artificial pancreas device system 
S1037: Receiver (monitor); external, for use with artificial pancreas device system

Benefit Application
BlueCard/National Account Issues
State or federal mandates (eg, FEP) may dictate that all devices approved by FDA may not be considered investigational. Therefore, FDA-approved devices may be assessed on the basis of their medical necessity.

State mandates regarding coverage of diabetic supplies may apply; however, some state mandates may only apply to those supplies that are no longer considered investigational.

Rationale  
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function -- including benefits and harms. Every clinical condition has specific outcomes that are important to patients and tomanagingthe course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

This review was informed by a TEC Assessment(2013) on artificial pancreas device systems (APDS).8,This evidence review addresses artificial pancreas devices that have been approved bythe U.S. Food and Drug Administration.

Low-Glucose Suspend Devices
Clinical Context and Therapy Purpose
The purpose ofAPDS with a low-glucose suspend (LGS) featurein patients who havetype 1 diabetes(T1D) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of anAPDS withan LGSfeature improve the net health outcome for individuals with type 1 diabetes?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interestisindividuals withtype 1 diabetes. Persons with T1D are especially prone to develop hypoglycemia. Alterations in the counterregulatory hormonal responses inherent in the disease, variable patient adherence and iatrogenic hypoglycemia caused by aggressive prevention of hyperglycemia are responsible for this propensity. Hypoglycemia affects many aspects of cognitive function, including attention, memory, and psychomotor and spatial ability. Severe hypoglycemia can cause serious morbidity affecting the central nervous system (eg, coma, seizure, transient ischemic attack, stroke), heart (eg, cardiac arrhythmia, myocardial ischemia, infarction), eye (eg, vitreous hemorrhage, worsening of retinopathy), as well as cause hypothermia and accidents that may lead to injury. Fear of hypoglycemia symptoms can also cause decreased motivation to adhere strictly to intensive insulin treatment regimens.

Interventions
The therapy being considered is anAPDS thatintegrates a continuous glucose monitor and insulin pump and includesan LGSfeature that can automatically and temporarilysuspendinsulin delivery when glucose levels fall below a prespecified level. The device alarms and the user must take an action to assess glycemic level and resume insulin infusion.

APDS are used by persons with type1 diabetes when they have experienced hypoglycemic and/or hypoglycemic episodes that cannot be managed with intermittent self-monitoring of glucose and self-administration of insulin.APDSareused by persons with type1 diabetes in “free-living” and home settings, with monitoring by primary care clinicians, diabetologists, and endocrinologists.

Comparators
The following therapies are currently being used to treat type 1 diabetes: nonintegrated continuous glucose monitoring (CGM) plus insulin pump (open-loop) or self-monitoring blood glucose and multiple dose insulintherapy.

Outcomes 
The general outcomes of interest areglycatedhemoglobin (HbA1c) levels, time in range or target of glucose levels, and rates of hypoglycemia and hyperglycemia. Other outcomes of interest include quality of life and changes in health care utilization (eg, hospitalizations). The duration of follow-up is life-long. 

Systematic Reviews 
A TEC Assessment (2013) reviewed studies that reported on theuseof APDSs in patients with type 1 or type 2 diabetes taking insulin who were 16 years and older.8,It included studies that compared an APDS containingan LGSfeature with the best alternative treatment in the above population, had at least 15 patients per arm, and reported on hypoglycemic episodes. A single trial met the inclusion criteria, and the TEC Assessment indicated that, although the trial results weregenerallyfavorable, the study was flawed and further research was needed. Reviewers concluded that there was insufficient evidence todraw conclusions aboutthe impact of anAPDS, withan LGSfeature, on health outcomes. 

Randomized Controlled Trials 
The single trial assessed in the TEC Assessment was the in-home arm of the Automation to Simulate Pancreatic Insulin Response (ASPIRE) trial, reported by Bergenstalet al(2013).9,This industry-sponsored trial used the Paradigm Veo insulin pump. A total of 247 patients were randomized to an experimental group, in which a continuous glucose monitor with the LGS feature was used (n=121), or a control group, which used the continuous glucose monitor but not the LGS feature (n=126). Key eligibility criteria were 16-to-70 years old, type 1 diabetes, andHbA1clevels between 5.8% and 10.0%.In addition, patients had to have more than6months of experience with insulin pump therapy and at least2nocturnal hypoglycemic events (≤65 mg/dL) lasting more than 20 minutes during a 2-week run-in phase. The randomized intervention phase lasted 3 months. Patients in the LGS group were required to use the feature at least between 10PMand 8AM. The threshold value was initially set at 70 mg/dL and couldbe adjustedto between 70 mg/dL and 90 mg/dL. Seven patients withdrew early from the trial; all 247were includedin the intention-to-treat analysis. The primary efficacy outcome was the area under the curve (AUC) for nocturnal hypoglycemia events.Thiswas calculatedby multiplying the magnitude (in milligrams per deciliter) and duration (in minutes) of each qualified hypoglycemic event. The primary safety outcomewas changeinHbA1clevels. 

The primaryendpoint, mean (standard deviation [SD]) AUC for nocturnal hypoglycemic events, was 980 (1200) mg/dL/min in the LGS group and 1568 (1995) mg/dL/min in the control group. The difference between groups was statistically significant (p<0.001), favoring the intervention group. 

Similarly, the mean AUC for combined daytime and nighttime hypoglycemic events (a secondary outcome) significantly favored the intervention group (p<0.001). Mean (SD) AUC values were 798 (965) mg/dL/min in the intervention group and 1164 (1590) mg/dL/min in the control group. Moreover, the intervention group experienced fewer hypoglycemic episodes (mean, 3.3 per patient-week; SD=2.0) than the control group (mean, 4.7 per patient-week; SD=2.7; p<0.001). For patients in the LGS group, the mean number of times the featurewas triggeredper patient was 2.08 per 24-hour period and 0.77 each night (10PM-8AM). The median duration of nighttime threshold suspend eventswas11.9 minutes; 43% of events lasted for less than 5minutes,and 19.6% lasted more than 2 hours. In both groups, the mean sensor glucose value at the beginning of nocturnal events was 62.6 mg/dL. After 4 hours, the mean value was 162.3 mg/dL in the LGS group and 140.0 mg/dL in the control group. 

Regardingsafety outcomes and adverse events, change in HbA1clevel was minimal, and there was no statistically significant difference between groups. MeanHbA1clevels decreased from 7.26 to 7.24 mg/dL in the LGS group and from 7.21 to 7.14 mg/dL in the control group. During the study period, there were no severe hypoglycemic events in the LGS group and4events in the control group (range of nadir glucose sensor values in these events, 40-76 mg/dL). There were no deaths or serious device-related adverse events. 

Before reporting on in-home findings, the ASPIRE researchers (Garget al [2012]) published data from the in-clinic arm of the study.10,This randomized crossover trial included 50 patients with type 1 diabetes who had at least3months of experience with an insulin pump system. After a 2-week run-in period to verify and optimize basal rates, patients underwent 2 in-clinic exercise sessions to induce hypoglycemia. The LGS feature on the insulin pump was turned on in1session and off in the other session, in random order. When on, the LGS feature was set to suspend insulin delivery for 2 hours when levels reached 70 mg/dL or less. The goal of the study was to evaluate whether the severity and duration of hypoglycemiawere reducedwhen the LGS featurewas used. The study protocol called for patients to start exercise with glucose levels between 100 mg/dL and 140 mg/dL and to use a treadmill or stationary bicycle until their plasma glucose levels were 85 mg/dL or less. The study outcome (duration of hypoglycemia)was definedas theperiod of timeglucose values were lower than 70 mg/dL and above 50 mg/dL, and hypoglycemia severity was defined as the lowest observed glucose value. A successful session was defined as an observation period of 3 to 4 hours and with glucose levels above 50 mg/dL. Patients who did not attain success could repeat the experiment up to 3 times. 

The 50 patients attempted 134 exercise sessions; 98 of them were successful. Duration of hypoglycemia was significantly shorter during the LGS-on sessions (mean, 138.5 minutes; SD=68) than the LGS-off sessions (mean, 170.7 minutes; SD=91; p=0.006). Hypoglycemia severitywas significantly reducedin the LGS-on group. The mean (SD) lowest glucose level was 59.5 (72) mg/dL in the LGS-on group and 57.6 (5.7) mg/dL in the LGS-off group (p=0.015). Potential limitations of the Garg study included evaluation of the LGS feature in a research setting and shortassessmentperiod. 

A second RCT evaluated thein-homeuse of the Paradigm Veo System.11,The trial by Lyet al(2013) in Australia was excluded from the 2013 TEC Assessment due to the inclusion of children and adults and lack of analyses stratified by age group (the artificial pancreas system approved in the United States at the time of the review was only intended for individuals ≥16 years). The Ly trial included 95 patients with type 1 diabetes between 4 and 50 years of age (mean age, 18.6 years; >30% of sample <18 years old) who had used an insulin pump for at least6months.In addition, participants had to have anHbA1clevel of 8.5%orless and have impaired awareness of hypoglycemia (defined as a score of at least4on the modified Clarke questionnaire). Patients were randomized to 6 months of in-home use of the Paradigm Veo System with automated insulin suspension when the glucose sensor reached a preset threshold of 60 mg/dL or to continued use of an insulin pump without the LGS feature. The primary study outcome was thecombinedincidence of severe hypoglycemic events (defined as hypoglycemic seizure or coma) and moderate hypoglycemic events (defined as an event requiring assistancefromanother person). As noted, findings were not reported separately for children and adults. 

The baseline rate of severe and moderate hypoglycemia was significantly higher in the LGS group (129.6 events per 100 patient-months) than in the pump-only group (20.7 events per 100 patient-months). After6months of treatment, and controlling for the baseline hypoglycemia rate, the incidence rate per 100 patient-months was 34.2 (95% confidence interval [CI], 22.0 to 53.3) in the pump-only group and 9.6 (95% CI, 5.2 to 17.4) in the LGS group. The incidence rate ratio was 3.6 (95% CI, 1.7 to 7.5), which was statistically significant favoring the LGS group. Although results were not reported separately for children and adults, the trialists conducted a sensitivity analysis in patients younger than 12 years (15 patients in each treatment group). The high baseline hypoglycemia rates couldbe explainedin part by 2 outliers (children ages 9 and 10 years). When both childrenwere excludedfrom the analysis, the primary outcome was no longer statistically significant. The incidence rate ratio for moderate and severe events excluding the2children was 1.7 (95% CI, 0.7 to 4.3). MeanHbA1clevels (a secondary outcome) did not differ betweengroups at baselineor at6months. Change in HbA1clevelsduring the treatment period was -0.06% (95% CI, -0.2%to 0.09%) in the pump-only group and -0.1% (95% CI,-0.3% to 0.03%) in the LGS group; the difference between groups was not statistically significant. 

Retrospective Studies 
Agrawalet al(2015) retrospectively analyzed use of the threshold suspend feature associated with the Paradigm Veo System in 20,973 patients, most of whom were treated outside of the United States.12,This noncontrolled descriptive analysis provided information on the safety of the device when used in a practice setting. The threshold suspend featurewasenabled for 100% of the time by 14673 (70%) patients, 0% of the time by 2249 (11%) patients, and the remainder used it intermittently. The mean (SD) setting used to trigger suspension of insulin was a sensor glucose level of 62.8 (5.8) mg/dL. On days when the threshold suspend featurewas enabled, there was a mean of 0.82 suspend events per patient-day. Of these, 56% lasted for 0 to 5minutes,and 10% lasted the full 2 hours. (Data on the length of the other 34% of eventswere not reported.) On days when the threshold suspend feature was on, sensor glucose values were 50 mg/dL or less 0.64% of the time compared with 2.1% of sensor glucose values 50 mg/dL or less on days when the feature was off. Reduction in hypoglycemia was greatest at night. Sensor glucose percentages equivalent to 17 minutes per night occurred when the threshold suspend feature was offvsglucose percentages equivalent to 5 minutes per night when the threshold suspend feature was on. Data on the use of the device has suggested fewer and shorter hypoglycemic episodes. The length and severity of hypoglycemic episodeswere not fully discussedin this article. 

Prospective Observational Studies 
Gómez et al (2017) published the results of a cohort of 111 type 1 diabetic individuals with documented hypoglycemia and hypoglycemia unawareness who received a sensor-augmented insulin pump with LGS therapy.13,Participants used a combination system with the Medtronic Paradigm 722 or Paradigm Veo pump connected to the MiniMed CGM device. At a mean follow-up of 47 months (SD=22.7), total daily insulin dose was reduced (mean difference, -0.22 U/kg; 95% CI, -0.18 to -0.26 U/kg; p<0.001).HbA1clevels were reduced from a baseline value of 8.8% (SD=1.9%) to 7.5% (SD=1.0%) at 5 months (mean difference, -1.3%; 95% CI, -1.09% to -1.50%; p<0.001) and 7.1% (SD=0.8%; mean difference, -1.7%; 95% CI, -1.59% to -1.90%; p<0.001). At baseline, 80% of subjects had had at least 1 episode of hypoglycemic awareness compared with 10.8% at last follow-up (p<0.001). Episodes of severe hypoglycemia decreased from 66.6% to 2.7% (p<0.001). 

Section Summary: LGS Devices 
For individuals who have type 1 diabetes (T1D) who receive an artificial pancreas device system with a low-glucose suspend feature, the evidence includestworandomized controlled trials (RCTs) conducted in home settings. Relevant outcomes are symptoms, change in disease status, morbid events, resource utilization, and treatment-related morbidity.Primary eligibility criteria of the key RCT, theAutomation to Simulate Pancreatic Insulin Response (ASPIRE) trial, wereages 16-to-70 years old,T1D , glycated hemoglobin levels between 5.8% and 10.0%, and at least 2 nocturnal hypoglycemic events (≤65 mg/dL) lasting more than 20 minutes during a 2-week run-in phase.Both trials required at least six months of insulin pump use. Both RCTs reported significantly less hypoglycemia in the treatment group than in the control group. In both trials, primary outcomes were favorable for the group using an artificial pancreas system; however, findings fromonetrialwere limitedby nonstandard reporting of hypoglycemic episodes, and findings from the other trial were no longer statistically significant when two outliers (children)were excludedfrom analysis.The RCT limited to adults showed an improvement in the primary outcome (area under the curve for nocturnal hypoglycemic events). The area under the curveis not usedfor assessment in clinicalpractice but the current technology does allow user and provider review of similar trend data withcontinuous glucose monitoring. 

Results from the ASPIRE study suggested that there were increased risks of hyperglycemia and potential diabetic ketoacidosis in subjects using the threshold suspend feature. This finding may be related to whether or not actions are taken by the user to assess glycemic status, etiology of the low glucose (activity, diet or medication) and to resume insulin infusion. 

Both retrospective and prospective observational studies have reported reductions in rates and severity of hypoglycemic episodes in automated insulin delivery system users.The evidence is sufficient that the magnitude of reduction for hypoglycemic events in the T1D population is likely to be clinically significant. Limitations of the published evidence preclude determining the effects of the technology on overall glycemic control as assessed by HbA1c and other parameters and thus, net health outcomes. 

Evidence reported through clinical input supports that the outcome of hypoglycemia prevention provides a clinically meaningful improvement in net health outcome, and this use is consistent with generally accepted medical practice. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. 

Patient selection criteria considering FDA label and inclusion criteria in the evidence include: age 14 and older; glycated hemoglobin level between 5.8% and 10.0%; used insulin pump therapy for more than 6 months; and at least 2 documented nocturnal hypoglycemic events in a 2-week period. 

Hybrid Closed-Loop Insulin Delivery Systems 
Clinical Context and Therapy Purpose 
The purpose of ahybrid closed-loop insulin delivery systemin patients who havetype 1 diabetesis to provide a treatment option that is an alternative to or an improvement on existing therapies. 

The question addressed in this evidence review is: Does the use of ahybrid closed-loop insulin delivery systemimprove the net health outcome for individuals with type 1 diabetes? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest is individuals withtype 1 diabetes. Persons with T1D are especially prone to develop hypoglycemia. Alterations in the counterregulatory hormonal responses inherent in the disease, variable patient adherence and iatrogenic hypoglycemia caused by aggressive prevention of hyperglycemia are responsible for this propensity. Hypoglycemia affects many aspects of cognitive function, including attention, memory, and psychomotor and spatial ability. Severe hypoglycemia can cause serious morbidity affecting the central nervous system (eg, coma, seizure, transient ischemic attack, stroke), heart (eg, cardiac arrhythmia, myocardial ischemia, infarction), eye (eg, vitreous hemorrhage, worsening of retinopathy), as well as cause hypothermia and accidents that may lead to injury. Fear of hypoglycemia symptoms can also cause decreased motivation to adhere strictly to intensive insulin treatment regimens. 

Interventions 
The therapy being considered is ahybrid closed-loop insulin delivery system. A hybrid closed-loop system continuously adjusts insulin delivery. However, at mealtime, the patient enters thenumberof carbohydrates being consumed in order for the insulin pump to determine the bolus meal dose of insulin. 

APDSareused by persons with Type1 diabetes when they have experienced hypoglycemic and/or hypoglycemic episodes that cannot be managed with intermittent self-monitoring of glucose and self-administration of insulin.These devices are used in “free-living” and home settings, with monitoring by primary care clinicians, diabetologists, and endocrinologists. 

Comparators 
The following therapies are currently being used to treat type 1 diabetes: anautomated insulin delivery system with LGS feature, nonintegrated CGM plus insulin pump (open-loop), or self-monitoring blood glucose and multiple dose insulintherapy. 

Outcomes 
The general outcomes of interest areHbA1clevels, time in range or target of glucose levels, and rates of hypoglycemia and hyperglycemia. Other outcomes of interest include quality of life and changes in health care utilization (eg, hospitalizations). The duration of follow-up is life-long. 

Prospective Studies 
Bergenstalet al(2016) published a prospective single-arm study on the safety of the hybrid closed-loop system in patients with type 1 diabetes.14,It included 124 patients ages 14-to-75 years old who had type 1 diabetes for at least2years, hadHbA1clevelsless than 10.0%, and who had used an insulin pump for at least6months. There was an initial run-in period at baseline for patients to learn how to use the device followed by a 3-month period of device use. The study period included a 6-day hotelstaywith a 1-day period of frequent sampling of venous blood glucose levels to verify device accuracy. The primary safetyend pointswere the incidence of severe hypoglycemia and diabetic ketoacidosis and the incidence of device-related and serious adverse events. 

There were no episodes of severe hypoglycemia or ketoacidosis during the study. A total of 28 device-related adverse events occurred, all of which couldbe resolvedat home. There were 4 serious adverse events, 1 case each of appendicitis, bacterial arthritis, worsening rheumatoid arthritis, andClostridiumdifficilediarrhea. There were alsoa number ofpredefined descriptiveend points(but no statistically powered efficacyend points). The device was in theclosed-loopmode for a median of 97% of the study period. Mean (SD)HbA1clevels were 7.4% (0.9%) at baseline and 6.9% (0.6%) at the end of the study, and the percentage of sensor glucose values within the target range was 66.7% at baseline and 72.2% at the end of the study. A related study in children is ongoing (NCT02660827). 

A multicenter pivotal trial published by Garget al(2017) evaluated the safety of Medtronic’s hybrid closed-loop system, using methods similar to those of Bergenstal et al (2016), (NCT02463097) and employing the same device (MiniMed 670G).15,Of 129 subjects, 124 completed the trial; 30 were adolescents (age range, 14-21 years) and 94 were adults (age range, 22-75 years), all of whom had type 1 diabetes for at least2yearsbeforethe study, and used insulin pump therapy for6months or more. As with Bergenstalet al (2016), a 3-month study period was preceded by a run-in period for subjects to be more familiar with the equipment, and the sensor glucose valueswere confirmedby an extended hotel stay (6-day/5-night with daily exercise).In both the adolescent and adult cohorts, the trial found improvements during the study phase over the run-in phase, with an increased percentage of glucose values in the favorable range (for adults, a mean improvement of 68.8% to 73.8%; for adolescents, a mean improvement of 60.4% to 67.2%; p<0.001 for both cohorts).Similarly, the authors reported a decrease in the percentage of values outside of the target range (<70 mg/dL or >180 mg/dL): for adults, time spent below the target range decreased from 6.4% to 3.4% (p<0.001); time above the range decreased from 24.9% to 22.8% (p=0.01). For both cohorts, HbA1clevels showed a significant reduction between baseline and the end of the study: for adults, the mean decreased from 7.3% to 6.8% (p<0.001), while for adolescents, the mean decreased from 7.7% to 7.1% (p<0.001). Secondary outcomes, which included a reduction of nocturnal hyperglycemia and hypoglycemia, increase in mean overall body weight, and a reduction of basal insulin, were favorable for the study phase, compared with the run-in phase; measurements from the hotel stay verified the in-home glucose values. However, there were several limitations in the trial, including its nonrandomized design, the exclusion of individuals who had recently experienced diabetic ketoacidosis or severe hypoglycemia, and the interaction between subjects and site personnel. Additionally, most of the adult cohort were already using CGM, and baseline HbA1clevels were lower than average for both cohorts; both baseline characteristics potentially limit the generalizability of the results. 

One type of hybrid insulin delivery system employs a predictive algorithm to keep the patient’s glucose levels within a specific range or zone, only increasing or decreasing insulin levels if the device detects that glucose levels are going to fall outside the defined zone. Forlenzaet al(2017) published a randomized controlled crossover trial comparing the efficacy of a zone model predictive control algorithm with that ofsensor-augmentedpump therapy; the trial included 20 subjects (19 completed), all with type 1 diabetes and having at least3months treatment with a subcutaneous insulin infusion pump.16,The six-week,in-homestudywas dividedinto 2-week blocks, with 2 randomized groups alternating treatment between an artificial pancreas system (DiAsweb monitoring) orsensor-augmentedpump therapy (Dexcom Share); subjects in both arms reported glucose values and, if applicable, sensor failure.For several primary endpoints, which included percentage of time in the target glucose range (70-180 mg/dL) and reduction in hypoglycemia (<70 mg/dL), the algorithm-controlled artificial pancreas system was found to be superior to the sensor-augmented pump therapy (71.6 vs 65.2%, p=0.008; 1.3 vs 2%, p= 0.001, respectively); however, while the mean glucose value was lower in the artificial pancreas system than in the control group, the difference between them was not significant (p=0.059).Measurements of nocturnal hypoglycemia were consistent with day-to-day findings. For the secondaryendpoint(safety of both systems after extended wear), the study found that the mean glucose did not change between the first and seventh day of wear. A limitation of the trial was its use of remote monitoring of subjects; also, the trialists noted that, given the marked difference in outcomes between responders and nonresponders, an errormighthave occurred in setting basal rates. 

The remainder of the review is focused on additional studies that recently evaluated hybrid closed-loop (HCL) systems in children and adolescents with T1D. These studies are summarized in Tables 3 and 4. 

The RCT by Tauschman, et al (2018) evaluated individuals with uncontrolled T1D as reflected in mean Hb1c >8 %. Approximately, 50% of the subjects were between 6-21 years of age and 25% are 6-12 years old. Both groups achieved a reduction in HbA1c but were statistically greater in the HCL group compared to the control group. The investigators reported that the HbA1c improvements were not different among children, adolescents, and adults (data not shown in tables). No severe hypoglycemic events were reported consistent with a decrease in time spent with glucose <70mg/dl. 

Abraham et al (2018) reported the results of a 6 -month, multicenter, RCT in children and adolescents with T1D comparing use of an insulin pump with suspend before low or predictive low-glucose management (PLGM) with sensor-augmented insulin pump therapy (SAPT) alone. At 6 months, significant reductions were seen in day and night hypoglycemia and number of hypoglycemic events <63mg/dl lasting longer than 20 minutes. There were no differences in HbA1c at 6 months in either group. 

Forlenza et al (2019) reported the data and analysis of the supplemental information filed with the FDA to support the expanded indication for the MiniMed 670G system to children 7-13 years of age. The nonrandomized, single-arm multicenter study reported the day and night use of the automated insulin delivery and PLGM for 3 months in the home setting. There were no serious adverse events and use of the system was associated with reduction in HbA1c and increased time in target glucose range. 

Wood et al (2018) reported an in-clinic evaluation of a 7-13-year-old cohort ofthe 670G pivotal trial that was designed to evaluate the performance characteristics of the device when activity induced hypoglycemic patterns were used to set individual device parameters for ongoing use by the study participant. The suspend before low prevention capability was confirmed in 97.5% of patients experiencing a sensor glucose of ≤ 55mg/dl. 

Messer et al (2018) reported on a subanalysis of the adolescent and young adult participants in the 670G pivotal trial to better characterize the carbohydrate input and insulin bolus determination features of the device over a 3- month period. Participants successfully utilized the device without significant changes in total daily dose of insulin but improved percentage time in range (70-180 mg/dl). 

Table 3. Summary of Key Study Characteristics: HCL in T1D Children and Adolescents 

Study; Trial

Countries

Sites

Dates

Participants

Intervention Study Type

       

N

Age

Mean (SD)

   

Tauschmann (2018)17,

UK, US

6

05/12/2016-11/17/2017

86

>6 years

[6-12 years; n=23]

[13-21 years; n=19]

MiniMed

640G2

HCL

RCT

Intervention: SAPT with PLGM (n=46)

Screening HbA1c %(SD)

8.3( 0.6)

Control:

SAPT alone (n=40)

Screening HbA1c

%(SD)

8.5 (0.5)

Abraham (2018)18,

Australia

5

8/2014-NR

154

8-20 years

13.2(2.8)

MiniMed

640G2

HCL

RCT

Intervention: SAPT with PLGM (n=80)

Control:

SAPT alone (n=74)

Forlenza (2019)1

NCT0266082719,

US, Israel

9

4/18/2016-10/09/2017

105

7-13 years

10.8 (1.8)

MiniMed 670G3

HCL

Noncomparative pivotal trial

Wood (2018)1

(NCT02660827)20,

US, Israel

9

4/18/2016-10/09/2017

105

7-13 years

10.8 (1.8)

MiniMed 670G3

HCL

12-hour clinic evaluation of PLGM performance in conjunction with exercise4

Messer (2018)

(NCT02463097)20,

US

3

2015-2018

31

14-26

17.8 (3.9)

MiniMed 670G3

HCL

Sub-study of FDA pivotal trial for device: insulin delivery characteristics and time in range

HCL: hybrid closed loop; FDA: Food and Drug Administration; PLGM: predictive low glucose suspend (suspend before low); PMA: premarket approval; RCT: randomized controlled trial; SAPT: sensor-augmented pump therapy; SD: standard deviation; NR: not reported; T1D: type 1 diabetes.
Data as submitted for FDA PMA Supplement P160017/S031.
MiniMed 640G is hybrid closed loop device approved for use outside of US.
MiniMed 670G is hybrid closed loop device approved for use in US.
Activity/exercise induced hypoglycemia protocol (walking, biking, playing Wii games, or other aerobic activities) intended to activate the “suspend before low” feature followed by evaluation up to 6 hours and at least 4 hours after insulin resumption.

Table 4. Summary of Key Study Results: HCL in T1D Children and Adolescents

Study

Primary Outcome

Primary Outcome

Secondary Outcome

Safety Outcome

Safety Outcome

Tauschmann(2018)17,

Group difference in time proportion in target glucose range (70-180md/dL) at 12 weeks

Mean (SD)

   

Hypoglycemia

A. <63mg/dl

B. <50mg/dl

Percent time in given range (SD)

 

SAPT with PLGM

SAPT alone

Difference

[95% CI]

P 

SAPT with PLGM

SAPT alone 

Difference

[95% CI]

P

 

 

68% (8)

54% (9)

10.8

[8.2,13.5]

<0.0001

 

HbA1c %(SD)

At 12 weeks 

7.4(0.6) 

7.7(0.5) 

-0.36

[-0.53, -0.19]

<0.0001

A.

1.4 (0.9, 1.9)

2.0 (0.9,3.0)

-0.83

[-1.4,-0.16]

0.0130

B.

0.3 (0.2, 0.6)

0.5 (0.2, 0.9)

-0.09

[-0.24, 0.01]

0.08 

 

Abraham(2018)18,

Change in average percent time in hypoglycemia (SG <63mg/dl) at 6 months

Change in average percent time in hypoglycemia (SG <54mg/dl) at 6 months

HbA1c

Mean %(SD)

Hypoglycemic events

(SG <63mg/dl for >20 minutes)

Events per patient-year

IAH2

(%) Clarke score≥4

N=90 (≥12 years)

SAPT with PLGM

n=76

2.8%âˆ������������ 1.4%

n=76

1.3%âˆ������������ 0.6%

7.5(0.8)������������ 7.8(0.8)

139

4%

SAPT alone

 

n=70

3%âˆ������������ 2.6%

n =70

1.4%âˆ������������ 1.2%

7.4(0.7) ������������ 7.6(1.0)

227

13%

Difference in LS means

[95% CI]

p

-0.95%

[-1.30, -0.61]

 <0.0001

-0.44%

[-0.64, -0.24]

<0.0001

0.09

[-0.10, 0.27]

=0.35

[221,234 vs 134,143]

<0.001

-.04

[-0.52,0.43]

0.86

Forlenza(2019)1

NCT0266082719, 

Baseline

Run-in phase

(n=106) 

3-month study phase

(n=105) 

P 

Baseline

Run-in phase

(n=106) 

3-month study phase

(n=105)

P

Baseline

Run-in phase

(n=106)

3-month study phase

(n=105)

p

 

HbA1c

Mean % (SD) 

7.9 (0.8)

7.5 (0.6) 

<0.001

 

 

Time in Range

(>70-180)

Mean %(SD) 

56.2(11.4) 

65 (7.7) 

<0.001

 

 

 

 

Hypogylcemia

A.

≤70mg/dl

B.

≤54mg/dl

Mean %(SD) 

A.≤70mg/dl

4.7(3.8) 

3.0 (1.6) 

<0.001 

B.≤54 mg/dl

1.3 (1.5)

0.8 (0.7)

<0.001 

 

Wood(2018)1

(NCT0266087)20, 

Reference range3 

≤55 mg/dl

≤60 mg/dl

≤65 mg/dl

 

N=79 participant activations of suspend before low 

Rate of “Suspend before Low” (%)

77 (97.5)

71 (89.9)

63 (79.7)

 

 

       

Messer(2018)1(NCT02463097)20, 

Days 1-7

Days 22-28

Days 50-56

Days 78-84

Mean percentage time in range (70-180 mg/dl) using HCL mode4

Mean % (SD)

69.7 (10.6)

69.5 (8.5)

71.9 (8.1)

71.5 (10.3)

       

CI: confidence interval; HCL: hybrid closed loop; IAH: impaired awareness of hypoglycemia; LS: least squares; PLGM: predictive low glucose suspend (suspend before low); SD: standard deviation; SAPT: sensor-augmented pump therapy; SG: sensor glucose; ������������ : delta meaning change in status; T1D: type 1 diabetes.
Data as submitted for FDA PMA Supplement P160017/S031.
Clarke score:uses 8 questions to characterize an individual's exposure to episodes of moderate and severe hypoglycemia to assess the glycemic threshold for and symptomatic response to hypoglycemia. A value ≥ 4 indicates IAH.
Simultaneous testing with either intravenous sampling or self-monitoring blood glucometer.
Open loop manual mode was used in a run-in phase to develop personalized parameters for HCL/Auto Mode phase.

Section Summary: Hybrid Closed-Loop Insulin Delivery Systems
For individuals who have T1D who receive an artificial pancreas device system with a hybrid closed-loop insulin delivery system, the evidence includesmulticenter pivotaltrials using devices cleared by the Food and Drug Administration, supplemental data and analysis for expanded indications and more recent studies focused on children and adolescents. Three crossover RCTs using a similar first- generation device approved outside the United States have been reported. Relevant outcomes are symptoms, change in disease status, morbid events, resource utilization, and treatment-related morbidity.Of the three crossover RCTs assessing a related device conducted outside the United States, two found significantly better outcomes (ie, time spent in nocturnal hypoglycemia and time spent in preferred glycemic range) with the device than with standard care and the other had mixed findings (significant difference in time spent in nocturnal hypoglycemia and no significant difference in time spent in preferred glycemic range).For the U.S. regulatory registration pivotal trial, the primary outcomes were safety and not efficacy. Additional evidence from device performance studies and clinical studies all demonstrate reductions in time spent in various levels of hypoglycemia, improved time in range (70-180mg/dl), rare diabetic ketoacidosis and few device-related adverse events. The evidence is sufficient that the magnitude of reduction for hypoglycemic events in the T1D population is likely to be clinically significant. The variations in the definition of primary and secondary outcomes in the study design and conduct of the published evidence are limitations that preclude determining the effects of the technology on net health outcomes. Evidence reported through clinical input supports that the use of hybrid closed loop APDS systems provides a clinically meaningful improvement in net health outcome and is consistent with generally accepted medical practice. Reduction in the experience of hypoglycemia and inappropriate awareness of hypoglycemia and glycemic excursions were identified as important acute clinical outcomes in children, adolescents, and adults and are related to the future risk for end-organ complications. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Patient selection criteria considering the FDA label and inclusion criteria in the evidence include: age seven and older; glycated hemoglobin level between 5.8% and 10.0%; used insulin pump therapy for more than six months, and at least two documented nocturnal hypoglycemic events in a two-week period.

Summary of Evidence
The following conclusions are based on a review of the evidence, including but not limited to, published evidence and clinical expert opinion, solicited via BCBSA’s Clinical Input Process.

For individuals who have type 1 diabetes (T1D) who receive an artificial pancreas device system with a low-glucose suspend feature, the evidence includestworandomized controlled trials (RCTs) conducted in home settings. Relevant outcomes are symptoms, change in disease status, morbid events, resource utilization, and treatment-related morbidity.Primary eligibility criteria of the key RCT, theAutomation to Simulate Pancreatic Insulin Response (ASPIRE) trial, wereages 16-to-70 years old,T1D , glycated hemoglobin levels between 5.8% and 10.0%, and at least 2 nocturnal hypoglycemic events (≤65 mg/dL) lasting more than 20 minutes during a 2-week run-in phase.Both trials required at least six months of insulin pump use. Both RCTs reported significantly less hypoglycemia in the treatment group than in the control group. In both trials, primary outcomes were favorable for the group using an artificial pancreas system; however, findings fromonetrialwere limitedby nonstandard reporting of hypoglycemic episodes, and findings from the other trial were no longer statistically significant when two outliers (children)were excludedfrom analysis.The RCT limited to adults showed an improvement in the primary outcome (area under the curve for nocturnal hypoglycemic events). The area under the curveis not usedfor assessment in clinicalpractice but the current technology does allow user and provider review of similar trend data withcontinuous glucose monitoring.Results from the ASPIRE study suggested that there were increased risks of hyperglycemia and potential diabetic ketoacidosis in subjects using the threshold suspend feature. This finding may be related to whether or not actions are taken by the user to assess glycemic status, etiology of the low glucose (activity, diet or medication) and to resume insulin infusion. Both retrospective and prospective observational studies have reported reductions in rates and severity of hypoglycemic episodes in automated insulin delivery system users.The evidence is sufficient that the magnitude of reduction for hypoglycemic events in the T1D population is likely to be clinically significant. Limitations of the published evidence preclude determining the effects of the technology on overall glycemic control as assessed by HbA1c and other parameters and thus, net health outcomes. Evidence reported through clinical input supports that the outcome of hypoglycemia prevention provides a clinically meaningful improvement in net health outcome, and this use is consistent with generally accepted medical practice. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have T1D who receive an artificial pancreas device system with a hybrid closed-loop insulin delivery system, the evidence includesmulticenter pivotaltrials using devices cleared by the Food and Drug Administration, supplemental data and analysis for expanded indications and more recent studies focused on children and adolescents. Three crossover RCTs using a similar first- generation device approved outside the United States have been reported. Relevant outcomes are symptoms, change in disease status, morbid events, resource utilization, and treatment-related morbidity.Of the three crossover RCTs assessing a related device conducted outside the United States, two found significantly better outcomes (ie, time spent in nocturnal hypoglycemia and time spent in preferred glycemic range) with the device than with standard care and the other had mixed findings (significant difference in time spent in nocturnal hypoglycemia and no significant difference in time spent in preferred glycemic range).For the U.S. regulatory registration pivotal trial, the primary outcomes were safety and not efficacy. Additional evidence from device performance studies and clinical studies all demonstrate reductions in time spent in various levels of hypoglycemia, improved time in range (70-180mg/dl), rare diabetic ketoacidosis and few device-related adverse events. The evidence is sufficient that the magnitude of reduction for hypoglycemic events in the T1D population is likely to be clinically significant. The variations in the definition of primary and secondary outcomes in the study design and conduct of the published evidence are limitations that preclude determining the effects of the technology on net health outcomes. Evidence reported through clinical input supports that the use of hybrid closed loop APDS systems provides a clinically meaningful improvement in net health outcome and is consistent with generally accepted medical practice. Reduction in the experience of hypoglycemia and inappropriate awareness of hypoglycemia and glycemic excursions were identified as important acute clinical outcomes in children, adolescents, and adults and are related to the future risk for end-organ complications. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Clinical Input
CI - Objective
In 2019, clinical input was sought to help determine whether the use of an artificial pancreas device system with a hybrid closed-loop insulin delivery system for individuals with type 1 diabetes would provide a clinically meaningful improvement in net health outcome and whether the use is consistent with generally accepted medical practice.

Respondents
Clinical input was provided by the following specialty societies and physician members identified by a specialty society or clinical health system:

  • Chaitanya Mamillapalli, MD, MRCP, FAPCR, Endocrinology, Springfield Clinic, identified by American Association of Clinical Endocrinologists (AACE)
  • Javier Morales, MD, FACP, FACE, Diabetology, Advanced Internal Medicine Group, PC, identified by American Association of Clinical Endocrinologists (AACE)
  • Vijay Shivaswamy, MBBS, Endocrinology, The University of Nebraska Medical Center and Omaha VA Medical Center, identified byAmerican Association of Clinical Endocrinologists (AACE)
  • Anonymous, MD, Pediatric Endocrine, identified by the American Academy of Pediatrics (AAP)**

* Indicates that no response was provided regarding conflicts of interest related to the topic where clinical input is being sought.

** Indicates that conflicts of interest related to the topic where clinical input is being sought were identified by this respondent (see Appendix).

Clinical input provided by the specialty society at an aggregate level is attributed to the specialty society. Clinical input provided by a physician member designated by a specialty society or health system is attributed to the individual physician and is not a statement from the specialty society or health system. Specialty society and physician respondents participating in the Evidence Street® clinical input process provide a review, input, and feedback on topics being evaluated by Evidence Street. However, participation in the clinical input process by a specialty society and/or physician member designated by a specialty society or health system does not imply an endorsement or explicit agreement with the Evidence Opinion published by BCBSA or any Blue Plan.

Clinical Input Responses

 

* Indicates that no response was provided regarding conflicts of interest related to the topic where clinical input is being sought.

** Indicates that conflicts of interest related to the topic where clinical input is being sought were identified by this respondent (see Appendix).

Additional comments:

  • “Part of the challenges managing diabetics with full physiologic replacement, such as those with type 1 diabetes, includes trying to manage glycemic excursions and minimizing significant hypoglycemia from occurring.From a physiologic standpoint, in patients who have experienced hypoglycemia, hygolycemia unawareness continues to exist further propagating additional hypoglycemic events. Such events could lead to sudden catastrophe and cardiac death on the basis of electrolyte shifts that have been noted in several different studies. In addition, glycemic swings could also account for microvascular complications and progression of the such.” (Dr. Morales, identified by AACE)

See Appendix for additional responses.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2019
In response to requests, while this topic was under review in 2019, clinical input on theuse of an artificial pancreas device system with a hybrid closed-loop insulin delivery system for individuals with type 1 diabeteswas received from 4 respondents, including 4 physician-level responses identified through 2 specialty societies including physicians with academic medical center affiliations. Evidence from clinical input is integrated within the Rationale section summaries and the Summary of Evidence.

2015
In response to requests, input on artificial pancreas device systems was received from 2 physician specialty societies and 4 academic medical centers when the policy was under review in 2015. Input was mixed on whether artificial pancreas systems, including closed-loop monitoring devices with a low-glucose suspend threshold feature, are considered medically necessary. Most reviewers thought there are sufficient supportive data on devices with a low-glucose suspend feature in patients at high risk of hypoglycemia, but some thought the data insufficient.

Practice Guidelines and Position Statements
American Diabetes Association
TheAmericanDiabetes Association has released multiple publications on controlling type 1 diabetes (see Table 5).

Table 5. Recommendations on Diabetes

Date

Title

Publication Type

Recommendation

LOE

2019 Standards of Medical Care in Diabetes Guideline standard Automated insulin delivery systems may be considered in children (>7 years) and adults with type 1 diabetes to improve glycemic control. B

2017

Standardizing Clinically Meaningful Outcome Measures Beyond HbA1c for Type 1 Diabetes

Consensus report21,,a

Developed definitions for hypoglycemia, hyperglycemia, time in range, and diabetic ketoacidosis in type 1 diabetes

N/A

HbA1c: hemoglobin A1c;LOE: Level of Evidence.
a  Jointly published withtheAmerican Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange.

American Association of Clinical Endocrinologists et al
The American Association of Clinical Endocrinologists and American College of Endocrinology (2018) published a joint position statement on the integration of insulin pumps and continuous glucose monitoring in patients with diabetes.22,The statement emphasized the use of continuous glucose monitoring and insulin pump therapy for type 1 diabetes patients who are not in glycemic target ranges despite intensive attempts at self-blood glucose monitoring and multiple insulin injection therapy.

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this revieware listedin Table 6.

Table 6. Summary of Key Trials

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

     

NCT02748018

Multi-center, Randomized, Parallel, Adaptive, Controlled Trial in Adult and Pediatric Patients With Type 1 Diabetes Using Hybrid Closed Loop System and Control (CSII, MDI, and SAP) at Home

1,500

Dec 2021

NCT03859401

Hypoglycemia Prevention During and After Moderate Exercise in Adults With Type 1 Diabetes Using anArtificial Pancreas With Exercise Behavior Recognition

33

Dec 2019

NCT02733211

An Open-label, Two-center, Randomized, Cross-over Study to Evaluate the Safety and Efficacy of Night Closed-loop Control Using the MD-LogicAutomated Insulin Delivery SystemCompared to Sensor Augmented Pump Therapy in Poorly Controlled Patients With Type 1 Diabetes at Home

28

Dec 2019

NCT03739099

Assessment of the Efficacy of Closed-loop Insulin Therapy (Artificial Pancreas) on the Control of Type 1 Diabetes in Prepubertal Child in Free-life: Comparison Between Nocturnal and 24-hour Use on 18 Weeks, Followed by an Extension on 18 Weeks

120

Sep 2020

NCT03844789a

The International Diabetes Closed Loop (iDCL) Trial: Clinical Acceptance of theArtificial Pancreas in Pediatrics: A Study of t:Slim X2 With Control-IQ Technology

101

Mar 2020

NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial. 

 References 

  1. Agiostratidou G, Anhalt H, Ball D, et al. Standardizing clinically meaningful outcome measures beyond HbA1c for type 1 diabetes: A Consensus Report of the American Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange. Diabetes Care. Dec 2017;40(12):1622-1630. PMID 29162582.
  2. American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in Diabetes-2019. Diabetes Care. Jan 2019;42(Suppl 1):S61-s70. PMID 30559232.
  3. Abraham MB, Jones TW, Naranjo D, et al. ISPAD Clinical Practice Consensus Guidelines 2018: Assessment and management of hypoglycemia in children and adolescents with diabetes. Pediatr Diabetes. Oct 2018;19 Suppl 27:178-192. PMID 29869358.
  4. Food and Drug Administration (FDA). Guidance for Industry and Food and Drug Administration Staff: The Content of Investigational Device Exemption (IDE) and Premarket Approval (PMA) Applications for Artificial Pancreas Device Systems [draft]. 2012; https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM259305.pdf. Accessed October 31, 2018.
  5. Food and Drug Administration (FDA). Premarket Approval (PMA): MINIMED 530G SYSTEM. 2013; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P120010. Accessed October 31, 2018.
  6. Food and Drug Administration (FDA). Premarket Approval (PMA): MINIMED 630G SYSTEM WITH SMARTGUARD(TM). 2016; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?ID=320606. Accessed October 31, 2018.
  7. Food and Drug Administration (FDA). Premarket Approval (PMA): MiniMed 670G System. 2016; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P160017. Accessed October 31, 2018.
  8. Blue Cross and Blue Shield Technology Evaluation Center (TEC). Artificial Pancreas Device Systems. TEC Assessments. 2013;Volume 28:Tab 14. PMID.
  9. Bergenstal RM, Klonoff DC, Garg SK, et al. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med. Jul 18 2013;369(3):224-232. PMID 23789889.
  10. Garg S, Brazg RL, Bailey TS, et al. Reduction in duration of hypoglycemia by automatic suspension of insulin delivery: the in-clinic ASPIRE study. Diabetes Technol Ther. Mar 2012;14(3):205-209. PMID 22316089.
  11. Ly TT, Nicholas JA, Retterath A, et al. Effect of sensor-augmented insulin pump therapy and automated insulin suspension vs standard insulin pump therapy on hypoglycemia in patients with type 1 diabetes: a randomized clinical trial. JAMA. Sep 25 2013;310(12):1240-1247. PMID 24065010.
  12. Agrawal P, Zhong A, Welsh JB, et al. Retrospective analysis of the real-world use of the threshold suspend feature of sensor-augmented insulin pumps. Diabetes Technol Ther. May 2015;17(5):316-319. PMID 25611577.
  13. Gomez AM, Marin Carrillo LF, Munoz Velandia OM, et al. Long-term efficacy and safety of sensor augmented insulin pump therapy with low-glucose suspend feature in patients with type 1 diabetes. Diabetes Technol Ther. Feb 2017;19(2):109-114. PMID 28001445.
  14. Bergenstal RM, Garg S, Weinzimer SA, et al. Safety of a hybrid closed-loop insulin delivery system in patients with type 1 diabetes. JAMA. Oct 4 2016;316(13):1407-1408. PMID 27629148.
  15. Garg SK, Weinzimer SA, Tamborlane WV, et al. Glucose outcomes with the in-home use of a hybrid closed-loop insulin delivery system in adolescents and adults with type 1 diabetes. Diabetes Technol Ther. Mar 2017;19(3):155-163. PMID 28134564.
  16. Forlenza GP, Deshpande S, Ly TT, et al. Application of zone model predictive control artificial pancreas during extended use of infusion set and sensor: a randomized crossover-controlled home-use trial. Diabetes Care. Aug 2017;40(8):1096-1102. PMID 28584075.
  17. Tauschmann M, Thabit H, Bally L, et al. Closed-loop insulin delivery in suboptimally controlled type 1 diabetes: a multicentre, 12-week randomised trial. Lancet. Oct 13 2018;392(10155):1321-1329. PMID 30292578.
  18. Abraham MB, Nicholas JA, Smith GJ, et al. Reduction in Hypoglycemia With the Predictive Low-Glucose Management System: A Long-term Randomized Controlled Trial in Adolescents With Type 1 Diabetes. Diabetes Care. Feb 2018;41(2):303-310. PMID 29191844.
  19. Forlenza GP, Pinhas-Hamiel O, Liljenquist DR, et al. Safety Evaluation of the MiniMed 670G System in Children 7-13 Years of Age with Type 1 Diabetes. Diabetes Technol Ther. Jan 2019;21(1):11-19. PMID 30585770.
  20. Wood MA, Shulman DI, Forlenza GP, et al. In-Clinic Evaluation of the MiniMed 670G System "Suspend Before Low" Feature in Children with Type 1 Diabetes. Diabetes Technol Ther. Nov 2018;20(11):731-737. PMID 30299976
  21. Messer LH, Forlenza GP, Sherr JL, et al. Optimizing Hybrid Closed-Loop Therapy in Adolescents and Emerging Adults Using the MiniMed 670G System. Diabetes Care. Apr 2018;41(4):789-796. PMID 29444895.
  22. American Diabetes Association. 7. Diabetes Technology: Standards of Medical Care in Diabetes-2019. Diabetes Care. Jan 2019;42(Suppl 1):S71-s80. PMID 30559233. 

Coding Section 

Codes Number Description
CPT 95920 Ambulatory continuous glucose monitoring of interstitial tissue fluid via subcutaneous sensor for a minimum of 72 hours; sensor placement, hook-up, calibration of monitor, patient training, removal of sensor, and printout of recording
  95251 ; physician interpretation and report
ICD-9 Procedure    
ICD-9 Diagnosis 250.00-250.93 Diabetes mellitus range of codes
HCPCS  S1034 Artificial pancreas device system (eg, low glucose suspend (LGS) feature) including continuous glucose monitor, blood glucose device, insulin pump and computer algorithm that communicates with all of the devices
  S1035 Sensor; invasive (eg, subcutaneous), disposable, for use with artificial pancreas device system, 1 unit = 1 day supply
  S1036 Transmitter; external, for use with artificial pancreas device system
  S1037 Receiver (monitor); external, for use with artificial pancreas device system
ICD-10-CM (effective 10/01/15) E10.10-E13.9 Diabetes mellitus code range
ICD-10-PCS (effective 10/01/15)   ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this monitoring
Type of Service Medicine  
Place of Service Outpatient  

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

02/10/2020 

Annual review, no change to policy intent. updating background, regulatory status, rationale and references. 

02/21/2019 

Annual review, no change to policy intent. Updating regulatory status. 

02/27/2018 

Annual review. Expanding investigational statement to include: Use of hybrid closed loop insulin delivery system (including the Food and Drug Administration approved device for age 14 and older) as an artificial pancreas device system is considered INVESTIGATIONAL.". Also updating background, description, regulatory status, rationale and references. 

02/02/2017 

Annual review, no change to policy intent. Updating background, description, regulatory status, rationale and references.

02/01/2016 

Annual review, no change to policy intent. Updated background, description, guidelines, rationale, references and coding. 

04/27/2015 

Added additional coding: E0784, A9276, and A9277 , no other changes.

02/05/2015

New Policy


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