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Horizon BCBSNJ
Uniform Medical Policy ManualSection:D M E
Policy Number:045
Effective Date: 07/14/2020
Original Policy Date:02/24/2015
Last Review Date:07/14/2020
Date Published to Web: 03/02/2017
Subject:
Artificial Pancreas Device Systems

Description:
_______________________________________________________________________________________

IMPORTANT NOTE:

The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.

Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.

__________________________________________________________________________________________________________________________

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

PopulationsInterventionsComparatorsOutcomes
Individuals:
    • With type 1 diabetes
Interventions of interest are:
    • Artificial pancreas device system with a low-glucose suspend feature
Comparators of interest are:
    • Nonintegrated continuous glucose monitoring plus insulin pump
    • Self-monitoring blood glucose and multiple dose insulin injection therapy
Relevant outcomes include:
    • Symptoms
    • Change in disease status
    • Morbid events
    • Resource utilization
    • Treatment-related morbidity
Individuals:
    • With type 1 diabetes
Interventions of interest are:
    • Artificial pancreas device system with a hybrid closed-loop insulin delivery system
Comparators of interest are:
    • Artificial pancreas device system with low-glucose suspend feature
    • Nonintegrated continuous glucose monitoring plus insulin pump
    • Self-monitoring blood glucose and multiple dose insulin injection therapy
Relevant outcomes include:
    • Symptoms
    • Change in disease status
    • Morbid events
    • Resource utilization
    • Treatment-related morbidity

BACKGROUND

Diabetes and Glycemic Control

Tight glucose control in patients with diabetes has been associated with 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 on a number of factors including the glucose nadir, the presence of 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.

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

Table 1. Outcome Measures for Type 1 Diabetes
MeasureDefinitionGuideline typeOrganizationDate
HypoglycemiaStakeholder survey, expert opinion with evidence reviewType 1 Diabetes Outcome Programa1,2017
Level 1
Level 2
Level 3
Glucose < 70m g/dl but ≥ 54 mg/dl
Glucose < 54 mg/dl
Event characterized by altered mental/physical status requiring assistance
HypoglycemiaSame as Type 1 Diabetes Outcome ProgramaProfessional Practice Committee with systematic literature reviewADA 2,2019
Hypoglycemia
Clinical alert for evaluation and/or treatment
Clinically important or serious
Severe hypoglycemia

Glucose < 70 mg/dl
Glucose < 54 mg/dl
Severe cognitive impairment requiring external assistance by another person to take corrective action
Clinical Practice ConsensusISPAD 3,2018
Hyperglycemia
Level 1
Level 2

Glucose > 180 mg/dL and ≤250 mg/dL
Glucose > 250 mg/dL
Type 1 Diabetes Outcome Programa4,2017
Time in RangebPercentage of glucose readings in the range of 70–180 mg/dL per unit of time
Type 1 Diabetes Outcome Programa2017
Diabetic ketoacidosis (DKA)Elevated serum or urine ketones > ULN
Serum bicarbonate <15 mEq/L
Blood pH <7.3
Type 1 Diabetes Outcome Programa2,2017
ADA: American Diabetes Association, ISPAD: International Society for Pediatric and Adolescent Diabetes; ULN: upper limit of normal.
a
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, type 1 diabetes Exchange.
b
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 is insulin 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 component of diabetes self-management is specifically addressed in a separate policy on 'Continuous or Intermittent Monitoring of Glucose in the Interstitial Fluid' (Policy #009 in the DME Section).

Restoration of pancreatic function is potentially available through islet cell or allogeneic pancreas transplantation. Please refer to separate policies on 'Allogeneic Pancreas Transplant' (Policy #088 in the Surgery Section) and 'Islet Transplantation' (Policy #091 in the Surgery Section).

Regulatory Status

The U.S. Food and Drug Administration (FDA) describes the basic design of an artificial pancreas device system as a continuous glucose monitoring linked to an insulin pump with the capability to automatically stop, reduce, or increase insulin infusion based on specified thresholds of measured interstitial glucose.5,

The artificial pancreas device system 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 artificial pancreas device system control algorithm is embedded in software in an external processor or controller that receives information from the continuous glucose monitoring and performs a series of mathematical calculations. Based on these calculations, the controller sends dosing instructions to the infusion pump.

Different artificial pancreas device system types are currently available for clinical use. Sensor augmented pump therapy with low glucose suspend (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 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 (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 continuous glucose monitoring 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 continuous glucose monitoring 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 continuous glucose monitoring). 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 artificial pancreas device system 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 the number of carbohydrates they are eating in order for the insulin pump to determine the bolus meal dose of insulin. A hybrid system option with the patient administration of a premeal or partial premeal insulin bolus can be used in either control-to-range or control-to-target systems.

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 670G Systemc (HCL, LGS or PLGM)
≥14 y
≥7-13 y
Medtronic
Sep 2016
Jul 2018
P160017/OZP
P160017/S031
t:slim X2 Insulin Pump with Basal-IQ Technology (LGS)6,
>6 y
Tandem
Jun 2018
P180008/OZO, PQF
t:slim X2 Insulin Pump with Control-IQ Technology (HCL)
>6y
Tandem
Dec 2019
DEN180058/QFG
FDA: U.S. Food and Drug Administration; LGS: low glucose suspend; OZO: Artificial Pancreas Device System, threshold suspend; OZP: Automated Insulin Dosing Device System, Single Hormonal Control; PMA: premarket approval; PLGM: predictive low glucose management.
a
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).
b
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).
c
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 low glucose suspend feature.7, The threshold suspend tool 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.8,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 the values provided 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 on Low alarm 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.9,The system includes a low glucose suspend 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 continuous glucose monitoring 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.5,

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.10, The System consists of the t:slim X2 Insulin Pump paired with the Dexcom G5 Mobile Continuous Glucose Monitoring, 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 continuous glucose monitoring. The t:slim X2 Insulin Pump running the Basal-IQ Technology can be used to suspend insulin delivery based on continuous glucose monitoring sensor readings.

In December 2019, FDA approved the t:slim X2 Insulin Pump with Control-IQ Technology through the De Novo process.11, The device uses the same pump hardware as the insulin pump component of the systems approved in t:slim X2 Insulin Pump with Basal-IQ Technology (P180008) and P140015. A custom disposable cartridge is motor-driven to deliver patient programmed basal rates and boluses through an infusion set into subcutaneous tissue.

Related Policies

  • Continuous or Intermittent Monitoring of Glucose in the Interstitial Fluid (Policy #009 in the DME Section)
  • Allogeneic Pancreas Transplant (Policy #088 in the Surgery Section)
  • Islet Transplantation (Policy #091 in the Surgery Section)

Policy:
(NOTE: For Medicare Advantage, Medicaid and FIDE-SNP, please refer to the Coverage Sections below for coverage guidance.)


I. Use of a U.S. Food and Drug Administration approved automated insulin delivery system (artificial pancreas device system) with a low-glucose suspend feature is considered medically necessary in members with insulin dependent diabetes who meet all of the following criteria:

    • Age 6 years and older
    • Glycated hemoglobin level 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.
II. Use of a U.S. Food and Drug Administration approved automated insulin delivery system (artificial pancreas device system) designated as hybrid closed-loop insulin delivery system (with a low-glucose suspend and suspend before low features) is considered medically necessary in members with insulin dependent diabetes who meet all of the following criteria:
    • Age 6 years and older
    • Glycated hemoglobin level 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.

III. In pump naive members, use of a U.S. FDA-approved automated insulin delivery system with a low-glucose suspend feature, or a hybrid closed loop insulin delivery system is also considered medically necessary if the member meets all of the criteria for an insulin pump and a continuous glucose monitoring system (CGMS).

    (NOTE: Please refer to separate policies on 'Insulin Infusion Pumps' [Policy #016 in the DME section] and 'Continuous or Intermittent Monitoring of Glucose in the Interstitial Fluid' [Policy #009 in the DME section].)

IV. Use of an automated insulin delivery system (artificial pancreas device system) is considered investigational for members who do not meet the above criteria.

V. Use of an automated insulin delivery system (artificial pancreas device system) not approved by the FDA is investigational.


Medicare Coverage:
Per Noridian Healthcare Solutions, LLC , LCD L33794, HCPCS code E0787 is an external ambulatory insulin infusion pump, with dose rate adjustment using therapeutic continuous glucose sensing. Coverage for HCPCS code E0787 is only met if the beneficiary meets all the coverage criteria for insulin pumps outlined in LCD L33794 and all criteria for a therapeutic Continuous Glucose Monitor (CGM) as outlined in the Noridian Healthcare Solutions, LLC , Glucose Monitor policy (LCD L33822).

For additional information and eligibility, refer to the below LCDs and Articles:

Local Coverage Determination (LCD): External Infusion Pumps (L33794)

Local Coverage Determination (LCD):Glucose Monitors (L33822)

Local Coverage Article:Glucose Monitor - Policy Article (A52464)

FUTURE Local Coverage Determination (LCD):External Infusion Pumps (L33794)

FUTURE Local Coverage Article:E xternal Infusion Pumps - Policy Article (A52507) effective 5/31/20

Local Coverage Article: Standard Documentation Requirements for All Claims Submitted to DME MACs (A55426)

LCDS and Articles: Available to be accessed at Noridian Healthcare Services, LLC, (DME MAC), Local Coverage Determinations (LCDs) search page: https://www.cms.gov/medicare-coverage-database/indexes/lcd-list.aspx?Cntrctr=389&ContrVer=1&CntrctrSelected=389*1&s=38&DocType=1&bc=AAgAAAAAAAAA&#aFinal.

Per NCD 40.3, use of the closed loop blood glucose device (CBGCD) is covered for short-term management of insulin dependent diabetics in crisis situations, in a hospital inpatient setting, and only under the direction of specially trained medical personnel. For additional information and eligibility, refer to National Coverage Determination (NCD) for Closed-Loop Blood Glucose Control Device (CBGCD) (40.3). Available at: https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=92&ncdver=1&bc=AAAAQAAAAAAA&

Medicaid Coverage:

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP Coverage:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.



Policy Guidelines: (Information to guide medical necessity determination based on the criteria contained within the policy statements above.)

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.


[RATIONALE: This policy was created in 2015 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through March 5, 2020.

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.

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 function¾including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the 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 use 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.12,This policy addresses artificial pancreas devices that have been approved by the U.S. Food and Drug Administration.

Low-Glucose Suspend Devices

Clinical Context and Therapy Purpose

The purpose of artificial pancreas device system with a low-glucose suspend feature in patients who have type 1 diabetes is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does the use of an artificial pancreas device system with a low glucose suspend feature improve the net health outcome for individuals with type 1 diabetes?

The following PICO was used to select literature to inform this review.

Patients

The relevant population of interest is individuals with type 1 diabetes. Persons with type 1 diabetes 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 an artificial pancreas device system that integrates a continuous glucose monitor and insulin pump and includes a low glucose suspend feature that can automatically and temporarily suspend insulin 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.

Artificial pancreas device systems are used by persons with type 1 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. Artificial pancreas device system are used by persons with type 1 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 plus insulin pump (open-loop) or self-monitoring blood glucose and multiple dose insulin therapy.

Outcomes

The general outcomes of interest are glycated hemoglobin A1c (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.

Review of Evidence

Systematic Reviews

A TEC Assessment (2013) reviewed studies that reported on the use of artificial pancreas device systems in patients with type 1 or type 2 diabetes taking insulin who were 16 years and older.12,It included studies that compared an artificial pancreas device system containing a low glucose suspend feature 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 were generally favorable, the study was flawed and further research was needed. Reviewers concluded that there was insufficient evidence to draw conclusions about the impact of an artificial pancreas device system, with a low glucose suspend feature, 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 Bergenstal et al(2013).13,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 low glucose suspend feature was used (n=121), or a control group, which used the continuous glucose monitor but not the low glucose suspend feature (n=126). Key eligibility criteria were 16-to-70 years old, type 1 diabetes, and hemoglobin A1c (HbA1c) levels between 5.8% and 10.0%.In addition, patients had to have more than 6 months of experience with insulin pump therapy and at least 2 nocturnal 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 low glucose suspend group were required to use the feature at least between 10 PM and 8AM. The threshold value was initially set at 70 mg/dL and could be adjusted to between 70 mg/dL and 90 mg/dL. Seven patients withdrew early from the trial; all 247 were included in the intention-to-treat analysis. The primary efficacy outcome was the area under the curve (AUC) for nocturnal hypoglycemia events.This was calculated by multiplying the magnitude (in milligrams per deciliter) and duration (in minutes) of each qualified hypoglycemic event. The primary safety outcome was change in hemoglobin A1c (HbA1c) levels.

The primary endpoint, mean (standard deviation [SD]) area under the curve (AUC) for nocturnal hypoglycemic events, was 980 (1200) mg/dL/min in the low glucose suspend 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 area under the curve (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 low glucose suspend group, the mean number of times the feature was triggered per patient was 2.08 per 24-hour period and 0.77 each night (10PM-8AM). The median duration of nighttime threshold suspend events was 11.9 minutes; 43% of events lasted for less than 5 minutes, 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 low glucose suspend group and 140.0 mg/dL in the control group.

Regarding safety outcomes and adverse events, change in HbA1c level was minimal, and there was no statistically significant difference between groups. Mean HbA1c levels decreased from 7.26 to 7.24 mg/dL in the low glucose suspend 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 low glucose suspend group and 4 events 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.14,This randomized crossover trial included 50 patients with type 1 diabetes who had at least 3 months 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 low glucose suspend feature on the insulin pump was turned on in 1 session and off in the other session, in random order. When on, the low glucose suspend 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 hypoglycemia were reduced when the low glucose suspend feature was 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 defined as the period of time glucose 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 low glucose suspend on sessions (mean, 138.5 minutes; SD=68) than the low glucose suspend off sessions (mean, 170.7 minutes; SD=91; p=0.006). Hypoglycemia severity was significantly reduced in the low glucose suspend on group. The mean (SD) lowest glucose level was 59.5 (72) mg/dL in the low glucose suspend on group and 57.6 (5.7) mg/dL in the low glucose suspend off group (p=0.015). Potential limitations of the Garg study included evaluation of the low glucose suspend feature in a research setting and short assessment period.

A second RCT evaluated the in-home use of the Paradigm Veo System.15,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 least 6 months. In addition, participants had to have an HbA1c level of 8.5% or less and have impaired awareness of hypoglycemia (defined as a score of at least 4 on 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 low glucose suspend feature. The primary study outcome was the combined incidence of severe hypoglycemic events (defined as hypoglycemic seizure or coma) and moderate hypoglycemic events (defined as an event requiring assistance from another 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 low glucose suspend group (129.6 events per 100 patient-months) than in the pump-only group (20.7 events per 100 patient-months). After 6 months 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 low glucose suspend group. The incidence rate ratio was 3.6 (95% CI, 1.7 to 7.5), which was statistically significant favoring the low glucose suspend 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 could be explained in part by 2 outliers (children ages 9 and 10 years). When both children were excluded from the analysis, the primary outcome was no longer statistically significant. The incidence rate ratio for moderate and severe events excluding the 2 children was 1.7 (95% CI, 0.7 to 4.3). Mean HbA1c levels (a secondary outcome) did not differ between groups at baseline or at 6 months. Change in HbA1c levels during 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 low glucose suspend group; the difference between groups was not statistically significant.

The Predictive Low-Glucose Suspend for Reduction Of LOw Glucose (PROLOG) Trial was a 6-week crossover RCT of the t:slim X2 pump with Basal-IQ integrated with a Dexcom G5 sensor and a predictive low glucose suspend algorithm compared to sensor-augmented pump therapy.16, Participants (N=103) were ages 6-72 years; 58% were less than 18 years old, 16% were 6 to 11 years old, 43% were 12 to 17 years old, and 42% were 18 years or older. The primary outcome was continuous glucose monitoring measured percentage of time <70 mg/dL in each 3-week period. Median time <70 mg/dL was reduced from 3.6% at baseline to 2.6% during the 3-week period in the predictive low glucose suspend system (PLGS) arm compared with 3.2% in the sensor augmented pump arm (difference [PLGS − sensor augmented pump] = −0.8%, 95% CI −1.1 to −0.5, P < 0.001). There was one severe hypoglycemic event in the sensor augmented pump arm and none in the predictive low glucose suspend arm.

Retrospective Studies

Agrawal et 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.17,This noncontrolled descriptive analysis provided information on the safety of the device when used in a practice setting. The threshold suspend feature was enabled 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 feature was enabled, there was a mean of 0.82 suspend events per patient-day. Of these, 56% lasted for 0 to 5 minutes, and 10% lasted the full 2 hours. (Data on the length of the other 34% of events were 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 off vs glucose 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 episodes were not fully discussed in 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 low glucose suspend therapy.18,Participants used a combination system with the Medtronic Paradigm 722 or Paradigm Veo pump connected to the MiniMed continuous glucose monitoring 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). HbA1c levels 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: Low-Glucose Suspend Devices

For individuals who have type 1 diabetes who receive an artificial pancreas device system with a low-glucose suspend feature, the evidence includes two 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 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 from one trial were limited by nonstandard reporting of hypoglycemic episodes, and findings from the other trial were no longer statistically significant when two outliers (children)were excluded from 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 curve is not used for assessment in clinical practice but the current technology does allow user and provider review of similar trend data with continuous 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 type 1 diabetes 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 a hybrid closed-loop insulin delivery system in patients who have type 1 diabetes is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does the use of a hybrid closed-loop insulin delivery system improve the net health outcome for individuals with type 1 diabetes?

The following PICO was used to select literature to inform this review.

Patients

The relevant population of interest is individuals with type 1 diabetes. Persons with type 1 diabetes 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 a hybrid closed-loop insulin delivery system. A hybrid closed-loop system continuously adjusts insulin delivery. However, at mealtime, the patient enters the number of carbohydrates being consumed in order for the insulin pump to determine the bolus meal dose of insulin.

Artificial pancreas device system are used by persons with Type 1 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: an automated insulin delivery system with low glucose suspend feature, nonintegrated continuous glucose monitoring plus insulin pump (open-loop), or self-monitoring blood glucose and multiple dose insulin therapy.

Outcomes

The general outcomes of interest are 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.

Review of Evidence

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.19,It included 124 patients ages 14-to-75 years old who had type 1 diabetes for at least 2 years, had HbA1c levels less than 10.0%, and who had used an insulin pump for at least 6 months. 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 hotel stay with a 1-day period of frequent sampling of venous blood glucose levels to verify device accuracy. The primary safety end points were 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 could be resolved at home. There were 4 serious adverse events, 1 case each of appendicitis, bacterial arthritis, worsening rheumatoid arthritis, and Clostridium difficile diarrhea. There were also a number of predefined descriptive end points(but no statistically powered efficacy end points). The device was in the closed-loop mode for a median of 97% of the study period. Mean (SD) HbA1c levels 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).20, 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 least 2 years before the study, and used insulin pump therapy for 6 months or more. As with Bergenstal et 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 values were confirmed by 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, HbA1c levels 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 continuous glucose monitoring, and baseline HbA1c levels 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. Forlenza et al (2017) published a randomized controlled crossover trial comparing the efficacy of a zone model predictive control algorithm with that of sensor-augmented pump therapy; the trial included 20 subjects (19 completed), all with type 1 diabetes and having at least 3 months treatment with a subcutaneous insulin infusion pump.9, The six-week,in-home study was divided into 2-week blocks, with 2 randomized groups alternating treatment between an artificial pancreas system (DiAs web monitoring) or sensor-augmented pump 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 secondary endpoint(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 error might have occurred in setting basal rates.

The remainder of the review is focused on additional studies that recently evaluated hybrid closed-loop systems in children and adolescents with type 1 diabetes. These studies are summarized in Tables 3 and 4.

The RCT by Tauschman, et al (2018) evaluated individuals with uncontrolled type 1 diabetes as reflected in mean Hb1c >8 %. Approximately, 50% of the subjects were between 6-21 years of age and 25% were 6-12 years old.21, Both groups achieved a reduction in HbA1c but were statistically greater in the hybrid closed loop 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 <70 mg/dl.

Abraham et al (2018) reported the results of a 6 -month, multicenter, RCT in children and adolescents with type 1 diabetes comparing use of an insulin pump with suspend before low or predictive low-glucose management with sensor-augmented insulin pump therapy alone. At 6 months, significant reductions were seen in day and night hypoglycemia and number of hypoglycemic events <63 mg/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.6, The nonrandomized, single-arm multicenter study reported the day and night use of the automated insulin delivery and predictive low glucose management 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 of the 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.22, The suspend before low prevention capability was confirmed in 97.5% of patients experiencing a sensor glucose of ≤ 55 mg/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: Hybrid Closed-Loop in Type 1 Diabetes Children and Adolescents
Study; TrialCountriesSitesDatesParticipantsIntervention Study Type
N
Age
Mean (SD)
Tauschmann (2018)21,UK, US605/12/2016 - 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)23,Australia58/2014 - 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)1NCT0266082714,US, Israel94/18/2016 - 10/09/2017
    • 105
    • 7-13 years
    • 10.8 (1.8)
    • MiniMed 670G3
    • HCL
Noncomparative pivotal trial
Wood (2018)1(NCT02660827)22,US, Israel94/18/2016 - 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)24,US32015 - 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: U.S. Food and Drug Administration; PLGM: predictive low glucose management; PMA: premarket approval; RCT: randomized controlled trial; SAPT: sensor-augmented pump therapy; SD: standard deviation; NR: not reported; T1D: type 1 diabetes.
1
Data as submitted for FDA PMA Supplement P160017/S031.
2
MiniMed 640G is hybrid closed loop device approved for use outside of US.
3
MiniMed 670G is hybrid closed loop device approved for use in US.
4
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: Hybrid Closed-Loop in Type 1 Diabetes Children and Adolescents
StudyEfficacy OutcomesSafety Outcomes
Tauschmann (2018)21,
Outcome MeasureGroup difference in time proportion in target glucose range (70-180md/dL) at 12 weeks
Mean (SD)
HbA1c % (SD)
At 12 weeks
Hypoglycemia
    A. <63 mg/dl
    B. <50 mg/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
    • 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)23,
Outcome MeasureChange in average percent time in hypoglycemia (SG <63mg/dl) at 6 monthsChange in average percent time in hypoglycemia (SG <54mg/dl) at 6 monthsHbA1c
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% ∆1.4%
    • n=76
    • 1.3% ∆ 0.6%
7.5(0.8) ∆ 7.8(0.8)1394%
SAPT alone
    • n=70
    • 3% ∆2.6%
    • n =70
    • 1.4% ∆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)NCT0266082714,
BaselineRun-in phase (n=106)
    • 3-month study phase (n=105)
    • P
BaselineRun-in phase (n=106)
3-month study phase (n=105)
P

BaselineRun-in phase (n=106)
3-month study phase (n=105)
p







Outcome MeasureHbA1c

Mean % (SD)

Time in Range

(>70-180)

Mean %(SD)

Hypogylcemia

A..≤70mg/dl

B. ≤54mg/dl

Mean %(SD)

    • 7.9 (0.8)
    • 7.5 (0.6)
      <0.001
    • 65 (7.7)
      <0.001
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)22,
Outcome MeasureN=79 participant activations of suspend before low
Rate of “Suspend before Low” (%)
Reference range3
    • ≤55 mg/dl
    • ≤60 mg/dl
    • ≤65 mg/dl
    • 77 (97.5)
    • 71 (89.9)
    • 63 (79.7
Messer (2018)1(NCT02463097)24,
Outcome measureMean percentage time in range (70-180 mg/dl) using
HCL mode
4

Mean % (SD)

Days
    • Days 1-7
    • Days 22-28
    • Days 50-56
    • Days 78-84
    • 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 management; SD: standard deviation; SAPT: sensor-augmented pump therapy; SG: sensor glucose; ∆: delta meaning change in status; T1D: type 1 diabetes.
1
Data as submitted for FDA PMA Supplement P160017/S031.
2
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.
3
Simultaneous testing with either intravenous sampling or self-monitoring blood glucometer.
4
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 type 1 diabetes who receive an artificial pancreas device system with a hybrid closed-loop insulin delivery system, the evidence includes multicenter pivotal trials 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 (70-180 mg/dl), rare diabetic ketoacidosis and few device-related adverse events. The evidence is sufficient that the magnitude of reduction for hypoglycemic events in the type 1 diabetes 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 artificial pancreas device system 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

For individuals who have type 1 diabetes who receive an artificial pancreas device system with a low-glucose suspend feature, the evidence includes two 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 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 from one trial were limited by nonstandard reporting of hypoglycemic episodes, and findings from the other trial were no longer statistically significant when two outliers (children) were excluded from 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 curve is not used for assessment in clinical practice but the current technology does allow user and provider review of similar trend data with continuous 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 type 1 diabetes 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 hemoglobin A1c (HbA1c) and other parameters and thus, net health outcomes.

For individuals who have type 1 diabetes who receive an artificial pancreas device system with a hybrid closed-loop insulin delivery system, the evidence includes multicenter pivotal trials using devices cleared by the U.S. 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 (70-180 mg/dl), rare diabetic ketoacidosis and few device-related adverse events. The evidence is sufficient that the magnitude of reduction for hypoglycemic events in the type 1 diabetes 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.

SUPPLEMENTAL INFORMATION

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 the use of an artificial pancreas device system with a hybrid closed-loop insulin delivery system for individuals with type 1 diabetes was 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

The American Diabetes Association has released multiple publications on controlling type 1 diabetes (see Table 5).

Table 5. Recommendations on Diabetes
DateTitlePublication TypeRecommendationLOE
2020Standards of Medical Care in DiabetesGuideline standard17,Automated insulin delivery systems may be considered in children and adults with type 1 diabetes to improve glycemic control.A (adults)
B (children)
2017Standardizing Clinically Meaningful Outcome Measures Beyond HbA1c for Type 1 DiabetesConsensus report25,,aDeveloped definitions for hypoglycemia, hyperglycemia, time in range, and diabetic ketoacidosis in type 1 diabetesN/A
HbA1c: hemoglobin A1c; LOE: Level of Evidence.
a Jointly published with the American 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

In 2018, the American Association of Clinical Endocrinologists and American College of Endocrinology published a joint position statement on the integration of insulin pumps and continuous glucose monitoring in patients with diabetes.26,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 review are listed in Table 6.

Table 6. Summary of Key Trials
NCT No.Trial Name
Planned Enrollment
Completion Date
Ongoing
NCT02748018aMulti-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
1500
Dec 2021
Artificial Pancreas With Exercise Behavior Recognition
NCT03739099Assessment 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
NCT03844789aThe International Diabetes Closed Loop (iDCL) Trial: Clinical Acceptance of the Artificial Pancreas in Pediatrics: A Study of t:Slim X2 With Control-IQ Technology
101
Mar 2020
Unpublished
NCT03859401Hypoglycemia Prevention During and After Moderate Exercise in Adults With Type 1 Diabetes Using an Artificial Pancreas With Exercise Behavior Recognition
18 (actual)
Jan 2020
NCT02733211An Open-label, Two-center, Randomized, Cross-over Study to Evaluate the Safety and Efficacy of Night Closed-loop Control Using the MD-Logic Automated Insulin Delivery System Compared to Sensor Augmented Pump Therapy in Poorly Controlled Patients With Type 1 Diabetes at Home
28
Dec 2019 (Withdrawn)
NCT: national clinical trial.
a
Denotes industry-sponsored or cosponsored trial.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Artificial Pancreas Device Systems
Artificial Pancreas
MiniMed 530G System
Threshold Suspend Device System
Low Glucose Suspend
530G System
MiniMed 630G System
MiniMed 670G System
630G System
670G System

References:
1. American Diabetes Association. 6. Glycemic Targets. Diabetes Care. Jan 2017;40(Suppl 1):S48-S56. PMID 27979893

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. 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

5. 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 March 19, 2020

6. Forlenza GP, Li Z, Buckingham BA, et al. Predictive Low-Glucose Suspend Reduces Hypoglycemia in Adults, Adolescents, and Children With Type 1 Diabetes in an At-Home Randomized Crossover Study: Results of the PROLOG Trial. Diabetes Care. Oct 2018; 41(10): 2155-2161. PMID 30089663

7. 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 March 19, 2020

8. 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 March 19, 2020

9. 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 March 19, 2020.

10. Food and Drug Administration (FDA). t:slim X2 Insulin Pump with Basal-IQ Technology Premarket Approval (2018). https://www.accessdata.fda.gov/cdrh_docs/pdf18/P180008A.pdf. Accessed March 19, 2020.

11. Faulds ER, Zappe J, Dungan KM. REAL-WORLD IMPLICATIONS OF HYBRID CLOSE LOOP (HCL) INSULIN DELIVERY SYSTEM. Endocr Pract. 2019 May;25(5). PMID 30865545

12. Blue Cross and Blue Shield Technology Evaluation Center (TEC). Artificial Pancreas Device Systems. TEC Assessments. 2013;Volume 28:Tab 14

13. 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

14. 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

15. 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

16. Forlenza GP, Ekhlaspour L, Breton M et al. Successful At-Home Use of the Tandem Control-IQ Artificial Pancreas System in Young Children During a Randomized Controlled Trial. Diabetes Technol. Ther. 2019 Apr;21(4). PMID 30888835

17. American Diabetes Association. 7. Diabetes Technology: Standards of Medical Care in Diabetes-2020. Diabetes Care. Jan 2020; 43(Suppl 1): S77-S88. PMID 31862750

18. 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

19. Beato-Vibora PI, Gamero-Gallego F, Lazaro-Martin L et al. Prospective analysis of the impact of commercialised hybrid closed-loop system on glycaemic control, glycaemic variability and patient-related outcomes in children and adults: a focus on superiority over predictive low glucose suspend technology. Diabetes Technol. Ther. 2019 Dec. PMID 31855446

20. 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

21. 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

22. 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. 2018 Nov;20(11). PMID 30299976

23. 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

24. 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

25. Brown SA, Kovatchev BP, Raghinaru D et al. Six-Month Randomized, Multicenter Trial of Closed-Loop Control in Type 1 Diabetes. N. Engl. J. Med. 2019 Oct;381(18). PMID 31618560

26. 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

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

    HCPCS
      S1034
      S1035
      S1036
      S1037

    * CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.

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