Background

Islet Transplantation

In autologous islet transplantation during the pancreatectomy procedure, islet cells are isolated from the resected pancreas using enzymes, and a suspension of the cells is injected into the portal vein of the patient's liver. Once implanted, the beta cells in these islets begin to make and release insulin.

Allogeneic islet transplantation potentially offers an alternative to whole-organ pancreas transplantation. In the case of allogeneic islet cell transplantation, cells are harvested from a deceased donor's pancreas, processed, and injected into the recipient's portal vein. Up to three donor pancreas transplants may be required to achieve insulin independence. However, a limitation of islet transplantation is that two or more donor organs are usually required for successful transplantation, although experimentation with single-donor transplantation is occurring. A pancreas that is rejected for whole-organ transplant is typically used for islet transplantation. Therefore, islet transplantation has generally been reserved for patients with frequent and severe metabolic complications who have consistently failed to achieve control with insulin-based management. Allogeneic transplantation may be performed in the radiology department.

In 2000, a modified immunosuppression regimen increased the success of allogeneic islet transplantation. This regimen is known as the "Edmonton protocol."

Regulatory Status

The U.S. Food and Drug Administration regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation Title 21, parts 1270 and 1271. Allogeneic islet cells are included in these regulations.

Related Policies

• Chronic Intermittent Intravenous Insulin Therapy (CIIIT) (Policy #050 in the Medicine Section)
• Allogeneic Pancreas Transplant (Policy #088 in the Surgery Section)

I. Autologous pancreas islet transplantation is considered medically necessary as an adjunct to a total or near total pancreatectomy in members with chronic pancreatitis.

II. Allogeneic islet transplantation is considered investigational for the treatment of type 1 diabetes.

III. Islet transplantation is considered investigational in all other situations.


Medicare Coverage:
Per NCD 260.3.1, Medicare will pay for the routine costs, as well as transplantation and appropriate related items and services, for Medicare beneficiaries participating in a National Institutes of Health (NIH)-sponsored clinical trial(s). The term 'routine costs' means reasonable and necessary routine patient care costs, including immunosuppressive drugs and other follow-up care, as defined in section 310.1 of the NCD Manual.

National Coverage Determination (NCD) for Routine Costs in Clinical Trials (310.1). Available to be accessed at CMS National Coverage Determinations (NCDs) Alphabetical Index search page: https://www.cms.gov/medicare-coverage-database/indexes/ncd-alphabetical-index.aspx.

Specifically, Medicare will cover transplantation of pancreatic islet cells, the insulin producing cells of the pancreas. Coverage will include the costs of acquisition and delivery of the pancreatic islet cells, as well as clinically necessary inpatient and outpatient medical care and immunosuppressants.

Partial pancreatic tissue transplantation or islet cell transplantation performed outside the context of a clinical trial is not covered.

For additional information and eligibility, refer to National Coverage Determination (NCD) for Islet Cell Transplantation in the Context of a Clinical Trial. Available to be accessed at CMS National Coverage Determinations (NCDs) Alphabetical Index search page: https://www.cms.gov/medicare-coverage-database/indexes/ncd-alphabetical-index.aspx

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.

[RATIONALE: The policy was created in 2009 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through June 10, 2019.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the 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 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 technology, two domains are examined: the relevance, and 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.

Chronic Pancreatitis

Clinical Context and Therapy Purpose

The purpose of autologous pancreas islet transplantation for patients with chronic pancreatitis who are undergoing total or near-total pancreatectomy 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 autologous pancreas islet transplantation improve the net health outcome in individuals who have chronic pancreatitis who are undergoing total or near-total pancreatectomy?

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

Patients

The relevant population of interest are individuals who have chronic pancreatitis who are undergoing total or near-total pancreatectomy. Primary risk factors for chronic pancreatitis may be categorized as the following: toxic-metabolic, idiopathic, genetic, autoimmune, recurrent and severe acute, or obstructive (TIGAR-O classification system). Patients with chronic pancreatitis may experience intractable pain that can only be relieved with a total or near-total pancreatectomy. However, the pain relief must be balanced against the certainty that the patient will be rendered an insulin-dependent diabetic.

Interventions

The therapy being considered is autologous pancreas islet transplantation. Islet transplantation is provided in a hospital setting with specialized staff who are equipped to perform the cell isolation and re-infusion procedures and manage post-transplant care.

Comparators

The following practice is currently being used to make decisions about managing chronic pancreatitis: medical management, which may include medications or endoscopy.

Outcomes

The general outcomes of interest are overall survival (OS), insulin independence, change in disease status, medication use, resource utilization, and treatment-related morbidity.

Short-term follow-up (30 days) is required to monitor for transplant-related complications; long-term follow-up-1 to 3, 5, or even 10 years—is required to establish the durability of glucose control.^1,

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

There are several systematic reviews of the literature on chronic pancreatitis patients. Wu et al (2015) published a systematic review of studies on islet transplantation after total pancreatectomy for chronic pancreatitis.^2, Studies could use any design type but had to include at least five patients or have a median follow-up of at least six months. Twelve studies (total n=677 patients) met reviewers' inclusion criteria. The mean age was 38 years and the mean duration of pancreatitis was 6.6 years. A meta-analysis of the insulin-independence rate at 1 year (5 studies, 362 patients) was 28.4% (95% confidence interval [CI], 15.7% to 46.0%). At 2 years, the pooled insulin-independence rate (3 studies, 297 patients) was 19.7% (95% CI, 5.1% to 52.6%). The pooled 30-day mortality rate (11 studies) was 2.1% (95% CI, 1.2% to 3.8%). Long-term mortality data were not pooled.

Dong et al (2011) published a systematic review that included studies irrespective of design or sample size.^3, After reviewing 84 studies, 15 observational studies met eligibility criteria. Eleven studies assessed total pancreatectomy, two studies evaluated partial pancreatectomy, and two studies included both types of surgery. Sample sizes in individual studies ranged from 3 to 173 patients. Thirteen studies included patients with chronic pancreatitis and two included patients with benign pancreatic tumors. The pooled 30-day mortality rate was 5% (95% CI, 2% to 10%), and the cumulative mortality at 1 year (reported by 10 studies) was 4.9% (95% CI, 2.6% to 7.3%). In a pooled analysis of data from 14 studies, the rate of insulin dependence at last follow-up was 4.6 per 100 person-years (95% CI, 1.53 to 7.62). The pooled rate of insulin independence was 27% (95% CI, 21% to 33%) at 1 year (5 studies) and 21% (95% CI, 16% to 27%) at 2 years (3 studies).

Table 1 provides a crosswalk of studies included in the systematic reviews discussed. Tables 2 and 3 provide the characteristics and results of these systematic reviews.

Table 1. Comparison of Studies Included in the Systematic Reviews

Study	Wu et al (2015)2,	Dong et al (2011)3,
Cameron et al (1981)	X	X
Hinshaw et al (1981)	X	X
Toledo-Pereyra et al (1983)		X
Fontana et al (1994)		X
Rastellini et al (1997)	X	X
Jindal et al (1998)		X
Rabkin et al (1999)		X
Oberholzer et al (2000)	X	X
Berney et al (2004)		X
Ahmad et al (2005)	X	X
Argo et al (2008)	X	X
Dixon et al (2008)	X	X
Sutherland et al (2008)		X
Webb et al (2008)		X
Jung et al (2009)		X
Takita et al (2010)	X
Sutherland et al (2012)	X
Walsh et al (2012)	X
Dorlon et al (2013)	X
Garcea et al (2013)	X

Table 2. Characteristics of Systematic Reviews Assessing Autologous Pancreas Islet Transplants

Study	Dates	Trials	Participants	N (Range)	Design	Duration, mo
Wu et al (2015)2,	1977-2014	12	Individuals with chronic pancreatitis	677 (5-409)	Case series	1-210
Dong et al(2011)3,	1977-2007	15	Individuals with chronic pancreatitis or benign pancreatic disease	384 (3-173)	Case series	3-100

Table 3. Results of Systematic Reviews Assessing Autologous Pancreas Islet Transplants

Study	Insulin-Independence Rate	Mortality Rate
Wu et al (2015)2,
n		672
30-day follow-up (95% confidence interval)		2.1 (1.2 to 3.8)
I2, %		0
n	362
1-year follow-up (95% confidence interval)	28.4 (15.7 to 46.0)
I2, %	69
n	297
2-year follow-up (95% confidence interval)	19.7 (5.1 to 52.6)
I2, %	87
Dong et al(2011)3,
n		176
30-day follow-up (95% confidence interval)		5 (2 to 10)
I2, %		0
n	221
1-year follow-up (95% confidence interval)	27 (21 to 33)
I2, %	Not reported
n	201
2-year follow-up (95% confidence interval)	21 (16 to 27)
I2, %	Not reported

Nonrandomized Studies

Wilson et al (2014) reported on 166 patients with chronic pancreatitis who underwent total pancreatectomy and islet transplantation at a single-center.^4, Actutimes survival rate at 5 years was 94.6%. Five or more years of data were available for 112 (67%) patients. At 1 year, 38% of patients were insulin-independent and that declined to 27% at the 5-year follow-up. Daily insulin requirement, however, remained stable over the five years. Fifty-five percent of patients were independent of opioid analgesics at 1 year and this improved to 73% at 5 years.

Chinnakotla et al (2014) included 484 patients with chronic pancreatitis who underwent total pancreatectomy and immediate islet autotransplantation.^1, The actutimes 10-year survival rate was 84%. Patient survival at 5 years was 90.3% in the 80 patients with hereditary/genetic pancreatitis and 89.7% in the 404 patients with nonhereditary pancreatitis; the difference between groups was not statistically significant. Pancreatitis pain decreased significantly after the procedures, and there was no statistically significant difference in the rate of pancreatitis pain between the groups.

Sutherland et al (2012) reported on 409 patients with chronic pancreatitis who underwent total pancreatectomy and islet transplantation at a single-center.^5, Fifty-three (13%) of the 409 patients were children between the ages of 5 and 18 years. Actutimes survival postsurgery was 96% in adults and 98% in children after 1 year and 89% in adults and 98% in children after 5 years. A total of 15.9% of patients experienced surgical complications requiring reoperation during the initial admission. The most common reason for reoperation was bleeding, occurring in 9.5% of patients. At 3 years, 30% of patients were insulin-independent (25% of adults, 55% of children). A survey of quality of life outcomes was initiated in 2008; responses were available for 102 patients. At baseline, all 102 patients reported using opioid analgesia for pain control. At 12 months, the proportion of patients on narcotics decreased to 56% (n=32), and at 24 months, 41% of respondents (n=21) reported using narcotics.

Tables 4 and 5 provide the characteristics and results of the nonrandomized studies assessed.

Table 4. Summary of Key Nonrandomized Study Characteristics

Study	Study Type	Country	Dates	Participants	Treatment	F/U, y
Wilson et al (2014)4,	Cohort	U.S.	2000-2013	Individuals with chronic pancreatitis	Total pancreatectomy and islet auto-transplantation (n=166)	≥ 5
Chinnakotla et al (2014)1,	Cohort	U.S.	1977-2012	Individuals with chronic pancreatitis	Total pancreatectomy and islet auto-transplantation (n=484)	NR
Sutherland et al (2012)5,	Cohort	U.S.	1977-2011	Individuals with chronic pancreatitis	Total pancreatectomy and islet auto-transplantation (n=409)	NR

F/U: follow-up; NR: not reported.

Table 5. Summary of Key Nonrandomized Study Results

Study	Survival	Rate	Insulin-Independence Rate
	1-Year	5-Year	1-Year	3-Year	5-Year
Wilson et al (2014)4,	98.2	94.6	38	NR	27
Chinnakotla et al (2014)1,
Hereditary/genetic pancreatitis		90.27	20.0	NR	NR
Nonhereditary pancreatitis		89.72	32.9	NR	NR
p		0.166	0.022
Sutherland et al (2012)5,	97	90	26	30	NR

NR: Not reported.

Section Summary: Chronic Pancreatitis

Autologous islet transplantation is frequently performed as an adjunct to a total or near-total pancreatectomies for chronic pancreatitis. Evidence from case series and systematic reviews has demonstrated that autologous islet transplantation decreases the incidence of diabetes in the setting of pancreatectomies for the treatment of chronic pancreatitis.

Type 1 Diabetes

Clinical Context and Therapy Purpose

The purpose of allogeneic pancreas islet transplantation for 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 allogeneic pancreas islet transplantation improve the net health outcome in individuals with type 1 diabetes?

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

Patients

The relevant population of interest are individuals with type 1 diabetes.

Glucose control is a challenge for individuals with type 1 diabetes. Failure to prevent disease progression can lead to long-term complications such as retinopathy, neuropathy, nephropathy, and cardiovascular disease.[1]

Interventions

The therapy being considered is allogeneic pancreas islet transplantation. Islet transplantation is provided in a hospital setting with specialized staff who are equipped to perform the cell isolation and re-infusion procedures and manage post-transplant care.

Comparators

The following practice is currently being used to make decisions about managing type 1 diabetes: medical management, which generally includes daily insulin injections as well as diet and lifestyle changes.

Outcomes

The general outcomes of interest are OS, insulin independence, change in disease status, medication use, resource utilization, and treatment-related morbidity.

According to U.S. Food and Drug Administration (2009) industry guidance on evaluating allogeneic pancreatic islet cell products, single-arm trials with historical controls may be acceptable alternatives to RCTs for evaluating the safety and efficacy of islet cell products in patients with metabolically unstable type 1 diabetes.^6, Attainment of a normal hemoglobin A_1c (HbA_1c) range (i.e., ≤6.5%) and elimination of hypoglycemia are acceptable primary endpoints. To assess the durability of the islet cell procedure, primary endpoints should be measured at least 12 months after the final infusion. Other key clinical outcomes include insulin independence, measures of glucose metabolic control such as fasting plasma glucose level and loss of hypoglycemia unawareness.

Short-term (30 days) follow-up is required to monitor for transplant-related complications; the long-term follow-up to assess the durability of glucose control and monitor immunosuppression is lifelong.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

A systematic review by Health Quality Ontario (2015) reported on islet transplantation for patients with type 1 diabetes.^7, Case series derived from single-centers constitutes most of the evidence. For nonuremic patients, rates of insulin independence ranged from 30% to 70% from observational case series at 1 year after islet transplantation. For uremic patients, reported insulin-independence rates ranged from 20% to 67%. Evidence of changes in secondary complications such as diabetic retinopathy and nephropathy were conflicting across different studies.

TEC Assessment (2004) evaluated the evidence on islet cell transplantation in type 1 diabetes.^8, The Assessment found that published data on clinical outcomes of islet-alone transplantation were limited by small sample sizes (i.e., ≤35 enrolled patients), few transplant centers, short duration of follow-up, and lack of standardized methods of reporting clinical outcomes. Also, rare, serious adverse events have occurred in patients given islet transplants, although recent procedure modifications reportedly minimized risks of these adverse events. No procedure-related deaths, cytomegalovirus infection, or posttransplantation lymphoproliferative disease have been reported for islet-alone transplantation.

Randomized Controlled Trials

Lablanche et al (2018) published a multicenter, open-label, RCT (TRIMECO trial) evaluating patients who had type 1 diabetes with severe hypoglycemia or after kidney transplantation.^9, Patients received immediate islet transplantation (n=25) or intensive insulin therapy followed by delayed islet transplantation (n=22). Median follow-up was six months for both groups. The primary endpoint was a composite score (β score) which has not been validated and which reflected fasting glucose, HbA_1c level, C-peptide, and insulin independence. At 6 months, 16 of 25 patients in the immediate transplantation group and none of 22 patients in the control group had a modified β score of 6 or higher (p<0.001). Of note, few patients in the insulin group used continuous glucose monitoring or other technologies to monitor for hypoglycemia. At 6 months, insulin independence was achieved in 44% of patients in the immediate transplantation group (n=25; p<0.001). After the entire cohort received islet transplantation, the 1-year insulin independence rate was 59% (n=46; p<0.001). Subsequent to islet transplantation, 6% of patients had bleeding complications. Trial limitations included possible bias from open-label design as well as an inadequate follow-up period to demonstrate transplant durability.

Registry Studies

In a report from the Collaborative Islet Transplant Registry, which collects and monitors data on allogeneic islet transplantation in North America, Europe, and Australia, Alejandro et al (2008) assessed data on 325 adult recipients.^10,Three years after the first cell infusions, 23% of islet-alone recipients were insulin-independent (defined as insulin-independent ³2 weeks), 29% were insulin-dependent with detectable C-peptide, 26% had lost function, and 22% had missing data. Seventy percent achieved insulin independence at least once, 71% of whom were still insulin-independent 1 year later and 52% at 2 years. Factors that favored primary outcomes were a higher number of islet infusions, a greater number of total islet equivalents infused, lower pretransplant HbA_1c levels, processing centers related to the transplant center, and larger islet size.

Barton et al (2012) updated the Collaborative Islet Transplant Registry report, which focused on changes in outcomes over time.^11, The number of patients receiving islet transplants was 214 from 1999 to 2002, 255 between mid-2003 and 2006, and 208 from 2007 to 2010. A total of 575 (85%) of the 677 islet transplant recipients received islets only; the remainder underwent simultaneous kidney and islet transplants. In the 1999-2002 group, rates of insulin independence were 51% after 1 year, 36% after 2 years, and 27% after 3 years. Rates for the 2007-2010 group were 66%, 55%, and 44%, respectively. The incidence of clinically reportable adverse events in the first year after infusion decreased from a range of 50% to 53% in 1999-2006 to 38% in 2007-2010. The rates of peritoneal hemorrhage or gallbladder infusion were 5.4% in 1999-2003 and 3.1% in 2007-2010. The authors did not report findings separately for the subset of patients who underwent islet-only transplants.

Thompson et al (2011) in Canada published findings from a prospective crossover study of intensive medical therapy (pretransplant) vs islet cell transplantation in patients with type 1 diabetes.^12, The article reported on 45 patients; at the time of data analysis, 32 had received islet cell transplants. Median follow-up was 47 months pretransplant and 66 months posttransplant. The overall mean HbA_1c level was 7.8% pretransplant and 6.7% posttransplant (p<0.001). In the 16 patients for whom sufficient pre- and posttransplant data were available on renal outcomes, the median decline in glomerular filtration rate was -6.7 mL/min/1.73 m²/y pretransplant and -1.3 mL/min/1.73 m²/y posttransplant (p=0.01). Retinopathy was assessed using a scale that categorized nonproliferative diabetic retinopathy as mild, moderate, or severe. Retinopathy progressed in 10 (12%) of 82 eyes pretransplant vs 0 of 51 posttransplant (p<0.01). (The numbers of patients in the retinopathy analyses were not reported.) The authors noted that their finding of reduced microvascular complications after islet transplantation might have been due, in part, to their choice of maintenance immunosuppression. The study used a combination of tacrolimus and mycophenolate mofetil.

Other small case series have reported some success and also adverse events.^13,14,15, For example, O'Connell et al (2013) reported on 17 patients with type 1 diabetes and severe hypoglycemia who underwent islet transplantation in Australia.^14, Fourteen (82%) patients attained the primary endpoint, which was an HbA_1c level of less than 7% and no severe hypoglycemic events 2 months after the initial transplant. Nine (53%) patients attained insulin independence for a median of 26 months. Most adverse events related to immunosuppression. Seven (41%) of the 17 patients developed mild lymphopenia and 1 developed Clostridium difficile colitis; all responded to treatment. Eight patients developed anemia shortly after transplant and one required a blood transfusion. Procedure-related complications included one partial portal vein thrombosis and three postoperative bleeds; two of the bleeds required transfusion.

Section Summary: Type 1 Diabetes

Allogeneic islet transplantation has been investigated in the treatment of type 1 diabetes. One RCT found that quality of life was significantly improved after islet transplantation; however, the short length of follow-up limits these conclusions. Evidence from case series and systematic reviews has demonstrated varying ranges of insulin independence posttransplantation. There is conflicting evidence that allogeneic islet transplantation reduces long-term diabetic complications. Long-term comparative studies are required to determine the effects of allogeneic islet transplantation in type 1 diabetics and posttransplant immunosuppression.

Summary of Evidence

For individuals with chronic pancreatitis undergoing total or near-total pancreatectomy who receive autologous pancreas islet transplantation, the evidence includes case series and systematic reviews. The relevant outcomes are OS, change in disease status, medication use, resource utilization, and treatment-related morbidity. Autologous islet transplants are performed in the context of total or near-total pancreatectomies to treat intractable pain from chronic pancreatitis. The procedure appears to decrease significantly the incidence of diabetes after total or near-total pancreatectomy in patients with chronic pancreatitis. Also, this islet procedure is not associated with serious complications and is performed in patients who are already undergoing a pancreatectomy procedure. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals with type 1 diabetes who receive allogeneic pancreas islet transplantation, the evidence includes an RCT, case series, and systematic reviews. The relevant outcomes are OS, change in disease status, medication use, resource utilization, and treatment-related morbidity. Results of a 2018 randomized trial have suggested some reduction in the number of severe hypoglycemic incidence annually, but limited follow-up and other trial limitations reduce the certainty in conclusions drawn. A wide range of insulin independence has been reported in case series. There is conflicting evidence on whether allogeneic islet transplantation reduces long-term diabetic complications. Long-term comparative studies are required to determine the effects of allogeneic islet transplantation in type 1 diabetics. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

National Institute for Health and Care Excellence

Guidance from the National Institute for Health and Care Excellence (2008) indicated the evidence on allogeneic pancreatic islet cell transplantation for type 1 diabetes has shown that serious procedure-related complications may occur, and the long-term immunosuppression required is associated with risk of adverse events.^16, A related 2008 guidance addressed autologous islet cell transplantation for improved glycemic control after pancreatectomy and stated that studies have shown "some short-term efficacy, although most patients require insulin therapy in the long term... complications result mainly from the major surgery involved in pancreatectomy (rather than from the islet cell transplantation)."^17,

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this policy are listed in Table 6.

Table 6. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT02505893	Minimal Islet Transplant at Diabetes Onset (MITO)	6	May 2018 (last updated February 2018)
NCT00160732	Allogenic Islet Cell Transplantation	50	Oct 2025
NCT00706420	Islet Transplantation Alone (ITA) in Patients With Difficult to Control Type I Diabetes Mellitus Using a Glucocorticoid-free Immunosuppressive Regimen	20	Dec 2019
NCT00306098	Islet Cell Transplantation Alone in Patients With Type 1 Diabetes Mellitus: Steroid-Free Immunosuppression	40	May 2021
NCT01909245	Islet Cell Transplant for Type 1 Diabetes (TCD)	30	Jul 2021
NCT01974674	Allogeneic Islet Transplantation for the Treatment of Type 1 Diabetes (GRIIF)	19	Jan 2022
NCT01897688	A Phase 3 Single Center Study of Islet Transplantation in Non-uremic Diabetic Patients	40	Mar 2027
NCT00679042	Islet Transplantation in Type 1 Diabetic Patients Using the University of Illinois at Chicago (UIC) Protocol	36	Jul 2027

NCT: national clinical trial.]
________________________________________________________________________________________

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.

___________________________________________________________________________________________________________________________

Index:
Islet Transplantation
Islet Cell Transplantation

References:
1. Chinnakotla S, Radosevich DM, Dunn TB, et al. Long-term outcomes of total pancreatectomy and islet auto transplantation for hereditary/genetic pancreatitis. J Am Coll Surg. Apr 2014;218(4):530-543. PMID 24655839.

2. Wu Q, Zhang M, Qin Y, et al. Systematic review and meta-analysis of islet autotransplantation after total pancreatectomy in chronic pancreatitis patients. Endocr J. Mar 30 2015;62(3):227-234. PMID 25735805.

3. Dong M, Parsaik AK, Erwin PJ, et al. Systematic review and meta-analysis: islet autotransplantation after pancreatectomy for minimizing diabetes. Clin Endocrinol (Oxf). Dec 2011;75(6):771-779. PMID 21605156.

4. Wilson GC, Sutton JM, Abbott DE, et al. Long-term outcomes after total pancreatectomy and islet cell autotransplantation: is it a durable operation? Ann Surg. Oct 2014;260(4):659-665; discussion 665-657. PMID 25203883.

5. Sutherland DE, Radosevich DM, Bellin MD, et al. Total pancreatectomy and islet autotransplantation for chronic pancreatitis. J Am Coll Surg. Apr 2012;214(4):409-424. PMID 22397977.

6. Food and Drug Administration (FDA). Guidance for Industry: Considerations for Allogeneic Pancreatic Islet Cell Products. 2009; https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/ CellularandGeneTherapy/UCM182441.pdf. Accessed August 29, 2019.

7. Health Quality Ontario. Pancreas islet transplantation for patients with type 1 diabetes mellitus: a clinical evidence review. Ont Health Technol Assess Ser. Dec 2015;15(16):1-84. PMID 26644812.

8. Piper M, Seidenfeld J, Aronson N. Islet transplantation in patients with type 1 diabetes mellitus. Evid Rep Technol Assess (Summ). Jul 2004(98):1-6. PMID 15366369.

9. Lablanche S, Vantyghem MC, Kessler L, et al. Islet transplantation versus insulin therapy in patients with type 1 diabetes with severe hypoglycaemia or poorly controlled glycaemia after kidney transplantation (TRIMECO): a multicentre, randomised controlled trial. Lancet Diabetes Endocrinol. May 15 2018 6(7):527-537. PMID 29776895.

10. Alejandro R, Barton FB, Hering BJ, et al. 2008 Update from the Collaborative Islet Transplant Registry. Transplantation. Dec 27 2008;86(12):1783-1788. PMID 19104422.

11. Barton FB, Rickels MR, Alejandro R, et al. Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care. Jul 2012;35(7):1436-1445. PMID 22723582.

12. Thompson DM, Meloche M, Ao Z, et al. Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation. Feb 15 2011;91(3):373-378. PMID 21258272.

13. Caiazzo R, Vantyghem MC, Raverdi V, et al. Impact of procedure-related complications on long-term islet transplantation outcome. Transplantation. May 2015;99(5):979-984. PMID 25393157.

14. O'Connell PJ, Holmes-Walker DJ, Goodman D, et al. Multicenter Australian trial of islet transplantation: improving accessibility and outcomes. Am J Transplant. Jul 2013;13(7):1850-1858. PMID 23668890.

15. Rickels MR, Kong SM, Fuller C, et al. Improvement in insulin sensitivity after human islet transplantation for type 1 diabetes. J Clin Endocrinol Metab. Nov 2013;98(11):E1780-1785. PMID 24085506.

16. National Institute for Health and Care Excellence (NICE). Allogenic pancreatic islet cell transplantation for type 1 diabetes mellitus [IPG257]. 2008; https://www.nice.org.uk/Guidance/IPG257. Accessed August 29, 2019.

17. National Institute for Health and Care Excellence (NICE). Autologous pancreatic islet cell transplantation for improved glycaemic control after pancreatectomy [IPG274]. 2008; https://www.nice.org.uk/Guidance/IPG274. Accessed August 29, 2019.

18. Centers for Medicare & Medicaid. National Coverage Determination (NCD) for ISLET CELL Transplantation in the Context of a Clinical Trial (260.3.1). 2004; https://www.cms.gov/medicare-coverage-database/details/ncd- details.aspx?NCDId=286&ncdver=1&CoverageSelection=Both&ArticleType=All&PolicyType=Final&s=All&KeyW ord=islet+cell&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAAABAAAAAA&. Accessed August 29, 2019.

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*

48160
48999
0141T
0142T

G0341
G0342
G0343
S2102