Pancreatic Islet Transplantation Into the Anterior Chamber of the Eye
Keywords
Abstract
Description
The impact of Type 1 Diabetes. In the U.S. alone, approximately 1.3 million people, including children and adolescents, suffer from type 1 diabetes (T1D); the disease incidence is increasing in many countries, also in children and adolescents. Chronic autoimmune T cell responses against pancreatic beta -cells are considered the primary cause of T1D, leading to loss of beta cell mass and insulin secretion and in turn a life-long dependence on insulin injections.
The disease severely impacts quality of life and confers risk of both acute and chronic complications linked to significant morbidity and mortality, such as end-stage renal disease, blindness, cardiovascular disease, diabetic ketoacidosis and hypoglycemia. The economic burden caused by T1D amounts to approximately $14.4 billion in medical costs and lost income. There is a significant need to develop new therapies or improve existing ones to prevent, treat, and cure T1D. Diabetes socioeconomic impact primarily stems from the serious complications associated with it. Such complications include blindness, amputations, kidney failure, heart and vascular disease, stroke, nerve damage, and even birth defects during pregnancy.
Although the specific etiology of T1D remains unknown, it is well established that T1D results from the autoimmune destruction of the insulin-producing beta cells in the endocrine pancreas (i.e., the islets of Langerhans). Consequently, treatment options in T1D are limited to insulin supplementation. Insulin supplementation can be either in the form of multiple insulin injections daily, or biological replacement of the insulin-producing beta cells which provides a natural source of insulin. On the one hand, conventional insulin supplementation via injection has saved countless lives of diabetic patients since the discovery of insulin in the early 1900s. However, it is well established that exogenous insulin injection therapy is suboptimal in preventing hyper- and hypo-glycemia fluctuations. On the other hand, it has been shown that even a partial level of endogenous insulin secretion protects from chronic diabetic complications such as hypoglycemia and diabetic ketoacidosis, which can lead to death.
Therefore, beta cell replacement therapy through transplantation of isolated pancreatic islets offers a great therapeutic option in T1D. Several approaches of beta cell replacement have been pursued in the last few decades. Regenerative approaches such as regeneration of existing mature beta cells, differentiation of stem cells and/or trans-differentiation of other endocrine or non-endocrine (e.g., ductal and exocrine) cells into insulin-producing cells hold great promise in treating T1D. However, these approaches have yet to materialize into safe and reliable clinical application. Transplantation is also another option of biological replacement but has limitations as well. Limited availability of donor tissue remains a significant obstacle in transplantation therapies in general, including pancreatic islets. Other limitations of transplantation therapy are associated with the mandatory use of systemic anti-rejection immunosuppressive drugs. Chronic systemic immunosuppression exposes transplant recipients to serious and potentially deadly side-effects and complications such as increased susceptibility to infections, sepsis and cancer. Therefore, immunosuppressive agents are continuously being improved and new ones are being developed to better protect transplanted tissues (e.g., pancreatic islets) while reducing undesired side-effects of systemic immunosuppression and its associated complications.
T1D patients currently receive transplant therapy either in the form of whole pancreas or isolated pancreatic islets. On the one hand, whole pancreas transplantation has been shown to achieve insulin independence in T1D patients, but it is also very invasive and is associated with high risk of complications and adverse events including mortality. On the other hand, transplantation of isolated pancreatic islets is minimally invasive and has significantly less complications compared to whole pancreas transplant, but survival of the islet graft might be severely limited due to complications associated with the current site for clinical islet transplant, the portal (venous) system of the liver. Nevertheless, hundreds of T1D patients have received islet transplants in the liver in the last three decades of clinical trials of islet transplantation. These studies have demonstrated that islet transplant recipients benefit from improved glycemic control, reduced hypoglycemia episodes, and prevention of diabetes-associated complications. These benefits improve the patients' quality of life significantly. Importantly, it has been shown in transplanted T1D patients that restored hypoglycemia awareness following transplant is maintained even after some of these patients had to get back on insulin therapy due to rejection or loss of the islet graft. Therefore, transplantation of isolated pancreatic islets has emerged as a promising therapy for T1D. Consequently, islet transplantation has become standard-of-care in many countries and is on the verge of being so in the United States.
Dates
| Last Verified: | 04/30/2020 |
| First Submitted: | 07/17/2016 |
| Estimated Enrollment Submitted: | 07/21/2016 |
| First Posted: | 07/26/2016 |
| Last Update Submitted: | 05/29/2020 |
| Last Update Posted: | 06/01/2020 |
| Actual Study Start Date: | 12/04/2019 |
| Estimated Primary Completion Date: | 12/30/2022 |
| Estimated Study Completion Date: | 12/30/2026 |
Condition or disease
Intervention/treatment
Biological: Human Pancreatic Islet Transplantation
Phase
Arm Groups
| Arm | Intervention/treatment |
|---|---|
| Other: Human Pancreatic Islet Transplantation Islet transplantation into the anterior chamber of the eye single arm | Biological: Human Pancreatic Islet Transplantation Human Pancreatic Islet Transplantation in the Eye Anterior Chamber of legally blind Type 1 Diabetic Patients with or without a Stable Prior Kidney Transplant |
Eligibility Criteria
| Ages Eligible for Study | 18 Years To 18 Years |
| Sexes Eligible for Study | All |
| Accepts Healthy Volunteers | Yes |
| Criteria | Inclusion Criteria: - Patients who meet all of the following criteria are eligible for participation in the study: Ophthalmic inclusion criteria: 1. Patient with at least one eye with extensive loss of vision from hand motion to no light perception. 2. No evidence of advanced or uncontrolled diabetic retinopathy (D.R.; i.e., proliferative D.R.). 3. Phakic (with lens) or pseudophakic (synthetic lens) with a stable intraocular lens in the blind eye. 4. Normal cornea with good visualization of the anterior segment. 5. Normal anterior segment anatomy including the iris bed. General and metabolic inclusion criteria: 1. Male and female subjects age 18 to 70 years of age and no history of non-compliance. 2. Stable kidney function with or without kidney transplant, if applicable. 3. Ability to provide written informed consent. 4. Mentally stable and able to comply with the procedures of the study protocol. 5. Clinical history compatible with T1D with onset of disease at <40 years of age, insulin-dependence for >5 years at the time of enrollment, and a sum of subject age and insulin-dependent diabetes duration of ≥23. 6. Absent stimulated c-peptide (<0.3 ng/mL) in response to a mixed meal tolerance test (MMTT; Boost®Plus 6 mL/kg body weight to a maximum of 360 mL; another product with equivalent caloric and nutrient content may be substituted for Boost®Plus) measured at 60 and 90 min after the start of consumption. 7. Involvement in intensive diabetes management, defined as self-monitoring of glucose values no less than a mean of three times each day averaged over each week and by the administration of three or more insulin injections each day or insulin pump therapy. Such management must be under the direction of an endocrinologist, diabetologist, or diabetes specialist, with at least 3 clinical evaluations during the 12 months prior to study enrollment. 8. Reduced awareness of hypoglycemia as defined by a Clarke score of 4 or more; OR HYPO score greater than or equal to the 90th percentile (1047) during the screening period; OR marked glycemic lability characterized by wide swings in BG despite optimal diabetes therapy and defined by an LI score greater than or equal to the 90th percentile (433 mmol/L2/h·wk-1) during the screening period; OR composite of a Clarke score of less than 4 and a HYPO score greater than or equal to the 75th percentile (423) and a LI greater than or equal to the 75th percentile (329) during the screening period. 9. For islet transplant alone (i.e., without an existing kidney transplant), at least 1 (one) episode of severe hypoglycemia in the 12 months prior to study enrollment; OR time in hypoglycemia range (< 70mg/dL) ≥ 8% during 24 h as assessed by continuous glucose monitoring. Exclusion Criteria: - Patients who meet any of these criteria are not eligible for participation in the study: Ophthalmic exclusion criteria (only in surgical eye): 1. Poor visualization of the anterior chamber (corneal opacity, corneal edema, Herpes Keratitis). 2. Aphakic status (no lens). 3. Narrow angle of iris anatomy: Spade Scale IV. 4. History of glaucoma that had required surgical intervention (trabeculectomy, shunting devices), and uncontrolled glaucoma or neovascularization. 5. History of uveitis. 6. Untreated diabetic retinopathy in either eye. General and metabolic exclusion criteria: 1. Positive c-peptide. 2. Poor compliance history. 3. Body Mass Index (BMI) >30 kg/m2 or patient weight ≤50 kg. 4. Insulin requirement of >1.0 U/kg/day or <15 U/day. 5. HbA1c >10%. 6. Blood Pressure: SBP >160 mmHg or DBP >100 mmHg. 7. Calculated GFR of ≤ 40 mL/min/1.73 m2, for islet transplant after kidney or <80 mL/min/1.73 m2 for islet transplant alone, using the subject's measured serum creatinine and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation1. 8. Strict vegetarians (vegans) will be excluded only if their estimated GFR is ≤ 35mL/min/1.73 m2 for islet transplant after kidney or <70 mL/min/1.73 m2 for islet transplant alone. 9. Proteinuria (albumin/creatinine ratio or ACr >300mg/dl) of new onset or since kidney transplantation if applicable. 10. Calculated panel-reactive anti-HLA antibodies > 50% for islet transplant after kidney. Subjects with calculated panel reactive anti-HLA antibodies ≤ 50% will be excluded if any of the following are detected: i. Positive cross-match. ii. Islet donor-directed anti-HLA antibodies detected by Luminex Single Antigen specificity bead assay including weakly reactive antibodies that would not be detected by flow cross-match. iii. Antibodies to the renal donor (i.e. presumed de-novo), if applicable. 11. For islet transplant alone, presence or history of panel-reactive anti-HLA antibodies above background by flow cytometry. 12. For female subjects: Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study and 4 months after discontinuation. For male subjects: intent to procreate during the duration of the study or within 4 months after discontinuation or unwillingness to use effective measures of contraception. Oral contraceptives, Norplant®, Depo-Provera®, and barrier devices with spermicide are acceptable contraceptive methods; condoms used alone are not acceptable. 13. Presence or history of active infection including hepatitis B, hepatitis C, HIV, or tuberculosis (TB). Subjects with laboratory evidence of active infection are excluded even in the absence of clinical evidence of active infection. 14. Negative screen for Epstein-Barr Virus (EBV) by IgG determination. 15. Invasive aspergillus, histoplasmosis, and coccidioidomycosis infection within one year prior to study enrollment. 16. Any history of malignancy except for completely resected squamous or basal cell carcinoma of the skin. 17. Known active alcohol or substance abuse. 18. Baseline Hb below the lower limits of normal at the local laboratory; lymphopenia (<1,000/µL), neutropenia (<1,500/µL), or thrombocytopenia (platelets <100,000/µL). Participants with lymphopenia are allowed if the investigator determines there is no additional risk and obtains clearance from a hematologist. 19. Severe co-existing cardiac disease, characterized by any one of these conditions: i. Recent myocardial infarction (within past 6 months). ii. Evidence of ischemia on functional cardiac exam within the last year. iii. Left ventricular ejection fraction <30%. 20. Hyperlipidemia despite medical therapy (fasting low-density lipoprotein [LDL] cholesterol > 130 mg/dL, treated or untreated; and/or fasting triglycerides > 200 mg/dL). 21. Receiving treatment for a medical condition requiring chronic use of systemic steroids, except for the use of ≤5 mg prednisone daily, or an equivalent dose of hydrocortisone, for physiological replacement only. 22. Treatment with any anti-diabetic medications other than insulin within 4 weeks of enrollment. 23. Use of any investigational agents within 4 weeks of enrollment. 24. Administration of live attenuated vaccine(s) within 2 months of enrollment. 25. Any medical condition that, in the opinion of the investigator, will interfere with the safe participation in the trial. 26. A previous islet transplant. 27. A previous pancreas transplant, unless the graft failed within the first two (2) weeks due to thrombosis, followed with or without pancreatectomy of graft and the transplant occurred more than 6 months prior to enrollment. |
Outcome
Primary Outcome Measures
1. Reduction (≥ 50%) of glycemia fluctuations [6 months after transplant]
2. Reduction (≥ 25%) in exogenous insulin requirements [6 months after transplant]
3. Increased (≥ 1x) unstimulated serum c-peptide (corrected to glycemia) compared to baseline before transplant [Baseline; 6 months after transplant]
4. HbA1C ≤ 7% or a ≥ 2.5 decrease from baseline (before transplant) [Baseline; 1 year after transplant]
