Clinical trial NCT05973734: Islet Transplantation With Recipient T-Reg Cells or Deceased Donor Vertebral Bone Marrow Therapy
Official title: Clinical Islet Transplantation With Apheresis, Isolation and Reintroduction of Recipient Regulatory T Cells or Administration of Deceased Donor Vertebral Bone Marrow in Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
Conditions: Islet Transplantation
Lead sponsor: Stanford University
Sponsor class: OTHER
Collaborators: name: University of California, San Francisco
First posted: 2023-08-03
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: All patients are planned to receive an islet transplantation. The patients will also receive either Arm 1) recipient T regulatory cell infusion or arm 2) same donor vertebral body derived bone marrow cell infusion. Attribution to either arm will be based on the availability of either cell product in specific cases.
Primary purpose: TREATMENT

Brief summary: The goal of this clinical trial is to learn if patients who have brittle type 1 diabetes receiving an islet transplantation will have better control of their sugars if they also receive one of 2 types of immune cells along with the islet transplant. The participants will receive either their own immune cells, called regulatory T cells, or immune cells from the bone marrow of the islet donor.

Detailed description: Islet transplantation success remains limited by the immediate loss of islet after transplantation, rejection, and side effect from immunosuppression. Preclinical animal models provide evidence that donor bone marrow cells OR regulatory T cells infused at the time of islet transplantation can improve the survival of islets after transplantation and reduce the need for immunosuppression. The purpose of this study is to evaluate the feasibility and safety of combining an islet transplant with the recipient's Tregs OR deceased donor bone marrow cells in patients with brittle type 1 diabetes.

Eligibility criteria: Inclusion Criteria:

* Male and female patients age 18 to 70 years of age.
* Ability to provide written informed consent.
* Mentally stable and able to comply with the procedures of the study protocol.
* Clinical history compatible with T1D with onset of disease at \< 45 years of age, insulin- dependence for ≥ 5 years at the time of enrollment, or a sum of patient age and insulin dependent diabetes duration of ≥ 28.
* Absence of stimulated C peptide (\< 0.3 ng/mL) in response to a mixed meal tolerance test measured at 60 and 90 minutes after the start of consumption
* 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.
* At least two episodes of severe hypoglycemia in the 12 months prior to study enrollment.
* Reduced awareness of hypoglycemia as defined by a Clarke score of 4 or more OR a HYPO score greater than or equal to the 90th percentile (1047) during the screening period and within the last 6 months prior to randomization.
* Women of childbearing potential may be enrolled if a pregnancy test is negative, and they agree to the use of 2 forms of contraception from Screening to the end of the study. Males must agree to use 2 forms of contraception from Screening to the end of the study if their partners are of childbearing potential.
* Acceptable methods of birth control which must be used together are:

  * Oral contraceptive and condom (combination oral contraceptives containing the second- generation progestin (levonorgestrel) and \<30 μg of estrogen should be utilized),
  * IUD and condom,
  * Diaphragm with spermicide and condom
* Subject must complete training on how to use the Tandem X2 pump with Control IQ technology by a certified Diabetes Educator or physician. Patients must complete at least 2 hour training to the satisfaction of the educator and show proficiency and understanding in its use as judged by the educator.
* Patients with prior kidney transplantation on immunosuppressive medications are eligible provided they meet all eligibility criteria above excluding the need for hypoglycemia unawareness. Patients should not be candidates for solid organ pancreas transplant or have declined the surgical option.
* Exclusion Criteria:
* Body mass index (BMI) \>30 kg/m2 or patient weight ≤50kg.
* Insulin requirement of \>1.0 IU/kg/day or \<15 U/day. 3. HbA1c \>10%.
* Treatment with any anti-diabetic medication other than insulin within 4 weeks of Screening
* Untreated proliferative diabetic retinopathy.
* Blood Pressure: SBP \>180 mmHg or DBP \>100 mmHg on optimal treatment.
* Estimated glomerular filtration rate of \<50 mL/min/1.73m2.
* Presence or history of macroalbuminuria (\>500mg/g creatinine).
* Presence or history of panel-reactive anti-HLA antibodies \>50%. Negative cross- match by flow cytometry and no DSA to organ donor by standard methods.
* 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 participants: intent to procreate during the duration of the study or within 4 months after discontinuation or unwillingness to use effective measures of contraception
* Presence 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.
* Negative screen for Epstein-Barr Virus (EBV) by IgG determination.
* Invasive aspergillus, histoplasmosis, or coccidioidomycosis infection within one year prior to study enrollment.
* Any history of malignancy except for completely resected squamous or basal cell carcinoma of the skin.
* Known active alcohol or substance abuse.
* Baseline Hb below the lower limits of normal; neutropenia (\<1,500/7L), or thrombocytopenia (platelets \<100,000/7L).
* Any coagulopathy or medical condition requiring long-term anticoagulant therapy (e.g., warfarin) after islet transplantation (low-dose aspirin treatment is allowed) or patients with an international normalized ratio (INR) \>1.5.
* Severe co-existing cardiac disease, characterized by any one of these conditions:

  * recent myocardial infarction (within past 6 months).
  * evidence of uncorrectable ischemia on functional cardiac exam within the last year.
  * left ventricular ejection fraction \<30%.
* Persistent elevation of liver function tests at the time of study entry. Persistent serum glutamic-oxaloacetic transaminase (SGOT \[AST\]), serum glutamate pyruvate transaminase (SGPT \[ALT\]), or total bilirubin, with values \> 1.5 times normal upper limits will exclude a patient.
* Acute or chronic pancreatitis.
* Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment.
* Use of any investigational agents within 4 or more weeks of enrollment, depending upon the pharmacokinetics of the investigational agent and durability of changes with treatment in immune function or glycemic regulation.
* Administration of live attenuated vaccine(s) within 2 months of enrollment.
* Any medical condition that, in the opinion of the investigator, will interfere with safe participation in the trial.
* A previous islet transplant.
* History of medical non-adherence or poor social support.
* Individuals with selective IgA deficiencies (IgA level less than 15 mg/dL) who have known antibody against IgA.

Primary outcomes:
measure: Occurrence of Grade 3 to 5 cytokine release syndrome / acute infusion reaction after Treg administration infusion reaction after Treg administration
timeFrame: within 3 months
measure: Occurrence of grade 4 or greater adverse events of islet transplantation
timeFrame: Within two years
measure: Number of patients who receive Treg infusions (Arm1) or Donor Derived Vertebral Bone Marrow (Arm2) and islet transplantation (feasibility)
timeFrame: Within two years
Secondary outcomes:
measure: HbA1c ≤6.5%
timeFrame: assessed at 6, 12 and 24 months post-islet transplantation
measure: Absence of severe hypoglycemic events
timeFrame: assessed at 6, 12 and 24 months post-islet transplantation
measure: Decrease of insulin mean requirements (u/kg) from prior to transplantation by 50% of total daily dose
timeFrame: assessed at 6, 12 and 24 months post-islet transplantation
measure: Clarke hypoglycemia severity (HYPO) score less than 2 (0 to >4, >4 indicate severe hypoglycemia unawareness)
timeFrame: assessed at 6, 12 and 24 months post-islet transplantation
measure: Basal C-peptide at levels e >0.5 ng/mL (>0.17 nmol/L) fasting or stimulated.
timeFrame: assessed at 6, 12 and 24 months post-islet transplantation
measure: Target of glucose variability and hypoglycemia duration derived from the CGMS <Standard Deviation and Coefficient targets>
timeFrame: assessed at 6, 12 and 24 months post-islet transplantation
measure: Measurement of donor Specific Antibody, cPRA
timeFrame: assessed at 6, 12 and 24 months post-islet transplantation
measure: Quality of life (QOL) assessment
timeFrame: assessed at 6, 12 and 24 months post-islet transplantation
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University
state: California
Study officials:
affiliation: Stanford University
name: Stephan Busque, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ryan EA, Shandro T, Green K, Paty BW, Senior PA, Bigam D, Shapiro AM, Vantyghem MC. Assessment of the severity of hypoglycemia and glycemic lability in type 1 diabetic subjects undergoing islet transplantation. Diabetes. 2004 Apr;53(4):955-62. doi: 10.2337/diabetes.53.4.955.
citation: Kessler L, Passemard R, Oberholzer J, Benhamou PY, Bucher P, Toso C, Meyer P, Penfornis A, Badet L, Wolf P, Colin C, Morel P, Pinget M; GRAGIL Group. Reduction of blood glucose variability in type 1 diabetic patients treated by pancreatic islet transplantation: interest of continuous glucose monitoring. Diabetes Care. 2002 Dec;25(12):2256-62. doi: 10.2337/diacare.25.12.2256.
citation: Streja D. Can continuous glucose monitoring provide objective documentation of hypoglycemia unawareness? Endocr Pract. 2005 Mar-Apr;11(2):83-90. doi: 10.4158/EP.11.2.83.
citation: Diabetes Control and Complications Trial Research Group; Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, Rand L, Siebert C. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993 Sep 30;329(14):977-86. doi: 10.1056/NEJM199309303291401.
citation: Hirsch IB. Insulin analogues. N Engl J Med. 2005 Jan 13;352(2):174-83. doi: 10.1056/NEJMra040832. No abstract available.
citation: Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care. 2003 Jun;26(6):1902-12. doi: 10.2337/diacare.26.6.1902.
citation: Gold AE, MacLeod KM, Frier BM. Frequency of severe hypoglycemia in patients with type I diabetes with impaired awareness of hypoglycemia. Diabetes Care. 1994 Jul;17(7):697-703. doi: 10.2337/diacare.17.7.697.
citation: Larsen JL. Pancreas transplantation: indications and consequences. Endocr Rev. 2004 Dec;25(6):919-46. doi: 10.1210/er.2002-0036.
citation: Cryer PE, Fisher JN, Shamoon H. Hypoglycemia. Diabetes Care. 1994 Jul;17(7):734-55. doi: 10.2337/diacare.17.7.734. No abstract available.
citation: Ryan EA, Paty BW, Senior PA, Bigam D, Alfadhli E, Kneteman NM, Lakey JR, Shapiro AM. Five-year follow-up after clinical islet transplantation. Diabetes. 2005 Jul;54(7):2060-9. doi: 10.2337/diabetes.54.7.2060.
citation: Hering BJ, Clarke WR, Bridges ND, Eggerman TL, Alejandro R, Bellin MD, Chaloner K, Czarniecki CW, Goldstein JS, Hunsicker LG, Kaufman DB, Korsgren O, Larsen CP, Luo X, Markmann JF, Naji A, Oberholzer J, Posselt AM, Rickels MR, Ricordi C, Robien MA, Senior PA, Shapiro AM, Stock PG, Turgeon NA; Clinical Islet Transplantation Consortium. Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia. Diabetes Care. 2016 Jul;39(7):1230-40. doi: 10.2337/dc15-1988. Epub 2016 Apr 18.
citation: Krzystyniak A, Golab K, Witkowski P, Trzonkowski P. Islet cell transplant and the incorporation of Tregs. Curr Opin Organ Transplant. 2014 Dec;19(6):610-5. doi: 10.1097/MOT.0000000000000130.
citation: Pierini A, Iliopoulou BP, Peiris H, Perez-Cruz M, Baker J, Hsu K, Gu X, Zheng PP, Erkers T, Tang SW, Strober W, Alvarez M, Ring A, Velardi A, Negrin RS, Kim SK, Meyer EH. T cells expressing chimeric antigen receptor promote immune tolerance. JCI Insight. 2017 Oct 19;2(20):e92865. doi: 10.1172/jci.insight.92865.
citation: Cryer PE. Banting Lecture. Hypoglycemia: the limiting factor in the management of IDDM. Diabetes. 1994 Nov;43(11):1378-89. doi: 10.2337/diab.43.11.1378.
citation: Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000 Jul 27;343(4):230-8. doi: 10.1056/NEJM200007273430401.
citation: Markmann JF, Deng S, Huang X, Desai NM, Velidedeoglu EH, Lui C, Frank A, Markmann E, Palanjian M, Brayman K, Wolf B, Bell E, Vitamaniuk M, Doliba N, Matschinsky F, Barker CF, Naji A. Insulin independence following isolated islet transplantation and single islet infusions. Ann Surg. 2003 Jun;237(6):741-9; discussion 749-50. doi: 10.1097/01.SLA.0000072110.93780.52.
citation: Meyer EH, Laport G, Xie BJ, MacDonald K, Heydari K, Sahaf B, Tang SW, Baker J, Armstrong R, Tate K, Tadisco C, Arai S, Johnston L, Lowsky R, Muffly L, Rezvani AR, Shizuru J, Weng WK, Sheehan K, Miklos D, Negrin RS. Transplantation of donor grafts with defined ratio of conventional and regulatory T cells in HLA-matched recipients. JCI Insight. 2019 May 16;4(10):e127244. doi: 10.1172/jci.insight.127244. eCollection 2019 May 16.
citation: Huber BC, Ransohoff JD, Ransohoff KJ, Riegler J, Ebert A, Kodo K, Gong Y, Sanchez-Freire V, Dey D, Kooreman NG, Diecke S, Zhang WY, Odegaard J, Hu S, Gold JD, Robbins RC, Wu JC. Costimulation-adhesion blockade is superior to cyclosporine A and prednisone immunosuppressive therapy for preventing rejection of differentiated human embryonic stem cells following transplantation. Stem Cells. 2013 Nov;31(11):2354-63. doi: 10.1002/stem.1501.
citation: Bellacen K, Kalay N, Ozeri E, Shahaf G, Lewis EC. Revascularization of pancreatic islet allografts is enhanced by alpha-1-antitrypsin under anti-inflammatory conditions. Cell Transplant. 2013;22(11):2119-33. doi: 10.3727/096368912X657701. Epub 2012 Oct 8.
citation: Hubbard RC, Sellers S, Czerski D, Stephens L, Crystal RG. Biochemical efficacy and safety of monthly augmentation therapy for alpha 1-antitrypsin deficiency. JAMA. 1988 Sep 2;260(9):1259-64.
citation: Baranovski BM, Ozeri E, Shahaf G, Ochayon DE, Schuster R, Bahar N, Kalay N, Cal P, Mizrahi MI, Nisim O, Strauss P, Schenker E, Lewis EC. Exploration of alpha1-antitrypsin treatment protocol for islet transplantation: dosing plan and route of administration. J Pharmacol Exp Ther. 2016 Dec;359(3):482-490. doi: 10.1124/jpet.116.236067. Epub 2016 Nov 7.
citation: Weir GC, Ehlers MR, Harris KM, Kanaparthi S, Long A, Phippard D, Weiner LJ, Jepson B, McNamara JG, Koulmanda M, Strom TB; ITN RETAIN Study Team. Alpha-1 antitrypsin treatment of new-onset type 1 diabetes: An open-label, phase I clinical trial (RETAIN) to assess safety and pharmacokinetics. Pediatr Diabetes. 2018 Aug;19(5):945-954. doi: 10.1111/pedi.12660. Epub 2018 May 7.
citation: Koulmanda M, Bhasin M, Fan Z, Hanidziar D, Goel N, Putheti P, Movahedi B, Libermann TA, Strom TB. Alpha 1-antitrypsin reduces inflammation and enhances mouse pancreatic islet transplant survival. Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15443-8. doi: 10.1073/pnas.1018366109. Epub 2012 Sep 4.
citation: Wang J, Sun Z, Gou W, Adams DB, Cui W, Morgan KA, Strange C, Wang H. alpha-1 Antitrypsin Enhances Islet Engraftment by Suppression of Instant Blood-Mediated Inflammatory Reaction. Diabetes. 2017 Apr;66(4):970-980. doi: 10.2337/db16-1036. Epub 2017 Jan 9.
citation: Berger M, Liu M, Uknis ME, Koulmanda M. Alpha-1-antitrypsin in cell and organ transplantation. Am J Transplant. 2018 Jul;18(7):1589-1595. doi: 10.1111/ajt.14756. Epub 2018 Apr 24.
citation: Taylor GD, Kirkland T, Lakey J, Rajotte R, Warnock GL. Bacteremia due to transplantation of contaminated cryopreserved pancreatic islets. Cell Transplant. 1994 Jan-Feb;3(1):103-6. doi: 10.1177/096368979400300114.
citation: Lloveras J, Farney AC, Sutherland DE, Wahoff D, Field J, Gores PF. Significance of contaminated islet preparations in clinical islet transplantation. Transplant Proc. 1994 Apr;26(2):579-80. No abstract available.
citation: Rickels MR, Kamoun M, Kearns J, Markmann JF, Naji A. Evidence for allograft rejection in an islet transplant recipient and effect on beta-cell secretory capacity. J Clin Endocrinol Metab. 2007 Jul;92(7):2410-4. doi: 10.1210/jc.2007-0172. Epub 2007 May 8.
citation: Rickels MR, Kearns J, Markmann E, Palanjian M, Markmann JF, Naji A, Kamoun M. HLA sensitization in islet transplantation. Clin Transpl. 2006:413-20.
citation: Olack BJ, Swanson CJ, Flavin KS, Phelan D, Brennan DC, White NH, Lacy PE, Scharp DW, Poindexter N, Mohanakumar T. Sensitization to HLA antigens in islet recipients with failing transplants. Transplant Proc. 1997 Jun;29(4):2268-9. doi: 10.1016/s0041-1345(97)00327-8. No abstract available.
citation: Mao Q, Terasaki PI, Cai J, Briley K, Catrou P, Haisch C, Rebellato L. Extremely high association between appearance of HLA antibodies and failure of kidney grafts in a five-year longitudinal study. Am J Transplant. 2007 Apr;7(4):864-71. doi: 10.1111/j.1600-6143.2006.01711.x.
citation: Terasaki PI, Ozawa M. Predicting kidney graft failure by HLA antibodies: a prospective trial. Am J Transplant. 2004 Mar;4(3):438-43. doi: 10.1111/j.1600-6143.2004.00360.x.
citation: Terasaki PI, Ozawa M, Castro R. Four-year follow-up of a prospective trial of HLA and MICA antibodies on kidney graft survival. Am J Transplant. 2007 Feb;7(2):408-15. doi: 10.1111/j.1600-6143.2006.01644.x. Epub 2007 Jan 4.
citation: Epidemiology of severe hypoglycemia in the diabetes control and complications trial. The DCCT Research Group. Am J Med. 1991 Apr;90(4):450-9.
citation: Ramsay RC, Goetz FC, Sutherland DE, Mauer SM, Robison LL, Cantrill HL, Knobloch WH, Najarian JS. Progression of diabetic retinopathy after pancreas transplantation for insulin-dependent diabetes mellitus. N Engl J Med. 1988 Jan 28;318(4):208-14. doi: 10.1056/NEJM198801283180403.
citation: Hirshberg B, Rother KI, Digon BJ 3rd, Lee J, Gaglia JL, Hines K, Read EJ, Chang R, Wood BJ, Harlan DM. Benefits and risks of solitary islet transplantation for type 1 diabetes using steroid-sparing immunosuppression: the National Institutes of Health experience. Diabetes Care. 2003 Dec;26(12):3288-95. doi: 10.2337/diacare.26.12.3288.
citation: Ryan EA, Lakey JR, Paty BW, Imes S, Korbutt GS, Kneteman NM, Bigam D, Rajotte RV, Shapiro AM. Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes. 2002 Jul;51(7):2148-57. doi: 10.2337/diabetes.51.7.2148.
citation: Ryan EA, Paty BW, Senior PA, Shapiro AM. Risks and side effects of islet transplantation. Curr Diab Rep. 2004 Aug;4(4):304-9. doi: 10.1007/s11892-004-0083-8.
citation: Froud T, Yrizarry JM, Alejandro R, Ricordi C. Use of D-STAT to prevent bleeding following percutaneous transhepatic intraportal islet transplantation. Cell Transplant. 2004;13(1):55-9. doi: 10.3727/000000004772664897.
citation: Hering BJ, Kandaswamy R, Ansite JD, Eckman PM, Nakano M, Sawada T, Matsumoto I, Ihm SH, Zhang HJ, Parkey J, Hunter DW, Sutherland DE. Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes. JAMA. 2005 Feb 16;293(7):830-5. doi: 10.1001/jama.293.7.830.
citation: Manciu N, Beebe DS, Tran P, Gruessner R, Sutherland DE, Belani KG. Total pancreatectomy with islet cell autotransplantation: anesthetic implications. J Clin Anesth. 1999 Nov;11(7):576-82. doi: 10.1016/s0952-8180(99)00100-2.
citation: Froberg MK, Leone JP, Jessurun J, Sutherland DE. Fatal disseminated intravascular coagulation after autologous islet transplantation. Hum Pathol. 1997 Nov;28(11):1295-8. doi: 10.1016/s0046-8177(97)90204-5.
citation: Mehigan DG, Bell WR, Zuidema GD, Eggleston JC, Cameron JL. Disseminated intravascular coagulation and portal hypertension following pancreatic islet autotransplantation. Ann Surg. 1980 Mar;191(3):287-93. doi: 10.1097/00000658-198003000-00006.
citation: Mittal VK, Toledo-Pereyra LH, Sharma M, Ramaswamy K, Puri VK, Cortez JA, Gordon D. Acute portal hypertension and disseminated intravascular coagulation following pancreatic islet autotransplantation after subtotal pancreatectomy. Transplantation. 1981 Apr;31(4):302-4. No abstract available.