National Institutes of Health–Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities

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Abstract

Eight manufacturing facilities participating in the National Institutes of Health–sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects with type 1 diabetes. Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis, and test methods. The process was compliant with Current Good Manufacturing Practices and Current Good Tissue Practices. This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results, including lot release. The results demonstrate the feasibility of implementing a harmonized process at multiple facilities for the manufacture of a complex cellular product. The quality systems and regulatory and operational strategies developed by the CIT Consortium yielded product lots that met the prespecified characteristics of safety, purity, potency, and identity and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no cases of primary nonfunction were observed.

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Improvement in Outcomes of Clinical Islet Transplantation: 1999–2010

Franca B Barton, Michael Rickels, Rodolfo Alejandro … (2012)

OBJECTIVE To describe trends of primary efficacy and safety outcomes of islet transplantation in type 1 diabetes recipients with severe hypoglycemia from the Collaborative Islet Transplant Registry (CITR) from 1999 to 2010. RESEARCH DESIGN AND METHODS A total of 677 islet transplant-alone or islet-after-kidney recipients with type 1 diabetes in the CITR were analyzed for five primary efficacy outcomes and overall safety to identify any differences by early (1999–2002), mid (2003–2006), or recent (2007–2010) transplant era based on annual follow-up to 5 years. RESULTS Insulin independence at 3 years after transplant improved from 27% in the early era (1999–2002, n = 214) to 37% in the mid (2003–2006, n = 255) and to 44% in the most recent era (2007–2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone). C-peptide ≥0.3 ng/mL, indicative of islet graft function, was retained longer in the most recent era (P < 0.001). Reduction of HbA1c and resolution of severe hypoglycemia exhibited enduring long-term effects. Fasting blood glucose stabilization also showed improvements in the most recent era. There were also modest reductions in the occurrence of adverse events. The islet reinfusion rate was lower: 48% by 1 year in 2007–2010 vs. 60–65% in 1999–2006 (P < 0.01). Recipients that ever achieved insulin-independence experienced longer duration of islet graft function (P < 0.001). CONCLUSIONS The CITR shows improvement in primary efficacy and safety outcomes of islet transplantation in recipients who received transplants in 2007–2010 compared with those in 1999–2006, with fewer islet infusions and adverse events per recipient.

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Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes.

P S Eckman, Sung-Hee Ihm, Tian-Zi Zhang … (2005)

Islet allografts from 2 to 4 donors can reverse type 1 diabetes. However, for islet transplants to become a widespread clinical reality, diabetes reversal must be achieved with a single donor to reduce risks and costs and increase the availability of transplantation. To assess the safety of a single-donor, marginal-dose islet transplant protocol using potent induction immunotherapy and less diabetogenic maintenance immunosuppression in recipients with type 1 diabetes. A secondary objective was to assess the proportion of islet transplant recipients who achieve insulin independence in the first year after single-donor islet transplantation. Prospective, 1-year follow-up trial conducted July 2001 to August 2003 at a single US center and enrolling 8 women with type 1 diabetes accompanied by recurrent hypoglycemia unawareness or advanced secondary complications. Study participants underwent a primary islet allotransplant with 7271 (SD, 1035) islet equivalents/kg prepared from a single cadaver donor pancreas. Induction immunosuppression was with antithymocyte globulin, daclizumab, and etanercept. Maintenance immunosuppression consisted of mycophenolate mofetil, sirolimus, and no or low-dose tacrolimus. Safety (assessed by monitoring the severity and duration of adverse events) and efficacy (assessed by studying the recipients' insulin requirements, C-peptide levels, oral and intravenous glucose tolerance results, intravenous arginine stimulation responses, glycosylated hemoglobin levels, and hypoglycemic episodes) associated with the study transplant protocol. There were no serious, unexpected, or procedure- or immunosuppression-related adverse events. All 8 recipients achieved insulin independence and freedom from hypoglycemia. Five remained insulin-independent for longer than 1 year. Graft failure in 3 recipients was preceded by subtherapeutic sirolimus exposure in the absence of measurable tacrolimus trough levels. The tested transplant protocol restored insulin independence and protected against hypoglycemia after single-donor, marginal-dose islet transplantation in 8 of 8 recipients. These results may be related to improved islet engraftment secondary to peritransplant administration of antithymocyte globulin and etanercept. These findings may have implications for the ongoing transition of islet transplantation from clinical investigation to routine clinical care.

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Variables in organ donors that affect the recovery of human islets of Langerhans.

M. Belén Suárez, N. Kneteman, Z Ao … (1996)

In an attempt to reduce the variability in the yields of human islets isolations and to identify donor factors that were potentially deleterious, we retrospectively reviewed 153 human islets isolations in our center over a 3-year period. Isolations were performed using controlled collagenase perfusion via the duct, automated dissociation, and Ficoll purification. Factors leading to successful isolations (recovery of >100,000 islet equivalents at a purity >50%) were analyzed retrospectively using univariate and multivariate analysis. Critical factors in the multiorgan cadaveric donors that were identified using univariate analysis included donor age (P 15 min) requiring high vasopressors (>15 microgram/kg/min dopamine or >5 microgram/kg/min Levophed) (P>0.01). Independent analysis of 19 donor variables using multivariate logistic stepwise regression showed six factors were statistically significant. Odds ratio (OR) showed that donor age (OR 1.1, P 10 mmol/L) (OR 0.63, P 50-year-old donor group was significantly reduced as compared with the 2.5- to 18-year-old group (P<0.02). Multiple regression analysis using postdigestion and postpurification islet recovery as outcome variables identified BMI, procurement team, pancreas weight, and collagenase digestion time factors tht can affect the recovery of human islets. Locally procured pancreases and donors with elevated minimum blood glucose levels were identified as factors that affect the insulin secretory capabilities of the isolated islets. This review of parameters suggests an improved approach to the prediction of successful islet isolation from human pancreases. Selection of suitable pancreases for processing may improve consistency in human islet isolation and thereby decrease costs.

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Author and article information

Journal

Journal ID (nlm-ta): Diabetes

Journal ID (iso-abbrev): Diabetes

Journal ID (hwp): diabetes

Journal ID (pmc): diabetes

Journal ID (publisher-id): Diabetes

Title: Diabetes

Publisher: American Diabetes Association

ISSN (Print): 0012-1797

ISSN (Electronic): 1939-327X

Publication date (Print): November 2016

Publication date (Electronic): 27 July 2016

Volume: 65

Issue: 11

Pages: 3418-3428

Affiliations

[1] ¹Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL

[2] ²National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

[3] ³Schulze Diabetes Institute and Department of Surgery, University of Minnesota, Minneapolis, MN

[4] ⁴Department of Surgery, University of California, San Francisco, San Francisco, CA

[5] ⁵Clinical Islet Transplant Program and Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada

[6] ⁶Institute for Diabetes, Obesity and Metabolism and Departments of Surgery and Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA

[7] ⁷Division of Transplantation, University of Illinois Hospital and Health Sciences System, Chicago, IL

[8] ⁸Division of Transplantation, Department of Surgery, Emory Transplant Center, Emory University, Atlanta, GA

[9] ⁹Clinical Trials Statistical and Data Management Center, University of Iowa, Iowa City, IA

[10] ¹⁰National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD

[11] ¹¹Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL

[12] ¹²Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA

[13] ¹³Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden

[14] ¹⁴Department of Clinical Immunology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

Author notes

Corresponding authors: Camillo Ricordi, ricordi@ 123456miami.edu , and Julia S. Goldstein, goldsteinj@ 123456niaid.nih.gov .

C.R., J.S.G., A.N.B., G.L.S., T.K., C.L., and C.W.C. are the primary authors who contributed equally to this work.

B.J.H., A.M.P., and A.M.J.S. are the senior authors who contributed equally to this work.

Article

Publisher ID: 0234

DOI: 10.2337/db16-0234

PMC ID: 5079635

PubMed ID: 27465220

SO-VID: dd7630c1-b2d4-4f9f-9250-f48b85aea777

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Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

History

Date received : 18 February 2016

Date accepted : 08 July 2016

Page count

Figures: 0, Tables: 6, Equations: 0, References: 53, Pages: 11

Funding

Funded by: National Institute of Allergy and Infectious Diseases;

Funded by: National Institute for Diabetes and Digestive and Kidney Diseases;

Award ID: U01-AI-089317

Award ID: U01-AI-089316

Award ID: U01-AI-065191

Award ID: U01-DK-085531

Award ID: 5U01-DK-070431-10

Award ID: U01-DK-070431

Award ID: U01-DK-070460

Award ID: U01-AI-065193

Award ID: U01-DK-070430

Award ID: U01-AI- 065192

Funded by: General Clinical Research Center Awards and Clinical and Translational Science Awards;

Award ID: UL1-TR-000454

Award ID: 5UL1-RR-025741

Award ID: 8UL1-TR-000150

Award ID: UL1-TR-000004

Award ID: UL1-TR-000050

Award ID: 1UL1-TR-000460

Award ID: 5M01-RR-000400

Award ID: UL1-TR-000114

Award ID: M01-RR-00040

Award ID: UL1-TR-000003

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National Institutes of Health–Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities

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Journal of the ASEAN Federation of Endocrine Societies

Most cited references 25

Improvement in Outcomes of Clinical Islet Transplantation: 1999–2010

Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes.

Variables in organ donors that affect the recovery of human islets of Langerhans.

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