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Clinical Islet Transplantation (Cit) Protocol Number Clinical Islet Transplantation (CIT) CONFIDENTIAL Page 1 of 113 CLINICAL ISLET TRANSPLANTATION (CIT) PROTOCOL NUMBER: CIT-03 Multi-center, open-label clinical trial of the efficacy of peritransplant administration of deoxyspergualin in promoting restoration of insulin independence after single-donor islet allotransplantation in non-uremic type 1 diabetic recipients Peritransplant deoxyspergualin in islet transplantation in type 1 diabetes Version 7.0 04 October 2012 BB-IND 9336 Study Sponsors: The National Institute of Allergy and Infectious Diseases (NIAID) The National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) Drug Manufacturer: Nippon Kayaku Co., Ltd. Representative in Europe and U.S.: Disphar International B.V CIT PRINCIPAL INVESTIGATORS MEDICAL MONITOR BERNHARD HERING, MD NANCY BRIDGES, MD University of Minnesota Chief, Clinical Transplantation Immunology Branch Division of Allergy, Immunology, and Transplantation XUNRONG LUO, MD, PHD National Institute of Allergy and Infectious Diseases Northwestern University 6610 Rockledge Dr.; Room 6325 Bethesda, MD 20892 ANDREW POSSELT, MD, PHD Phone: 301-451-4406 University of California, San Francisco Fax: 301-402-2571 E-mail: [email protected] BIOSTATISTICIAN SENIOR REGULATORY OFFICER WILLIAM CLARKE, PHD Julia Goldstein, MD Department of Biostatistics; CTSDMC Senior Regulatory Officer University of Iowa Division of Allergy, Immunology, and Transplantation 2400 UCC National Institute of Allergy and Infectious Diseases Iowa City, Iowa 52242 6610 Rockledge Dr. Rm 6717 Phone: 319-384-2833 Bethesda, MD 20892 Fax: 319-335-6535 Phone: 301-451-3112 E-mail: [email protected] Fax: 301-480-1537 E-mail: [email protected] Protocol Number: CIT03 Version 7.0 04 October 2012 Clinical Islet Transplantation (CIT) CONFIDENTIAL Page 2 of 113 PROJECT MANAGER Allison Priore, BS Project Manager Division of Allergy, Immunology, and Transplantation National Institute of Allergy and Infectious Diseases 6610 Rockledge Dr.; Room 6304B Bethesda, MD 20892 Phone: 301-560-4513 Fax: 301-402-2571 E-mail: [email protected] Confidentiality Statement The information contained within this document is not to be disclosed in any way without the prior permission of the CIT Principal Investigator, the Division of Allergy, Immunology and Transplantation, or the National Institute of Diabetes & Digestive & Kidney Diseases Protocol Number: CIT03 Version 7.0 04 October 2012 Clinical Islet Transplantation (CIT) CONFIDENTIAL Page 3 of 113 INVESTIGATOR SIGNATURE PAGE Protocol Number: Version/Date: CIT-03 7.0 / (04 October 2012) IND: CIT Principal Investigator: BB-IND 9336 Bernhard Hering, MD, Xunrong Luo MD, PhD, Andrew Posselt, MD, PhD Short Title: Peritransplant deoxyspergualin in islet transplantation in type 1 diabetes Study Sponsor(s): The National Institute of Allergy and Infectious Diseases (NIAID) The National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) INSTRUCTIONS: Please have the Principal Investigator print, sign, and date at the indicated location below. A copy should be kept for your records and the original signature page sent to the Data Coordinating Center. After signature, please return the original of this form by surface mail to: ATTN: Clinical Trials Statistical and Data Management Center Department of Biostatistics 201 S Clinton St Iowa City, IA 52240-4034 I confirm that I have read the above protocol in the latest version. I understand it, and I will work according to the principles of Good Clinical Practice (GCP) as described in the United States Code of Federal Regulations (CFR) – 21 CFR Parts 45, 50, 56, and 312, and the International Conference on Harmonization (ICH) document “Guidance for Industry: E6 Good Clinical Practice: Consolidated Guidance” dated April 1996. Further, I will conduct the study in keeping with local, legal, and regulatory requirements. As the Site Principal Investigator, I agree to conduct Protocol Number CIT-03, “Peritransplant deoxyspergualin in islet transplantation in type 1 diabetes”. I agree to carry out the study by the criteria written in the protocol and understand that no changes can be made to this protocol without written permission of the NIAID. ___________________________________ Site Principal Investigator (Print) ____________________________________ _________________ Site Principal Investigator (Signature) Date Protocol Number: CIT03 Version 7.0 04 October 2012 Clinical Islet Transplantation (CIT) CONFIDENTIAL Page 4 of 113 Protocol Synopsis Short Title Peritransplant deoxyspergualin in islet transplantation in type 1 diabetes Clinical Phase Phase 2 IND Sponsor DAIT/NIAID/NIH IND Number BB-IND 9336 Activation Date October 2006 Accrual Objective 14 Accrual Period 24 months Follow-up Period 24 months after the final transplant Study Design A prospective, multi-center, single-arm, open-label trial assessing the safety and efficacy of DSG on post-transplant islet function in subjects with long-standing type 1 diabetes that is refractory to intensive insulin therapy. Treatment Description Subjects will receive up to 3 separate islet transplants to achieve insulin independence. For immunosuppression, the subjects will receive ATG (1st transplant only), basiliximab (subsequent transplants only), etanercept, DSG, sirolimus and low-dose tacrolimus in an open-label fashion. Primary Endpoint The proportion of insulin-independent subjects at day 75 (± 5 days) following the first islet transplant. Secondary Endpoints The key secondary endpoint is the proportion of subjects with an HbA1c <7.0% AND free of severe hypoglycemic events from Day 28 to Day 365, inclusive, after the first islet transplant. The other secondary endpoint is the proportion of subjects with an HbA1c <7.0% AND free of severe hypoglycemic events from Day 28 to Day 365, inclusive, after the final islet transplant Secondary Efficacy Endpoints: At 75 ± 5 days following the first islet transplant and following each subsequent islet transplant(s): The percent reduction in insulin requirements HbA1c MAGE1 LI2 Ryan hypoglycemia severity (HYPO) score2 Basal (fasting) and 90-min glucose and C-peptide derived from the mixed-meal tolerance test (MMTT) β-score3 C-peptide: (glucose· creatinine) ratio Acute insulin response to glucose (AIRglu), insulin sensitivity, and disposition index (DI) derived from the insulin-modified frequently-sampled IV glucose tolerance (FSIGT)4,5 Glucose variability6 and hypoglycemia duration7 derived from the CGMS® QOL measures Protocol Number: CIT03 Version 7.0 04 October 2012 Clinical Islet Transplantation (CIT) CONFIDENTIAL Page 5 of 113 If a third transplant occurs less than 75 days after the second transplant, the 75 day endpoint data for the second transplant will not be collected. At 365 ± 14 days following the first and final islet transplant(s): The percent reduction in insulin requirements HbA1c MAGE LI Clarke score HYPO score Basal (fasting) and 90-min glucose and C-peptide (MMTT) β-score C-peptide: (glucose· creatinine) ratio Glucose variability6 and hypoglycemia duration7 derived from the CGMS® AIRglu, insulin sensitivity, and disposition index (DI) derived from the insulin-modified FSIGT4, 5 QOL measures The proportion of subjects receiving a second islet transplant The proportion of subjects receiving a third islet transplant Rate of favorable outcome at each center preparing islets (rate of subjects with an Hb1Ac <7.0% and free of severe hypoglycemic events) Secondary efficacy endpoints measured at 365+14 days following the final islet transplant will include the change in the above measures from the results obtained at 75+days following the final islet transplant. At two years (730+14 days) following the final islet transplant: The percent change from baseline insulin requirements. The number of severe hypoglycemic events from 28 days to two years. HbA1c. Clarke score. Basal (fasting) and 90-min glucose and c-peptide (MMTT). β-score. C-peptide: (glucose• creatinine) ratio. CGMS. QOL Secondary Safety Endpoints: Safety, including incidence of post-transplant infections, malignancies, morbidity, and other AES (e.g., increased body weight and hypertension) associated with conventional immunosuppression. Renal function as measured by serum creatinine, GFR and other relevant laboratory parameters. Protocol Number: CIT03 Version 7.0 04 October 2012 Clinical Islet Transplantation (CIT) CONFIDENTIAL Page 6 of 113 Lipid profiles (triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol) over time. At 75 ± 5 days following each transplant and 365 ± 14 days following the first and final islet transplant and at two years following the final islet transplant: The incidence and severity of AEs related to the islet transplant procedure including: bleeding (> 2 g/dL decrease in Hb concentration); segmental portal vein thrombosis; biliary puncture; wound complication (infection or subsequent hernia); and increased transaminase levels (> 5 times upper limit of normal [ULN]) The incidence and severity of AEs related to the immunosuppression including: allergy; reduction in GFR; increase in urinary albumin excretion; addition or intensification of anti-hypertensive therapy; addition or intensification of anti- hyperlipidemic therapy; oral ulcers; lower extremity edema; gastrointestinal toxicity; neutropenia, anemia, or thrombocytopenia; viral, bacterial, or fungal infections; and benign or malignant neoplasms The incidence of a change in the immunosuppression drug regimen The incidence
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