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Protocol CIT-04 Clinical Islet Transplantation (CIT) CONFIDENTIAL Page 1 of 116 Protocol CIT-04 CLINICAL ISLET TRANSPLANTATION (CIT) PROTOCOL CIT-04 Islet Transplantation in Type 1 Diabetes with LEA29Y (belatacept) Maintenance Therapy LEA29Y Emory Edmonton Protocol (LEEP) Version 8.0 (17 January 2013) BB-IND 9336 Study Sponsors: The National Institute of Allergy and Infectious Diseases (NIAID) and The National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) LEA29Y Manufacturer: Bristol-Myers Squibb (BMS) CIT PRINCIPAL INVESTIGATOR MEDICAL MONITOR AM James Shapiro, MD, PhD Nancy Bridges, MD Clinical Islet Transplant Program Chief, Transplantation Immunobiology Branch University of Alberta Division of Allergy, Immunology, and Transplantation 2000 College Plaza National Institute of Allergy and Infectious Diseases 8215-112 Street 6610 Rockledge Dr.; Room 6325 Edmonton Alberta T6G 2C8 Canada Bethesda, MD 20892 Phone: 780-407-7330 Phone: 301-451-4406 Fax: 780-407-6933 Fax: 301-402-2571 E-mail: [email protected] E-mail: [email protected] Nicole Turgeon, MD SENIOR REGULATORY OFFICER Department of Surgery Division of Transplantation Julia Goldstein, MD Emory University Senior Regulatory Officer 101 Woodruff Circle, Suite 5105- WMB Division of Allergy, Immunology, and Atlanta, GA 30322 Transplantation Phone: 404-727-3257 National Institute of Allergy and Infectious Fax: 404-712-4348 Diseases Email: [email protected] 6610 Rockledge Dr. Rm 6717 Bethesda, MD 20892 Phone: 301-451-3112 Fax: 301-480-1537 E-mail: [email protected] LEA29Y Emory Edmonton Protocol (LEEP) Version 8.0 (January 17, 2013) Clinical Islet Transplantation (CIT) CONFIDENTIAL Page 2 of 116 Protocol CIT-04 BIOSTATISTICIAN PROJECT MANAGER William Clarke, PhD Allison Priore, BS Department of Biostatistics Project Manager University of Iowa, CTSDMC Division of Allergy, Immunology, and Transplantation 2400 UCC National Institute of Allergy and Infectious Diseases Iowa City, Iowa 52242 6610 Rockledge Dr. Rm 6304B Phone: 319-384-2833 Bethesda, MD 20892 Fax: 319-335-6535 Phone: 301-560-4513 E-mail: [email protected] 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 prior permission of the CIT PI, the Division of Allergy, Immunology, and Transplantation, or the National Institute of Diabetes & Digestive & Kidney Diseases. LEA29Y Emory Edmonton Protocol (LEEP) Version 8.0 (January 17, 2013) Clinical Islet Transplantation (CIT) CONFIDENTIAL Page 3 of 116 Protocol CIT-04 INVESTIGATOR SIGNATURE PAGE Protocol Number: Version / Date: CIT-04 8.0/17 January 2013 IND: CIT Principal Investigators: BB-IND 9336 James Shapiro, MD and Nicole Turgeon, MD Short Title: LEA29Y Emory Edmonton Protocol (LEEP) Study Sponsors: The National Institute of Allergy and Infectious Diseases (NIAID) and 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 & 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 CIT-04, “LEA29Y Emory Edmonton Protocol (LEEP)”according to good clinical practices. 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 LEA29Y Emory Edmonton Protocol (LEEP) Version 8.0 (January 17, 2013) Clinical Islet Transplantation (CIT) CONFIDENTIAL Page 4 of 116 Protocol CIT-04 Protocol Synopsis Title Islet Transplantation in Type I Diabetes with LEA29Y (belatacept) Maintenance Therapy Short Title LEA29Y Emory Edmonton Protocol (LEEP) Clinical Phase Phase 2 IND Sponsor DAIT/NIAID/NIH IND Number BB-IND 9336 Activation Date March 2008 Accrual Objective 10 Accrual Period 24 months Study Duration 24 months after the final transplant Study Design This trial is a prospective, two-center, open-label, pilot study of islet transplantation assessing the safety and efficacy of a steroid-free, calcineurin inhibitor-free based immunosuppressive regimen with belatacept in subjects with long-standing type 1 diabetes (T1D) 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 belatacept, basiliximab, and mycophenolate mofetil administered 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. 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 • Mean amplitude of glycemic excursions (MAGE) • Glycemic lability index (LI) • Ryan hypoglycemia severity (HYPO) score LEA29Y Emory Edmonton Protocol (LEEP) Version 8.0 (January 17, 2013) Clinical Islet Transplantation (CIT) CONFIDENTIAL Page 5 of 116 Protocol CIT-04 • Basal (fasting) and 90-min glucose and c-peptide derived from the mixed-meal tolerance test (MMTT) • β-score • C-peptide: (glucose·X 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) test • Glucose variability and hypoglycemia duration derived from the continuous glucose monitoring system® (CGMS) • Quality of life (QOL) measures (DQOL, HSQ 2.0, Hypoglycemia Fear Survey-HFS) 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·X creatinine) ratio • AIRglu, insulin sensitivity, and disposition index (DI) derived from the FSIGT test • Glucose variability and hypoglycemia duration derived from the continuous glucose monitoring system® (CGMS) • 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 HbA1c < 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 ± 5 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 • HbA1c • Clarke score • Basal (fasting) and 90-min glucose and c-peptide (MMTT) • β-score • C-peptide: (glucose• creatinine) ratio LEA29Y Emory Edmonton Protocol (LEEP) Version 8.0 (January 17, 2013) Clinical Islet Transplantation (CIT) CONFIDENTIAL Page 6 of 116 Protocol CIT-04 • 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. • 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 hemoglobin 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;
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