Multicenter Trial of the Effect of AAT on Islet Transplant Engraftment and Durability After Renal Transplant

NCT02464878 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: Islet after Kidney - AAT
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

Patients meeting the study entry criteria will receive 1-3 infusion(s) of in vitro cultured islets. Patients will receive three times a week AAT infusions in the peri-transplant period for three weeks.

Conditions

Kidney Transplant; Type 1 Diabetes

Outcome Measures

Primary Outcomes (1)

• The Proportion of GLASSIA Versus Control CIT06 Subjects Achieving Insulin Independence After First Infusion of Single Donor Islets.

  Insulin Independence examined 75 days after 1st infusion; subject considered to be insulin independent if they are able to titrate off insulin therapy for \<1 week AND all of the following are met: 1. one HbA1c level, one fasting serum glucose level, and a Mixed Meal Tolerance Test (MMTT) documented within the visit window at Day 75 (Day 70-80) and 7 days of blood sugar and insulin readings are documented within +/- 7 days of the visit window (Day 63-87); 2. HbA1c \</= 6.5% or a \>/= 2.5% decrease from baseline (within 91 days prior to transplant); 3. fasting capillary glucose level should not exceed 140 mg/dL more than 3 times in 7 consecutive days; 4. post-prandial serum glucose \</= 180 mg/dL at 90 minutes during MMTT; 5. fasting serum glucose level \</= 126 mg/dL; (6) at least one MMTT fasting or stimulated c-peptide \>/= 0.5 ng/mL

  Day 75

Secondary Outcomes (8)

• The Proportion of GLASSIA Treated Versus Control CIT06 Subjects Who Are Insulin Independent After 1 or More Islet Infusions

  1 year after the first islet infusion, 1 year after the last islet infusion, 2 years after the first islet infusion, 2 years after the last islet infusion

• The Proportion of GLASSIA Treated Versus CIT06 Control Subjects With Both an HbA1c ≤ 6.5% AND an Absence of Severe Hypoglycemic Events

  From Day 28 to Day 365 after the first islet transplant, From Day 28 to Day 730 after the first islet transplant.

• The Proportion of GLASSIA Treated Versus Control Subjects With Both an HbA1c < 7.0% AND Free of Severe Hypoglycemic Events

  From Day 28 to Day 365 after the first islet transplant, From Day 28 to Day 730 after the first islet transplant.

• The Proportion of GLASSIA Treated Versus Control CIT06 Subjects A Reduction in HbA1c of 1 Point AND an Absence of Severe Hypoglycemia

  From Day 28 to Day 365 after the first islet transplant, From Day 28 to Day 730 after the first islet transplant.

• The Change in Clarke Score From Baseline in GLASSIA Treated Versus Control CIT06 Subjects

  1 year and 2 years after the first islet transplant

Study Arms (1)

Main study treatment

OTHER

Drug: Alpha 1-Antitrypsin; Procedure: Islet Transplantation; Drug: Thymoglobulin; Drug: Basiliximab; Drug: Etanercept

Interventions

Alpha 1-Antitrypsin DRUG

Patients will receive three times a week AAT infusions in the peri-transplant period for three weeks.

Also known as: Glassia

Main study treatment

Islet Transplantation PROCEDURE

Main study treatment

Thymoglobulin DRUG

Patients will receive a total of 5 doses between Day -2 and Day +2

Also known as: Antithymocyte Globulin

Main study treatment

Basiliximab DRUG

Basiliximab will be used for subsequent transplants.

Main study treatment

Etanercept DRUG

Etanercept will be given on the day of transplant and on Days 3, 7, and 10 post-transplant.

Also known as: Enbrel

Main study treatment

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female subjects age 18 to 70 years.
• Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol.
• Subjects must have one of the following payment mechanisms in place:
• Medicare,
• A third-party insurer who agrees, via pre-authorization, to pay for participation in the study, or
• Another mechanism of payment (self-pay, hospital, university, donations, etc.) for participation in the study.
• Clinical history compatible with T1D with disease onset \< 40 years of age and insulin-dependence for ≥ 5 years at the time of enrollment.
• Absent stimulated c-peptide (\< 0.3 ng/mL) in response to a MMTT \[Boost® 6 mL/kg body weight (BW) to a maximum of 360 mL; another product with equivalent caloric and nutrient content may be substituted for Boost®\] measured at 60 and 90 min after start of consumption.
• Subjects who are ≥ 3 months post-renal transplant who are taking appropriate calcineurin inhibitor (CNI) based maintenance immunosuppression (\[tacrolimus alone or in conjunction with sirolimus, mycophenolate mofetil, myfortic, or azathioprine; or cyclosporine in conjunction with sirolimus, mycophenolate mofetil, or myfortic\] ± Prednisone ≤ 10 mg/day).
• Stable renal function as defined by a creatinine of no more than one third greater than the average creatinine determination performed in the 3 previous months prior to islet transplantation, until rejection, obstruction or infection is ruled out.
• Subjects who meet one of the options in the following criterion are eligible for transplantation:
• Reduced awareness of hypoglycemia manifested by a Clarke score of 4 or more measured upon study enrollment and at least one episode of severe hypoglycemia in the 12 months prior to study enrollment.
• A subject must have a reduced awareness of hypoglycemia manifested by a Clarke score of 4 or more and at least 1 episode of severe hypoglycemia;
• Any subject not meeting the hypoglycemia option must have an HbA1c \> 7.5%.

You may not qualify if:

• Weight more than 100 kg or body mass index (BMI) \> 33 kg/m2.
• Insulin requirement of \>1.0 U/kg/day or, \> 60 U/day total, or \<15 U/day.
• Other (non-kidney) organ transplants except prior failed pancreatic graft where graft failure is attributed to thrombosis within the first 4 weeks or to other technical reasons that require graft pancreatectomy; with the graft pancreatectomy occurring more than 6 months ago.
• Untreated or unstable proliferative diabetic retinopathy.
• Blood Pressure: SBP \> 160 mmHg or DBP \>100 mmHg despite treatment with antihypertensive agents.
• Calculated GFR of ≤ 40 mL/min/1.73 m2 using the subject's measured serum creatinine and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation1. Strict vegetarians (vegans) will be excluded only if their estimated GFR is ≤ 35 mL/min/1.73 m2.
• \. Proteinuria (albumin/creatinine ratio or ACr \> 300mg/g) of new onset since kidney transplantation.
• Calculated panel-reactive anti-HLA antibodies \> 50%. Subjects with calculated panel reactive anti-HLA antibodies ≤ 50% will be excluded if any of the following are detected:
• Positive cross-match,
• Islet donor-directed anti-HLA antibodies detected by Luminex Single Antigen/specificity bead assay including weakly reactive antibodies that would not be detected by a flow cross-match, or
• Antibodies to the renal donor (i.e. presumed de novo).
• 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.
• 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.
• Negative screen for Epstein-Barr virus (EBV) by IgG determination at time of screening or previous kidney transplant.
• Invasive aspergillus, histoplasmosis, and coccidoidomycosis infection within the last year.

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator
• University of Iowa: collaborator

Study Sites (1)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

alpha 1-Antitrypsin; Islets of Langerhans Transplantation; thymoglobulin; Antilymphocyte Serum; Basiliximab; Etanercept

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Glycoproteins; Glycoconjugates; Carbohydrates; Serpins; Peptides; Amino Acids, Peptides, and Proteins; Acute-Phase Proteins; Blood Proteins; Proteins; Alpha-Globulins; Serum Globulins; Globulins; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Endocrine Surgical Procedures; Surgical Procedures, Operative; Transplantation; Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Biological Products; Complex Mixtures; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Immunoglobulin Fc Fragments; Immunoglobulin Fragments; Peptide Fragments; Immunoglobulin Constant Regions; Receptors, Tumor Necrosis Factor; Receptors, Cytokine; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins

Results Point of Contact

• Title: James Markmann
• Organization: Massachusetts General Hospital

jmarkmann@mgh.harvard.edu

617-643-4533

Study Officials

• Jim Markmann, M.D. Ph.D.

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief, Division of Transplant Surgery

Study Record Dates

• First Submitted: June 3, 2015
• First Posted: June 8, 2015
• Study Start: January 1, 2017
• Primary Completion: November 1, 2022
• Study Completion: December 1, 2022
• Last Updated: December 22, 2023
• Results First Posted: December 22, 2023

Record last verified: 2023-11

Locations

US (1)