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

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ClinicalTrials.gov Identifier: NCT02464878
Recruitment Status : Recruiting
First Posted : June 8, 2015
Last Update Posted : March 21, 2018
Sponsor:
Collaborators:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Iowa
Information provided by (Responsible Party):
James F. Markmann, MD, PhD, Massachusetts General Hospital

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.

Condition or disease Intervention/treatment Phase
Kidney Transplant Type 1 Diabetes Drug: Alpha 1-Antitrypsin Procedure: Islet Transplantation Drug: Thymoglobulin Drug: Basiliximab Drug: Etanercept Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Study Start Date : January 2017
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : January 2020

Resource links provided by the National Library of Medicine



Intervention Details:
  • Drug: Alpha 1-Antitrypsin
    Patients will receive three times a week AAT infusions in the peri-transplant period for three weeks.
    Other Name: Glassia
  • Procedure: Islet Transplantation
  • Drug: Thymoglobulin
    Patients will receive a total of 5 doses between Day -2 and Day +2
    Other Name: Antithymocyte Globulin
  • Drug: Basiliximab
    Basiliximab will be used for subsequent transplants.
  • Drug: Etanercept
    Etanercept will be given on the day of transplant and on Days 3, 7, and 10 post-transplant.
    Other Name: Enbrel


Primary Outcome Measures :
  1. The proportion of GLASSIA versus control CIT06 subjects achieving insulin independence after first infusion of single donor islets. [ Time Frame: Day 75 ]
  2. Estimated engrafted islet mass by FSIGT at post islet infusion comparing Glassia treated versus control subjects. [ Time Frame: Day 75 ]

Secondary Outcome Measures :
  1. The proportion of GLASSIA treated versus control CIT06 subjects who are insulin independent after 1 or more islet infusions [ Time Frame: 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 ]
  2. Percent change from baseline insulin requirement comparing GLASSIA treated versus control CIT06 subjects [ Time Frame: Day 75, 1 year and 2 years following the first and last islet transplant(s) ]
  3. The relative functional engrafted islet mass comparing GLASSIA treated versus control CIT06 subjects using FSIGT testing [ Time Frame: Day 75 after the first islet transplant , 1 year after the first islet transplant , 2 years after the first islet transplant ]
  4. Correlation of markers of early islet loss as assessed by the rapid release of TAT, C3 and c-peptide, and insulin specific DNA with FSIGT and clinical markers of islet function [ Time Frame: Month 1 ]
  5. The proportion of GLASSIA treated versus CIT06 control subjects with both an HbA1c ≤ 6.5% AND an absence of severe hypoglycemic events [ Time Frame: From Day 28 to Day 365 after the first islet transplant, From Day 28 to Day 730 after the first islet transplant. ]
  6. The proportion of GLASSIA treated versus control subjects with both an HbA1c < 7.0% AND free of severe hypoglycemic events [ Time Frame: From Day 28 to Day 365 after the first islet transplant, From Day 28 to Day 730 after the first islet transplant. ]
  7. The proportion of GLASSIA treated versus control CIT06 subjects A reduction in HbA1c of 1 point AND an absence of severe hypoglycemia [ Time Frame: From Day 28 to Day 365 after the first islet transplant, From Day 28 to Day 730 after the first islet transplant. ]
  8. ber of severe hypoglycemic events comparing GLASSIA treated versus control CIT06 subjects [ Time Frame: 1 year and 2 years following the first and last islet transplant(s) ]
  9. HbA1c comparing GLASSIA treated versus control CIT06 subjects [ Time Frame: 1 year and 2 years following the first and last islet transplant(s) ]
  10. The change in Clarke score from baseline in GLASSIA treated versus control CIT06 subjects [ Time Frame: 1 year and 2 years after the first islet transplant ]
  11. β-score comparing GLASSIA treated versus control CIT06 subjects [ Time Frame: 1 year and 2 years following the first and last islet transplant(s) ]
  12. Glucose variability and hypoglycemia duration derived from the CGMS comparing GLASSIA treated versus control CIT06 subjects [ Time Frame: 1 year and 2 years following the first and last islet transplant(s) ]
  13. Basal (fasting) and 90-min glucose and c-peptide derived from the mixed-meal tolerance test (MMTT) comparing GLASSIA treated versus control CIT06 subjects [ Time Frame: 1 year and 2 years following the first and last islet transplant(s) ]
  14. MAGE comparing GLASSIA treated versus control CIT06 subjects [ Time Frame: 1 year and 2 years following the first and last islet transplant(s) ]
  15. Glycemic lability index (LI) comparing GLASSIA treated versus CIT06 control subjects [ Time Frame: 1 year and 2 years following the first and last islet transplant(s) ]
  16. Ryan hypoglycemia severity (HYPO) Score comparing GLASSIA treated versus control CIT06 Subjects [ Time Frame: 1 year and 2 years following the first and last islet transplant(s) ]
  17. C-peptide: (glucose· creatinine) ratio (CPGCR) comparing GLASSIA treated versus control CIT06 subjects [ Time Frame: 1 year and 2 years following the first and last islet transplant(s) ]
  18. Rate of favorable outcome at each center preparing islets (rate of subjects with HbA1c < 6.5% and absence of severe hypoglycemic events, or reduction in HbA1c of 1 point and absence of severe hypoglycemia [ Time Frame: Day 28 to Day 730 ]
  19. The proportion of subjects receiving a second islet transplant comparing GLASSIA treated versus control CIT06 subjects [ Time Frame: 1 year and 2 years following the first and last islet transplant(s) ]
  20. The proportion of subjects receiving a third islet transplant comparing GLASSIA treated versus control CIT06 subjects [ Time Frame: 1 year and 2 years following the first and last islet transplant(s) ]
  21. Cardiovascular events [death, cerebrovascular accident (CVA), myocardial infarction (MI)] and changes in atherogenic profile for GLASSIA treated versus control subjects [ Time Frame: 1 year and 2 years following the first and last islet transplant(s) ]
  22. Renal impact measures including renal allograft survival and function measured by serum creatinine (SCr) and urinary albumin creatinine ratio comparing GLASSIA treated versus control subjects [ Time Frame: 1 year and 2 years following the first and last islet transplant(s) ]

Other Outcome Measures:
  1. Assessment of the effect of AAT on serum cytokines released in the early post transplant period (1 month) comparing GLASSIA versus control subjects from CIT06 [ Time Frame: 1 month ]
    Exploratory Mechanistic Endpoints

  2. Assessment of the effect of AAT on the inflammatory gene transcriptional profile of PBL [ Time Frame: day 14 and 75 ]
    Exploratory Mechanistic Endpoints

  3. Correlation of reaching target AAT levels with metabolic outcomes [ Time Frame: 1 Year ]
    Exploratory Mechanistic Endpoints

  4. Histological survival of subcutaneous islets in subcutaneous auxiliary graft and correlation with overall graft survival [ Time Frame: 1 Year ]
    Exploratory Mechanistic Endpoints



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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:

    1. Medicare,
    2. A third-party insurer who agrees, via pre-authorization, to pay for participation in the study, or
    3. 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%.

Exclusion Criteria:

  • 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.

    7. 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.
  • Any history of malignancy except for completely resected squamous or basal cell carcinoma of the skin.
  • Known active alcohol or substance abuse.
  • Any coagulopathy or medical condition requiring long-term anticoagulant therapy (e.g. warfarin) after islet transplantation (low-dose aspirin treatment [325 mg PO] is allowed) or subjects with international normalized ratio (INR) > 1.5. The use of Plavix is allowed only in conjunction with mini- laparotomy procedure at the time of islet transplant.
  • Severe co-existing cardiac disease, characterized by any one of these conditions:

    • Recent MI (within past 6 months);
    • Evidence of ischemia on functional cardiac exam within the last year;
    • Left ventricular ejection fraction < 30%; or
    • Valvular disease requiring replacement with prosthetic valve.
  • Persistent serum glutamic-oxaloacetic transaminase (SGOT [AST]), serum glutamate pyruvate transaminase (SGPT [ALT],) alkaline phosphatase or total bilirubin, with values > 1.5 times normal upper limits will exclude a subject.
  • Active infections (except mild skin and nail fungal infections).
  • Acute or chronic pancreatitis.
  • Active peptic ulcer disease, symptomatic gallstones, or portal hypertension.
  • Use of any investigational agents within 4 weeks of enrollment.
  • Administration of live attenuated vaccine(s) within 2 months of enrollment.
  • Any medical condition that, in the opinion of the investigator, will interfere with the safe participation in the trial. (Cancer screenings should be performed per current American Cancer Society guidelines).
  • Positive screen for BK virus by polymerase chain reaction (PCR) performed at time of screening.
  • A kidney transplant patient with type 1 diabetes who has an HbA1c < 7.5 and no history of severe hypoglycemia.
  • Selective or severe IgA deficiency (levels < 5-7 mg/dL)
  • AAT deficiency (defined as < 1.0ng/mg AAT)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02464878


Contacts
Contact: James F Markmann, M.D. Ph.D. 617-643-4533 jmarkmann@mgh.harvard.edu
Contact: Kerry Crisalli, RN BSN CRCC 617-643-4087 kcrisalli@mgh.harvard.edu

Locations
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: James F Markmann, MD, PhD    617-643-4533    jmarkmann@mgh.harvard.edu   
Contact: Kerry Crisalli, RN, BSN    617-643-4087    kcrisalli@mgh.harvard.edu   
Principal Investigator: James F Markmann, MD, PhD         
Sponsors and Collaborators
Massachusetts General Hospital
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Iowa
Investigators
Principal Investigator: Jim Markmann, M.D. Ph.D. Massachusetts General Hospital

Responsible Party: James F. Markmann, MD, PhD, Chief, Division of Transplant Surgery, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT02464878     History of Changes
Other Study ID Numbers: Islet after Kidney - AAT
First Posted: June 8, 2015    Key Record Dates
Last Update Posted: March 21, 2018
Last Verified: March 2018

Studies a U.S. FDA-regulated Drug Product: Yes

Additional relevant MeSH terms:
Diabetes Mellitus, Type 1
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Etanercept
Thymoglobulin
Basiliximab
Antilymphocyte Serum
Alpha 1-Antitrypsin
Protein C Inhibitor
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Gastrointestinal Agents
Immunosuppressive Agents
Immunologic Factors
Trypsin Inhibitors
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action