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Islet Transplantation in Type 1 Diabetes

11. juli 2019 opdateret af: National Institute of Allergy and Infectious Diseases (NIAID)
Type 1 diabetes is an autoimmune disease in which the insulin-producing pancreatic beta cells are destroyed, resulting in poor blood sugar control. The purpose of this study is to determine the safety and effectiveness of islet transplantation, combined with immunosuppressive medications, for treating type 1 diabetes in individuals experiencing hypoglycemia unawareness and severe hypoglycemic episodes.

Studieoversigt

Status

Afsluttet

Betingelser

Intervention / Behandling

Detaljeret beskrivelse

Type 1 diabetes is commonly treated with the administration of insulin, either by multiple insulin injections or by a continuous supply of insulin through a wearable pump. Insulin therapy allows long-term survival in individuals with type 1 diabetes; however, it does not guarantee constant normal blood sugar control. Because of this, long-term type 1 diabetic survivors often develop vascular complications, such as diabetic retinopathy, an eye disease that can cause poor vision and blindness, and diabetic nephropathy, a kidney disease that can lead to kidney failure. Some individuals with type 1 diabetes develop hypoglycemia unawareness, a life-threatening condition that is not easily treatable with medication and is characterized by reduced or absent warning signals for hypoglycemia. For such individuals, transplantation of pancreatic islets is a possible treatment option. Unfortunately, insulin independence among islet transplant recipients tends to decline over time. New strategies aimed at promoting engraftment of transplanted islets are needed to improve the clinical outcomes associated with this procedure. The purpose of this study is determine the safety and efficacy of islet transplantation, when combined with an immunosuppressive medication regimen, for treating type 1 diabetes in individuals experiencing hypoglycemia unawareness and severe hypoglycemic episodes. This study will also seek to improve the understanding of determinants of success and failure of islet transplants for type 1 diabetes.

Eligible participants will be randomly assigned to this study or a site-specific Phase 2 islet transplantation study. Participants in this study will receive up to three separate islet transplants and a regimen of immunosuppressive medications consisting of antithymocyte globulin (ATG), sirolimus, and low-dose tacrolimus.

Transplantations will involve an inpatient hospital stay and infusion of islets into a branch of the portal vein. Participants who do not achieve or maintain insulin independence by Day 75 post-transplant will be considered for a second islet transplant. Participants who remain dependent on insulin for longer than 1 month after the second transplant and who show partial graft function will be considered for a third islet transplant. Basiliximab will be used in place of ATG for the second and third transplants, if they are necessary. Participants who do not meet the criteria for a subsequent transplant and do not have a functioning graft will enter a reduced follow-up period.

There will be up to 19 study visits following each transplant. A physical exam, review of adverse events, and blood collection will occur at most visits. A chest x-ray, abdominal ultrasound, electrocardiogram, quality of life questionnaires, urine collection, and glomerular filtrating rate (GFR) testing will occur at some visits. Participants will also test their own blood glucose levels at least five times per day throughout the study. A 24-month follow-up period will take place after the participant's last transplant.

Undersøgelsestype

Interventionel

Tilmelding (Faktiske)

48

Fase

  • Fase 3

Kontakter og lokationer

Dette afsnit indeholder kontaktoplysninger for dem, der udfører undersøgelsen, og oplysninger om, hvor denne undersøgelse udføres.

Studiesteder

  • Canada
    • Alberta
      • Edmonton, Alberta, Canada, T6G028
        • University of Alberta
  • Forenede Stater
    • California
      • San Francisco, California, Forenede Stater, 94143
        • University of Callifornia, San Francisco
    • Florida
      • Miami, Florida, Forenede Stater, 33136
        • University of Miami
    • Georgia
      • Atlanta, Georgia, Forenede Stater, 30322
        • Emory University
    • Illinois
      • Chicago, Illinois, Forenede Stater, 60611
        • Northwestern University
      • Chicago, Illinois, Forenede Stater, 60612
        • University of Illinois, Chicago
    • Minnesota
      • Minneapolis, Minnesota, Forenede Stater, 55455
        • University of Minnesota
    • Pennsylvania
      • Philadelphia, Pennsylvania, Forenede Stater, 19104
        • University of Pennsylvania

Deltagelseskriterier

Forskere leder efter personer, der passer til en bestemt beskrivelse, kaldet berettigelseskriterier. Nogle eksempler på disse kriterier er en persons generelle helbredstilstand eller tidligere behandlinger.

Berettigelseskriterier

Aldre berettiget til at studere

18 år til 65 år (Voksen, Ældre voksen)

Tager imod sunde frivillige

Ingen

Køn, der er berettiget til at studere

Alle

Beskrivelse

Inclusion Criteria:

  • Mentally stable and able to comply with study procedures
  • Clinical history compatible with type 1 diabetes with onset of disease at less than 40 years of age, insulin dependence for at least 5 years at study entry, and a sum of age and insulin dependent diabetes duration of at least 28
  • Absent stimulated C-peptide (less than 0.3 ng/ml) 60 and 90 minutes post-mixed-meal tolerance test

  • Involvement of intensive diabetes management, defined as:

    1. Self-monitoring of glucose values no less than a mean of three times each day averaged over each week
    2. Administration of three or more insulin injections each day or insulin pump therapy
    3. Under the direction of an endocrinologist, diabetologist, or diabetes specialist with at least three clinical evaluations during the past 12 months prior to study enrollment
  • At least one episode of severe hypoglycemia in the past 12 months, defined as an event with one of the following symptoms: memory loss; confusion; uncontrollable behavior; irrational behavior; unusual difficulty in awakening; suspected seizure; seizure; loss of consciousness; or visual symptoms, compatible with hypoglycemia in which the individual required assistance of another subject was unable to treat him/herself person and which was associated with either a blood glucose level less than 54 mg/dl or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration in the 12 months prior to study enrollment
  • Reduced awareness of hypoglycemia. More information about this criterion, including specific definition of hypoglycemia unawareness, is in the protocol.

Exclusion Criteria:

  • Body mass index (BMI) greater than 30 kg/m2 or weight less than or equal to 50 kg
  • Insulin requirement of more than 1.0 IU/kg/day or less than 15 U/day
  • HbA1c greater than 10%
  • Untreated proliferative diabetic retinopathy
  • Systolic blood pressure higher than 160 mmHg or diastolic blood pressure higher than 100 mmHg
  • Measured glomerular filtration rate using iohexol of less than 80 ml/min/1.73mm2. More information about this criterion is in the protocol.
  • Presence or history of macroalbuminuria (greater than 300 mg/g creatinine)
  • Presence or history of panel-reactive anti-HLA antibody levels greater than background by flow cytometry. More information about this criterion is in the protocol.
  • Pregnant, breastfeeding, or unwilling to use effective contraception throughout the study and 4 months after study completion
  • Presence or history of active infection, including hepatitis B, hepatitis C, HIV, or tuberculosis.
  • Negative for Epstein-Barr virus by IgG determination
  • Invasive aspergillus, histoplasmosis, or coccidioidomycosis infection in the past year
  • History of malignancy except for completely resected squamous or basal cell carcinoma of the skin
  • Known active alcohol or substance abuse
  • Baseline Hgb below the lower limits of normal, lymphopenia, neutropenia, or thrombocytopenia
  • History of Factor V deficiency
  • Any coagulopathy or medical condition requiring long-term anticoagulant therapy after transplantation or individuals with an INR greater than 1.5

  • Severe coexisting cardiac disease, characterized by any one of the following conditions:

    1. Heart attack within the last 6 months
    2. Evidence of ischemia on functional heart exam within the year prior to study entry
    3. Left ventricular ejection fraction less than 30%
  • Persistent elevation of liver function tests at the time of study entry
  • Symptomatic cholecystolithiasis
  • Acute or chronic pancreatitis
  • Symptomatic peptic ulcer disease
  • Severe unremitting diarrhea, vomiting, or other gastrointestinal disorders that could interfere with the ability to absorb oral medications
  • Hyperlipidemia despite medical therapy, defined as fasting LDL cholesterol greater than 130 mg/dl (treated or untreated) and/or fasting triglycerides greater than 200 mg/dl
  • Currently receiving treatment for a medical condition that requires chronic use of systemic steroids except for the use of 5 mg or less of prednisone daily, or an equivalent dose of hydrocortisone, for physiological replacement only
  • Treatment with any antidiabetic medication other than insulin within the past 4 weeks
  • Use of any study medications within the past 4 weeks
  • Received a live attenuated vaccine(s) within the past 2 months

  • Any medical condition that, in the opinion of the investigator, might interfere with safe participation in the trial

    • Treatment with any immunosuppressive regimen at the time of enrollment.
    • A previous islet transplant.
    • A previous pancreas transplant, unless the graft failed within the first week due to thrombosis, followed by pancreatectomy and the transplant occurred more than 6 months prior to enrollment.

Studieplan

Dette afsnit indeholder detaljer om studieplanen, herunder hvordan undersøgelsen er designet, og hvad undersøgelsen måler.

Hvordan er undersøgelsen tilrettelagt?

Design detaljer

  • Primært formål: Behandling
  • Tildeling: N/A
  • Interventionel model: Enkelt gruppeopgave
  • Maskning: Ingen (Åben etiket)

Våben og indgreb

Deltagergruppe / Arm
Intervention / Behandling
Eksperimentel: Islet Transplantation
Participants will receive up to three separate islet transplants and a regimen of immunosuppressive medications consisting of antithymocyte globulin (ATG), sirolimus, and low-dose tacrolimus.
Biologisk: Allogeneic Pancreatic Islet Cells
200 ml suspension of allogenic human purified islets
Biologisk: Antithymocyte Globulin
Participants will begin receiving ATG 2 days prior to the first islet transplant. ATG will continue to be given until Day 2 post-transplant.
Medicin: Sirolimus
Participants will begin receiving sirolimus 2 days prior to the first islet transplant and will be given for the duration of the study.
Andre navne:
  • Rapamycin
Medicin: Tacrolimus
On Day 1 post-transplant, participants will receive tacrolimus, which will also be taken for the duration of the study.
Andre navne:
  • Fujimycin
  • FK-506
Biologisk: Etanercept
Etanercept will be taken on the day of transplant and Days 3, 7, and 10 post-transplant.
Procedure: Islet Transplantation
Transplantation of pancreatic islet cell
Biologisk: Basiliximab
Basiliximab will be used in place of ATG for the second and third transplants, if they are necessary.
Andre navne:
  • kimærisk mus-human antiCD25
  • Ig gamma-1 chain C region

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Proportion of participants with a HbA1c less than 7.0% AND free of severe hypoglycemic events
Tidsramme: From Day 28 to Day 365 (inclusive) following the first islet transplant, with the day of transplant designated Day 0
The proportion of participants with HbA1c ≤7.0% AND free of severe hypoglycemic events from Day 28 to Day 365 inclusive, following the first islet transplant, with the day of transplant designated Day 0.
From Day 28 to Day 365 (inclusive) following the first islet transplant, with the day of transplant designated Day 0

Sekundære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Incidence and severity of adverse events related to the islet transplant procedure
Tidsramme: 75 days following each transplant and 365 days following the first and final islet transplant
75 days following each transplant and 365 days following the first and final islet transplant
Incidence of worsening retinopathy
Tidsramme: 365 days following the first islet transplant
365 days following the first islet transplant
Percent reduction in insulin requirements
Tidsramme: 75 days following the first and subsequent islet transplant
75 days following the first and subsequent islet transplant
HbA1c on Day 75 Status Post the First and Subsequent Islet Transplant
Tidsramme: 75 days following the first and subsequent islet transplant
The target level for HbA1c for this study is 7.0%. This value is the level recommended by the American Diabetes Association and is considered to be the clinically relevant goal for subjects with Type 1 diabetes (T1D). A HbA1c level of 6.5% is the goal recommended by the American College of Endocrinology.
75 days following the first and subsequent islet transplant
Mean amplitude of glycemic excursions (MAGE)
Tidsramme: 75 days following the first and subsequent islet transplant
A MAGE >11.1 mmol/L (200 mg/dL) is indicative of marked glycemic lability.
75 days following the first and subsequent islet transplant
Glycemic liability index (LI)
Tidsramme: 75 days following the first and subsequent islet transplant
75 days following the first and subsequent islet transplant
Ryan hypoglycemia severity score (HYPO)
Tidsramme: 75 days following the first and subsequent islet transplant
75 days following the first and subsequent islet transplant
Basal (fasting) and 90-minute glucose and C-peptide derived from mixed meal tolerance test (MMTT)
Tidsramme: 75 days following the first and subsequent islet transplant
75 days following the first and subsequent islet transplant
β-score on Day 75 Status Post the First and Subsequent Islet Transplant
Tidsramme: 75 days following the first and subsequent islet transplant
Beta-score: an assessment of beta-cell function after islet transplantation.
75 days following the first and subsequent islet transplant
C-peptide:glucose creatinine ratio
Tidsramme: 75 days following the first and subsequent islet transplant
75 days following the first and subsequent islet transplant
Acute insulin response to glucose, insulin sensitivity, and disposition index derived from the insulin-modified frequently sampled intravenous glucose tolerance (FSIGT) test
Tidsramme: 75 days following the first and subsequent islet transplant
75 days following the first and subsequent islet transplant
Glucose variability and hypoglycemia duration derived from the continuous glucose monitoring system (CGMS)
Tidsramme: 75 days following the first and subsequent islet transplant
75 days following the first and subsequent islet transplant
Assessment of Quality of Life Using the Short Form 36 Health Survey: Day 75 Status Post First and Final Islet Transplant
Tidsramme: 75 days following the first and subsequent islet transplant
The Short-Form 36 Health Survey (SF-36®) is comprised of 36 items and 2 component scores, the Physical Component Score and the Mental Component Score. Each component is transformed into a 0-100 scale (higher numbers indicate greater quality of life) and normalized to have a mean of 50 and standard deviation of 10 for the 1998 general US population. SF-36 results unit of measure: Units on a Scale.
75 days following the first and subsequent islet transplant
Proportion of insulin-independent Participants on Day 365 Status Post the First and Final Islet Transplant
Tidsramme: 365 days following the first and final islet transplant
365 days following the first and final islet transplant
Percent reduction in insulin requirements
Tidsramme: 365 days following the first and final islet transplant
365 days following the first and final islet transplant
HbA1c on Day 365 Status Post the First and Final Islet Transplant
Tidsramme: 365 days following the first and final islet transplant
The target level for HbA1c for this study is 7.0%. This value is the level recommended by the American Diabetes Association and is considered to be the clinically relevant goal for subjects with Type 1 diabetes (T1D). A HbA1c level of 6.5% is the goal recommended by the American College of Endocrinology.
365 days following the first and final islet transplant
MAGE
Tidsramme: 365 days following the first and final islet transplant
A MAGE >11.1 mmol/L (200 mg/dL) is indicative of marked glycemic lability.
365 days following the first and final islet transplant
Glycemic liability index (LI): Day 365 Status Post First and Final Islet Transplant
Tidsramme: 365 days following the first and final islet transplant
365 days following the first and final islet transplant
Clarke score
Tidsramme: 365 days following the first and final islet transplant
The Clarke survey provides a composite indices of hypoglycemia frequency, severity, and symptom recognition.
365 days following the first and final islet transplant
HYPO score
Tidsramme: 365 days following the first and final islet transplant
The HYPO(glycemia) score provides a composite indices of hypoglycemia frequency, severity, and symptom recognition.
365 days following the first and final islet transplant
Basal (fasting) and 90-minute glucose and C-peptide (MTT)
Tidsramme: 365 days following the first and final islet transplant
365 days following the first and final islet transplant
β-score on Day 365 Status Post First and Final Islet Transplant
Tidsramme: 365 days following the first and final islet transplant
Beta-score: an assessment of beta-cell function after islet transplantation.
365 days following the first and final islet transplant
C-peptide: glucose creatinine ratio
Tidsramme: 365 days following the first and final islet transplant
365 days following the first and final islet transplant
Assessment of Quality of Life Using the Short Form 36 Health Survey: Day 365 Status Post First and Final Islet Transplant
Tidsramme: 365 days following the first and final islet transplant
The Short-Form 36 Health Survey (SF-36®) is comprised of 36 items and 2 component scores, the Physical Component Score and the Mental Component Score. Each component is transformed into a 0-100 scale (higher numbers indicate greater quality of life) and normalized to have a mean of 50 and standard deviation of 10 for the 1998 general US population. SF-36 results unit of measure: Units on a Scale.
365 days following the first and final islet transplant
Proportion of participants receiving a second islet transplant
Tidsramme: 365 days following the first and final islet transplant
365 days following the first and final islet transplant
Proportion of participants receiving a third islet transplant
Tidsramme: 365 days following the first and final islet transplant
365 days following the first and final islet transplant
Incidence and severity of adverse events related to the immunosuppression therapy
Tidsramme: 75 days following each transplant and 365 days following the first and final islet transplant
75 days following each transplant and 365 days following the first and final islet transplant
Incidence of a change in the immunosuppression drug regimen
Tidsramme: 75 days following each transplant and 365 days following the first and final islet transplant
75 days following each transplant and 365 days following the first and final islet transplant
Incidence of immune sensitization defined by detecting anti-HLA antibodies not present prior to transplantation
Tidsramme: 75 days following each transplant and 365 days following the first and final islet transplant
75 days following each transplant and 365 days following the first and final islet transplant
Proportion of insulin-independent participants on Day 75 Status Post First and Subsequent Islet Transplant
Tidsramme: 75 days following first and subsequent islet transplant
75 days following first and subsequent islet transplant
Acute insulin response to glucose insulin sensitivity, and disposition index derived from the FSIGT test
Tidsramme: 365 days following the first and final islet transplant
Frequently Sampled Intravenous Glucose Tolerance (FSIGT), a measure of insulin-independence, a clinically relevant measure of islet graft function.
365 days following the first and final islet transplant

Samarbejdspartnere og efterforskere

Det er her, du vil finde personer og organisationer, der er involveret i denne undersøgelse.

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Samarbejdspartnere

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Efterforskere

  • Studiestol: Bernhard Hering, MD, University of Minnesota
  • Studiestol: Olle Korsgren, PhD, Uppsala University Hospital
  • Studiestol: Ali Naji, PhD, University of Pennsylvania
  • Studiestol: Camillo Ricordi, MD, University of Miami
  • Studiestol: James Shapiro, MD, PhD, University of Alberta
  • Studiestol: Andrew Posselt, MD, PhD, University of California, San Francisco
  • Studiestol: Nicole Turgeon, MD, Emory University
  • Studiestol: Xunrong Luo, MD, PhD, Northwestern Univerity

Publikationer og nyttige links

Den person, der er ansvarlig for at indtaste oplysninger om undersøgelsen, leverer frivilligt disse publikationer. Disse kan handle om alt relateret til undersøgelsen.

Generelle publikationer

Hjælpsomme links

Datoer for undersøgelser

Disse datoer sporer fremskridtene for indsendelser af undersøgelsesrekord og resumeresultater til ClinicalTrials.gov. Studieregistreringer og rapporterede resultater gennemgås af National Library of Medicine (NLM) for at sikre, at de opfylder specifikke kvalitetskontrolstandarder, før de offentliggøres på den offentlige hjemmeside.

Studer store datoer

Studiestart

1. oktober 2006

Primær færdiggørelse (Faktiske)

1. september 2012

Studieafslutning (Faktiske)

1. maj 2014

Datoer for studieregistrering

Først indsendt

9. februar 2007

Først indsendt, der opfyldte QC-kriterier

9. februar 2007

Først opslået (Skøn)

13. februar 2007

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Faktiske)

17. juli 2019

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

11. juli 2019

Sidst verificeret

1. juli 2019

Mere information

Begreber relateret til denne undersøgelse

Nøgleord

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • DAIT CIT-07

Plan for individuelle deltagerdata (IPD)

Planlægger du at dele individuelle deltagerdata (IPD)?

JA

IPD-planbeskrivelse

Participant level data access and additional relevant materials are available to researchers and the public at: https://www.immport.org/home.

The study Identifier in ImmPort is SDY1178.

IPD-delingstidsramme

The data is available. ImmPort is a long-term archive of clinical and mechanistic data.

IPD-delingsadgangskriterier

Register for ImmPort at: https://www.immport.org/registration and submit a rationale for the purpose of requesting study data access.

ImmPort is a long-term archive of clinical and mechanistic data, a National Institute of Allergy and Infectious Diseases Division of Allergy, Immunology and Transplantation (NIAID DAIT)-funded data repository. This archive is in support of the NIH mission to share data with the public. Data shared through ImmPort is provided by NIH-funded programs, other research organizations and individual scientists, ensuring these discoveries will be the foundation of future research.

IPD-deling Understøttende informationstype

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE

Studiedata/dokumenter

  1. Studieprotokol
    Informations-id: SDY1178
    Oplysningskommentarer: ImmPort study ID is SDY1178.
  2. Komplet sæt af beskrivende data og resultater
    Informations-id: SDY1178
    Oplysningskommentarer: ImmPort is a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts. This archive is in support of the NIH mission to share data with the public.

Lægemiddel- og udstyrsoplysninger, undersøgelsesdokumenter

Studerer et amerikansk FDA-reguleret lægemiddelprodukt

Ja

Studerer et amerikansk FDA-reguleret enhedsprodukt

Ingen

Disse oplysninger blev hentet direkte fra webstedet clinicaltrials.gov uden ændringer. Hvis du har nogen anmodninger om at ændre, fjerne eller opdatere dine undersøgelsesoplysninger, bedes du kontakte register@clinicaltrials.gov. Så snart en ændring er implementeret på clinicaltrials.gov, vil denne også blive opdateret automatisk på vores hjemmeside .

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