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Aralast NP in Islet Transplant

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ClinicalTrials.gov Identifier: NCT02520076
Recruitment Status : Active, not recruiting
First Posted : August 11, 2015
Last Update Posted : April 16, 2019
Sponsor:
Collaborator:
Shire
Information provided by (Responsible Party):
University of Alberta

Brief Summary:

Islet transplantation is a relatively new procedure used in people with difficult to control Type 1 diabetes. Insulin producing cells (islets) are isolated from a pancreas donated by the next of kin of a person who is brain dead. After the cells are prepared, the islets are transplanted into the recipient's liver and produce insulin. Patients who receive an islet transplant take medication that suppresses their immune system and prevent rejection of the islet tissue.

The investigators have also learned that there is general inflammation at the time of the transplant that is not fully controlled with our standard medications. The investigators believe this inflammation may cause some islet cell death around the time of transplant. Due to this islet death around the time of transplant, most recipients need 2 or 3 separate transplant procedures.

The investigators are studying the use of Alpha-1 Antitrypsin (AAT) in islet transplant to decrease the amount of cell death caused by general inflammation. In this study, the investigators hope to decrease the need for more than one transplant procedure by controlling inflammation, before and after transplant, with Alpha-1 Antitrypsin (Aralast NP).

Alpha-1 Antitrypsin is a protein made in healthy humans that helps to prevent tissue damage during times of inflammation. Alpha-1 Antitrypsin is obtained from healthy plasma donors. There have been studies in Islet Transplant in monkeys using this medication and it has shown to protect the islets from inflammation.

This study involves using Alpha-1 Antitrypsin in addition to our current Standard of Care medications used in Islet Transplant.


Condition or disease Intervention/treatment Phase
Type 1 Diabetes Mellitus Drug: Alpha-1 Antitrypsin Phase 1 Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Improving Single Donor Success Rate in Clinical Islet Transplantation Using Alpha-1 Antitrypsin (Aralast NP)
Study Start Date : August 2015
Estimated Primary Completion Date : March 2020
Estimated Study Completion Date : March 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: AAT treated group
Study subjects will receive Alpha-1 Antitrypsin (AAT) study drug intravenously in 4 doses over 15 days around the time of their transplant. The islets will also be prepared in a solution of AAT.
Drug: Alpha-1 Antitrypsin

Subjects will receive their islets treated with Aralast NP during islet isolation process.

Subjects will receive Aralast NP at a dose of 120 mg/kg (at an infusion rate of 0.2 mL/kg/min or less), dependent on patient tolerance, based on Day -1 admission weight and dose rounded to the nearest 20 mg) at the following time points:

  • Pre-transplant Day -1
  • Post-transplant Day 3
  • Post-transplant Day 7
  • Post-transplant Day 14




Primary Outcome Measures :
  1. To demonstrate AAT efficacy in preventing non-immunologic loss of transplanted islet mass in a single-donor islet transplant. [ Time Frame: Day 90 post-transplant ]
    Insulin independence at day 90 post-transplant (initial, single-donor transplant)


Secondary Outcome Measures :
  1. To demonstrate safety of AAT during islet isolation and culture [ Time Frame: Day -1 pre-transplant ]

    Post-isolation measurements, compared to current standard protocol isolation data, for the following parameters:

    • Endotoxin level
    • Microbiological culture [bacterial (both aerobic and anaerobic), fungal, mycoplasma, and mycobacterium culture]

  2. To demonstrate efficacy of AAT to improve islet isolation quantity and quality [ Time Frame: Day -1 pre-transplant ]

    Post-isolation measurements, compared to current standard protocol isolation data, for the following parameters:

    • Islet yield
    • Viability (SytoGreen/ethidium bromide)
    • Purity
    • Beta cell specific viability
    • Cell composition assay
    • Glucose stimulated insulin release
    • DNA content

  3. To demonstrate safety of AAT in islet transplantation. [ Time Frame: Year 1 post-transplant ]

    Adverse Event/Serious Adverse Event morbidity within 1 year post-transplant, which includes the following:

    • Primary non-function (PNF)
    • End-organ dysfunction
    • Malignancy
    • Opportunistic infection
    • Inpatient hospitalization
    • Prolongation of existing hospitalization
    • A life-threatening event
    • Persistent or significant disability
    • Congenital anomaly or birth defect
    • Patient death

  4. To demonstrate AAT efficacy in the prevention of long-term metabolic burn-out. [ Time Frame: Year 1 post-transplant ]
    • Full graft function at 1 year after initial single-donor transplant, compared to retrospective controls (current standard of care induction).
    • Partial graft function at 1 year after initial single-donor transplant compared to retrospective controls (current standard of care induction).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 68 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • To be eligible the participant must have had Type 1 Diabetes Mellitus (T1DM) for more than 5 years, complicated by at least 1 of the following situations that persist despite intensive insulin management efforts:

    1. Reduced awareness of hypoglycemia, as defined by the absence of adequate autonomic symptoms at plasma glucose levels < 3.0 mmol/L, indicated by, 1 or more episodes of severe hypoglycemia requiring third party assistance within 12 months, a Clarke score ≥4, HYPO score ≥1,000, lability index (LI) ≥400 or combined HYPO/LI >400/>300.
    2. Metabolic instability, characterized by erratic blood glucose levels that interfere with daily activities and or 1 or more hospital visits for diabetic ketoacidosis over the last 12 months.
  • Participants must be capable of understanding the purpose and risks of the study and must sign a statement of informed consent.

Exclusion Criteria:

  1. Hypersensitivity to Aralast NP, history of immunoglobulin A (IgA) deficiency, or assessed low IgA (< 0.70 g/L).
  2. Severe co-existing cardiac disease, characterized by any one of these conditions: (a) recent (within the past 6months) myocardial infarction; (b) left ventricular ejection fraction <30%; or (c) evidence of ischemia on functional cardiac exam.
  3. Active alcohol or substance abuse, to include cigarette smoking (must be abstinent for 6 months prior to listing for transplant).
  4. Psychiatric disorder making the subject not a suitable candidate for transplantation, (e.g., schizophrenia, bipolar disorder, or major depression that is unstable or uncontrolled on current medication).
  5. History of non-adherence to prescribed regimens.
  6. Active infection including Hepatitis C, Hepatitis B, HIV, or tuberculosis (TB) (subjects with a positive purified protein derivative (PPD) performed within one year of enrollment, and no history of adequate chemoprophylaxis).
  7. Any history of, or current malignancies except squamous or basal skin cancer.
  8. BMI > 35 kg/m2 at screening visit.
  9. Age less than 18 or greater than 68 years.
  10. Measured glomerular filtration rate <60 mL/min/1.73 m2.
  11. Presence or history of macroalbuminuria (>300 mg/g creatinine).
  12. Clinical suspicion of nephritic (hematuria, active urinary sediment) or rapidly progressing renal impairment (e.g. Increase in serum creatinine of 25% within the last 3-6 months).
  13. Baseline Hb < 105 g/L in women, or < 120 g/L in men.
  14. Baseline screening liver function tests (LFT) outside of normal range, with the exception of uncomplicated Gilbert's Syndrome. An initial LFT panel with any values >1.5 times the upper limit of normal (ULN) will exclude a patient without a re-test; a re-test for any values between ULN and 1.5 times ULN should be made, and if the values remain elevated above normal limits, the patient will be excluded.
  15. Untreated proliferative retinopathy.
  16. Positive pregnancy test, intent for future pregnancy or male subjects' intent to procreate, failure to follow effective contraceptive measures, or presently breast-feeding.
  17. Previous transplant or evidence of significant sensitization on panel reactive antibody (PRA) (at the discretion of the investigator).
  18. Insulin requirement >1.0 U/kg/day
  19. Hemoglobin A1c (HbA1c) >12%.
  20. Uncontrolled hyperlipidemia [fasting LDL cholesterol > 3.4 mmol/L, treated or untreated; and/or fasting triglycerides > 2.3 mmol/L)].
  21. Under treatment for a medical condition requiring chronic use of steroids.
  22. Use of coumadin or other anticoagulant therapy (except aspirin) or subject with prothrombin time / international normalized ratio (PT/INR) > 1.5.
  23. Untreated Celiac disease.
  24. Patients with Graves disease will be excluded unless previously adequately treated with radioiodine ablative therapy.

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): NCT02520076


Locations
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Canada, Alberta
University of Alberta
Edmonton, Alberta, Canada, T6G 2C8
Sponsors and Collaborators
University of Alberta
Shire
Investigators
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Principal Investigator: James Shapiro, MD, PhD University of Alberta

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Responsible Party: University of Alberta
ClinicalTrials.gov Identifier: NCT02520076     History of Changes
Other Study ID Numbers: Pro00047923
First Posted: August 11, 2015    Key Record Dates
Last Update Posted: April 16, 2019
Last Verified: May 2018

Keywords provided by University of Alberta:
Islet Transplantation

Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Alpha 1-Antitrypsin
Protein C Inhibitor
Trypsin Inhibitors
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action