Caspase Inhibition in Islet Transplantation

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2012 by University of Alberta
Sponsor:
Collaborator:
Conatus Pharmaceuticals Inc.
Information provided by (Responsible Party):
James Shapiro, University of Alberta
ClinicalTrials.gov Identifier:
NCT01653899
First received: July 12, 2012
Last updated: July 27, 2012
Last verified: July 2012
  Purpose

This is an Investigator Initiated, Phase I/II study, where Type 1 diabetic participants will receive a 14 day oral treatment of the investigational caspase inhibitor drug IDN-6556 following their first islet transplant. Two pilot studies are proposed to establish the optimal safety and efficacy dose of IDN-6556 (25 mg or 100 mg twice daily). Participants of both pilot studies will receive islet cell transplants under the University of Alberta's standard-of-care therapy.

The primary objective of this protocol is to assess the safety of the IDN-6556 caspase inhibitor in adult Type 1 diabetic participants receiving their first islet transplant.

Secondary objectives include:

  1. To determine the proportion of subjects treated with IDN-6556 who achieve and maintain insulin independence after the first or subsequent islet transplant.
  2. To obtain preliminary data on the efficacy of IDN-6556 to maintain adequate immunological protection against both allo- and autoimmunity of islet transplant recipients.

Condition Intervention Phase
Diabetes
Drug: IDN-6556
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Improving Engraftment, Islet Survival and Metabolic Reserve in Clinical Islet Transplantation Using Caspase Inhibitor - IDN-6556

Resource links provided by NLM:


Further study details as provided by University of Alberta:

Primary Outcome Measures:
  • To assess the safety of the IDN-6556 caspase inhibitor in adult Type 1 diabetic participants receiving their first islet transplant [ Time Frame: 3 years post-initial transplant ] [ Designated as safety issue: Yes ]
    The primary objective of this protocol is to assess the safety of the IDN-6556 caspase inhibitor in adult Type 1 diabetic participants receiving their first islet transplant. A tracking log will document adverse events and unexpected complications associated with IDN-6556 using a grading classification as per protocol.


Secondary Outcome Measures:
  • 1. To determine the proportion of subjects treated with IDN-6556 who achieve and maintain insulin independence after the first or subsequent islet transplant. [ Time Frame: 3 years post-initial transplant ] [ Designated as safety issue: No ]
    The proportion of study participants achieving and maintaining insulin independence (c-peptide, HbA1c level) with good glycemic control (blood sugar measurement) at Day 90 and 1, 2, 3 years post-initial islet transplant.

  • 2. To obtain preliminary data on the efficacy of IDN-6556 to maintain adequate immunological protection against both allo- and autoimmunity of islet transplant recipients. [ Time Frame: 3 years post-initial transplant ] [ Designated as safety issue: No ]
    Immune monitoring for HLA and panel reactive antibody will be performed using serum samples


Estimated Enrollment: 12
Study Start Date: June 2012
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: IDN-6556
Drug
Drug: IDN-6556
14 day oral treatment of the investigational caspase inhibitor drug IDN-6556 following first islet transplant at 25 mg twice daily.
Other Name: Emricasan

  Eligibility

Ages Eligible for Study:   18 Years to 68 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

  • 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
  • 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. Severe co-existing cardiac disease, characterized by any one of these conditions: (a) recent myocardial infarction (within past 6 months); (b) left ventricular ejection fraction < 30%; or (c) evidence of ischemia on functional cardiac exam.
  2. Active alcohol or substance abuse, to include cigarette smoking (must be abstinent for 6 months prior to transplant).
  3. 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).
  4. History of non-adherence to prescribed regimens.
  5. Active infection including Hepatitis C, Hepatitis B, HIV, TB (subjects with a positive PPD performed within one year of enrollment, and no history of adequate chemoprophylaxis).
  6. Any history of or current malignancies except squamous or basal skin cancer.
  7. BMI > 35 kg/m2 at screening visit.
  8. Age less than 18 or greater than 68 years.
  9. Measured glomerular filtration rate (GFR) < 60 mL/min/1.73 m2.
  10. Presence or history of macroalbuminuria (> 300 mg/g creatinine).
  11. 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).
  12. Baseline Hb < 105g/L (< 10.5 g/dL) in women, or < 120 g/L (< 12 g/dL) in men.
  13. Baseline screening liver function tests 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.
  14. Untreated proliferative retinopathy.
  15. Positive pregnancy test, intent for future pregnancy or male subjects' intent to procreate, failure to follow effective contraceptive measures, or presently breast feeding.
  16. Previous transplant or evidence of significant sensitization on PRA (at the discretion of the investigator).
  17. Insulin requirement > 1.0 U/kg/day
  18. HbA1C > 12%.
  19. Uncontrolled hyperlipidemia [fasting LDL cholesterol > 3.4 mmol/L (133 mg/dL), treated or untreated; and/or fasting triglycerides > 2.3 mmol/L (90 mg/dL)].
  20. Under treatment for a medical condition requiring chronic use of steroids.
  21. Use of coumadin or other anticoagulant therapy (except aspirin) or subject with PT INR > 1.5.
  22. Untreated Celiac disease.
  23. Patients with Graves disease will be excluded unless previously adequately treated with radioiodine ablative therapy.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01653899

Contacts
Contact: Andrew Malcolm, MD PhD 780-407-6952 andrew.malcolm@ualberta.ca
Contact: Parastoo Dinyari, BSc 780-407-3904 parastoo@islet.ca

Locations
Canada, Alberta
University of Alberta Recruiting
Edmonton, Alberta, Canada
Contact: Andrew Malcolm, PhD    780-407-6952    andrew.malcolm@ualberta.ca   
Contact: Parastoo Dinyari, BSc    780-407-3904    parastoo@islet.ca   
Principal Investigator: A.M. James Shapiro, MD PhD         
Sponsors and Collaborators
University of Alberta
Conatus Pharmaceuticals Inc.
Investigators
Principal Investigator: A.M. James Shapiro, MD PhD University of Alberta
  More Information

No publications provided

Responsible Party: James Shapiro, Director, Clinical Islet Transplant Program, University of Alberta
ClinicalTrials.gov Identifier: NCT01653899     History of Changes
Other Study ID Numbers: Pro00024049
Study First Received: July 12, 2012
Last Updated: July 27, 2012
Health Authority: Canada: Health Canada

Keywords provided by University of Alberta:
Type I Diabetes

Additional relevant MeSH terms:
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Caspase Inhibitors
Cysteine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 27, 2014