Clinical Study Using Antiaging Glycopeptide (PKX-001) in Islet Transplantation
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- University of Alberta
- Enrollment
- 18
- Locations
- 1
- Primary Endpoint
- Adverse event morbidity
Study Overview
Brief Summary
Islet Transplantation is a procedure used in people with difficult to control Type 1 Diabetes. Insulin producing cells (islets) are isolated from a deceased donor pancreas. After the cells are carefully isolated from the donor pancreas, the islets are transplanted into the recipient's liver. These transplanted islets may produce insulin.
One of the challenges with islet transplant is the death of some of the transplanted islets due to inflammation, oxidative stress and exposure to diabetogenic immunosuppressive agents associated with islet functional impairment and graft loss, especially linked to the use of calcineurin inhibitors, including tacrolimus (Tac).
Antiaging glycopeptide (PKX-001) is a small, stable, synthetic replica of antifreeze proteins (AFPs), which naturally occur in Arctic and Antarctic fish and have been shown protecting cells against harmful conditions. PKX-001 is a new drug that has been shown in lab studies to help islet cells survive isolation and keep them healthy and functioning. Most importantly, animal studies have shown that islets treated with PKX-001 were protected from the immunosuppressant (Tac) toxicity and retained their function in animals receiving islet transplant.
This study will involve up to 10 participants from the islet transplant waiting list at the Clinical Islet Transplant Program. All participants will receive islets treated with the medication PKX-001. PKX-001 will be used only in the islet preservation process, and will not be given to participants as medication.
The purpose of this study is to confirm the safety of transplantation of PKX-001 treated islets and to evaluate the cytoprotective capacity of PKX-001 in islet transplantation, especially its capacity to protect against Tac induced graft dysfunction.
Detailed Description
Background
Clinical islet transplantation is today an accepted modality to treat selected diabetic patients with frequent hypoglycemic events and severe glycemic liability. Although islet transplantation outcomes have improved significantly in highly specialized centers with a 5-year insulin independence rate exceeding 50%, a proportion of patients require reintroduction of insulin later on. Tac may be partly responsible for the limited islet durability and the need for multiple donors for each recipient in spite of its ability to prevent rejection and autoimmune recurrence. In vitro studies of islets exposed to immunosuppressants have shown that Tac levels above 10-100 mg/L cause vacuolization and destruction of islets in culture.
Antifreeze proteins (AFPs) have generated considerable interest for their ability to protect cells under a variety of conditions. However, their large size restricts their use in medicine as they are unable to pass through capillaries into interstitial tissue and are unable to reach target cells.
With these disadvantages of AFPs in mind, Dr. Geraldine-Castelot-Deliencourt (Rouen, France) invented Antiaging glycopeptide, which is later manufactured by ProtoKinetix Inc. (St. Marys, West Virginia, US). ProtoKinetix' anti-aging glycopeptide, PKX-001, is a small, stable, synthetic replica of the larger, less stable AFP.
PKX-001 has gone through a series of tests in various outsourced laboratories in Europe and North America. These tests have proven its ability to protect a multitude of cell lines (Hela cells, adult fibroblast, neonatal fibroblasts, human neuronal stem cells, mouse neuronal stem cells, mouse islet cells, blood platelets, cluster of differentiation 34+ (CD34+) cells, and keratinocytes) against ultraviolet A (UVA), ultraviolet C (UVC), Hydrogen Peroxide, Inflammatory (ILβ), Time, Temperature (-196°C, -80°C, -3°C, 3°C, 4°C, 15°C and 22°C) and Low Serum induced cell death at pHs from 5.3 -10.5. In addition to protecting cell survival PKX-001 also preserves cell functionality. This has been tested via stem cell markers, CD34+ functionality tests, and in vivo studies where PKX-001 treated transplanted islet cells were found to reduce blood glucose concentrations in diabetic mice by 40% by day 40 in comparison to islet cells which were transplanted into mice without first being exposed to PKX-001.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 68 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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:
- •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, hypoglycemic (HYPO) score ≥1,000, lability index (LI) ≥400 or combined HYPO/LI >400/>
- •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.
- •Retrospective Control Inclusion Criteria:
- •All control participants will be included according to the immunosuppression / engraftment regimen used in this pilot, specifically the current standard of care islet transplant at the University of Alberta Hospital: Alemtuzumab/Basiliximab, Anakinra, Etanercept, Mycophenolate Mofetil and Tacrolimus.
Exclusion Criteria
- •History of enrollment in any other islet transplant trials (at the discretion of the investigator).
- •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.
- •Active alcohol or substance abuse, to include cigarette smoking (must be abstinent for 6 months prior to listing for transplant).
- •Psychiatric disorder making the patient not a suitable candidate for transplantation (e.g., schizophrenia, bipolar disorder, or major depression that is unstable or uncontrolled on current medication).
- •History of non-adherence to prescribed regimens.
- •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).
- •Any history of, or current malignancies except squamous or basal skin cancer.
- •BMI > 35 kg/m2 at screening visit.
- •Age less than 18 or greater than 68 years.
- •Measured glomerular filtration rate (GFR) <60 mL/min/1.73 m
- •Presence or history of macroalbuminuria (>300 mg/g creatinine).
- •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).
- •Baseline Hb < 105g/L (<10.5 g/dL) in women, or < 120 g/L (<12 g/dL) in men.
- •Baseline screening liver function tests outside of normal range, with the exception of uncomplicated Gilbert's Syndrome. An initial liver function test (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.
- •Untreated proliferative retinopathy.
- •Positive pregnancy test, intent for future pregnancy or male subjects' intent to procreate, failure to follow effective contraceptive measures, or presently breast-feeding.
- •Evidence of significant sensitization on panel reactive antibody (PRA) (at the discretion of the investigator).
- •Insulin requirement >1.0 U/kg/day
- •HbA1C >12%.
- •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)].
- •Under treatment for a medical condition requiring chronic use of steroids.
- •Use of coumadin or other anticoagulant therapy (except aspirin) or patient with prothrombin time (PT) / international normalized ratio (INR) > 1.
- •Untreated Celiac disease.
- •Patients with Graves disease will be excluded unless previously adequately treated with radioiodine ablative therapy.
Arms & Interventions
Treatment Group
PKX-001 will be supplemented to islet preservation CMRL-1066 medium at final concentration of 3 mg/mL during islet isolation process. On the day of transplantation, preserved islets supplemented with PKX-001 are collected and washed with Transplant Media, which does not contain PKX-001, as a standard procedure. The isolation team will evaluate the final islet product based on standard assays. Islets are maintained for minimal 6 hours up to 72 hours in supplemented CMRL1066-based media containing PKX-001 until the time of transplant. When product release minimal criteria are met, islets will be clinically transplanted into patients intraportally.
Intervention: Antiaging Glycopeptide (Drug)
Outcomes
Primary Outcomes
Adverse event morbidity
Time Frame: Up to 1 year post-transplant
Adverse event morbidity within 1 year post-transplant
Serious adverse event morbidity
Time Frame: Up to 1 year post-transplant
Adverse event morbidity within 1 year post-transplant
Secondary Outcomes
- Islet yield(Day 0)
- Engraftment index(Day 90 post-transplant)
- Islet viability(Day 0)
- Oxygen consumption ratio(Day 0)
- Number of participants with insulin independence(Day 90 post-transplant)
- Insulin requirement(Day 0)
- Glucose stimulated insulin release(Day 0)
- Beta-2 score(Day 0)