Islet Transplantation Using PKX-001
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|ClinicalTrials.gov Identifier: NCT03073577|
Recruitment Status : Active, not recruiting
First Posted : March 8, 2017
Last Update Posted : November 9, 2020
|First Submitted Date ICMJE||February 26, 2017|
|First Posted Date ICMJE||March 8, 2017|
|Last Update Posted Date||November 9, 2020|
|Actual Study Start Date ICMJE||February 16, 2017|
|Estimated Primary Completion Date||September 2022 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE||Same as current|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Islet Transplantation Using PKX-001|
|Official Title ICMJE||Clinical Study Using Antiaging Glycopeptide (PKX-001) in Islet Transplantation|
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.
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.
In light of the beneficial roles of PKX-001 on cellular survival and functionality preservation, our team have evaluated the cytoprotective capacity of PKX-001 in islet transplant, especially its capacity of protection against the diabetogenic effect of Tac.
In vitro assessment of human islets in culture with PKX-001 supplementation has also showed enhanced quality and yield of post-preservation human islets and protection against acute exposure to Tac at clinical relevant doses compared with those without PKX-001 supplementation. Further analysis indicated that islets treated with PKX-001 had decreased oxidative stress, improved insulin release by increasing islet exocytosis, decreased islet loss during preservation due to apoptosis, even in the presence of Tac.
In vivo studies have complemented all in vitro findings above, which demonstrated that PKX-001 supplementation suppressed early inflammation and improved islet engraftment with long-term efficacy.
The proposed study is a phase I, non-randomized, open-label, single arm, prospective trial using retrospective controls.
Ten adult Islet transplant candidates (18 years and older), deemed appropriate for standard islet transplant at the University of Alberta Hospital will be enrolled in this investigation.
Retrospective data from 10 islet transplant patients consented for chart review (Protocol #: 000001120 entitled: "On-going review of islet transplant patients at the University of Alberta" and Protocol #: 000001122 entitled: "Collaborative Islet Transplant Registry") will be also collected.
The standard of Care controls will be identified from the Islet Transplant program database (period: 2014 - 2016) and anonymized by a simple numbering system.
Transplantation of PKX-001 treated islets is safe and improves graft outcomes.
To demonstrate safety of transplantation of PKX-001 treated islets.
To assess efficacy of transplantation of PKX-001 treated islets To assess efficacy of addition of PKX-001 during islet preservation
Prior to transplantation, the patient is screened, qualified, listed for transplant, and signs the informed consent form.
At the time a suitable islet preparation becomes available, the patient will receive allogeneic islet cells transplanted into patients intraportally by percutaneous transhepatic access.
Islet transplant will be performed under the current immunosuppression regimen including: induction (Alemtuzumab/Basiliximab) and long-term immunosuppression (Prograf/Cellcept). The engraftment regimen includes anti-inflammatory medications (Etanercept/Anakinra) and intravenous insulin and heparin. The only additional intervention used in this pilot trial is the addition of the investigational agent, PKX-001 to islet processing.
Participants will undergo a 3-month follow-up period following their initial or subsequent islet transplant.
There are no study-specific follow-up visits required for this study. Study subjects will be followed as per standard of care. For the purpose of evaluating the primary and secondary endpoints, the following measurements collected on study subjects at the time points indicated as per standard of care, will be chart reviewed and recorded up to Day 30 post-transplant:
Clinical Assessment by Transplant Fellow or Staff; Post-Transplant Blood work (as per Standard of Care); Metabolic testing: Ensure (or Arginine); Glucose Records for Self-Monitoring. Incidence of Primary Non-Function (see Glossary for definition); Incidence of Adverse Events or Serious Adverse Events can be reported on any day post transplant; Abdominal Ultrasound with Doppler report (clinically significant findings). The study will remain open to collect all 10 recipients' follow-up data to 3 month post-transplant. Primary and secondary outcome reporting will occur 90 days following the transplant of the last patient to the trial.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 1|
|Study Design ICMJE||Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Condition ICMJE||Type 1 Diabetes Mellitus|
|Intervention ICMJE||Drug: Antiaging Glycopeptide
Antiaging Glycopeptide (PKX-001) will be supplemented to islet preservation medium 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 used in standard of care practice. When product release minimal criteria are met, islets will be clinically transplanted into patients intraportally by percutaneous transhepatic access.
|Study Arms ICMJE||Experimental: 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: Drug: Antiaging Glycopeptide
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Active, not recruiting|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Estimated Study Completion Date ICMJE||January 2023|
|Estimated Primary Completion Date||September 2022 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
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.
|Ages ICMJE||18 Years to 68 Years (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Canada|
|Removed Location Countries|
|NCT Number ICMJE||NCT03073577|
|Other Study ID Numbers ICMJE||Pro00067564|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Responsible Party||University of Alberta|
|Study Sponsor ICMJE||University of Alberta|
|Collaborators ICMJE||ProtoKinetix Inc.|
|PRS Account||University of Alberta|
|Verification Date||November 2020|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP