AZD1656 in Transplantation With Diabetes tO PromoTe Immune TOleraNce

Study Overview
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Brief Summary
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AZD1656 in Transplantation with Diabetes tO PromoTe Immune TOleraNce: a single site, placebo-controlled, double-blind randomised clinical trial of AZD1656 in renal transplant patients with Type 2 diabetes

Detailed Description
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Transplant recipients with pre-existing Type 2 diabetes frequently experience a deterioration in glycaemic control in the early post-transplant period, largely due to the significant immunosuppression burden at this stage. Elevated glucose profiles have been associated with poorer graft outcomes. The glucokinase activator AZD1656 has been shown to be a potent anti diabetic medication and safe in patients with T2DM, including those with chronic kidney disease. Recent data has shown that glucokinase activation increases regulatory T cell (Treg) migration and trafficking. The investigators propose to study the safety and efficacy of AZD1656 in optimising the glycaemic control and in stimulating Treg migration to the transplant kidney in a population of renal transplant patients with pre-existing T2DM. ADOPTION is a single site, placebo-controlled, double-blind randomised clinical trial of AZD1656 in patients with Type 2 diabetes who have received a new renal transplant. Eligible, consented patients are randomised to a 3 month course of either active drug or placebo within 24 hours of transplantation. Clinical and laboratory data will be collected and assessed at baseline and throughout their participation in the study. The study plans to enrol 50 patients. There are no interim analyses planned. The primary endpoint will be the mean change in peripheral Tregs between baseline and 3 months as analysed by flow cytometry. Ethical approval was obtained from the East of England - Cambridge East Ethics Committee (REC 19/EE/0209) prior to commencing the study. All study-related data will be used by the Sponsor in accordance with local data protection law. Results of the trial will be submitted for publication in a peer-reviewed journal.

Official Title
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AZD1656 in Transplantation With Diabetes tO PromoTe Immune TOleraNce

Conditions
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Type 2 Diabetes, Diabetes Mellitus, Type 2, Renal Transplant, Kidney Transplant; Complications, End Stage Renal Disease

Intervention / Treatment
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* Drug: AZD1656
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females or males aged 18 years and above Having undergone renal transplantation at the Royal London Hospital within the previous 24 hours A pre-transplant diagnosis of Type 2 diabetes Provision of written, informed consent prior to any study specific procedures In women of childbearing potential* documentation of a negative pregnancy test during admission for renal transplant. Women of childbearing potential are defined as women following menarche until becoming post-menopausal, unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A post-menopausal state is defined as the absence of menses for 12 months without an alternative medical cause. Exclusion Criteria: Unable to consent Known allergy/intolerance to AZD1656 Pregnant or breastfeeding women Planning on becoming pregnant/unwilling to use highly effective contraception* during the 3 month treatment period and for 2 weeks afterwards (i) In the case of men with sexual partners who are women of childbearing potential: refusal to wear a condom and female partner planning on becoming pregnant/unwilling to use highly effective contraception* during the 3 month treatment period and for 2 weeks afterwards Clinically significant history of abnormal physical and/or mental health as judged by the investigator other than conditions related to chronic kidney disease Current or planned use of strong inhibitors of CYP2C8 Participation in an investigational drug trial in the 3 months prior to administration of the initial dose of study drug Highly effective contraception methods are defined as those that can achieve a failure rate of <1% per year when used correctly and consistently. These include: Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation - either oral, transvaginal or transdermal Progestogen-only hormonal contraception associated with inhibition of ovulation - either oral, injectable or implantable Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) Bilateral tubal occlusion Vasectomised partner - provided that the partner is the sole sexual partner of the participant and that the vasectomised partner has received medical assessment of surgical success

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Single site, placebo controlled, double blind randomised clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD1656<br>AZD1656 100mg BD for 3 months | Drug: AZD1656<br>* active drug<br>|
| Placebo Comparator: placebo<br>placebo 100mg BD for 3 months | Drug: Placebo<br>* placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| peripheral regulatory T cells | Change in mean peripheral Treg cell number between baseline and 3 months measured using flow cytometry analysis (FACS) in AZD1656 and placebo arms | 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| regulatory T cells in renal transplant | Histological staining for Treg cells in renal biopsy tissue between baseline and 3 month protocol biopsy | 3 months | 
| delayed graft function | Incidence of delayed graft function, defined as the need for dialysis within 1 week post-transplant | 1 week | 
| glycemic control: HbA1c | Diabetic control between baseline and month 3 using change in HbA1c measurement | 3 months | 
| number of participants with increase or decrease in concurrent anti-diabetic medication | Dose of other anti-diabetic medication between baseline and month 3 (descriptive) | 3 months | 
| incidence of treatment emergent adverse events | safety endpoints including hypoglycaemic episodes | 3 months | 
| change in HOMA-IR measurement between baseline and month 3 | Insulin resistance: HOMA IR measurement at month 3 | 3 months | 
| kidney transplant function | Graft function: (eGFR) at month 3 | 3 months | 
| kidney transplant rejection | Episodes of acute rejection (defined as biopsy proven acute rejection) | 3 months | 
| incidence of treatment emergent adverse events (with particular reference to episodes of infection) | Episodes of opportunistic infections: bacterial and viral (descriptive) | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes Mellitus, Diabetes Mellitus, Renal transplantation, Regulatory T cells, AZD1656