ADOPTION: AZD1656 in Transplantation With Diabetes tO PromoTe Immune TOleraNce

Sponsor

Queen Mary University of London (Other)

Overall Status

Recruiting

CT.gov ID

NCT05216172

Collaborator

AstraZeneca (Industry)

Enrollment

Location

Arms

31.3

Anticipated Duration (Months)

1.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Diabetes Mellitus, Type 2 Renal Transplant Kidney Transplant; Complications End Stage Renal Disease	Drug: AZD1656 Drug: Placebo	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Single site, placebo controlled, double blind randomised clinical trialSingle site, placebo controlled, double blind randomised clinical trial

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

This is a double blind placebo study: both the patient and the study team will be blinded to the treatment intervention. Pharmacy staff who dispense the study medication will not be blinded, nor will Sponsor Office staff responsible for reporting unblinded SUSAR reports to the MHRA.

Primary Purpose:

Treatment

Official Title:

AZD1656 in Transplantation With Diabetes tO PromoTe Immune TOleraNce

Actual Study Start Date :

Jan 21, 2020

Anticipated Primary Completion Date :

Sep 1, 2022

Anticipated Study Completion Date :

Sep 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AZD1656 AZD1656 100mg BD for 3 months	Drug: AZD1656 active drug
Placebo Comparator: placebo placebo 100mg BD for 3 months	Drug: Placebo placebo

Arm

Intervention/Treatment

Experimental: AZD1656

AZD1656 100mg BD for 3 months

Drug: AZD1656

active drug

Placebo Comparator: placebo

placebo 100mg BD for 3 months

Drug: Placebo

placebo

Outcome Measures

Primary Outcome Measures

peripheral regulatory T cells [14 weeks]
Change in mean peripheral Treg cell number between baseline and 3 months measured using flow cytometry analysis (FACS) in AZD1656 and placebo arms

Secondary Outcome Measures

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

Other Outcome Measures

Comparison of patient and placebo group at 1 year post transplant: number of participants experiencing episodes of infection, rejection; comparison of renal function and diabetic control [1 year]
12-month graft function (eGFR) and diabetic control (HbA1c; medication review) to assess legacy effect
T cell profile [3 months]
Differences in other peripheral T cell populations, measured by FACS analysis
regulatory T cells in renal transplant: biopsy for cause [3 months]
Histological staining for Treg cells in any renal biopsy taken for clinical indications between baseline and month 3 protocol biopsy
regulatory T cells: functional assay [3 months]
Differences in the functional phenotype of the Treg cells

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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