AZD1656 in Transplantation With Diabetes tO PromoTe Immune TOleraNce (ADOPTION)

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

Study Overview

• Status: Active, not recruiting
• Conditions: Diabetes Mellitus, Type 2; End Stage Renal Disease; Type 2 Diabetes; Renal Transplant; Kidney Transplant; Complications
• Intervention / Treatment: Drug: Placebo; Drug: AZD1656

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 Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, E1 1BB
    • Royal London Hospital Barts Health Nhs Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Females or males aged 18 years and above
2. Having undergone renal transplantation at the Royal London Hospital within the previous 24 hours
3. A pre-transplant diagnosis of Type 2 diabetes
4. Provision of written, informed consent prior to any study specific procedures

5. 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:

1. Unable to consent
2. Known allergy/intolerance to AZD1656
3. Pregnant or breastfeeding women
4. 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
5. Clinically significant history of abnormal physical and/or mental health as judged by the investigator other than conditions related to chronic kidney disease
6. Current or planned use of strong inhibitors of CYP2C8

7. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	12-month graft function (eGFR) and diabetic control (HbA1c; medication review) to assess legacy effect	1 year
T cell profile	Differences in other peripheral T cell populations, measured by FACS analysis	3 months
regulatory T cells in renal transplant: biopsy for cause	Histological staining for Treg cells in any renal biopsy taken for clinical indications between baseline and month 3 protocol biopsy	3 months
regulatory T cells: functional assay	Differences in the functional phenotype of the Treg cells	3 months

Collaborators and Investigators

• Sponsor: Queen Mary University of London
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Kieran McCafferty, M.B., B.Chir, Barts Health NHS Trust; Queen Mary University London

Study record dates

Study Major Dates

• Study Start (Actual): January 21, 2020
• Primary Completion (Anticipated): May 28, 2023
• Study Completion (Anticipated): August 1, 2023

Study Registration Dates

• First Submitted: January 17, 2022
• First Submitted That Met QC Criteria: January 17, 2022
• First Posted (Actual): January 31, 2022

Study Record Updates

• Last Update Posted (Actual): May 17, 2023
• Last Update Submitted That Met QC Criteria: May 16, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Diabetes Mellitus; Type 2 Diabetes Mellitus; Renal transplantation; Regulatory T cells; AZD1656
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Kidney Diseases; Urologic Diseases; Endocrine System Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Diabetes Mellitus; Diabetes Mellitus, Type 2; Kidney Failure, Chronic
• Other Study ID Numbers: 252155

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in any published article, after de-identification (text, tables, figures, and appendices)
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication

IPD Sharing Access Criteria

Investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose.

The data may be used for individual participant data meta-analysis.

Proposals may be submitted up to 36 months following article publication. After 36 months the data will be available in our University's data warehouse but without investigator support other than deposited metadata. Information regarding submitting proposals and accessing data may be found at [email corresponding author??]

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No