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

Primary Purpose

Type 2 Diabetes, Diabetes Mellitus, Type 2, Renal Transplant

Status
Active
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
AZD1656
Placebo
Sponsored by
Queen Mary University of London
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Type 2 Diabetes focused on measuring Type 2 Diabetes Mellitus, Diabetes Mellitus, Renal transplantation, Regulatory T cells, AZD1656

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Royal London Hospital Barts Health NHS Trust

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

AZD1656

placebo

Arm Description

AZD1656 100mg BD for 3 months

placebo 100mg BD for 3 months

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Full Information

First Posted
January 17, 2022
Last Updated
May 16, 2023
Sponsor
Queen Mary University of London
Collaborators
AstraZeneca
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1. Study Identification

Unique Protocol Identification Number
NCT05216172
Brief Title
AZD1656 in Transplantation With Diabetes tO PromoTe Immune TOleraNce
Acronym
ADOPTION
Official Title
AZD1656 in Transplantation With Diabetes tO PromoTe Immune TOleraNce
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 21, 2020 (Actual)
Primary Completion Date
May 28, 2023 (Anticipated)
Study Completion Date
August 1, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Queen Mary University of London
Collaborators
AstraZeneca

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes, Diabetes Mellitus, Type 2, Renal Transplant, Kidney Transplant; Complications, End Stage Renal Disease
Keywords
Type 2 Diabetes Mellitus, Diabetes Mellitus, Renal transplantation, Regulatory T cells, AZD1656

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Single site, placebo controlled, double blind randomised clinical trial
Masking
ParticipantCare ProviderInvestigatorOutcomes 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.
Allocation
Randomized
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
AZD1656
Arm Type
Experimental
Arm Description
AZD1656 100mg BD for 3 months
Arm Title
placebo
Arm Type
Placebo Comparator
Arm Description
placebo 100mg BD for 3 months
Intervention Type
Drug
Intervention Name(s)
AZD1656
Intervention Description
active drug
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
placebo
Primary Outcome Measure Information:
Title
peripheral regulatory T cells
Description
Change in mean peripheral Treg cell number between baseline and 3 months measured using flow cytometry analysis (FACS) in AZD1656 and placebo arms
Time Frame
14 weeks
Secondary Outcome Measure Information:
Title
regulatory T cells in renal transplant
Description
Histological staining for Treg cells in renal biopsy tissue between baseline and 3 month protocol biopsy
Time Frame
3 months
Title
delayed graft function
Description
Incidence of delayed graft function, defined as the need for dialysis within 1 week post-transplant
Time Frame
1 week
Title
glycemic control: HbA1c
Description
Diabetic control between baseline and month 3 using change in HbA1c measurement
Time Frame
3 months
Title
number of participants with increase or decrease in concurrent anti-diabetic medication
Description
Dose of other anti-diabetic medication between baseline and month 3 (descriptive)
Time Frame
3 months
Title
incidence of treatment emergent adverse events
Description
safety endpoints including hypoglycaemic episodes
Time Frame
3 months
Title
change in HOMA-IR measurement between baseline and month 3
Description
Insulin resistance: HOMA IR measurement at month 3
Time Frame
3 months
Title
kidney transplant function
Description
Graft function: (eGFR) at month 3
Time Frame
3 months
Title
kidney transplant rejection
Description
Episodes of acute rejection (defined as biopsy proven acute rejection)
Time Frame
3 months
Title
incidence of treatment emergent adverse events (with particular reference to episodes of infection)
Description
Episodes of opportunistic infections: bacterial and viral (descriptive)
Time Frame
3 months
Other Pre-specified Outcome Measures:
Title
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
Description
12-month graft function (eGFR) and diabetic control (HbA1c; medication review) to assess legacy effect
Time Frame
1 year
Title
T cell profile
Description
Differences in other peripheral T cell populations, measured by FACS analysis
Time Frame
3 months
Title
regulatory T cells in renal transplant: biopsy for cause
Description
Histological staining for Treg cells in any renal biopsy taken for clinical indications between baseline and month 3 protocol biopsy
Time Frame
3 months
Title
regulatory T cells: functional assay
Description
Differences in the functional phenotype of the Treg cells
Time Frame
3 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kieran McCafferty, M.B., B.Chir
Organizational Affiliation
Barts Health NHS Trust; Queen Mary University London
Official's Role
Principal Investigator
Facility Information:
Facility Name
Royal London Hospital Barts Health NHS Trust
City
London
ZIP/Postal Code
E1 1BB
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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??]

Learn more about this trial

AZD1656 in Transplantation With Diabetes tO PromoTe Immune TOleraNce

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