ENvarsus for Impaired Glucose Tolerance Post REnal transplAnT (ENTREAT)
Primary Purpose
Renal Transplant Failure
Status
Withdrawn
Phase
Not Applicable
Locations
United Kingdom
Study Type
Interventional
Intervention
Envarsus
Adoport
Sponsored by
About this trial
This is an interventional treatment trial for Renal Transplant Failure
Eligibility Criteria
Inclusion Criteria
- Females or males aged 18 years and above
- Having undergone renal transplantation within the previous 2 years
- Current treatment with tacrolimus
- Evidence of impaired glucose tolerance (defined as a blood glucose level between 7.8-11.1 mmol/L after a two hour oral glucose tolerance test)
- Provision of written, informed consent prior to any study specific procedures
Exclusion Criteria
- Unable to consent
- Planning on becoming pregnant/unwilling to use highly effective contraception during the 3-month treatment period or breastfeeding.
- Clinically significant history of abnormal physical and/or mental health as judged by the investigator other than conditions related to chronic kidney disease
- History of Type 1 or Type 2 diabetes mellitus; or on treatment with anti-diabetic medications
- Prior therapy with Envarsus
- Exposure to an investigational drug withing the preceding 3 months, or 5 half-lives whichever is greater.
Sites / Locations
- Barts Health NHS Trust
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Active Comparator
Arm Label
ENVARSUS
ADOPORT
Arm Description
ENVARSUS used as per licence
ADOPTION used as per licence
Outcomes
Primary Outcome Measures
The proportion of patients who normalise their IGT (defined as a blood glucose level between <7.8mmol/l) after a two-hour oral glucose tolerance test at three months after randomisation.
The proportion of patients who normalise their IGT (defined as a blood glucose level between <7.8mmol/l) after a two-hour oral glucose tolerance test at three months after randomisation.
Secondary Outcome Measures
Change in HOMA-IR test between 0 and 3 months post-randomisation This parameter will be compared on the ITT dataset using unpaired T test. P values of < 0.05 will be considered statistically significant
Change in HOMA-IR test between 0 and 3 months post-randomisation
Proportion of patients developing PTDM during the study
Proportion of patients developing PTDM during the study as defined by a positive two-hour OGTT >11.1 mmol/L at 3 months
Change in HbA1c between baseline and 3 months This parameter will be compared on the ITT dataset using unpaired T test. P values of < 0.05 will be considered statistically significant.
Change in HbA1c between baseline and 3 months
Change in eGFR between baseline and 3 months This parameter will be compared on the ITT dataset using unpaired T test. P values of < 0.05 will be considered statistically significant.
Change in eGFR between baseline and 3 months
Change in fasting blood sugar between randomisation and month 3 This parameter will be compared on the ITT dataset using unpaired T test. P values of < 0.05 will be considered statistically significant.
Change in fasting blood sugar between randomisation and month 3
Change in 2h OGTT blood result between randomisation and month 3 This parameter will be compared on the ITT dataset using unpaired T test. P values of < 0.05 will be considered statistically significant.
Change in 2h OGTT blood result between randomisation and month 3
Safety endpoints: SAEs, AEs AE and SAE will be categorised into categories as per CRF.
Frequency of SAEs and AEs occurring during the study
Full Information
NCT ID
NCT04973982
First Posted
July 12, 2021
Last Updated
March 21, 2022
Sponsor
Barts & The London NHS Trust
1. Study Identification
Unique Protocol Identification Number
NCT04973982
Brief Title
ENvarsus for Impaired Glucose Tolerance Post REnal transplAnT
Acronym
ENTREAT
Official Title
ENvarsus for Impaired Glucose Tolerance Post REnal transplAnT
Study Type
Interventional
2. Study Status
Record Verification Date
July 2021
Overall Recruitment Status
Withdrawn
Why Stopped
Lack of capacity
Study Start Date
January 31, 2022 (Anticipated)
Primary Completion Date
August 1, 2022 (Anticipated)
Study Completion Date
October 1, 2022 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Barts & The London NHS Trust
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Our hypothesis is that switching from the current standard of care twice daily Adoport (Tacrolimus) to once daily Envarsus (tacrolimus) in patients who have impaired glucose tolerance post-transplant will lead to an improvement in their glucose tolerance, and may reduce the subsequent incidence of PTDM.
Detailed Description
Kidney transplantation is widely held to be the optimal form of renal replacement therapy for patients with end-stage renal disease, leading to a longer survival and improved quality of life in patients receiving a renal transplant compared to those that remain on dialysis. However renal transplantation brings with it a new set of challenges for the clinician. One of the most important of these is post-transplant diabetes mellitus (PTDM). The prevalence of PTDM has increased over time and may occur in up to a third of all post-transplant patients making it a critical challenge for transplant physicians.
PTDM represents a significant risk factor to both patient and graft survival, with some studies suggesting an increase of 60% in graft failure and an almost 90% increase in mortality. This morbidity and mortality is due to the greatly increased risk of cardiovascular disease associated with PTDM. In addition to the clinical consequences of PTDM for patients, there is also a huge economic impact on healthcare, with a diagnosis of PTDM doubling the cost of healthcare for a transplant patient.
Important risks factors for PTDM include: Black/Asian race, male sex, older patients, receipt of a 'Donation after cardiac death' kidney, family history of diabetes, BP, raised body-mass index, Hepatitis C disease, Cytomegalovirus (CMV) viraemia, hyperparathyroidism, low HDL cholesterol, and hypomagnesaemia.
In addition, PTDM is caused by multiple factors associated with renal transplantation. Steroid use impairs pancreatic beta-cell function, induces gluconeogenesis and glycolysis, inhibits glycogenesis and leads to insulin resistance. Tacrolimus, a calcineurin inhibitor (CNI), has been associated with increased rates of PTDM when compared to other CNIs (i.e. cyclosporine). It leads to hyperglycaemia via reduction of pancreatic insulin secretion and a reduction of GLUT-4 mediated glucose uptake into cells. In addition, it may directly cause beta cell toxicity and down regulate insulin gene expression. High tacrolimus concentrations have been associated with the development of PTDM; however, due to its enhanced efficacy in prevention of acute and chronic rejection, it has become the most widely used immunosuppressive medication in renal transplantation.
Over 30% of patients post renal transplant have evidence of impaired glucose tolerance (IGT). IGT is a key step in the development of PTDM and an opportunity for intervention to prevent the development of PTDM.
Higher peak tacrolimus levels have been associated with islet cell damage leading to hyperglycaemia, with evidence that this damage may be reversible with changing tacrolimus exposure .
Not all tacrolimus based regimens may have the same side effects. Envarsus is a newer tacrolimus formulation, which has significantly altered pharmacokinetic properties and bioavailability compared to other tacrolimus based regimens.
Envarsus has significantly lower peak to trough ratios and a 30% lower peak concentration. Both of these unique properties may reduce the beta cell toxicity seen with older tacrolimus based regimens and lead to an improvement in impaired glucose tolerance.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Renal Transplant Failure
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Prospective, open label, single centre, randomised parallel-group controlled trial
Masking
None (Open Label)
Allocation
Randomized
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
ENVARSUS
Arm Type
Active Comparator
Arm Description
ENVARSUS used as per licence
Arm Title
ADOPORT
Arm Type
Active Comparator
Arm Description
ADOPTION used as per licence
Intervention Type
Drug
Intervention Name(s)
Envarsus
Intervention Description
3 month treatment, given once daily, oral tablet. Dose titrated according to levels target 6-10ng/ml
Intervention Type
Drug
Intervention Name(s)
Adoport
Other Intervention Name(s)
Tacrolimus
Intervention Description
3 month treatment, given twice daily, oral tablet. Dose titrated according to levels target 6-10ng/ml
Primary Outcome Measure Information:
Title
The proportion of patients who normalise their IGT (defined as a blood glucose level between <7.8mmol/l) after a two-hour oral glucose tolerance test at three months after randomisation.
Description
The proportion of patients who normalise their IGT (defined as a blood glucose level between <7.8mmol/l) after a two-hour oral glucose tolerance test at three months after randomisation.
Time Frame
3 months
Secondary Outcome Measure Information:
Title
Change in HOMA-IR test between 0 and 3 months post-randomisation This parameter will be compared on the ITT dataset using unpaired T test. P values of < 0.05 will be considered statistically significant
Description
Change in HOMA-IR test between 0 and 3 months post-randomisation
Time Frame
3 month
Title
Proportion of patients developing PTDM during the study
Description
Proportion of patients developing PTDM during the study as defined by a positive two-hour OGTT >11.1 mmol/L at 3 months
Time Frame
3 month
Title
Change in HbA1c between baseline and 3 months This parameter will be compared on the ITT dataset using unpaired T test. P values of < 0.05 will be considered statistically significant.
Description
Change in HbA1c between baseline and 3 months
Time Frame
3 month
Title
Change in eGFR between baseline and 3 months This parameter will be compared on the ITT dataset using unpaired T test. P values of < 0.05 will be considered statistically significant.
Description
Change in eGFR between baseline and 3 months
Time Frame
3 month
Title
Change in fasting blood sugar between randomisation and month 3 This parameter will be compared on the ITT dataset using unpaired T test. P values of < 0.05 will be considered statistically significant.
Description
Change in fasting blood sugar between randomisation and month 3
Time Frame
3 month
Title
Change in 2h OGTT blood result between randomisation and month 3 This parameter will be compared on the ITT dataset using unpaired T test. P values of < 0.05 will be considered statistically significant.
Description
Change in 2h OGTT blood result between randomisation and month 3
Time Frame
3 month
Title
Safety endpoints: SAEs, AEs AE and SAE will be categorised into categories as per CRF.
Description
Frequency of SAEs and AEs occurring during the study
Time Frame
3 month
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 within the previous 2 years
Current treatment with tacrolimus
Evidence of impaired glucose tolerance (defined as a blood glucose level between 7.8-11.1 mmol/L after a two hour oral glucose tolerance test)
Provision of written, informed consent prior to any study specific procedures
Exclusion Criteria
Unable to consent
Planning on becoming pregnant/unwilling to use highly effective contraception during the 3-month treatment period or breastfeeding.
Clinically significant history of abnormal physical and/or mental health as judged by the investigator other than conditions related to chronic kidney disease
History of Type 1 or Type 2 diabetes mellitus; or on treatment with anti-diabetic medications
Prior therapy with Envarsus
Exposure to an investigational drug withing the preceding 3 months, or 5 half-lives whichever is greater.
Facility Information:
Facility Name
Barts Health NHS Trust
City
London
ZIP/Postal Code
E1 1BB
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
Undecided
IPD Sharing Plan Description
aggregated data will be shared
Learn more about this trial
ENvarsus for Impaired Glucose Tolerance Post REnal transplAnT
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