Renal Transplant FailureENTREATNCT04973982
ENvarsus for Impaired Glucose Tolerance Post REnal transplAnT
A study testing Envarsus and Adoport in people with Renal Transplant Failure, run by Barts & The London NHS Trust at 1 site in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Renal Transplant Failure
- What is being tested?
- Envarsus and Adoport
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 31 Jan 2022to 1 Oct 2022
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the 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.
- Conditions
- Renal Transplant Failure
- Being tested
- Envarsus, Adoport
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EnvarsusDrug
3 month treatment, given once daily, oral tablet. Dose titrated according to levels target 6-10ng/ml
AdoportDrug
Also called Tacrolimus
3 month treatment, given twice daily, oral tablet. Dose titrated according to levels target 6-10ng/ml
| Study group | Role | What they receive |
|---|---|---|
| ENVARSUS | Active comparator | ENVARSUS used as per licence Receives: Drug: Envarsus |
| ADOPORT | Active comparator | ADOPTION used as per licence Receives: Drug: Adoport |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 3 months
Secondary outcomes (7)
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
Measured: 3 month
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
Measured: 3 month
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
Measured: 3 month
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
Measured: 3 month
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
Measured: 3 month
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
Measured: 3 month
Safety endpoints: SAEs, AEs AE and SAE will be categorised into categories as per CRF.
Frequency of SAEs and AEs occurring during the study
Measured: 3 month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jul 2021
- Study start31 Jan 2022 (estimated)
- Primary completion1 Aug 2022 (estimated)
- Study completion1 Oct 2022 (estimated)
Why it stopped: Lack of capacity
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Renal Transplant FailureStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Prospective, open label, single centre, randomised parallel-group controlled trial
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Barts & The London NHS Trust
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04973982
- Sponsor's protocol ID
- 012280
- Acronym
- ENTREAT
- Status last verified
- Jul 2021
- First submitted
- 12 Jul 2021
- Last updated
- 1 Apr 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: aggregated data will be shared
Study at a glance
From the registry record, last updated by the sponsor on 1 Apr 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- ENvarsus for Impaired Glucose Tolerance Post REnal transplAnT
- ClinicalTrials.gov ID
- NCT04973982
- Acronym / sponsor ID
- ENTREAT / 012280
- Conditions
- Renal Transplant Failure
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Lack of capacity
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Barts & The London NHS TrustUniversity, hospital or other
- Study start
- 31 Jan 2022 (estimated)
- Primary completion
- 1 Aug 2022 (estimated)
- Study completion
- 1 Oct 2022 (estimated)
- First posted
- 22 Jul 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Prospective, open label, single centre, randomised parallel-group controlled trial
| Arm | Type | Receives |
|---|---|---|
| ENVARSUS | Active comparator | Drug: EnvarsusENVARSUS used as per licence |
| ADOPORT | Active comparator | Drug: AdoportADOPTION used as per licence |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (6 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Envarsus3 month treatment, given once daily, oral tablet. Dose titrated according to levels target 6-10ng/ml | Drug | ENVARSUS |
| AdoportAlso: Tacrolimus3 month treatment, given twice daily, oral tablet. Dose titrated according to levels target 6-10ng/ml | Drug | ADOPORT |
Primary outcome
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
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.
7 secondary outcomes
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
Time frame: 3 month
Proportion of patients developing PTDM during the study
Time frame: 3 month
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.
Time frame: 3 month
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.
Time frame: 3 month
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.
Time frame: 3 month
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.
Time frame: 3 month
Safety endpoints: SAEs, AEs AE and SAE will be categorised into categories as per CRF.
Time frame: 3 month
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Apr 2022.
- Individual participant dataSharing planned: Undecided. aggregated data will be shared
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Envarsus and Adoport in people with Renal Transplant Failure, run by Barts & The London NHS Trust at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 1 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Apr 2022.