Insulin Therapy for the Prevention of New Onset Diabetes After Transplantation Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients

Study Overview
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Brief Summary
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This study aims to assess the effects of early basal insulin therapy in previously non-diabetic de novo kidney transplant patients in reducing the incidence of new onset diabetes in particular and abnormal glucose metabolism in general during subsequent follow-up.The ITP NODAT study should be seen in connection with the Vienna SAPT-NODAT study (clinicaltrials.gov record number: NCT01680185), as for the final analysis, the data yielded from the three arms in those two studies will be used for an pooled analysis.

Detailed Description
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New-onset diabetes after transplantation (NODAT) is strongly associated with postoperative hyperglycemia, and reduced patient as well as graft survival. In our recent proof-of-concept clinical trial (TIP), we have shown that immediate post-transplant basal insulin therapy decreases hyperglycemia and reduces the prevalence of NODAT by improving pancreatic β-cell function. In consequence, this study as an interventional trial comparing aggressive glycemic control with early institution of insulin therapy to standard of care (dietary precaution, life-style modification, oral hypoglycemic agents and/or insulin as needed) aims to assess the effects of early basal insulin therapy in previously non-diabetic de novo kidney transplant patients in reducing the incidence of new onset diabetes in particular and abnormal glucose metabolism in general during subsequent follow-up. Patients will be enrolled through the University of Michigan and the Medical University of Vienna, Austria (MUV), who is the official sponsor of the European part of the ITP-NODAT study. This record only refers to the European part of the ITP-NODAT study, specifically to all study patients from the following study Centers: MUV; Medical University of Graz, Austria; Charité Berlin, Germany; Hospital Del Mar, Barcelona, Spain. For the patients enrolled through the University of Michigan (i.e., the US-part of the ITP-NODAT study), a separate records exists (responsible PI: Dr. Akinlolu Ojo). This study will involve previously non-diabetic ESRD patients undergoing kidney transplantation with either a deceased or living donor kidney who will receive standard triple immunosuppression regimen including a calcineurin inhibitor (once-daily tacrolimus in Europe, twice-daily tacrolimus in the U.S.), an anti-metabolite (mycophenolate mofetil) and corticosteroids (prednisone) and be followed at each transplant center's outpatient clinic for at least 2 years following transplantation according to the established standard center protocol. Methods: Combining the study presented here (ITP-NODAT) and the SAPT-NODAT study mentioned above will yield three study arms, with 28 patients in each arm, namely: [1] the control arm, treated by standard-of-care; [2] the basal insulin arm, treated predominantly with intermediate acting NPH insulin (human insulin isophane, Humulin N, Eli Lilly); [3] the SAPT arm, treated with short acting insulin (Insulin lispro, Humalog, Eli Lilly), applied continuously by SAPT technology. Adult patients with absence of diabetes will be randomized prior to renal transplantation and stratified by deceased donor or living donor, if they are capable of understanding the study and are willing to give informed written consent for all three study arms. Patients will receive standard triple immunosuppressive medications (twice-daily tacrolimus, mycophenolate mofetil or mycophenolic sodium and steroids) with predefined tacrolimus targets and steroid doses. The algorithm for insulin administration is designed to account for the prominent evening peak of hyperglycemia observed in our previous TIP-study. The primary endpoint is HbA1c (in rel.%), at 3 months, and superiority will be assumed if a statistically significant difference between the SAPT-treatment group versus the standard-of-care control group can be determined, by two-sided Student's t-test. Secondary endpoints will be compared between all three groups and will include hypoglycemic events, glycemic variability, 2h glucose ≥200 mg/dL (by oral glucose tolerance test [OGTT] to determine prevalence of diabetes, prediabetes and normal glucose tolerance), beta cell function and insulin sensitivity derived from OGTT, serum creatinine, quality of life measures, patient and graft survival. All secondary endpoint comparisons relying on OGTTs will be made at 6, 12 and 24 months after kidney transplantation, respectively. The result of the 6-months OGTT will be blinded to patients and investigators to prevent subsequent treatment bias.

Official Title
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Insulin Therapy for the Prevention of New Onset Diabetes After Transplantation (ITP-NODAT) Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients

Conditions
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Hyperglycemia

Intervention / Treatment
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* Drug: Human insulin isophane, Humulin N (Eli Lilly)
* Drug: Standard of care
* Drug: Insulin lispro, Humalog (Eli Lilly) in insulin pump


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients with end stage renal disease undergoing kidney transplantation with a deceased or living donor kidney. Absence of diabetes prior to kidney transplantation, defined according to American Diabetes Association guideline (not on oral hypoglycemic agents or insulin with fasting glucose < 126 mg/dl). Receiving standard triple immunosuppressive medications that include tacrolimus (once-daily in Europe, twice-daily in the U.S.), mycophenolate mofetil or mycophenolic sodium and steroids. Capable of understanding the study and willing to give informed written consent for study participation. Exclusion Criteria: Patients with a diagnosis of diabetes mellitus prior to kidney transplantation, or receiving anti-diabetic medications, or having pre-transplant fasting glucose level equal or greater than 126 mg/dl on two occasions at least three days apart. Patients receiving an organ transplant other than kidney. Patients receiving an unlicensed drug or therapy within one month prior to study entry. Patients with history of hypersensitivity to injectable insulin. Patients with documented HIV infection.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Basal insulin<br>NPH Insulin Titration Regimen : Pre-dinner Capillary blood glucose NPH dose initiation (IU/day) NPH dose adjustment(IU/day) > 240 mg/dl 14 Increase by 4 > 180 mg/dl 12 Increase by 4 > 140 mg/dl 10 Increase by 4 > 120 mg/dl 0 Increase by 2 100 to 119 mg/dl 0 Maintain the dose 80 - <100 mg/dl 0 Decrease by 4 60 - <80 mg/dl 0 Decrease by 8 < 60 mg/dl 0 Give ½ of previous dose | Drug: Human insulin isophane, Humulin N (Eli Lilly)<br>* Human insulin isophane, Humulin N (Eli Lilly)<br>|
| Active Comparator: Standard of care<br>Patients assigned in this arm will receive standard of care following their kidney transplantation | Drug: Standard of care<br>* Sliding scale short acting insulin for hyperglycemia; Sulphonylurea for NODAT<br>|
| Active Comparator: Sensor-augmented Insulin Pump<br>Continuous subcutaneous sensor-augmented insulin-pump therapy (SAPT) with an insulin pump from Medtronic (Paradigm® Velo) for a period of approximately 3 months post-transplantation. | Drug: Insulin lispro, Humalog (Eli Lilly) in insulin pump<br>* Insulin lispro, Humalog (Eli Lilly) in insulin pump<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| incidence of NODAT | The incidence of NODAT 12 months after kidney transplantation defined according to American Diabetes Association criteria | month 12 after kidney transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of NODAT at 24 months after kidney transplantation | The incidence of NODAT at 24 months after kidney transplantation | month 24 | 
| Glycemia profile during the time of insulin therapy in arm A (intervention) comparing that of arm B (control). | Glycemia profile during the time of insulin therapy in arm A (intervention) comparing that of arm B (control). | week 0 to week 6 | 
| The glycemia control using A1c levels, overall and among patients with NODAT, through study period 6, 12 and 24 months after kidney transplantation. | The glycemia control using A1c levels, overall and among patients with NODAT, through study period 6, 12 and 24 months after kidney transplantation. | month 6, month 12, month 24 | 
| Incidence of impaired fasting glycemia and impaired glucose tolerance 6, 12 and 24 months after transplantation. | Incidence of impaired fasting glycemia and impaired glucose tolerance 6, 12 and 24 months after transplantation. | month 6, month 12, month 24 | 
| Pancreatic beta-cell function at 6, 12 and 24 months after kidney transplantation, measured as insulin secretion during an OGTT in relation to the glucose stimulation (insulinogenic index - total and early phase) | Pancreatic beta-cell function at 6, 12 and 24 months after kidney transplantation, measured as insulin secretion during an OGTT in relation to the glucose stimulation (insulinogenic index - total and early phase) | month 6, month 12, month 24 | 
| Fasting insulin resistance (mostly liver) at 6, 12 and 24 months after kidney transplantation, measured by HOMA-R and by QUICKI (insulin sensitivity) from fasting (basal) glucose and insulin concentration | Fasting insulin resistance (mostly liver) at 6, 12 and 24 months after kidney transplantation, measured by HOMA-R and by QUICKI (insulin sensitivity) from fasting (basal) glucose and insulin concentration | month 6, month 12, month 24 | 
| Dynamic insulin sensitivity (mostly muscle and adipose tissues) at 6, 12 and 24 months after kidney transplantation, measured by OGIS and ISIcomp from OGTT data | Dynamic insulin sensitivity (mostly muscle and adipose tissues) at 6, 12 and 24 months after kidney transplantation, measured by OGIS and ISIcomp from OGTT data | month 6, month 12, month 24 | 
| Renal function at 6, 12 and 24 months after kidney transplantation, measured by serum creatinine | Renal function at 6, 12 and 24 months after kidney transplantation, measured by serum creatinine | month 6, month 12, month 24 | 
| Patient and graft survival 6, 12 and 24 months after kidney transplantation | Patient and graft survival 6, 12 and 24 months after kidney transplantation | month 6, month 12, month 24 | 
| Mental component summary (MCS) and physical component summary (PCS) derived from the Kidney Disease Quality of Life Short Form (KDQoL-SFTM) at 6, 12 and 24 months after kidney transplantation | Mental component summary (MCS) and physical component summary (PCS) derived from the Kidney Disease Quality of Life Short Form (KDQoL-SFTM) at 6, 12 and 24 months after kidney transplantation | month 6, month 12, month 24 |