Treat-to-target Trial of Basal Insulin in Post-transplant Hyperglycemia (TIP)

Tracking Information
First Submitted Date ICMJE	January 26, 2009
First Posted Date ICMJE	January 27, 2009
Last Update Posted Date	September 3, 2012
Study Start Date ICMJE	January 2009
Actual Primary Completion Date	December 2010 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: February 25, 2011)	The primary endpoint is the difference in HbA1c between the two study arms. [ Time Frame: post-transplant day 90 ]
Original Primary Outcome Measures ICMJE; (submitted: January 26, 2009)	The primary endpoint is the difference in HbA1c between the two study arms. [ Time Frame: post-transplant day 90 and day 180 ]
Change History	Complete list of historical versions of study NCT00830297 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: February 25, 2011)	Capillary blood glucose profiles in each group [ Time Frame: post-transplant day 1-21 ]; Number of patients and overall number of days with hyperglycemia >140 mg/dl before supper (in each group) [ Time Frame: post-transplant day 1 - 21 ]; Number of patients and overall number of days with hyperglycemia >200 mg/dl (in each group) [ Time Frame: post-transplant day 1-21 ]; Number of patients and overall number of days with hypoglycemia <60 mg/dl in each group [ Time Frame: post-transplant day 1-21 ]; Number of patients with abnormal glucose tolerance [ Time Frame: post-transplant day 90, 180 and 360 ]; Difference in HbA1c between the two study arms [ Time Frame: post-transplant day 180 and 360 ]
Original Secondary Outcome Measures ICMJE; (submitted: January 26, 2009)	Capillary blood glucose profiles in each group [ Time Frame: post-transplant day 1-21 ]; Number of patients and overall number of days with hyperglycemia >140 mg/dl before supper (in each group) [ Time Frame: post-transplant day 1 - 21 ]; Number of patients and overall number of days with hyperglycemia >250 mg/dl (in each group) [ Time Frame: post-transplant day 1-21 ]; Number of patients and overall number of days with hypoglycemia <72 mg/dl (4 mmol/l) in each group [ Time Frame: post-transplant day 1-21 ]; Number of patients with abnormal glucose tolerance [ Time Frame: post-transplant day 90 and 180 ]
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Treat-to-target Trial of Basal Insulin in Post-transplant Hyperglycemia
Official Title ICMJE	Treat-to-target Trial of Basal Insulin in Post-transplant Hyperglycemia (TIP): Efficacy and Safety of a Novel Protocol in Renal Transplant Recipients Receiving a Tacrolimus-based Immunosuppression
Brief Summary	Treat-to-target trial of basal Insulin in Post-transplant hyperglycemia (TIP): efficacy and safety of a novel protocol in renal transplant recipients receiving a tacrolimus-based immunosuppression DESCRIPTION: A prospective, randomized safety and efficacy study of long-acting insulin (Insulatard®) as therapy against post-transplant hyperglycemia in renal transplant recipients OBJECTIVES: Primary Objective: To demonstrate superiority of long-acting insulin (Insulatard®) against post-transplant hyperglycemia, in comparison to conventional treatment, and as evaluated by HbA1c Secondary Objectives: To assess the average post-transplant glucose levels in renal transplant patients under conventional blood-glucose lowering therapy during a period of at least 14 days after transplantation by measuring the capillary blood glucose levels four times daily in both groups of patients (fasting, before lunch, before supper, after supper); To detect the number of post-transplant patients who - without any history of pre-transplant diabetes - develop at least one episode of post-transplant hyperglycemia (> 140 mg/dl before supper); To detect the average number of hyperglycemic episodes in post-transplant patients with at least one episode of post-transplant hyperglycemia and without any history of diabetes; To assess the amount of (long-acting) insulin (in IU) needed in order to obtain a target capillary blood glucose level in the range of 110 mg/dl to 120 mg/dl before supper in post-transplant patients with incidence of hyperglycemia; To assess the safety of long-acting insulin in controlling post-transplant hyperglycemia (especially with regards to episodes of hypoglycemia (glucose-level < 60 mg/dl); To assess the prevalence of post-transplant diabetes, as diagnosed by an abnormal oral glucose tolerance on days 90, 180 and 360 after transplantation, in the group of patients which has been treated with long-acting insulin, in comparison to patients who received conventional treatment; To assess the morbidity (hospitalization, infections, subsequent episodes of surgery, requirement of non-immunosuppressive, non- blood glucose lowering medication) in the group of patients with long-acting insulin for hyperglycemia, in comparison to patients randomized into the group receiving conventional treatment; To assess the renal outcome (creatinine levels, rejections) in the group of patients which is foreseen to be treated with long-acting insulin for hyperglycemia, in comparison to patients randomized into the group receiving conventional treatment
Detailed Description	DESIGN / PHASE: Prospective, single-center, randomized, parallel group, controlled, phase II study. STUDY PLANNED DURATION: First patient First visit 1Q 2009 Last patient First visit 4Q 2009 Last patient Last visit 4Q 2010 CENTERS: Department of Internal Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Austria, Department of Surgery, Division of Transplantation, Medical University of Vienna, Austria PATIENTS / GROUPS: 50 patients in 2 groups 25 patients per group Randomization ratio 1:1, no stratification Capillary blood glucose will be measured four times daily: before breakfast (7:30 am), before lunch (12 pm), before supper (5:30 pm) and after supper (9 pm) in both groups by the nursing personnel/academic investigators. In group No.1 (study arm A), patients will be treated with long-acting insulin (Insulatard) as soon as the glucose-level before supper surpasses 140 mg/dl. The normoglycemic goal in this group will be from 110 to 120 mg/dl. In group No.2 (study arm B), the glucose levels will be recorded, but the treatment will be left up to the ward, which is relying on conventional morning glucose measurements. For safety, any glucose levels >180 mg/dl will be reported, and all measures taken by the ward will be recorded. As there are no available guidelines however concerning the so called "conventional" blood glucose-lowering therapy in renal transplant patients, especially during this very early post-transplant phase, the following suggestions will be brought to the attention of the ward in order to standardize the treatment of the patients in study arm B: 1. Treatment in this group should be initiated if the fasting glucose level surpasses the renal glucose threshold, i.e. 180 mg/dl. 2. As the proposed life-style modifications for the treatment of NODAT1 are not feasible during this very early post-transplant phase, the basis of the conventional therapy will be proposed to be sulfonyl urea drugs (i.e. Gliclazide - Diamicron®, 30 mg, not more than three times daily). 3. Short-acting insulin will be strongly recommended to be used for corrections of capillary blood glucose levels above 250 mg/dl. EFFICACY ENDPOINTS: Primary: - HbA1c levels Secondary: capillary blood glucose profile in patients treated with long-acting insulin and in the control group, as evaluated by the daily measurements; number of patients and overall number of days with hyperglycemia > 140 mg/dl (in each group); number of patients and overall number of days with hyperglycemia > 200 mg/dl (in each group); number of patients and overall number of days with hypoglycemia < 60 mg/dl in each group; number of patients with abnormal glucose tolerance on days 90, 180 and 360 after transplantation TOLERABILITY / SAFETY ENDPOINTS: - Number of incidences of symptomatic hypoglycemia, confirmed by capillary blood glucose levels < 60 mg/dl PHARMACOKINETIC / PHARMACODYNAMIC ENDPOINTS: Doses of (long-acting) insulin STATISTICAL METHODOLOGY: Primary Endpoint: HbA1c (rel %) Null and alternative hypotheses: H0 Treatment of hyperglycemia > 140 mg/dl before supper with long-acting insulin in renal transplant recipients for a period of at least 14 days after transplantation is equal to conventional treatment in reducing the HbA1c (measured on day 90 after transplantation). H1: Treatment of hyperglycemia > 140 mg/dl before supper with long-acting insulin in renal transplant recipients for a period of at least 14 days after transplantation is superior to conventional treatment in reducing the HbA1c (measured on day 90 after transplantation). Type-I and -II errors - power: α=0.05 ß=0.2 Statistical methodology: One-sided t-test of HbA1c on day 90 after transplantation, one-sided t-test of number of days with hyperglycemia > 140 mg/dl before supper, comparison of capillary blood glucose levels by ANOVA Sample size calculation: Based on a two-sided testing and an expected standard deviation of HbA1c of 10%, an α=0.05 and a ß=0.2, a sample size of 25 patients per group was determined. Main analysis set: Per-protocol (efficacy) and intention to treat (ITT) for safety Other endpoints: descriptive statistics
Study Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Hyperglycemia
Intervention ICMJE	Drug: Insulatard (long-acting insulin) In group No.1 (study arm 1 (=A)), patients will be treated with long-acting insulin (Insulatard) as soon as the glucose-level before supper surpasses 140 mg/dl. The normoglycemic goal in this group will be from 110 to 120 mg/dl.; Drug: Conventional In group No.2 (study arm 2 (=B)), patients will be treated conventionally according to the decisions taken by the physicians on the ward. The following suggestions will be brought to the attention of the ward in order to standardize the treatment of the patients in study arm B: 1. Treatment in this group should be initiated if the fasting glucose level surpasses the renal glucose threshold, i.e. 180 mg/dl. 2. As the proposed life-style modifications for the treatment of NODAT1 are not feasible during this very early post-transplant phase, the basis of the conventional therapy will be proposed to be sulfonyl urea drugs (i.e. Gliclazide - Diamicron®, 30 mg, not more than twice daily). 3. Short-acting insulin will be strongly recommended to be used for corrections of capillary blood glucose levels above 250 mg/dl.
Study Arms	Active Comparator: 1 Insulatard (long-acting insulin) Intervention: Drug: Insulatard (long-acting insulin); Active Comparator: 2 Conventional treatment Intervention: Drug: Conventional
Publications *	Davidson JA, Wilkinson A; International Expert Panel on New-Onset Diabetes after Transplantation. New-Onset Diabetes After Transplantation 2003 International Consensus Guidelines: an endocrinologist's view. Diabetes Care. 2004 Mar;27(3):805-12.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: January 26, 2009)	50
Original Estimated Enrollment ICMJE	Same as current
Actual Study Completion Date	May 2011
Actual Primary Completion Date	December 2010 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: renal transplantation (deceased or living donor); eligibility for the standard immunosuppression of our center, consisting of tacrolimus, mycophenolate mofetil or mycophenolic acid, dexamethasone/prednisone triple therapy; informed consent of the patient Exclusion Criteria: patients with type 1 or type 2 diabetes; allergy against long-acting insulin
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Austria
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00830297
Other Study ID Numbers ICMJE	EudraCT: 2008-005951-84
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Marcus Saemann, Medical University of Vienna
Study Sponsor ICMJE	Marcus Saemann
Collaborators ICMJE	Not Provided
Investigators ICMJE	Study Chair: Wilfred Druml, MD Medical University of Vienna
PRS Account	Medical University of Vienna
Verification Date	August 2012
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP