Conditions: Prevention of New Onset Diabetes Among Kidney Transplant Patients
Keywords: Kidney transplant New onset diabetes Prevention Insulin
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 251
Healthy volunteers: no

Brief summary:
Specific Aim 1: To determine the clinical efficacy of early initiation of insulin therapy in decreasing the incidence of NODAT among de novo kidney transplant patients with manifested post-transplant hyperglycemia during the first week after transplantation.

Hypothesis 1: Early initiation of insulin therapy protects beta-cell from early stress related to the surgery and use of higher doses of immunosuppressive medications, and leads to lower incidence of NODAT at 1 and 2 years.

Specific Aim 2: To determine the improvement in overall glycemic control with the early initiation of insulin therapy.

Hypothesis 2: Early initiation of insulin therapy results in greater overall control of glycemia compared to standard care of dietary counseling, life-style modification, oral hypoglycemic agents and/or insulin as needed at 1 year.

Specific Aim 3: To determine the improvement in beta-cell function among patients assigned to the early initiation of insulin therapy at one year post-transplantation.

Hypothesis 3: Early initiation of insulin therapy protects beta-cell from glucotoxicity of post-transplant hyperglycemia and preserves better beta-cell function at 1 year.

Detailed description:

Arms:
arm 1: Neutral Protamine Hagedorn (NPH) Insulin Titration Regimen, based on pre-dinner capillary blood glucose measurements (CPG) expressed in mg/dl; All NPH initiation doses and dose adjustments are presented in IU/day For pts. with CPG \> 240, NPH initiation: 14, dose increases by 4; For pts. with CPG \> 180 mg/dl, NPH initiation: 12, dose increases by 4; For pts. with CPG \> 140 mg/dl, NPH initiation: 10, dose increases by 4; For pts. with CPG \> 120 mg/dl, NPH initiation: 0, dose increases by 2; For pts. with CPG 100-119 mg/dl, NPH initiation: 0, maintain dose; For pts. with CPG 80-\<100 mg/dl, NPH initiation: 0, dose decrease by 4; For pts. with CPG 60-\<80 mg/dl, NPH initiation: 0, decrease by 8; For pts. with CPG \<60 mg/dl, NPH initiation: 0, ½ of previous dose. arm 2: Patients assigned in this arm will receive standard of care following their kidney transplantation.

Interventions: intervention 1: Insulin treatment for hyperglycemia
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
CONFIDENTIAL  
 
 
 
Page 1 of 44 
ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
 
A Clinical Trial to Prevent New Onset Diabetes After Transplantation    
NCT01683331 
1R01DK092475-01    
 
November 20, 2017 
 
 
 
 
 
 
 


 
 
 
 
 
CONFIDENTIAL  
 
 
 
Page 2 of 44 
ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
Insulin Therapy for the Prevention of New Onset Diabetes after 
Transplantation (ITP-NODAT) 
Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
Version 03/November 20, 2017 
This study is sponsored by the National Institute of Diabetes, Digestive and Kidney 
Disease (NIDDK) 
Site Investigator: 
Principal Investigator: 
Biostatistician: 
Marcus Saemann, M.D. 
Assistant Professor of Medicine 
Medical University of Vienna 
Währinger Gürtel 18-20 
1090 Vienna, Austria 
Phone: +43-1-40400-5593 
Fax: +43-1-40400-4392 
Email: 
marcus.saemann@meduniwien.ac.at 
Akinlolu O. Ojo, M.D., Ph.D. 
Professor of Medicine 
Medical School 
University of Michigan 
1500 East Medical Center Drive 
Ann Arbor, MI 48109 
Phone:1-734-763-9041 
Fax:1-734-936-9621 
Email: aojo@med.umich.edu 
Peter Song, Ph.D. 
Professor of Biostatistics 
School of Public Health 
University of Michigan 
M4140 SPH II 
Ann Arbor, MI 48109 
Phone: 1-734-764-9328 
Email: pxsong@umich.edu 
NIDDK Contact: 
NIDDK Project Officer: 
 
 
John Kusek, Ph.D. 
National Institute of Diabetes 
and Digestive and Kidney 
Disease 6707 Democracy 
Boulevard 
Room 617, MSC 
5458Bethesda, Maryland 20892 
Phone: 1-301-593-7735 
Fax: 1-301-480-3510 
Email: jk61x@nih.gov 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, potential sponsors, study staff and independent ethic committees or institutional review 
boards. The contents of this document shall not be disclosed to others without written authorization from 
NIDDK, unless it is necessary to obtain informed consent from potential study participants. 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
Protocol Approval 
Protocol: ITP-NODAT Prospective 
Study in Non-Diabetic De Novo Kidney 
Transplant Recipients 
Version/Date: 
IND: 
N/A 
Site Investigator: 
 
Study Sponsor: 
National Institute of Diabetes, Digestive and Kidney Disease (NIDDK) 
INSTRUCTIONS:  The Site Investigator must print, sign, and date below.  A copy of 
this signature page should be kept in the site’s records.  After signature, please return 
the original page to NIDDK at the address listed below:  
John, Kusek 
Division of Kidney, Urologic, and Hematologic Disease 
National Institute of Diabetes, Digestive and Kidney Diseases 
6707 Democracy Boulevard, Room 617, MSC 5458 
Bethesda, MD 20892 
 
I confirm that I have read the above protocol in the latest version.  I understand it, and I 
will work according to the principles of Good Clinical Practice (GCP) as described in the 
United States Code of Federal Regulations (CFR) – 21 CFR Parts 45, 50, 56, and 312, 
and the International Conference on Harmonization (ICH) document “Guidance for 
Industry:  E6 Good Clinical Practice:  Consolidated Guidance” dated April 1996.  
Further, I will conduct the study in keeping with local, legal, and regulatory 
requirements.   
As the Site Investigator, I agree to conduct and to carry out the study by the criteria 
written in the protocol and understand that no changes can be made to this protocol 
without written permission of the NIDDK. 
 
 
Site Investigator (Type or Print) 
 
Site Investigator (Signature) 
Date 
 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
Table of Contents 
1 
BACKGROUND AND RATIONALE …………………………………………. 
7 
1.1 
BACKGROUND…………………………………………………………………. 
7 
1.2 
RATIONALE…………………………………………………………………….. 
9 
2 
RISKS AND BENEFITS……………………………………………………..... 
12 
2.1 
RISKS……………………………………………………………………………. 
12 
2.2 
BENEFITS………………………………………………………………………. 
13 
3 
OBJECTIVES…………………………………………………………………… 
14 
3.1 
PRIMARY OBJECTIVE………………………………………………………… 14 
3.2 
SECONDARY OBJECTIVES…………………………………………………. 
14 
4 
STUDY DESIGN AND ENDPOINTS…………………………………………. 
15 
4.1 
STUDY DESIGN…………………………………………………………………
15 
4.2 
ENDPOINTS…………………………………………………………………….. 15 
4.2.1 
Primary Endpoint……………………………………………………………… 
15 
4.2.2 
Secondary Endpoints…………………………………………………………... 15 
5 
STUDY ELIGIBILITY CRITERIA……………………………………….. 17 
5.1 
INCLUSION CRITERIA………………………………………………………… 17 
5.2 
EXCLUSION CRITERIA……………………………………………………….. 
17 
6 
STUDY SETTINGS, PATIENT ENROLLMENT AND 
RADOMIZATION……………………………………………………........ 
18 
6.1 
STUDY SETTINGS…………………………………………………………….. 
18 
6.2 
PATIENT ENROLLMENT……………………………………………………… 18 
6.3 
RANDOMIZATION AND STRATIFICATION………………………………… 
18 
7 
STUDY PROCEDURES, CONCURRENT THERAPIES, TESTS AND 
FOLLOW-UP, AND STUDY END…………………………………………..... 
19 
7.1 
STUDY PROCEDURES……………………………………………………….. 
19 
7.1.1 
Group A (intervention group)………………………………………………….. 
19 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
7.1.2 
Group B (standard of care group)…………………………………………..... 
21 
7.2 
CONCURRENT THERAPIES…………………………………………………. 
21 
7.2.1 
Immunosuppression……………………………………………………………. 
21 
7.2.2 
Condition other than hyperglycemia and/or NODAT……………………….. 
22 
7.3 
TESTS AND FOLLOW-UP…………………………………………………….. 22 
7.4 
END OF STUDY………………………………………………………………… 23 
7.4.1 
Completion of study…………………………………………………………….. 23 
7.4.2 
Study withdrawal………………………………………………………………... 23 
8 
DATA COLLECTION, STORAGE, QUALITY CONTROL AND 
ASSURANCE ………………………………………………………………….. 
24 
8.1 
DATA COLLECTION…………………………………………………………… 24 
8.2 
DATA STORAGE……………………………………………………………….. 24 
8.3 
PERMITTING TO ACCESS DATA SOURCE………………………………. 
24 
8.4 
QUALITY CONTROL AND ASSURANCE…………………………………... 
24 
8.4.1 
Data handling…………………………………………………………………… 
25 
8.4.2 
Protection of Confidentiality…………………………………………………… 
25 
9 
STATISTICAL CONSIDERATIONS AND ANALYTICAL 
PLAN…………………………………………………………………………….. 
26 
9.1 
SAMPLE SIZE AND POWER CALCULATION….………………………….. 
26 
9.2 
INTERIM ANALYSES……………….………………………………………..... 27 
9.3 
INADEGUATE RECRUITMENT AND EXCESSIVE DROPOUT……. 
27 
10 
SAFETY MONITORING……………………………………………………….. 
28 
10.1 
DEFINITIONS…………………………………………………………………… 
28 
10.1.1 Adverse Event……………………………………………………………………
28 
10.1.2 Serious Adverse Event…………………………………………………………. 28 
10.1.3 Unexpected Adverse Event……………………………………………………. 28 
10.2 
EVENT COLLECTING AND RECORDING PROCEDURES……………… 
28 
10.3 
GRADING AND ATTRIBUTION………………………………………………. 
29 
10.4 
REPORTING CRITERIA……………………………………………………….. 29 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
10.5 
REPORTING TIMELINE……………………………………………………….. 30 
10.6 
DATA SAFETY MONITORING BOARD………………………………………
30 
11 
ETHICAL CONSIDERATION AND COMPLIANCE WITH GOOD 
CLINICAL PRACTICE ……………………………………………………….... 32 
11.1 
INFORMED CONSSENT…………………………………………………….... 
32 
11.2  PRIVACY AND CONFIDENTIALITY…………………………………………. 
32 
11.3 
PUBLICATION POLICY……………………………………………………….. 
32 
12 
REFERENCES…………………………………………………………………. 
34 
13 
APPENDICES: FIGURES AND TABLES………………………................. 
39 
 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
Glossary of Abbreviation 
NODAT: new onset diabetes after transplantation 
IFG: impaired fasting glucose 
IGT: impaired glucose tolerance 
IR: insulin resistance 
HOMA: homeostasis model assessment 
ESRD: end stage renal disease 
PHI: protected health information 
DCC: data coordinating center 
RedCap: research electronic data capture 
A1c: hemoglobin A1c 
DSMB: data safety monitoring board 
AE: adverse event 
SAE: serious adverse event 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
1. 
BACKGROUND AND RATIONALE 
1.1 
Background 
Abnormal glucose metabolism after kidney transplantation: Abnormal 
glucose metabolism is common early after kidney transplantation in previously 
non-diabetic patients and ranges from impaired fasting glycemia and glucose 
intolerance to full-blown diabetes (1). New onset diabetes after transplantation 
(NODAT) represents the most serious form of abnormal glucose metabolism 
occurring at estimated 25% to 30% kidney transplantation with highest risk in the 
early period following transplantation (2-6). NODAT incurs elevated risks for 
major cardiovascular events and has a negative impact on patient and kidney 
graft survival (7-10). In addition to NODAT, impaired fasting glucose (IFG) and 
impaired glucose tolerance (IGT) are even more common with prevalence 
reportedly as high as 36% at 10 weeks and 20 to 30 % beyond the first 6-12 
months post-transplantation (1, 11-14).  
Hyperglycemia occurs very early after kidney transplantation, within the first 
week, with 45% of patients having impaired fasting glucose (100 to 125 mg/dl) 
and 87% of patients having evidence of hyperglycemia (bedside glucose 
>200 mg/dl and/or physician–instituted insulin therapy) (1, 3, 15). Furthermore, 
recent studies have shown that the determination of early morning fasting 
glucose in kidney transplant patients exhibits a sensitivity that was too low for an 
accurate assessment of abnormal glucose metabolism post-transplantation and 
that pre-dinner time glucose measurements detect more patients with glycemia 
above 200 mg/dl whose morning fasting glycemia was only minimally abnormal 
(<126 mg/dl) (13, 16). These data imply that the pattern of hyperglycemia in 
newly transplanted patients is characterized by rising glucose concentrations 
throughout the day, but relatively low fasting glucose concentrations in the 
morning, a phenomenon that has been related to the routine post-transplant use 
of corticosteroids, with their effects on glycemia peaking between lunch and 
dinnertime when administered in the morning as typically practiced among the 
transplant communities (16, 17). Early hyperglycemia and its persistence are risk 
factors for late development of NODAT. 
Among many risk factors, surgery-related stress and the initiation of 
immunosuppressive agents at high doses, particularly corticosteroids and 
calcineurin inhibitors such as tacrolimus and cyclosporine, play a critical and 
negative role on glucose metabolism during early post-transplant period (18-20). 
Corticosteroids and calcineurin inhibitors are cornerstone of immunosuppressive 
medications currently employed in kidney transplant patients worldwide. In 
particular, all patients receive corticosteroids at the time of transplant surgery 
and more than 60 to 70% of them are maintained on corticosteroids for years 
during the subsequent follow-up (21, 22). On the other hand, up to 95% of all 
kidney transplant patients in the US receive tacrolimus (82%) or cyclosporine 
(12%) (22). 
Corticosteroids cause dose dependent peripheral insulin resistance and hepatic 
gluconeogenesis (12, 23, 24). Calcineurin inhibitors, tacrolimus and 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
cyclosporine A, impair insulin secretion by directly injuring β-cells (5, 25-28). 
Although both tacrolimus and cyclosporine A are responsible for the increased 
risk of NODAT, the diabetogenic property of tacrolimus is much higher than that 
of cyclosporine (2, 5). In fact, the reported 6 month incidence of NODAT was 
close to 21% among tacrolimus treated kidney transplant patients, twice as high 
as among patients receiving cyclosporine (5). The diabetogenic effects of 
immunosuppressive medications are time and dose dependent as the exposure 
of transplant patients to those agents is high in the early period following 
transplantation during which the incidence of abnormal glucose homeostasis is 
also highest (29). Finally, the early diagnosed post-transplant hyperglycemia 
and/or NODAT can improve or reverse as the dose of corticosteroids decreases 
(12). Thus, the early diagnosis of abnormal glucose metabolism could provide 
opportunity for therapeutic interventions to prevent the development of full blown 
NODAT.  
Insulin resistance (IR) is a common feature associated with type 2 DM and is 
frequently present in patients affected with metabolic syndrome (MS), a condition 
characterized by a cluster of clinical traits that include central obesity, impaired 
fasting glucose, elevated triglycerides, reduced HDL cholesterol, and 
hypertension (30-33). IR and MS are associated with increased risk for 
cardiovascular disease, renal disease and type 2 DM (34-37). MS is present in 
20 to 40% non-diabetic kidney transplant patients during the first year after 
transplantation and in a much higher number during the subsequent years (1, 38, 
39). MS is associated with reduced transplant renal function and transplant 
longevity, increased risk for IGT and NODAT, impaired cardiovascular risk 
profiles and patient death (1, 38, 40-43).  
Management of post-transplant hyperglycemia and NODAT: The role of 
insulin therapy in management of type 2 diabetes mellitus has been confirmed 
though not always used as the first line of agents, particularly in the early period 
after the diagnosis has been made. The current guideline in general population 
recommends the initiation of oral hypoglycemic agents combined with life-style 
modification while reserving the insulin therapy for those who fail to meet the 
target goal (44). In recent years, however, the need of aggressively lowering 
glycemia with the early institution of insulin therapy has been gaining more 
attention in the management of type 2 diabetic patients among general 
population (45). As UK Prospective Diabetes Study (UKPDS) has demonstrated 
the fact that β-cell function progressively deteriorates over time in people with 
type 2 diabetes mellitus, irrespective of life-style modification and the use of 
current pharmacological interventions, the concept of β-cell preservation or 
rejuvenation by aggressively lowering glycemia during early period following the 
diagnosis of type 2 diabetes mellitus has gained interest and been tested in 
several clinical studies (46-51). In particular, one recent study involving 382 
Chinese patients with newly diagnosed type 2 diabetes mellitus showed that 
early intensive insulin therapy led to a significantly higher rate of remission at 1 
year compared to oral hypoglycemic agents which was accompanied by an 
improvement in β-cell function (51).  


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
The current approaches in the management of NODAT mirror that of type 2 
diabetes mellitus in the general population (19, 52). The importance of early 
diagnosis for NODAT has been widely recognized (3, 10). However, the 
importance of early recognition of hyperglycemia below the level for a diagnosis 
of NODAT, particularly at the time of transplantation while patients are still in the 
hospital, remains mostly speculative as its long term impact on clinical outcome 
besides the risk for NODAT is largely unknown (3, 53). Furthermore, studies 
have shown that early diagnosed NODAT and/or hyperglycemia can improve 
over time as the exposure to immunosuppressive medications decreases (3, 12). 
All available data are consistent with the hypothesis that early post-transplant 
hyperglycemia is largely determined by increased insulin resistance related to 
the high amount of corticosteroids that more than 60 to 70% of kidney transplant 
patients receive nationwide, contributed in various degree by decreased insulin 
production (synthesis and/or release) with the use of calcineurin inhibitors (25, 
54-56).  
1.2 
Rationale 
The scientific basis of the current clinical trial is the emerging body of evidence 
that pancreatic β-cell function can be preserved or rejuvenated if exogenous 
insulin is used early after the diagnosis of type 2 DM (46-51). The UK 
Prospective Diabetes Study (UKPDS) demonstrated that β-cell function 
progressively deteriorates over time in people with type 2 DM notwithstanding 
life-style modification and the use of step-up care. In parallel, several clinical 
studies support the notion that β-cell preservation or rejuvenation can be 
accomplished by controlling hyperglycemia with injectable insulin during the early 
period following the diagnosis of type 2 DM (46-51). The most compelling 
evidence in support of this concept is a recent study of 382 Chinese patients with 
newly diagnosed type 2 DM which showed that early intensive insulin therapy 
(either as continuous infusion using an insulin pump or as intermittent injection 
using a combination of long and short acting insulin) for approximately two 
weeks after the diagnosis of type 2 DM was associated with remission rates after 
one year that were significantly higher in the insulin groups (51.1% and 44.9%, 
respectively) compared to a parallel group treated with oral hypoglycemic agents 
(26.7%). Aside from a type 2 DM risk reduction of 40% to 47% (p=0.0012), β-cell 
function measured by HOMA B and acute insulin response improved significantly 
in the early insulin treatment group (51). Aggressive lowering of hyperglycemia 
with the early institution of insulin therapy in type 2 DM is increasing in clinical 
practice as well (56). 
NODAT differs from type 2 DM of general population in two aspects. First, the 
time of onset of NODAT can be established with a reasonable precision among 
transplant patients, whereas the recognition of type 2 DM in general population is 
often delayed by years. Newly diagnosed type 2 DM in general does not equal 
newly developed type 2 DM. Second, in addition to some shared risk factors 
such as old age, obesity and family history, etc., NODAT has a unique set of risk 
factors, namely immunosuppressive medications, that varies in the intensity of 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
exposure over the time. These two unique characteristics of NODAT provide the 
opportunity for preventive intervention. 
Non-diabetic end stage renal disease (ESRD) patient population undergoing 
kidney transplantation represents a unique patient population in which the 
hypothesis of a beneficial effect of β-cell rest by prompt institution of insulin 
therapy in patients with exhibited abnormal glucose metabolism when their β-
cells are under the maximal stress, surgical and pharmacological, can be tested. 
Because of the nature of transplantation, the peak of stress is highest at the time 
of transplantation and shortly afterwards. Therefore, protecting β-cell by 
aggressively lowering early post-transplant hyperglycemia with the use of insulin 
therapy may translate into preservation of β-cell function for prolong period of 
time after kidney transplantation. This approach, in combination with dietary 
precaution and increased physical activity, may reduce the incidence of NODAT 
during subsequent months or years. 
At this time, the “step-up” strategies are generally recommended for the 
management of NODAT which involve non-pharmacological therapy, namely life-
style modification and dietary precaution, followed by oral hypoglycemic agents, 
and finally insulin therapy if the target goal for glycemic control is not achieved 
(57). In addition, there is no established consensus on the management of 
hyperglycemia that occurs in great majority of non-diabetic kidney transplant 
patients during early post-transplant period. While life-style modification is an 
important aspect in the management of NODAT, its’ implementation early after 
transplantation is much less likely to be successful due to limitation related to 
recent surgery and high amount of immunosuppressive medications. The 
resistance to early use of insulin therapy in the management of newly diagnosed 
type 2 diabetes mellitus in general population to a large extent is related to 
patients’ desire of avoiding insulin injection that would require increased self-care 
efforts and fear of potential adverse effects associated with insulin therapy such 
hypoglycemia and weight gain (58-61). There is no reason to think that kidney 
transplant patients will behave differently. 
Our approach will represent a radical shift from the current paradigm in the 
management of NODAT which is the only tip of an iceberg of a much larger 
problem, namely abnormal glucose metabolism. The optimal management of 
early abnormal glucose metabolism, including screening, diagnosis and 
treatment, is currently unknown and often depends on the timing after transplant 
and available resource (14). Complicating the matter further is the dependence 
of transplant recipients on various immunosuppressive medications with different 
risk for the emergence of abnormal glucose metabolism and immunological 
complication of a kidney transplant recipient can have, such as acute rejection 
requiring therapeutic intervention, particularly early after transplantation (5, 28, 
62). 
The uniqueness of current study includes emphasis on the improvement of 
glycemia control immediately after kidney transplantation when, as consequence 
of surgery and initiation of high doses of immunosuppressive medications, the 
stress on β-cells is high. Such therapeutic approach allows us to test the 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
hypothesis that aggressive glucose control with the use of insulin therapy in 
patients with newly onset post-transplant hyperglycemia, at the time of maximal 
β-cell stress, will result in reduced incidence of NODAT during subsequent 
follow-up. Reduction in the incidence of NODAT could have long lasting 
beneficial effects on cardiovascular risk profile of kidney transplant patients with 
potential for improvement in kidney graft and patient survival. It could ultimately 
prove to be cost-effective. 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
2. 
RISKS AND BENEFITS 
2.1 
Risks  
Hypoglycemia as a result of insulin therapy: Hypoglycemia resulting 
from the insulin treatment is the principal and most serious risk 
associated with this study. However, in comparison to short-acting 
insulin, episodes of hypoglycemia are reduced with long-acting insulin 
preparations such as NPH insulin. The most common symptoms or 
signs of low blood glucose levels (<60 mg/dl) include sweating, 
lightheadedness/dizziness/fainting spell, palpitation, tremor, hunger 
sensation, drowsiness, tingling sensation of extremities and lips/mouth, 
blurred vision, etc. all the way leading to extreme situations such as 
seizure, unconsciousness/death. The risk factors for developing 
hypoglycemia include missing or delaying meal, inadvertent insulin 
overdosing, changing routine physical activities, inter-current illness 
such as infections or gastroenteritis causing diarrhea and vomiting, 
drug-drug interaction, sudden declining in transplant renal function, 
etc. During the period of insulin therapy, patients will be instructed to 
recognise symptoms indicating possible hypoglycaemia and to obtain 
immediate capillary blood glucose-levels. In the case of hypoglycemia 
documented by glucose levels <60 mg/dl or requiring assistance insulin 
dose will be reduced and/or dose titration will be stopped for 4 days. 
When mean glucose values in the 120–140 mg/dl range will be 
obtained, investigators will be allowed to stop titration or temporarily 
reduce dosage when they believe that further titration will be 
hazardous. A telephone hotline with study coordinators/investigators on 
duty 24 hours x7 days per week will be given to all participants for the 
reporting of hypoglycemia and as needed assistance in such situation. 
Inconvenience with daily capillary glucose monitoring and oral 
glucose tolerance testing: The need for capillary blood glucose 
monitoring during inpatient and outpatient insulin treatment can be 
uncomfortable. Appropriated teaching for such monitoring will be 
provided. The oral glucose tolerance tests require ingestion of 75 
grams of glucose dissolved in 250 ml water and additional blood draw. 
Some subjects may experience some nausea with drinking such 
concentrated sugar-water. Venipuncture could cause some minor 
discomfort. Experienced phlebotomists at both academic centers will 
be employed and the amount of venous blood will be kept at minimum 
necessary (5 to 7 ml of whole blood, one tsp, at each time).  
Weight gain: Weight gain can be attributed to insulin therapy. 
However, weight gain post-transplantation is a frequent phenomenon 
and likely of multiple etiology. Patients will be provided detailed dietary 
counselling and life-style modification as appropriated according to the 
progress in their recovery following the transplant surgery. The weight 
changes will be recorded during the course of this study. 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
Unauthorized data release: There is a remote possibility of 
unauthorized release of protected health information (PHI) data about 
study participants. Such disclosure would be extremely unlikely to 
involve a threat to life, health, or safety but psychological and social 
risks might occur to participants of the study. The confidentiality of 
study participants will be maintained by assigning each subject an 
identification number that will be used to identify subjects in any 
individual tabulation related to the current study. The link between the 
identification numbers and patient identity will be maintained but stored 
separately for future researches. Personal information will be stored in 
a secure environment, and it will be transferred to the data 
coordinating center (DCC) using appropriate protections such as 
password protection and encryption. The study data will be maintained 
in a secure computer system with standard password protection 
accessible only to the investigators and dedicated study coordinator. 
The password will be updated on a quarterly basis. The leftover 
biological samples will be stored for future researches. Similarly, there 
is also a remote possibility of inappropriate sample handling. 
Precaution will be taken to prevent such improper handling: the 
research freezers are institutionally owned and securely locked with 
limited access to investigators and study coordinator, all samples are 
code identified and the link between code and patient’s identification 
will be maintained but stored separately in secured systems. 
2.2 
Benefits 
To the study participants: According to the study primary hypothesis that 
institution of insulin therapy among de novo previously non-diabetic kidney 
transplant recipients experiencing early hyperglycemia will result in less new 
onset diabetes at 1 year after transplantation, the likely benefit among patients 
assigned to the intervention group will be an overall improved glucose 
metabolism during subsequent follow-up: normal fasting glycemia, normal 
glucose tolerance and less diabetes. Even for patients assigned to the control 
group, being involved in the clinical trial with all the attention paid by investigators 
and/or study coordinators, they may learn to better handle the potential risks of 
developing abnormal glucose metabolism post-transplantation.  
To the society: On the other hand, the positive outcome of this study 
will have profound impact on our current understanding of new onset 
diabetes in patient population as unique as solid organ transplant 
recipients (kidney, liver, heart etc.) and will change the current 
paradigm in the management of NODAT. Improvement in glucose 
metabolism and reduced incidence in NODAT will translate into 
improved patient and transplant organ survival and ultimately cost-
saving for the society. 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
3. 
STUDY OBJECTIVES 
This study aims to assess the effects of early 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. 
3.1 
Primary Objective 
To determine the clinical efficacy of early initiation of insulin therapy in 
decreasing the incidence of NODAT among de novo kidney transplant patients 
with manifested post-transplant hyperglycemia early after transplantation. 
3.2 
Secondary Objectives 
1. To determine the improvement in overall glycemic control among patients 
managed with the early initiation of insulin therapy compared to standard of care 
management in patients experiencing abnormal glucose metabolism. 
2. To determine the improvement in β-cell function among patients assigned to the 
early initiation of insulin therapy compared to the standard of care management 
in patients experiencing abnormal glucose metabolism. 


 
 
 
 
 
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4. 
STUDY DESIGN AND ENDPOINTS 
4.1 
Study Design 
This is a prospective randomized multicenter clinical trial with un-blinded 
endpoint evaluation.  There will be two study groups and participants will be 
enrolled from the University of Michigan and the Medical University of Vienna, 
Austria (MUV).  The MUV study population will include participants from six 
additional clinical centers in Spain, France, and Germany.  The study is 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) (Appendices, figure 1). 
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 
(tacrolimus), 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. 
The study plans to enroll 360 patients, 150 patients at the University of Michigan 
Health System (UMHS) Transplant Center and 210 patients at seven European 
Transplant Centers [1) Medical University of Vienna, Austria; 2) Universitat 
Autonoma de Barcelona, Spain; 3) Charité Universitätsmedizin, Campus Charité 
Mitte, Berlin, Germany; 4) Charité Universitätsmedizin Berlin, Germany, Campus 
Virchow-Klinikum, Berlin, Germany; 5) Medical University of Graz, Austria; 6) 
University Hospital Hamburg Eppendorf, Germany; 7) Université Paris 
Descartes, France] coordinated by the Medical University Hospital of Vienna, 
Austria, over a period of 3 years with a minimal of 2 years follow-up. 
4.2 
Study Endpoints 
4.2.1 Primary Endpoint 
The incidence of NODAT 12 months after kidney transplantation defined 
according to American Diabetes Association criteria (63, 64). 
4.2.2 Secondary Endpoints 
1. The incidence of NODAT at 24 months after kidney transplantation. 
2. Glycemia profile during the time of insulin therapy in arm A (intervention) 
comparing that of arm B (control). 
3. The glycemia control using A1c levels, overall and among patients with NODAT, 
through study period 6, 12 and 24 months after kidney transplantation. 
4. Incidence of impaired fasting glycemia and impaired glucose tolerance 6, 12 and 
24 months after transplantation.  
5. Pancreatic β-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) (65). 


 
 
 
 
 
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6. 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 (66, 67). 
7. 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 (68). 
8. Renal function at 6, 12 and 24 months after kidney transplantation, measured by 
serum creatinine. 
9. Patient and graft survival 6, 12 and 24 months after kidney transplantation. 
 
 


 
 
 
 
 
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5. 
STUDY ELIGIBILITY CRITERIA 
5.1 
Inclusion Criteria 
1. Adult patients, 18 years and older, with end stage renal disease undergoing 
kidney transplantation with a deceased or living donor kidney. 
2. 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). 
3. Receiving standard triple immunosuppressive medications that include 
tacrolimus, mycophenolate mofetil or mycophenolic sodium and steroids. 
4. Capable of understanding the study and willing to give informed written consent 
for study participation. 
5.2 
Exclusion Criteria 
1. 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. 
2. Patients receiving an organ transplant other than kidney. 
3. Patients receiving an unlicensed drug or therapy within one month prior to study 
entry. 
4. Patients with history of hypersensitivity to injectable insulin. 
5. Patients with documented HIV infection. 


 
 
 
 
 
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6. 
STUDY SETTINGS, PATIENT ENROLLMENT AND 
RANDOMIZATION 
6.1 
Study Settings 
The University of Michigan Transplant Center and the Medical University of 
Vienna Transplant Center are two principal participating centers in this study.  
Six additional transplant programs from defined European Union’s countries will 
participate in the study under the coordination of the Medical University of 
Vienna Transplant Center. 
6.2 
Patient Enrollment 
All patients with end stage renal disease who have no history of diabetes and will 
undergo kidney transplantation from either a deceased or living donor at either 
transplant centers will be potential study participants. 
Potential study participants will be identified through the UMHS Organ 
Transplantation Information System (Otis) and the Medical University of Vienna 
Transplant Registry/the Transplant Registry at each participating center in the 
EU by the time of notification for transplantation. At the time of recruitment, a 
sincere discussion of the study procedures, risks and benefits, will take place 
between the dedicated study coordinators/investigators and the prospective 
study participants. A written informed consent for participation in the entire study 
will be obtained once patients agree to be part of the proposed study. 
Confidentiality and protected health information (PHI) will be protected according 
the institutional regulation. Participation into the study is completely voluntary. 
Any patient who refuses to take part in the proposed study will continue to 
receive standard of care at the UMHS transplant center and the respective 
European transplant programs. 
Upon inclusion, study participants will have baseline assessment comprising of 
comprehensive clinical assessment and laboratory testing.  
6.3 
Randomization and Stratification  
Prior to transplantation, participants will be randomized into one of two study 
arms, A (intervention arm) and B (standard of care arm). A blocked 
randomization ratio of 1:1 will be performed at each transplant center. The only 
criteria for stratification will the number of previous transplant: first transplant 
versus repeat transplant. A unique randomization number will be generated by a 
randomization software and is assigned to each patient (patient randomization 
number). Sealed envelopes will be used for each participant/randomization 
number. In the envelopes there will be a note stating whether the patient 
receives insulin therapy or not. The envelopes will be provided by a person not 
involved in the study. For participants who replace discontinuing participants 
before they had a drug intake on day 1 of the first investigation period, the 
substitute participant will receive the same randomization number as the subject 
he (she) replaces. 
 


 
 
 
 
 
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7. 
STUDY PROCEDURES, CONCURRENT THERAPIES, TESTS 
AND FOLLOW-UP, AND STUDY END 
7.1 
Study Procedures 
7.1.1 Group A (intervention group)  
Capillary glucose monitoring will be instituted immediately after the transplant 
surgery for all participants randomized to the intervention arm: before breakfast 
(7:30 am), before lunch (12:00 pm), before dinner (5:30 pm) and at bedtime 
(10:00 pm). This monitoring schedule will be continued during the initial 
hospitalization for the transplant surgery and after the discharge for a total 
duration of 4 weeks or longer if insulin therapy is instituted during the period of 
time (see below). The study investigators and coordinators will make daily 
assessment of study participants while inpatients with regard to their capillary 
glucose monitoring values. During the initial hospitalization, participants will 
receive individualized meal plans that incorporate consistent quantities of 
carbohydrates at each meal and snack.  Carbohydrate content of meals and 
snacks may vary from individual to individual according to personal preferences 
and habits, but should be consistent from day to day for each individual. Study 
participants will also receive appropriate education regarding dietary variation 
(such as skipping meals or frequent snacks), the capillary glucose monitoring 
techniques, maintenance of a log recording the 4 times daily capillary glucose 
values, injection of insulin if insulin therapy is initiated in hospital, recognition of 
symptoms suggestive of hypoglycemia and its appropriate management, etc. 
Following discharge, patients will continue 4 times daily capillary glucose 
monitoring at home and will maintain a log recording deviations from normal diet 
or physical activity, capillary glucose values and insulin doses. They will be given 
a toll-free phone number to communicate with study investigators and 
coordinators for all the necessary assistance in the management of glycemia and 
other medical care. 
During the initial 4 weeks of capillary glucose monitoring, if patients have pre-
dinner glucose levels of 140 mg/dl or greater, they will be started on insulin 
therapy with intermediate acting NPH insulin (human insulin isophane, Humulin 
N, Eli Lilly) in the morning before breakfast. The initial doses of NPH insulin are 
as following: 10 units in the morning for pre-dinner capillary glucose levels 
between 140 and 179 mg/dl, 12 units between 180 and 239 mg/dl, and 14 units 
for 240 mg/dl and higher (Appendices, table 1). Once started on insulin therapy, 
4 times daily capillary glucose monitoring will be continued. During therapy, the 
pre-dinner capillary glucose target is 110 mg/dl.  
During the inpatient stay following the surgery, the NPH insulin dose titration will 
be performed in a stepwise fashion according to pre-dinner capillary blood 
glucose levels. For values that are out of the target range without a clear-cut 
explanation (such as lunch time hypoglycemia or an unscheduled late afternoon 
snack): 2 to 4 unit increases or 4 unit decreases over the initial dosage will be 
made for above or below the target, respectively (Appendices, table 1). The NPH 
insulin dose adjustment will be made every day for up-titration in response to 


 
 
 
 
 
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otherwise unexplained elevation of pre-dinner glucose and daily for down-
titration in response to pre-dinner hypoglycemia. Down-titration may also be 
performed to account for the anticipated impact of the protocol-driven prednisone 
taper on glucose metabolism.  
Mealtime short acting insulin (Insulin lispro, Humalog, Eli Lilly) will be used to 
correct pre-lunch and bedtime hyperglycemia only (Appendices, table 2). If pre-
lunch glucose levels are persistently elevated, lispro will be added the following 
morning.  Similarly if bedtime glucose levels are persistently elevated, lispro will 
be added before dinner meal the following day.  The dose selection will be 
determined from Appendices table 2. For elevation in pre-dinner glucose levels, 
the adjustment in next morning NPH dose will performed as stated above 
following the titration scale (Appendices, table 1). If pre-breakfast glucose levels 
remains consistently above 200 mg/dl, an additional dose of NPH insulin at 
dinner will be considered at the discretion of the study investigators. 
In our previous proof-of-concept clinical trial of basal insulin for post-transplant 
hyperglycemia at the Medical University of Vienna (Hecking et al., manuscript 
currently under review), 2 of 25 patients in the insulin intervention group could 
not be managed with once-daily isophane insulin and short acting insulin alone, 
because of severe hyperglycemia. These patients were put on a 70/30 
formulation of isophane insulin and short acting insulin up to three times daily. It 
is currently not possible to determine a specific algorithm for such a treatment 
regimen in the present intervention group. Therefore, for patients requiring 
excessive NPH doses (usually ≥30 IU), a 75/25 formulation of intermediate and 
short acting insulin (Humalog Mix 75/25, Eli Lilly) may be used up to three times 
daily before breakfast, lunch, and dinner at the discretion of the primary study 
investigators. According to our previous experience, approximately 65% of the 
previous total daily insulin (NPH and short acting) should be administered by 2 
pm, further dose intensification will be made individually, at the discretion of the 
primary study investigator, and not according to a pre-specified algorithm. 
Following discharge from the initial hospitalization, patients will be contacted 
daily by the study coordinator/investigator. The insulin dose will be adjusted or 
insulin will be started according to the protocol (Appendices, table 1). They will 
be seen in the outpatient clinic on a weekly or biweekly base. Patients will bring 
their meters and the log of home capillary glucose monitoring results, insulin 
doses and unusual dietary changes to the clinic for investigators and 
coordinators to review. The dose of insulin, if started as an inpatient or following 
discharge but prior to the first clinic visit, will be further adjusted based on 
capillary glucose values reported during the week or days prior to clinic visit. 
Additional dose adjustment will be made as appropriate over the phone between 
clinic visits. Once the target levels of pre-dinner glycemia (<110 mg/dl) are 
achieved, patients will continue insulin therapy for 14 additional days with 
appropriate dose adjustment following the same principle as stated above (dose 
increases or dose decreases daily for pre-dinner capillary glucose value above or 
below the target ranges, respectively). After that, a trial of weaning insulin will 
begin in a stepwise fashion. During the weaning process, the same pre-dinner 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
glycemia targets will be used. Patients who are weaned off insulin therapy 
successfully will be monitored for the development of NODAT according to the 
study protocol during the first two years of kidney transplantation and cared as 
per the current transplant center practice. For those patients who cannot be 
successfully weaned off NPH insulin during the first six months post-transplant, 
NPH insulin treatment will be continued until the study investigators make 
additional assessment for the appropriateness of further attempts to wean the 
patient off insulin. 
For all patients who do not meet the criteria for the initiation of insulin therapy 
during the first 4 weeks post-transplant surgery, capillary glucose monitoring will 
be stopped after the initial 4 weeks.  
7.1.2 Group B (standard of care group)  
Patients will be managed according to the current transplant centers practice 
with no routine glycemia monitoring other than once daily fasting glucose level in 
the morning as part of a basic metabolic panel to follow renal function 
improvement following the surgery. Patients whose glucose values are above 
200 mg/dl will be monitored subsequently and, if confirmed, covered by short-
acting insulin according to a sliding scale during their in-hospital stay 
(Appendices: table 2). If a permanent antidiabetic medication is necessary, 
sulfonylureas will be the treatment of choice whenever possible. Upon discharge, 
only patients who cannot be controlled by sulfonylureas and have to be started 
on insulin will be instructed to have glycemia monitoring at home (four times a 
day: before each meal and at bedtime). For all others, no home glycemia 
monitoring will be instituted and patients will be followed up subsequently in the 
outpatient clinic. Any additional glucose abnormality observed during regular 
outpatient follow-up will be managed according to the current transplant center 
standard of care protocol in a stepwise approach: dietary consultation and 
attendance of diabetes education class, followed by the initiation of oral 
hypoglycemia agents, usually from the sulfonylurea class, of choice by a 
transplant physician caring for the given patient, and/or intermediate and long-
acting insulin added on as the last step by individual transplant physicians in 
consultation with an endocrinologist/diabetes specialist of choice. 
7.2 
Concurrent Therapies 
7.2.1 Immunosuppression 
1. Induction: will be used with approved various induction agents according to 
center protocol. However, no experimental agents should be used. 
2. Maintenance: will consist in twice-daily tacrolimus, twice-daily mycophenolate 
mofetil and once daily prednisone. The dose of tacrolimus will be adjusted 
according to 12 hours trough concentration levels as described in the table 3 
(Appendices). The dose of mycophenolate will be 2 grams twice daily or 
according to center practice protocol, and adjusted per adverse effects 
(gastroenteric intolerance and/or infection, etc.). The dose of prednisone will be 
tapered uniformly across the study patients as described (Appendices, table 3). 


 
 
 
 
 
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7.2.2 Conditions other than hyperglycemia and/or NODAT 
Hypertension, dyslipidemia and other medical conditions will be treated 
according to the UMHS transplant center’s cardiovascular disease prevention 
and treatment protocols, respectively according to best clinical practice at the 
European transplant centers, and determined by individual transplant physicians 
and surgeons caring for the given patients. 
Transplant organ function or dysfunction will be assessed according to the 
current transplant center protocols by individual transplant physicians and 
surgeons caring for the given patients. Appropriate diagnostic tests and/or 
procedures including transplant kidney biopsy will be ordered regardless their 
status as a participant of the study or whether they develop NODAT or not. 
Requirement for hospital admission for the condition other than related to the 
study will be determined by individual transplant physicians and surgeons. Once 
in the hospital, 4 times daily capillary glucose monitoring will be instituted for 
study participants from group A. Study investigators and coordinator will make 
daily assessment of their glycemic control and/or make appropriate insulin dose 
adjustment during their inpatient stay. 
7.3 
Tests, Procedures and Follow-up 
At the time of enrollment or prior to the transplant surgery, fasting glucose and 
insulin levels (at least 8 hours from the previous meal) and A1c levels will be 
obtained. An additional whole blood sample for potential future genetic (DNA and 
RNA) studies related to diabetes risk, and leftover biological samples (serum and 
urine) will be obtained with study participant’s informed consent. However, this 
remains optional. A refusal for such consent does not disqualify patients from the 
study. At the time of discharge or 72 hours after the surgery (whichever comes 
first) and 12 months post-transplant, one additional blood sample will be 
obtained and appropriately stored for future genetic studies (RNA samples). 
However, this remains optional with the possibility of a refusal from the 
participants without jeopardizing their eligibility for the study. Once discharged 
from the initial transplant hospitalization, for study participants randomized to the 
interventional arm (group A), the study coordinator and/or investigator will 
contact them daily inquiring the glucose monitoring results from the previous day 
whether they are started or not on insulin therapy during the initial hospitalization 
and guide them through the initiation and/or titration of insulin according the 
protocol (see above 7.1.1). All study patients will have study visits (coinciding 
with their routine transplant care visits whenever possible) in the transplant 
center outpatient clinic weekly for the first month, and biweekly in the second and 
third months. Subsequently, patients will be seen every three months during first 
post-transplant year and every 4 months during second post-transplant year 
(Appendices, table 4). During the study visits, investigators and coordinators will 
review and record the log sheet of home glucose monitoring, insulin dosage 
(NPH and/or short-acting coverage) change, diary of dietary changes/additional 
snacks, occurrence of adverse reaction (episodes of hypoglycemia, etc.) and 
perform study related procedures at pre-determined time points (Appendices, 
table 4). In particular, 2 hours oral glucose tolerance test will be performed at 6, 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
12 and 24 months (the results of 6 months OGTT will be blinded to study 
participants and investigators/coordinators). Their assigned transplant physicians 
will be in charge for their overall post-transplant care. Study related biological 
sample collection includes blood and urine samples as outlined in table 4. 
Unless otherwise specified (2 hours post glucose challenge) all blood samples 
will need to be collected at fasting state (at least 8 hours from the previous 
meals). 
Study related OGTT will be performed in the outpatient clinical research unit. On 
the day of testing, the study participant will arrive in the morning in a fasting state 
(at least 8 hours from the previous meal). An angiocatheter will be placed in a 
peripheral vein of forearm. A first blood sample will be collected (time 0, fasting). 
Thereafter, the study participant will ingest 75 grams of glucose dissolved in 
water. Subsequent blood samples will be collected at 30, 60, 90 and 120 
minutes. The plasma will be separated promptly for the whole blood and stored 
at - 80oC for various study-related measurements in a late time. 
7.4 
End of study 
7.4.1 Completion of study 
The completion of study is 24 months after the kidney transplantation. An end of 
study visit will be scheduled within a 2-week time frame with appropriate study 
related tests and/or procedure. Patients will continue to receive care for their 
medical conditions related or not to the study as per the UMHS transplant center, 
respectively the participating European transplant centers’ standard of care. 
7.4.2 Study withdrawal 
Patients may discontinue prematurely their participation in the study anytime for 
any of the following reasons: 
1. At their own request. 
2. Investigators feel that continuation in the study is not at the best interest of 
patients. 
3. Patient physicians feel that continuation in the study is not at the best interest of 
patients. 
4. DSMB feels that continuation in the study is not at the best interest of patients. 
A visit for the end of study will be scheduled within 10 days of premature 
withdrawal and the reasons of withdrawal will be documented. Patients will 
continue to receive care for their medical conditions according to the current 
UMHS transplant center, respectively the participating European transplant 
centers’ protocols. No further study related tests and/or procedure will be 
performed. All study materials up to the time of withdrawal will be retained and 
used for the final analyses unless a specific request is made otherwise. 


 
 
 
 
 
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8. 
DATA COLLECTION, STORAGE, QUALITY CONTROL AND 
ASSURANCE 
8.1 
Data Collection 
The proposed study will use a web-distributed data entry and a fully relational 
clinical research data management on the Research Electronic Data Capture 
(RedCap) platform.  RedCap is a commercially-developed regulatory-compliant 
web-based clinical research information system licensed to and supported by the 
Michigan Institute for Clinical and Health Research (MICHR) and CTSA 
Biomedical Informatics Program (BIP).  RedCap will be used for protocol 
management, subject scheduling and tracking, data management, reporting, 
budget and milestones, and account management.  The study will also use 
RedCap for integrated specimen management, and integration/federation of data 
with other research information systems, research administrative systems (IRB, 
consent management, research billing), and molecular databases.  All Case 
Report Forms (CRF) and questionnaires will be deployed in RedCap. Study 
personnel will undergo a central training in the use of RedCap which will be 
supplemented with annual recertification. RedCap will be used to generate 
quality control reports.  Edit checks will be performed online as the data is 
entered so that laboratory results can be seamlessly loaded into the database.  
Data collection forms and data entry screens will be aesthetically pleasing with 
minimal graphics to facilitate ease of use and to minimize keyboard response 
time. The questions on the data forms will be constructed in easy to understand 
language and placed in a logical sequence.  Edit checking will be conducted for 
codes, dates and ranges on an ongoing basis.  A reliable rekey verification 
system (twice entered) will be utilized for critical data elements.  A keystroke 
error rate in excess of 0.15% will trigger inquiry, retraining or other corrective 
steps that may be indicated.  RedCap meets 21 CFR part 11 and HIPAA 
regulatory standards, has built-in security features including login/password 
access, data authentication, user-based access to subject information, code-
base identification, ability to suppress subject information and automatic log-off.  
In addition, RedCap uses Secure Sockets Layer (SSL) encryption software for 
online protection and has protection capabilities for off-line use as well.   
8.2 
Data Storage 
The University of Michigan Transplant Center will serve as overall Data 
Coordinator Center (DCC) whereas Medical University of Vienna will serve as 
European data collection center for data generated through various participant 
European study centers. Final data will converge to the University of Michigan 
Transplant Center.  
8.3 
Permitting Access to Source Data 
Individual centers will be allowed to access the data of their own study 
participants for the purpose of quality control and assurance, 
8.4 
Quality Control and Assurance 


 
 
 
 
 
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The DCC will be responsible for regularly reviewing the conduct of the data 
collection process, for verifying adherence to the protocol, and for confirming the 
completeness, consistency, and accuracy of all documented data.  
8.4.1 Data Handling 
The investigator is required to ensure that all CRFs are completed for every 
participant entered in the trial. The data will be verified by a series of 
computerized edit checks, and all relevant data queries will be resolved regularly. 
When the CRFs are complete, they will be reviewed and signed by the 
investigator.  All data from the original signed CRF will be then entered in the 
database, and a comparison program will be run again.  All discrepancies will be 
reviewed, and any resulting queries will be resolved with the investigator and 
amended in the database. All elements of data entry (i.e., time, date, verbatim 
text, and the name of the person performing the data entry) will be recorded in 
an electronic audit trail to allow all data changes in the database to be monitored 
and maintained in accordance with federal regulations. 
8.4.2 Protection of Confidentiality 
Researchers will electronically transfer the source data to the DCC.  The DCC 
will collect, update and verify data on the study variables from the following 
sources at the respective transplant programs: archived paper medical records; 
system-wide and program-specific clinical information data management 
systems; and their respective organ transplant information systems. 
 
 
 
 


 
 
 
 
 
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9 
STATISTICAL CONSIDERATION AND ANALYSTIC PLAN 
9.1 
Sample Size and Power Calculations 
The sample size and power calculations revealed that 276 participants will be 
needed to have 85% power to detect a 15% difference in the proportions of 
participants who develop NODAT under the assumption that the baseline 
incidence of NODAT in the control treatment (group B) will be 30% at 12 months 
(1, 4). We plan to enroll 300 participants with a constant accrual rate. We 
estimate that the rate of loss to follow-up will be 6% in year one and 8% in year 
two (Appendices, table 5). These attrition rates would leave an end-of-study 
sample size of 280 participants out of the 300 enrolled. For the secondary 
endpoint, sample size calculations revealed that 54 participants (Appendices, 
table 6) will be needed to have 85% power to detect a difference of 0.5% in 
hemoglobin A1c under the assumption that the mean hemoglobin A1c at 12 
months post-transplantation will be 6.3% in participants randomized to the 
control treatment (group B). The power calculations are based on two-sided test 
of significance with an alpha level of 0.05. 
The two study groups will be compared using the Student t-test for continuous 
variables and the χ2 or Fisher’s exact test for categorical variables. We will 
evaluate the effect of the early insulin regimen vs. step-up approach on the risk 
of NODAT using the Cox proportional hazards model for the time to the failure 
event, adjusted for the clinical center effect (UMHS vs. other transplant centers). 
The Cox model takes the form λ(t) = λ0(t)expβ1d + β2s + β3(c), where λ(t) is the 
hazard function at time t and λ0(t) is the baseline hazard function, with treatment 
d (group assignment) and clinical center s being covariates of interest as 
defined. The hazard ratio comparing early insulin regimen to the step-up 
approach is quantified by eβ1. The null hypothesis is H0: β1=0, that is, the two 
treatment groups have the same hazard; we wish to show H1: β1 ≠ 0. At the type 
I error 0.05, the sample size needed with Brian O Fleming adjustment for one 
interim analysis is shown in table 5. The sample size calculation is based on a 
1:1 randomization ratio between the experimental arm (group A) and the control 
arm (group B). The Cox regression model’s assumption of proportionality will be 
assessed graphically using plots of Schoenfeld residuals against time and 
numerically via time-dependent interaction terms. Significant violations of the 
assumption by one or more covariates will be handled using time-dependent 
interactions or stratification of the model on the covariate. The planned sample 
size of 300 subjects with annualized rate of loss to follow-up of 6% (year 1) and 
8% (year 2) yield a power of 85% to detect a relative reduction of 0.50 (RR = 
0.50). 
For the secondary endpoint of hemoglobin A1c, we will use the Cochran-Mantel-
Haenszel test to assess the relationship between study groups and mean 
hemoglobin A1c. Based on our preliminary studies, we estimated that the mean 
hemoglobin A1c in the control treatment group (group 1) would be 6.3 + 0.7. 
Table 6 shows that the sample size is sufficiently robust to find a 0.5% difference 
in hemoglobin A1c if a power level of 85% is selected. 


 
 
 
 
 
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9.2 
Interim Analyses to Ensure Patient Safety 
Interim analyses for therapeutic efficacy will not be required for this study. 
However, regular monitoring for the occurrence of adverse events will be 
conducted and assessed among all study participants. 
9.3 
Inadequate Recruitment and Excessive dropout 
The most significant problem for any clinical trial is the ability to meet 
the recruitment goals within the specified timeline. Our preliminary 
assessment indicates that we will have more than 700 potentially eligible 
participants at the two clinical centers combined over the 30-month 
enrolment period. Our experience over the last 20 years suggests that 
we would achieve a participation rate of 50-60% among eligible 
participants leaving us with ample pool of potential participants. To 
ensure that we address recruitment problems in a timely fashion, each of 
the two clinical centers will be required to maintain a screening and 
recruitment log in RedCap and at the clinical center. The recruitment log 
will also be used to document the magnitude and reasons for non-
participation by eligible patients. A color-coded 3-stagewarning system 
will be utilized to manage the recruitment process on a monthly basis. A 
recruitment efficiency (R) will be automatically calculated according to 
the formula R= ∑(tk  tk1)[r(tk1) + r(tk)], where tk is the proportion of 
the recruitment period by unit of time k, the variable r is the fraction of 
the planned sample size recruited by time k and the variable k defines 
the entire recruitment period. The value of r for both Michigan and 
Vienna will be set at a target of 110%. A drop in the recruitment 
efficiency below 80% for two consecutive months (orange alert) will 
trigger an immediate review of all aspects of the recruitment operation 
by Drs. Ojo and Säemann. In order to protect the power for statistical 
analyses of main study hypotheses, it would be necessary to maintain a 
retention rate of 85% by the end of the study. Specific measures that will 
be taken to enhance retention of participants in the study include: (a) 
regular contact with referring physician practices; (b) use of only trained, 
certified study personnel to perform study visits and; (c) face-to-face 
meeting between study physician and each participant at least quarterly 
during study visits. Established practices such as mailings and personal 
telephone calls to remind participants about forthcoming study visits will 
also be incorporated. The study team will promptly provide results of 
study tests to referring physicians. Participants will be encouraged to 
include family members in their follow-up visits since this may enhance 
the participant support without extra costs. Follow-up visit appointments 
will be scheduled with large appointment windows to allow for more 
flexibility and participant’s convenience. 
 
 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
10 
SAFETY MONITORING 
10.1 Definitions 
10.1.1 Adverse Event 
An adverse event (AE) is any occurrence or worsening of an undesirable or 
unintended sign, symptom (including an abnormal laboratory finding), or disease 
that is temporally associated with the use of a medicinal product whether 
considered related to the medicinal product or not. 
An adverse event will be followed until it is resolved or until 30 days after a 
participant terminates from the study, whichever comes first. 
10.1.2 Serious Adverse Event 
A serious adverse event (SAE) is defined as “any adverse event occurring at any 
dose that suggests a significant hazard, contraindication, side effect, or 
precaution.” This includes, but is not limited to, any of the following events: 
1. Death: A death that occurs during the study or that comes to the attention of the 
investigator during the protocol-defined follow-up after the completion of therapy 
must be reported whether it is considered to be treatment related or not. 
2. A life-threatening event: A life-threatening event is any adverse therapy 
experience that, in the view of the investigator, places the patient or participant at 
immediate risk of death from the reaction as it occurred. 
3. Inpatient hospitalization or prolongation of existing hospitalization. 
4. Persistent or significant disability. 
5. An event that required intervention to prevent permanent impairment or damage. 
An important medical event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based on appropriate 
medical judgment, it may jeopardize the participant and may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
Regardless of the relationship of the adverse event to study drug, the event must 
be reported as an SAE if it meets any of the above definitions. 
10.1.3 Unexpected Adverse Event 
An adverse event is considered “unexpected” when its nature (specificity) or 
severity is not consistent with applicable product information, such as safety 
information provided in the package insert, the investigational plan, or the 
investigator’s brochure. 
10.2 Event Collecting and Recording Procedure 
Adverse events will be collected from the time the participant begins study 
treatment until the time the event is resolved or until 30 days after the participant 
completes study treatment, whichever comes first. 
Adverse events may be discovered through any of these methods: 
1. Observing the participant during clinical trial period. 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
2. Questioning the participant at interval follow-up visits which should be done in an 
objective manner. 
3. Receiving an unsolicited complaint from the participant. 
4. An abnormal value or result from a clinical or laboratory evaluation (e.g., a test 
result, a radiograph, an ultrasound, or an electrocardiogram) can also indicate an 
adverse event.  If this is the case, then the evaluation that produced the value or 
result should be repeated until the value or result returns to normal or can be 
explained and the participant’s safety is not at risk.  If an abnormal value or result 
is determined by the investigator to be clinically significant, it must be indicated 
as such on the appropriate laboratory evaluation form(s), and must also be 
reported as an adverse event on the adverse event form. 
Throughout the study the investigator will record all adverse events on the 
appropriate adverse event case report form (CRF) regardless of their severity or 
relation to study medication or study procedure. The investigator will treat 
participants experiencing adverse events appropriately and observe them at 
suitable intervals until their symptoms resolve or their status stabilizes. 
10.3 Grading and Attribution  
The study site will grade the severity of adverse events experienced by study 
participants according to the criteria set forth in the National Cancer Institute’s 
Common Terminology Criteria for Adverse Events Version 3.0 (NCT-CTCAE 
published June 10, 2003). This document (referred to herein as the NCI-CTCAE 
manual) provides a common language to describe levels of severity, to analyze 
and interpret data, and to articulate the clinical significance of all adverse events. 
Adverse events will be graded on a scale from 1 to 5 according to the following 
standards in the NCI-CTCAE manual: 
Grade 1 = Mild adverse event. 
Grade 2 = Moderate adverse event. 
Grade 3 = Severe and undesirable adverse event.  
Grade 4 = Life-threatening or disabling adverse event. 
Grade 5 = Death. 
All adverse events will be graded whether they are or are not related to disease 
progression or treatment. 
10.4 Reporting Criteria 
After the AE and/or SAE have been assessed, the event will be reported to the 
appropriate health authorities in the required manner based on the following 
criteria: 
1. No reporting: This requirement applies if the adverse event is deemed not 
serious by the medical liaison, the medical monitor, and the NIAID Medical 
Officer. 
2. Standard reporting:  This requirement applies if the adverse event is classified as 
any of the following:  


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
a. Serious, expected, and drug related.  
b. Serious, expected, and not drug related. 
c. Serious, unexpected, and not drug related. 
3. Expedited reporting:  This requirement applies if the adverse event is considered 
serious, unexpected, and drug related. This type of SAE must be reported by the 
sponsor to the appropriate health authorities within 15 days; fatal or life-
threatening events must be reported within 7 days.   
10.5 Reporting Timeline 
When an investigator identifies an SAE (as defined in section 10.1.2), he or she 
must notify the DSMB within 24 hours of discovering the event. In addition to 
telephone reporting, the investigator must ensure that these events are entered 
on the SAE report form and the adverse event CRF. Both forms will be faxed to 
the DSMB within 24 hours.   
The investigator will ensure the timely dissemination of SAE information, 
including expedited reports, to the IRB in accordance with applicable regulations 
and guidelines. 
10.6 Data Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) will convene to act in an advisory 
capacity to monitor participant safety and evaluate the ability of the investigators 
to conduct the proposed with utmost regard for participant protection and 
confidentiality. The DSMB will undertake the following tasks: 
1. Approve the initiation of the proposed study. 
2. Review the research protocol, informed consent documents, and plans for data 
safety and monitoring, including all proposed revisions. 
3. Evaluate the progress of the study, including periodic assessments of data 
quality and timeliness, participant recruitment, accrual and retention, participant 
risk versus benefit, performance of the two clinical centers, and other factors that 
may affect study outcomes. 
4. Consider factors external to the study when relevant information becomes 
available, such as scientific or therapeutic developments that may have an 
impact on the safety of the participants or the ethics of the study. 
5. Protect the safety of the study participants and report on the safety and progress 
of the study. 
6. Make recommendations to the study team and, if required, to the FDA and IRBs 
concerning continuation, termination, or other modifications of the study based 
on the observed beneficial or adverse effects of the study procedures. 
7. Review interim analysis data in accordance with stopping rules that are defined 
in advance of data analysis and have the approval of the DSMB. 
8. Ensure the confidentiality of the clinical trial data and the results of monitoring 
and assist the investigators by commenting on any problems with study conduct, 
enrollment, sample size, and/or data collection. 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
The DSMB will consist of five members: one biostatistician from the University of 
Michigan, one nephrologist and one endocrinologist each from the UMHS and 
MUV. Members of the DSMB shall have no financial, scientific, or other conflict 
of interest with the study. Collaborators or associates of the investigators in this 
application would not be eligible to serve on the DSMB. Written documentation 
attesting to absence of interest will be required of the DSMB members. All 
aspects of the clinical trial described in this application will be conducted with 
utmost regard for the welfare and privacy of the volunteer participants. The 
investigators on this application have developed a list of potential DSMB 
members who have the expertise and experience to discharge the 
responsibilities of the DSMB but have refrained from naming the possible slate of 
members to avoid potential contamination of the pool and to allow the NCMHD 
to have a significant input into the selection process. The DSMB shall conduct 
periodic meetings at a frequency no less than once every 6 months. The DSMB 
meetings shall be closed to the public because discussions may address 
confidential participant data. An emergency meeting of the DSMB may be called 
at any time by the Chair of the DSMB in the event of issues regarding participant 
safety. The format for DSMB meetings may be open, closed and/or executive 
session, as dictated by the agenda of the meeting. 
 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
11. 
ETHICAL CONSIDERATION AND COMPLIANCE WITH GOOD 
CLINICAL PRACTICE  
Before study initiation, the protocol will be reviewed and approved by an 
appropriate Internal Review Board (IRB) any by the Competent Authorities as 
applicable per local laws and regulations.  Any amendments to the protocol must 
also be approved before they are implemented. 
11.1 Informed Consent 
The informed consent form is a means of providing information about the trial to 
a prospective participant and allows for an informed decision about participation 
in the study. All participants (or their legally acceptable representative) must 
read, sign, and date a consent form before entering the study, taking study drug, 
or undergoing any study-specific procedures.  Consent materials for participants 
who do not speak or read English must be translated into the participants’ 
appropriate language. 
The informed consent form must be revised whenever important new safety 
information is available, whenever the protocol is amended, and/or whenever 
any new information becomes available that may affect participation in the trial. 
A copy of the informed consent will be given to a prospective participant for 
review.  The investigators or their designees (study coordinator), in the presence 
of a witness, will review the consent and answer questions. The prospective 
participant will be told that being in the trial is voluntary and that he or she may 
withdraw from the study at any time, for any reason. 
We will obtain informed consent from all study participants before conducting 
any study-related testing. Since the investigators and study coordinators 
approaching the study participants may be the same individuals who participated 
in their care during subsequent follow-up, extra precautions will be taken to 
ensure that the potential participants are not coerced or perceive coercion to 
participate in the study.   
11.2 Privacy and Confidentiality 
Each participant’s privacy and confidentiality will be respected throughout the 
study. Each participant will be assigned a sequential identification number, and 
these numbers rather than names, will be used in analytic datasets.  The study 
will require use of identifying information during the stages of (1) data collection 
from the centers, and (2) database linkages. 
11.3 Publication Policy 
The NIDDK policy on the publication of study results will apply to this trial. A 
publication subcommittee will be established to include study PIs, members of 
sponsoring agencies (NIDDK, etc.). Any abstract and/or manuscript generated by 
participating investigators using the data from the current study will be submitted 
to the subcommittee for review. Each member of the subcommittee will have 2 
weeks of time to review the documents for submission to a publishing entity 
(scientific meetings and/or peer reviewed scientific journals). The member can 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
approve the documents by 1) explicit approval or 2) no objection within the time 
frame of two weeks.  
The authorship will be determined by the subcommittee at the time of approval 
for submission. 
 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
11 
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65. 
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Pacini G, Mari A. Methods for clinical assessment of insulin sensitivity and beta-
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Mar;24(3):539-48. 
 
 


 
 
 
 
 
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12. 
APPENDICES 
 
Table 1. NPH Insulin Titration Regimen for Patients in Group A 
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 
 
 
 
 
 
Table 2. Sliding Scale for Short Acting Insulin Regimen 
Capillary blood glucose before meals and at bedtime 
(mg/dl)* 
Short-acting insulin dose 
(IU)** 
351 and above 
16 
301 to 350 
12 
251 to 300 
8 
201 to 250 
4 
*only high pre-lunch and at bedtime glucose levels will require short acting insulin 
coverage. 
**given the next day at the meal at breakfast or dinner for the high lunchtime or bedtime 
glucose levels, respectively.  Not to be administered at lunch or bedtime. 
 


 
 
 
 
 
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ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
Table 3. Tacrolimus and Corticosteroids Dosing Schedule 
 
Tacrolimus trough 
levels (ng/ml) 
Corticosteroids (mg)* 
Corticosteroids (mg)** 
At transplant 
(OR) 
 
Methylprednisolone 500 
mg intravenously 
Prednisone 250 mg 
Day 1 
8 to 12 
Prednisone 100 mg daily 
Prednisone 125 mg daily 
Day 2 
Prednisone 80 mg daily 
Prednisone 20 mg daily 
Day 3 
Prednisone 60 mg daily 
Prednisone 20 mg daily 
Day 4 
Prednisone 40 mg daily 
Prednisone 20 mg  daily  
Day 5 to 14 
Prednisone 20 mg daily 
Prednisone 20 mg daily 
Day 15 to 28 
Prednisone 15 mg daily 
Prednisone 15 mg daily 
Day 29 to 42 
Prednisone 15 mg daily 
Prednisone 10 mg daily 
Day 43 to 49 
Prednisone 15 mg daily 
Prednisone 5 mg daily 
Day 50 to 90 
Prednisone 10 mg daily 
Prednisone 5 mg daily 
Day 91 to 120 
5 to 8 
Prednisone 10 mg daily 
Prednisone 5 mg daily 
Day 121 to 180 
Prednisone 7.5 mg daily 
Withdrawal possible, but 
has to be reinforced by 
center practice in either all 
patients or none, regardless 
of glucose metabolism 
Day 181 and 
beyond 
Prednisone 5.0 mg daily 
* UMHS protocol (will be followed by UMHS and 3 EU centers. **Barcelona protocol 
(will be followed by 2 EU centers). 
 
 
 


 
 
 
 
 
CONFIDENTIAL  
 
 
 
Page 42 of 44 
ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
Table 5. Sample Size and Power Calculations for Incidence of NODAT 
Power 1 – β 
0.80 
0.85 
0.90 
Difference d  
0.10 
0.15 
0.20 
0.10 
0.15 
0.20 
0.10 
0.15 
0.20 
Sample Size N 
588 
242 
124 
672 
276 
142 
784 
322 
164 
 
 
 
Table 6. Sample Size and Power Calculation for Hemoglobin A1c 
Power 1 – β 
0.80 
0.85 
0.90 
Difference d  
0.3 
0.5 
0.7 
0.3 
0.5 
0.7 
0.3 
0.5 
0.7 
Sample Size N 
128 
48 
26 
146 
54 
30 
172 
64 
34 


 
CONFIDENTIAL 
Page 43 of 44
 
 
 
ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
Table 4. Follow-up schedule for study visits and study related-procedure 
*Comprehensive Clinical Assessment includes (a) medical history; (b) clinical examination; and (c) routine laboratory 
studies. **For all patients, even if they are on any anti-diabetic medications (insulin or oral hypoglycemic agents), with 
medication not withdrawn before the test. The results of 6 month’s OGTT will be blinded to study participants and 
investigators. ***Patients enrolled at the UM site only and optional. ****Study windows: ±2 weeks.
 
 
Screening & 
randomization 
At 
discharge 
Weekly/biweekly 
(month 1 to 3) 
Month 
3**** 
Month 
6**** 
Month 
12**** 
Month 
16**** 
Month 
20**** 
Month 
24**** 
Eligibility Assessment 
X 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical Record Consent 
X 
 
 
X 
X 
X 
X 
X 
X 
Contact Information 
X 
 
X 
X 
X 
X 
X 
X 
X 
Demographic Information 
X 
 
 
 
 
 
 
 
 
Eligibility Confirmation 
X 
 
X 
 
 
 
 
 
 
Comprehensive Clinical Assessment* 
X 
 
 
X 
X 
X 
X 
X 
X 
Fasting glycemia 
X 
 
X 
X 
X 
X 
X 
X 
X 
Hemoglobin A1c 
X 
 
 
X 
X 
X 
 
 
X 
Fasting insulin/pro-insulin 
X 
 
 
 
X 
X 
 
 
X 
Oral glucose tolerance test (OGTT)** 
 
 
 
 
X 
X 
 
 
X 
Microalbuminuria 
 
 
 
X 
 
X 
 
 
X 
Blood sample for future genetic (DNA & 
RNA) studies*** 
X 
X 
 
 
 
X 
 
 
 
Blood and urine samples for future 
studies 
X 
 
 
 
X 
X 
 
 
X 
Recent medical events 
X 
 
X 
X 
X 
X 
X 
X 
X 
Quality of life questionnaire 
X 
 
 
 
X 
X 
 
 
X 


 
CONFIDENTIAL 
Page 44 of 44
 
 
 
ITP-NODAT Prospective Study in Non-Diabetic De Novo Kidney Transplant Recipients 
 
Figure 1. Study Flow Chart 
Screening  
& 
Randomization 
Kidney 
Transplantati
Group A: 
Intervention 
Group B: 
Standard of care 
1. Glycemia monitoring AC and HS 
for 4 weeks and start insulin if 
pre-dinner glycemia > 140 mg/dl; 
2. Continue insulin for 2 weeks 
after reaching normoglycemia, 
then wean-off if possible; 
1. No monitoring unless fasting 
glycemia > 200 mg/dl; 
2. Diet, oral hypoglycemic agent 
and/or short acting insulin if 
criteria for DM is met; 
12 and 24 
months 
1. NODAT; 
2. Impaired; 
3. HOMA & IGI 
4. Clinical events