Clinical trial NCT01928199: Efficacy Study of Sitagliptin to Prevent New-onset Diabetes After Kidney Transplant
Official title: A Single Center, Randomized, Double-blind Controlled Trial of Sitagliptin Versus Placebo to Reduce the Incidence and Severity of New-onset Diabetes After Kidney Transplant
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Posttransplant Diabetes Mellitus
Keywords: diabetes
transplant
kidney
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2013-08-23
Enrollment: 61
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to determine whether sitagliptin is effective in preventing the development of new-onset diabetes after kidney transplant (NODAT). Up to one-third of previously non-diabetic patients develop NODAT after a kidney transplant. Corticosteroids and calcineurin inhibitors are two commonly utilized anti-rejection medications that contribute to diabetes development through multiple mechanisms; including decreased insulin production by the pancreas. Sitagliptin is an oral medication that results in increased insulin secretion. We hypothesize that administration of sitagliptin to transplant recipients identified to be at risk for diabetes development will reduce the incidence and severity of NODAT.

Detailed description: This will be a single-center, randomized, double-blind trial to evaluate the efficacy of sitagliptin to prevent the development of new-onset diabetes after transplant (NODAT) in previously non-diabetic patients with post-operative hyperglycemia following living-donor or deceased-donor kidney transplant. In this trial, previously non-diabetic adult patients with hyperglycemia (random blood sugar \>200mg/dL) in the first 72 hours following kidney transplant will be screened to determine eligibility based on inclusion/exclusion criteria. Patients that meet study entry criteria will be stratified based on HbA1c (\<5.7 or 5.7-6.4%) and randomized in a 1:1 ratio to one of two treatment groups: sitagliptin versus placebo. Fifty patients (25 per group) will be enrolled. Dosing period will be 3 months at which time study drug will be discontinued and patients will be followed for an additional 3 month period.

Study visits will occur at 0, 1, 3 and 6 months. A HbA1c and 2-hour oral glucose tolerance test (OGTT) will be obtained at the 3 and 6 month study visit.

Screening period (Visit 1)

All patients presenting for living-donor or deceased donor kidney transplant will have a medical history, medication history, vital signs, height, weight, body mass index, physical exam, random blood sugar (BS), HbA1c and EKG done as part of routine pre-transplant protocol at Barnes Jewish Hospital. Patients with hyperglycemia, defined as a random blood sugar ≥ 200 mg/dL, in the first 72 hours after kidney transplant will be screened to determine eligibility for the study based on inclusion and exclusion criteria.

Randomization (Visit 2)

Patients meeting study entry criteria and consenting to study participation will be stratified based on HbA1c (\<5.7 or 5.7-6.4%) and block randomized in blocks of eight in a 1:1 ratio to sitagliptin versus placebo. Sitagliptin dose will be 100mg/day, adjusted per creatinine clearance and tolerability. Patients will be instructed by a licensed diabetic educator on proper measurement and recording of fasting and post-prandial blood sugars. Subjects will be provided a log, standard glucometer and testing strips to maintain a blood sugar log post-discharge. Visit 2 will occur within 24 hours after Visit 1.

Drug dosing period (Visits 3-4)

Sitagliptin or placebo will be continued until 3 months post-transplant, at which time study medication will be discontinued and collected from the subject. At the 1 and 3 month visits, vital signs, height, weight, and BMI will be obtained. A physical exam will be performed. Blood sugar logs provided by the patient will be reviewed and adverse effects recorded. At the 3 month visit (Visit 4), a HbA1c, 2-hour OGTT, fasting C-peptide and insulin level will be obtained.

Follow-up (Visit 5)

At the 6 month final visit, 3 months following discontinuation of study medication, vital signs, height, weight, BMI, HbA1c, 2-hour OGTT, fasting C-peptide and insulin level will be obtained. A physical exam will be performed. Blood sugar logs provided by the patient will be reviewed and adverse effects recorded.

Eligibility criteria: Inclusion Criteria:

1. Adult (≥18 yo) recipient of living-donor or deceased donor kidney transplant
2. Blood sugar ≥ 200 mg/dL in first 72 hours after transplant
3. No history of diabetes or prior treatment with insulin or oral hypoglycemic agents

Exclusion Criteria:

1. A1c of ≥6.5% measured immediately pre-transplant
2. Recipient of simultaneous kidney-pancreas, kidney-liver, kidney-heart, or kidney-lung transplant
3. Prior non-renal solid organ transplant

Primary outcomes:
measure: 2-hour Oral Glucose Tolerance Test-derived Blood Sugar
timeFrame: 3 months
Secondary outcomes:
measure: Normal 2-hour Oral Glucose Tolerance Test-derived Blood Sugar
timeFrame: 3 months
measure: 6 Month OGTT Result (Completion of Washout From Study Drug)
timeFrame: 6 months
Other outcomes:
measure: Hemoglobin A1c, 3 Month
timeFrame: 3 months
measure: Hemoglobin A1c, 6 Month
timeFrame: 6 months
Locations:
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Rowena Delos Santos, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Yates CJ, Fourlanos S, Hjelmesaeth J, Colman PG, Cohney SJ. New-onset diabetes after kidney transplantation-changes and challenges. Am J Transplant. 2012 Apr;12(4):820-8. doi: 10.1111/j.1600-6143.2011.03855.x. Epub 2011 Nov 28.
citation: Caillard S, Eprinchard L, Perrin P, Braun L, Heibel F, Moreau F, Kessler L, Moulin B. Incidence and risk factors of glucose metabolism disorders in kidney transplant recipients: role of systematic screening by oral glucose tolerance test. Transplantation. 2011 Apr 15;91(7):757-64. doi: 10.1097/TP.0b013e31820f0877.
citation: Chakkera HA, Knowler WC, Devarapalli Y, Weil EJ, Heilman RL, Dueck A, Mulligan DC, Reddy KS, Moss AA, Mekeel KL, Mazur MJ, Hamawi K, Castro JC, Cook CB. Relationship between inpatient hyperglycemia and insulin treatment after kidney transplantation and future new onset diabetes mellitus. Clin J Am Soc Nephrol. 2010 Sep;5(9):1669-75. doi: 10.2215/CJN.09481209. Epub 2010 Jun 17.
citation: Herman GA, Bergman A, Stevens C, Kotey P, Yi B, Zhao P, Dietrich B, Golor G, Schrodter A, Keymeulen B, Lasseter KC, Kipnes MS, Snyder K, Hilliard D, Tanen M, Cilissen C, De Smet M, de Lepeleire I, Van Dyck K, Wang AQ, Zeng W, Davies MJ, Tanaka W, Holst JJ, Deacon CF, Gottesdiener KM, Wagner JA. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006 Nov;91(11):4612-9. doi: 10.1210/jc.2006-1009. Epub 2006 Aug 15.
citation: Lane JT, Odegaard DE, Haire CE, Collier DS, Wrenshall LE, Stevens RB. Sitagliptin therapy in kidney transplant recipients with new-onset diabetes after transplantation. Transplantation. 2011 Nov 27;92(10):e56-7. doi: 10.1097/TP.0b013e3182347ea4. No abstract available.