Clinical trial NCT02608177
Conditions: Chronic Kidney Diseases Type 2 Diabetes
Sponsor: University of Washington
Start date: 2015-11-01; Completion date: 2018-08-01
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The goal of this study is to test whether a dipeptidyl peptidase-4 inhibitor, compared with a sulfonylurea, improves time in normal blood glucose range and reduces blood glucose variability. Blood glucose is measured using a continuous glucose monitoring device.

Detailed description:
This is a proof-of-concept clinical trial testing the effects of linagliptin versus glipizide on glucose variability among people with type 2 diabetes and stage 3-4 CKD. In a cross-over design, each enrolled participant will receive 28 days of each study medication. Study medications will be provided in a randomly assigned order without blinding. The primary study outcome is glucose time in range, measured by blinded continuous glucose monitoring for the last 6 days of each 28-day treatment period. Secondary outcomes include indices of glycemic variability, hypoglycemia, and biomarkers of systemic inflammation, oxidative stress, and albuminuria. The overall goal of this research is to identify safe and effective treatments to control glycemia among patients with diabetes and CKD.

Arms: arm 1: Arm receives 4 weeks of study drug linagliptin followed by 4 weeks of glipizide arm 2: Arm receives 4 weeks of study drug glipizide followed by 4 weeks linagliptin
Interventions: intervention 1: Linagliptin intervention 2: Glipizide
Intervention descriptions: intervention 1: Receives 4 weeks of study drug linagliptin intervention 2: Receives 4 weeks of study drug glipizide

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
Continuous glucose monitoring to Assess glycemia in chroNic kiDneY disease – 
 ChANging glucosE management 
 
(An interventional trial)  
 
 
Protocol 
September 28, 2015 
 
 
Short title: 
CANDY-CANE 
  
 
Investigators:   
 Maryam Afkarian, MD, PhD 
Ian de Boer, MD, MS (PI) 
Irl Hirsch, MD 
Joshua Neumiller, PharmD 
Dace Trence, MD 
Katherine Tuttle, MD 
  
  
Supported by:  
American Diabetes Association 
Providence Sacred Heart Medical Center and Children’s Hospital 
MedTronic (equipment and supplies) 
Abbott (equipment and supplies) 
  
 Sponsor of IND:  
 N/A 
  
  


V. 4/24/2015 
2 
Abstract 
Chronic kidney disease (CKD) is a common and morbid complication of diabetes. Poor 
glycemic control underlies most cases of diabetes and CKD, but clinicians and patients have 
virtually no high-quality information to guide glucose management once this develops. Diabetes 
and CKD fundamentally alters the ascertainment and treatment of hyperglycemia due to changes 
in hemoglobin kinetics, limitations to the menu of available medications, decreased catabolism 
of insulin and oral hypoglycemic medications, and – in end stage renal disease – direct effects of 
renal replacement therapy on blood glucose and insulin secretion. This constellation of changes 
is widely believed to increase the risk of hypoglycemia, which may in turn contribute to the 
markedly elevated levels of systemic inflammation and oxidative stress observed in diabetes and 
CKD  and the high rates of arrhythmia and sudden death observed in this population. New 
medications that lower glucose with reduced risk of hypoglycemia are insufficiently evaluated 
among patients with CKD, who have frequently been excluded from clinical trials. 
This is a proof-of-concept clinical trial testing the effects of linagliptin versus glipizide on 
glucose variability among people with type 2 diabetes and stage 3-4 CKD.  In a cross-over 
design, each enrolled participant will receive 28 days of each study medication. Study 
medications will be provided in a randomly assigned order without blinding. The primary study 
outcome is glucose time in range, measured by ablinded continuous glucose monitoring for the 
last 6 days of each 28-day treatment period. Secondary outcomes include indices of glycemic 
variability, hypoglycemia, and biomarkers of systemic inflammation, oxidative stress, and 
albuminuria. The overall goal of this research is to identify safe and effective treatments to 
control glycemia among patients with diabetes  and CKD.  


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3 
1. Study Objectives 
Chronic kidney disease (CKD) is a common and 
devastating complication of diabetes. Specifically, 
albuminuria or reduced glomerular filtration rate (GFR) 
occurs in approximately 40% of patients with type 2 
diabetes and markedly increases risks of cardiovascular 
disease (CVD) and death. Poor glycemic control underlies 
most cases of diabetic CKD, but clinicians and patients 
have virtually no high-quality information to guide 
glycemia management once CKD develops. CKD 
fundamentally alters the ascertainment and treatment of 
hyperglycemia due to changes in hemoglobin kinetics, 
limitations to the menu of available medications, and 
decreased catabolism of insulin and oral hypoglycemic 
medications. This constellation of changes is widely 
believed to increase glucose variability and the risk of 
severe hypoglycemia, which may in turn contribute to the 
markedly elevated levels of systemic inflammation and 
oxidative stress and the high rates of CVD and death observed among people with diabetes and 
CKD. New medications that lower glucose with reduced risk of hypoglycemia are insufficiently 
evaluated among patients with CKD, who have been frequently excluded from clinical trials.  
The overall goal of our research is to improve the management and clinical outcomes of 
patients with diabetes and CKD. The goal of this study is to test whether a dipeptidyl 
peptidase-4 inhibitor, compared with a sulfonylurea, improves time in normoglycemia and 
reduces glycemic variability and hypoglycemic exposure. 
Hypothesis a: Linagliptin, compared with glipizide, increases time in normoglycemia and 
decreases glycemic variability and hypoglycemic exposure, at a similar level of mean 
glycemia. 
Hypothesis b: Linagliptin, compared with glipizide, reduces systemic inflammation, 
oxidative stress, and albuminuria, at a similar level of mean glycemia. 
2. Background and Rationale 
2.1. Chronic kidney disease is common. Chronic kidney disease (CKD), defined by elevated 
urine albumin excretion (“albuminuria”) and/or impaired glomerular filtration rate (GFR),1-4 is a 
tremendous problem from the perspectives of individual patients and the public health. CKD 
occurs in 40% or more of patients with type 2 diabetes.1-6 We demonstrated that the prevalence 
of diabetes and CKD in the United States increased by 34% to 6.9 million persons over the last 
20 years, driven by the increasing prevalence of diabetes itself (Figure 1, manuscript included 
with application).6 Diabetes is the leading cause of end stage renal disease (ESRD) requiring 
dialysis or kidney transplantation in the developed world.7  
2.2. Kidney disease identifies persons with diabetes at high risk of cardiovascular disease 
and death. Recent provocative data suggest that kidney disease captures all excess mortality risk 
associated with type 1 diabetes.8,9 Surprisingly, using data from the Third National Health and 
Nutrition Examination Survey linked to the National Death Index, we found that kidney disease 


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4 
also captured almost all excess mortality risk in type 2 diabetes.10 Specifically, kidney disease 
was associated with markedly increased 10-year cumulative mortality, particularly among people 
with diabetes, but diabetes was not associated 
with increased mortality risk absent kidney 
disease (Figure 2). These data expand on work by 
our group and others demonstrating that 
albuminuria and impaired GFR are strong, 
independent, and additive risk factors for 
cardiovascular disease (CVD) and death among 
persons with diabetes.11-16 
2.3. Kidney disease fundamentally alters 
glucose homeostasis, increasing the risk of 
hypoglycemia. Impaired GFR leads to a number 
of important perturbations in glucose 
homeostasis. These include decreased insulin 
catabolism, impaired metabolism and excretion of 
glucose-lowering medications (leading to 
prolonged sulfonylurea half-life and a contraindication to metformin use), decreased renal 
gluconeogenesis, malnutrition (in advanced DKD), and a blunted counter-regulatory response. 1-
4,17-21 Mounting data suggest that these changes lead to increased risk of hypoglycemia. Moen et 
al reported that inpatient and outpatient veterans with diabetes and CKD experienced double the 
incidence rates of laboratory glucose <70 mg/dL compared to veterans with diabetes and normal 
estimated GFR.22 Glucose <70 mg/dL was associated with markedly increased short-term 
mortality. A recent population-based Canadian study of diabetes and CKD reported a U-shaped 
association of hemoglobin A1c with all-cause mortality, again suggesting adverse effects of 
hypoglycemia.23 In the ACCORD trial, albuminuria and reduced estimated GFR (even with 
limited ranges) were associated with markedly increased risks of hypoglycemia, particularly with 
intensive glucose-lowering.24  
2.4. Evidence evaluating glucose control strategies in diabetes and CKD is lacking. 
Ironically, despite the fact that poor glycemic control underlies most cases of diabetic CKD, little 
is known regarding the impact of CKD on optimal glycemia targets and therapeutic strategies. 
Intensive diabetes therapy clearly reduces the risk of developing CKD,25-30 and many people with 
diabetes develop CKD in large part due to poor glycemic control. However, clinical trials 
ascertaining the risks and benefits of tight glycemic control have systematically excluded people 
with prevalent CKD.24-32 As a result, guidelines for clinical care commonly extrapolate treatment 
principles and hemoglobin A1c targets from studies that include few or no participants with 
kidney disease.4 This may be unsafe. In ACCORD, post-hoc analysis suggests that the widely 
publicized adverse effect of intensive glucose lowering on mortality was confined to participants 
with CKD at baseline.33 High-quality data on the benefits and in particular the risks of lowering 
blood glucose are needed to determine appropriate treatment strategies for patients with diabetes 
and CKD. 
2.5. Continuous glucose monitoring offers a novel approach to study glycemia in CKD. 
Rapid advancements in technology have facilitated the use of continuous glucose monitoring 
(CGM) for clinical care and research.34,35 CGM makes measurements of interstitial glucose 
concentration that accurately reflect blood glucose.36 These measurements have become the gold 


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5 
standard for measuring average glycemia and glycemic variability in high-quality studies such as 
the A1c-Derived Average Glucose (ADAG) Study,37-40 STAR-3,41 and the JDRF Sensor Study.42 
CGM has been applied in a number of small studies of CKD, mostly ESRD (Table 1).43-51 These 
studies demonstrated that CGM is accurate in the setting of even advanced. In comparison, a 
larger, more detailed study with longer periods of CGM could additionally define glycemic 
variability and ascertain the determinants and consequences of hypoglycemia in CKD. 
Table 1. Published studies of continuous glucose monitoring (CGM) among persons with kidney 
disease 
First 
author 
Participan
ts 
N 
CGM 
duratio
n 
Correlation of 
CGM with 
blood glucose 
Other 
Riveline 
T2D, HD 
19 
4d 
0.90 
Poor correlation of mean CGM glc & 
HbA1c 
Jung 
T2D, HD 
9 
6d 
0.8-0.9 
Hypoglycemia predominantly during & 
after HD 
Kazempou
r 
T2D, HD 
17 
48h 
N/A 
Frequent hypoglycemia, low glucose after 
HD 
Mirani 
T2D, HD 
12 
72h 
N/A 
Higher glucose variability after HD 
Sobngwi 
HD 
without 
diabetes 
14 
48h 
N/A 
CGM reflected blood glucose profile well, 
glucose concentrations were lower after 
HD 
Marshall 
CAPD 
8 
72h 
0.91 
Glucose variability correlated with 
dialysate 
Skubala 
CAPD 
30 
72h 
N/A 
Mean glucose dependent on dialysate 
glucose 
Vos 
DM, CKD 
25 
48h 
N/A 
Mean CGM glucose correlated better with 
glycated albumin than hemoglobin A1c 
Lo 
T2D, CKD 
43
* 
6d 
N/A 
GGM glc correlated well with HbA1c in 
stage 3 but not stage 4-5 CKD, affected by 
EPO use 
HD = hemodialysis; CAPD = continuous ambulatory peritoneal dialysis; CKD = chronic kidney disease 
not yet on dialysis; Correlation of CGM with blood glucose using venous phlebotomy; *subset (N<43) 
used CGM 
2.6. Inflammation and oxidative stress may link CKD, hypoglycemia, and death. High 
glucose variability leads to periods of hypoglycemia and increases systemic inflammation and 
oxidative stress.52-54 Patients with diabetes and CKD are known to have high levels of systemic 


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6 
inflammation and oxidative stress, and these biologic processes likely contribute to the excess 
CVD risk observed in this population.55-58 In particular, hypoglycemia may predispose to 
subclinical ventricular arrhythmia.59-61 A markedly increased risk of sudden cardiac death is a 
major cause of increased cardiovascular death among persons with CKD.62 Taken together, these 
data suggest that hypoglycemia may contribute to the high levels of inflammation, oxidative 
stress, and sudden cardiac death observed in diabetes and CKD. 
2.7 Linagliptin is shown to reduce blood glucose in Type 2 diabetes patients.  Linagliptin is 
a dipeptidyl peptidase-4 (DPP-4) inhibitor proven to reduce blood glucose among patients with 
type 2 diabetes and normal GFR, with an incidence of clinical hypoglycemia that is lower than 
that of sulfonylureas (SU).63 Linagliptin is primarily eliminated through non-renal routes and 
does not require dose adjustment with impaired GFR. In CKD, fixed-dose Linagliptin reduces 
hemoglobin A1c (compared with placebo) without a significant increase in clinically-recognized 
hypoglycemia.64,65 
2.8. Summary: why we should study glycemia in people with diabetes and CKD now.  It is 
critical to optimize treatment among patients with type 2 diabetes and CKD because they 
represent a large population at markedly increased risk of CVD and death. Risks and benefits of 
glucose-lowering strategies may differ in CKD because CKD fundamentally alters glucose 
homeostasis and its ascertainment and treatment. In particular, hypoglycemia and its biologic 
sequelae may be particularly common and detrimental in this population. However, virtually no 
high-quality data are available to guide glucose management in patients with CKD. CGM offers 
a novel opportunity to define fundamental aspects of impaired glucose homeostasis in CKD, 
including glycemic variability and hypoglycemia incidence rates, risk factors, and sequelae. 
Moreover, application of new diabetes treatments to patients with CKD may help prevent 
hypoglycemia in this high-risk population. 
3. Study Methods 
3.1 Overview This is a proof-of-concept clinical trial testing the effects of linagliptin versus 
glipizide on glucose variability among patients with type 2 diabetes and stage 3-4 CKD. 
Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor proven to reduce blood glucose among 
patients with type 2 diabetes and normal GFR, with an incidence of clinical hypoglycemia that is 
lower than that of sulfonylureas (SU).63 Linagliptin is primarily eliminated through non-renal 
routes and does not require dose adjustment with impaired GFR. In CKD, fixed-dose Linagliptin 
reduces hemoglobin A1c (compared with placebo) without a significant increase in clinically-
recognized hypoglycemia.64,65 We hypothesize, among patients with type 2 diabetes and CKD, 
that Linagliptin, compared to Glipizide (a SU), will increase glucose time in range (TIR) 
(ascertained using CGM) while reducing glycemic variability and time below range (TBR) and 
exerting similar effects on mean glycemia. Results may have direct implications for patient care, 
suggesting that use of linagliptin as a SU-sparing agent may improve patient safety, and will 
provide a useful framework for future studies targeting glycemic control while minimizing 
hypoglycemia in the CKD population. 
3.2 Study Design This is a cross-over trial in which each participant is treated with both 
linagliptin and glipizide, one medication at a time. Cross-over trials increase power and reduce 
cost by studying each participant on each treatment and comparing changes within each 
individual, as opposed to across individuals. We have successfully completed a crossover trial of 
similar size and duration with excellent recruitment and retention.66 The main limitation of cross-


V. 4/24/2015 
7 
over trials is the potential for treatment carry-over, in which effects of treatment from the first 
treatment period extend into the subsequent treatment period(s). Because the effects of 
linagliptin and glipizide on glucose are rapid, we have little concern for carry-over effects on 
glucose as measured by CGM, our primary outcome. (Hemoglobin A1c and other longer-term 
glycemic markers will only be evaluated in secondary, exploratory analyses.) Given rapid 
effects, we will have short treatment periods (4 weeks), which will enhance retention and 
adherence. A wash-out phase is not appropriate for this study because carry-over effects are not 
expected and withdrawal of both glucose-lowering medications would lead to relative 
hyperglycemia  
3.3 Study population This clinical trial will enroll 24 participants with type 2 diabetes and an 
estimated GFR 15-59 mL/min/1.73m2 who are currently using a SU to control blood glucose. We 
will further restrict eligibility to participants with hemoglobin A1c < 8%, for whom we expect 
substantial times in each of normoglycemia, hypoglycemia, and hyperglycemia. Eligibility 
criteria is described in table 2. When available, eligibility laboratory data will be obtained from 
the electronic medical record, or from the results of previous research studies (such as CANDY); 
values within 3 months will be considered acceptable.  
3.4 Recruiting 
We will primarily recruit participants 
from the CANDY study, approaching 
the eligible subset of these participants 
at the last CANDY study visit. The 
CANDY study is a longitudinal 
observational study of patients with 
type 2 diabetes and stage 3/4 CKD. The 
aims of CANDY are to characterize 
glucose variability, hypoglycemia and 
hyperglycemia using continuous 
glucose monitoring and to explore the 
biologic sequelae of glucose variability 
and hypoglycemia in diabetes with 
CKD. The inclusion and exclusion 
criteria for both CANDY and CANDY-
CANE are similar, making CANDY 
participants ideal candidates for the 
CANDY-CANE trial.  
Should additional participants be required, we will recruit these patients through mechanisms 
used for recruiting in the CANDY trial. For example, if needed we will recruit from Nephrology, 
Diabetes, and primary care clinics associated with the University of Washington, Harborview 
Medical Center, and Providence Medical Research Center/Sacred Heart Center in Spokane. 
Patients will be pre-screened through either the Mindscape or Orca computerized medical record 
system to access their records for limited information prior to obtaining their consent to 
determine eligibility. We will approach these potential participants at clinic visits after 
introduction by clinical staff OR by sending a mailed invitation postcard. In addition, we will 
advertise this study to patients seen in other Seattle-area Nephrology and Diabetes clinics 
Table 2.  Eligibility criteria 
Inclusion criteria: 
Type 2 diabetes 
eGFR 15-59 mL/min/1.73 m2 
Hemoglobin A1c < 8% 
Age ≥ 18 years 
Current use of sulfonylurea 
Exclusion criteria: 
BMI > 40 kg/m2 
Actively using CGM for clinical care 
End stage renal disease needing dialysis  
Kidney transplant 
History of acute pancreatitis 
Pregnant 
Unable to provide informed consent 
 


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8 
through distribution of the study brochure. Patients from these other Seattle-area clinics will self-
refer for screening if they are interested. 
3.5 Intervention Throughout the 8 weeks (total) of this trial, we will ask all participants to 
discontinue use of their prevalent SU but maintain other glucose-lowering medications (e.g. 
insulin) at unchanged doses. We will then prescribe linagliptin for 4 weeks and glipizide for 4 
weeks, in a randomly determined order. DPP-4 inhibitors are an attractive class of medications to 
lower blood glucose among patients at high risk of hypoglycemia because they enhance the 
actions of endogenous insulin, with little effect on insulin secretion or action when a source of 
oral glucose is absent. DDP-4 inhibitors may also have beneficial effects on microvascular 
complications, including CKD, independent of glucose.67,68 Linagliptin is particularly attractive 
for patients with CKD because it is primarily eliminated through non-renal routes and does not 
require dose adjustment or increased monitoring for adverse effects, even with advanced 
CKD.64,65 We will administer linagliptin at its standard fixed dose of 5 mg daily. For comparison, 
we will administer glipizide at a fixed dose of 5 mg daily. We selected glipizide because it has a 
relatively short half-life and is therefore commonly used in patients with CKD. While individuals 
will differ in their hypoglycemic responses to these medications and doses, we anticipate that 
mean glycemia will change to a similar extent with each intervention when averaged across 
participants. In addition, we will adjust for mean CGM blood glucose when comparing 
differences in hypoglycemia and glucose variability. 
3.5.1 Randomization Each participant will be prescribed linagliptin for 4 weeks and glipizide 
for 4 weeks. The order of these interventions will be randomly assigned by the Northwest 
Kidney Center Pharmacy, which will dispense all study medications. There will be no 
stratification or blocking.  
3.5.2 Blinding Participants will not be blinded to treatment assignment in order to reduce cost 
and maximize patient safety. However, data for the primary study outcome (time in range 
measured by CGM) will masked to participants, and study staff and investigators will be given 
only coded treatment assignments (“A” and “B”) until data analyses are completed. In this 
setting, lack of participant blinding is unlikely to bias results. 
4. Study procedures.   
Each participant will undergo blinded CGM for the last 6 days of each 4-
week treatment period (Figure 3). During each CGM period, participants 
will also be asked to self-monitor blood glucose concentrations, and 
blood and urine samples will be collected for measurements of 
inflammation, oxidative stress, and albuminuria. 
 
4.1. Continuous glucose monitoring.  
We will use Medtronic Enlite glucose sensors coupled to iPro2 recorders 
(Figure 4). The Enlite is an advanced glucose sensor, offering accurate 
glucose monitoring over days of use.  
An Enlite will be provided to participants at study visits 2 and 4. Study 
staff will insert the sensor into the subcutaneous tissue of the abdomen with the use of a 
disposable introducer needle. The sensor is attached to the iPro2 recorder, which with its 
predecessor (iPro recorder) has proved reliable in numerous clinical studies as a masked glucose 


V. 4/24/2015 
9 
sensor. Participants will be instructed in the use of the device including collection of self-
monitored blood glucose concentrations for device calibration using a study-provided glucose 
meter. A guide booklet will be provided for the participant to take home. The participant will be 
instructed to contact the site staff if any appreciable skin reaction occurs or for any other 
concerns or questions. Participants will return all CGM equipment after 6 days, and study 
personnel will upload the data. Participants who do not obtain an adequate amount of CGM 
glucose values will be asked to repeat use of the CGM so that a sufficient amount of data is 
obtained. CGM data will be masked to participants, study staff, and investigators. 
4.2. Self-monitored blood glucose. Participants will be asked to monitor blood glucose 
concentrations for calibration purposes. Participants will be provided with a Blood Glucose 
Meter and test strips. They will be asked to perform at least 4 finger-stick blood glucose 
measurements per day. Data from the Blood Glucose Meter will be directly uploaded at the end 
of the trial. 
4.3. Blood and urine collections. At least 3 nonfasting blood samples will be collected at study 
visits 3 and 5. Whole blood, serum and plasma samples will be aliquoted, and stored at -80°C as 
per Kidney Research Institute protocols. Spot urine collections will also be collected from 
patients at study visits 3 and 5. 
4.4. Inflammation and oxidative stress. Oxidative stress and inflammation are increased in 
diabetes and in chronic kidney disease and are likely to contribute to the pathogenesis of 
cardiovascular disease. We chose to measure two established markers of oxidative stress and two 
established markers of inflammation for this study. In addition, banked samples will be available 
for novel cardiovascular biomarker assays that are currently under development or will be 
developed in the future. Plasma and urine F2-isoprostanes (biomarkers of oxidative stress) will be 
measured by GC-MS as initially described by Roberts and Morrow69 in the University of 
Washington Mass Spectrometry Core Resource. As biomarkers of inflammation, plasma C-
reactive protein (CRP) concentrations will be determined by nephelometry and plasma 
interleukin-6 will be measured by ELISA (Biosource International) in the KRI laboratory. 
4.5. Hemoglobin A1c and other measurements of glycemic control. Hemoglobin A1c will be 
measured in real time by the University of Washington (UW) Clinical Laboratory and repeated 
by the University of Missouri. Measurement at UW is by HPLC, and quality control is verified 
daily with results calibrated to the DCCT laboratory as recommended by the NGSP. At the 
University of Missouri, Hemoglobin A1c will be measured using the Tosoh G8 analyzer, which 
employs an ion-exchange HPLC method and is one of the NGSP Secondary Reference 
Laboratory methods. The G8 is one of the most precise instruments for HbA1c analysis available 
and has shown long term CV at the University of Missouri of <0.5%.  Hemoglobin A1c poorly 
reflects glycemic variability and therefore may not correlate well with risk of hypoglycemia.38 
Moreover, existing evidence suggests that hemoglobin A1c correlates with average glycemia 
poorly in patients with kidney disease). Therefore, we will also measure glycated albumin and 
fructosamine concentrations. Glycated Albumin will be measured at the University of Missouri 
using the Lucica GA-L enzymatic glycated albumin assay kit on the Roche C311 analyzer (CV 
3-5%). Fructosamine will be measured at the University of Missouri using the Roche 
Fructosamine assay on the Roche C311 analyzer (CV 3-5%). 1,5-anhydroglucitol will be 
measured at UW using an enzymatic colorimetric assay (GlycoMark) 


V. 4/24/2015 
10
 
4.6. Schedule of study measurements. This study consists of one screening visit and 5 study 
visits. Additional telephone and in-person contacts may be scheduled as needed to trouble-shoot 
or repeat CGM.  
4.6.1. Screening Visit. The screening visit will last less than an hour and will assess eligibility 
criteria for the study. During the visit, informed consent will be administered by the study staff. 
The visit will include a focused medical history including review of the electronic medical 
record, an inventory of current and recent medications, and a blood draw to determine eligibility 
if necessary. If subjects have participated in the CANDY study, eligibility will be determined at 
the end of the CANDY study, and measurements used for that study may be used to determine 
eligibility. 
4.6.2. Study Visit 1 At the first study visit, a complete medical history and medication inventory 
will be taken. The subject will be administered a medical history questionnaire. Height, weight 
and vital signs (blood pressure, heart rate) will be taken. The subject will be assigned the order of 
study medications and the first medication will be prescribed. The subject will pick up their first 
medication from the pharmacy and begin taking the medication. Adverse effects will be 
assessed. 
4.6.2. Study Visit 2 At the second study visit, the CGM device will be introduced by the study 
staff. They will explain its purpose and functions in detail, place the CGM device, and 
thoroughly describe plans for trouble-shooting the CGM device. The study staff will also provide 
a study glucose meter and test strips for self-monitored blood glucose (SMBG) testing, explain 
expectations for tracking SMBG at home, provide logs for SMBG, and demonstrate proper use 
of the logs. Adverse effects will be assessed. 
4.6.3. Study Visit 3 At the third study visit, the CGM device will be removed from the subject 
by the study staff, and the SMBG log will be turned in to the study staff.  The subject will cease 
taking the first study medication on this day, and return any remaining prescription to the study 
staff. The visit will include a blood draw, and spot urine collection.. The subject will pick up 
their second medication from the pharmacy and begin taking the medication the following 
morning. Adverse effects will be assessed. 
4.6.4. Study Visit 4 At the fourth study visit, the CGM device will be reintroduced by the study 
staff. They will place the CGM device, and thoroughly describe plans for trouble-shooting the 
CGM device. The study staff will also provide a study glucose meter and test strips for self-


V. 4/24/2015 
11
monitored blood glucose (SMBG) testing, explain expectations for tracking SMBG at home, 
provide logs for SMBG, and demonstrate proper use of the logs. Adverse effects will be 
assessed. 
4.6.5. Study Visit 5 At the fifth study visit, the CGM device will be removed from the subject by 
the study staff, and the SMBG log will be turned in to the study staff.  The subject will cease 
taking the second study medication on this day, and return any remaining prescription to the 
study staff. The visit will include a blood draw, and spot urine collection. Adverse effects will be 
assessed.  
24-hour contact information will be given to all participants for questions that arise during the 
CGM periods. Participants who do not complete at least 4 days of CGM will be asked to repeat 
measurements or will be replaced by an alternate participant 
Table 3. Schedule of Procedures 
Procedure 
Screening 
Visit 
1 
Visit 2 
Visit 3  
Visit 4 
Visit 5  
Informed 
Consent 
X 
 
 
 
 
 
Medication 
inventory 
X 
 
 
 
 
 
Medical 
History 
X 
X 
 
 
 
 
Blood draw 
        *X  
 
 
X 
  
X 
Medical 
History 
Questionnaire 
 
X 
 
 
 
 
Physical 
measurements 
(height, 
weight, vital 
signs) 
 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Medication 
Prescribed 
 
X 
 
X 
 
 
Urine-spot 
 
 
 
X 
 
X 
CGM 
Provided 
 
 
X 
 
X 
 
CGM 
Returned 
 
 
 
X 
 
X 
Log provided 
 
 
X 
 
X 
 


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12
Log returned 
 
 
 
X 
 
X 
AE 
 
X 
X 
X 
X 
X 
* Blood draw at the screening visit will be completed only if creatinine and hemoglobin A1c 
values are not otherwise available within 90 days prior to the screening visit. 
5. Statistical analysis 
5.1 Data analysis. All analyses will be performed according to intention-to-treat, meaning that 
all participants who contribute data during treatment with linagliptin and glipizide will be 
included in analyses regardless of adherence or adverse effects. The primary study outcome will 
be glucose time in range (TIR, proportion of CGM glucose readings 70-180 mg/dL), a clinically 
relevant outcome that can be tested with high power because of its broad anticipated range 
within the study population and precise ascertainment using CGM.35,70,71 We will summarize 
time in range by treatment assignment, along with secondary outcomes including TBR (< 70 
mg/dL), hypoglycemia characteristics (episode number, nadir glucose, awareness, clinical 
severity), time above range (TAR), standard deviation of blood glucose concentration, mean 
blood glucose concentration, biomarkers of inflammation and oxidative stress, and urine albumin 
excretion rate. We will test differences in these outcomes by treatment assignment using linear 
regression (for continuous outcomes, using log transformation as needed) or using Poisson 
regression (for rate data). Models will be adjusted for mean CGM blood glucose to account for 
potential differential effects of linagliptin and glipizide on mean blood glucose.  
5.2 Power. Using the cross-over study design, two-sided alpha of 0.05, and glucose time in range 
(TIR quantified as proportion of time) as primary outcome, and assuming a TIR standard 
deviation of 19.5% (similar to published values70,71) and within-person correlation of TIR 0.7, we 
calculated a need for 24 participants (each studied on linagliptin and on glipizide) to detect a 
10% difference in TIR between treatment assignments with 90% power. Notably, power depends 
on the difference in TIR between treatment groups, rather than mean TIR (which we expect to be 
between 25% and 50%), as long as mean TIR is not near zero. Because the effect size (10% 
difference in TIR) and within-person correlation of TIR are not known in this population, we 
also present power for different combinations of these variables using a fixed sample size of 24 
in Table 4. We have excellent power for the most likely range of standard deviation and for 
clinically relevant treatment effects. 
 
Table 4. Power for intervention study  
 
Within-person correlation of time in range 
Difference in time in range (%) 
0.6 
0.7 
0.8 
8% 
62% 
74% 
89% 
10% 
80% 
**90%** 
98% 
12% 
92% 
97% 
> 99% 


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14% 
98% 
> 99% 
> 99% 
 
 
 
6. Safety and adverse events 
6.1.  Definitions 
6.1.1.  Adverse Event.  An adverse event (AE) is any symptom, sign, illness or experience that 
develops or worsens in severity during the course of the study.  Intercurrent illnesses or injuries 
should be regarded as adverse events.  Abnormal results of diagnostic procedures are considered 
to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
6.1.2.  Serious Adverse Event.  Adverse events are classified as serious or non-serious.  A 
serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance.  They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above.  For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious.  All adverse events that do not 
meet any of the criteria for serious will be regarded as non-serious adverse events.  
6.1.3.  Adverse Event Reporting Period.  Adverse events will be reported if they occur 
between the time that informed consent is granted through 30 days following the last study visit. 
6.1.4.  Post-study Adverse Event.  All unresolved adverse events will be followed by the PI 
until the events are resolved, the subject is lost to follow-up, or the adverse event is otherwise 
explained.  At the last scheduled visit, the investigator will instruct each subject to report any 
subsequent event(s) that the subject, or the subject’s personal physician, believes might 
reasonably be related to participation in this study.  The investigator will notify the study sponsor 
of any death or adverse event occurring at any time after a subject has discontinued or terminated 
study participation that may reasonably be related to this study.  The sponsor will also be notified 
if the investigator should become aware of the development of cancer or of a congenital anomaly 
in a subsequently conceived offspring of a subject that has participated in this study.  


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6.1.5.  Abnormal Laboratory Values.  A clinical laboratory abnormality will be documented as 
an adverse event if any one of the following conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
6.1.6.  Hospitalization, Prolonged Hospitalization or Surgery.  Any adverse event that results 
in hospitalization or prolonged hospitalization will be documented and reported as a serious 
adverse event unless specifically instructed otherwise in this protocol.  Any condition 
responsible for surgery will be documented as an adverse event if the condition meets the criteria 
for and adverse event. Neither the condition, hospitalization, prolonged hospitalization, nor 
surgery are reported as an adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition.  Surgery should not be reported as an outcome of an adverse 
event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 


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6.2.  Recording of Adverse Events.  At each contact with the subject, the investigator will seek 
information on adverse events by specific questioning and, as appropriate, by examination.  
Information on all adverse events will be recorded immediately in the source document, and also 
in the appropriate adverse event module of the case report form.  All clearly related signs, 
symptoms, and abnormal diagnostic procedures results will be recorded in the source document.  
All adverse events occurring during the study period will be recorded.  The clinical course of 
each event will be followed until resolution, stabilization, or until it has been determined that the 
study treatment or participation is not the cause.  Serious adverse events that are still ongoing at 
the end of the study period will be followed up to determine the final outcome.  Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation will be recorded and reported immediately. 
6.3.  Reporting of Serious Adverse Events.  Reports of all serious adverse events with a 
reasonable possibility of being related to the study (including follow-up information) will be 
submitted to the IRB, according to the IRB policy, within 10 working days.  Copies of each 
report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s binder.  Adverse events with a reasonable possibility of being related to the study 
which are not serious will be reported to the IRB as components of annual reports.  Because this 
is an observational study, no data safety and monitoring board will be created for this trial.  
Adverse events and recruitment will be monitored by the PI and reported to the IRB, as 
described above. 
7. Data Handling and Record Keeping 
7.1.  Confidentiality.  Information about study subjects will be kept confidential and managed 
according to the requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a signed subject authorization informing the subject of the 
following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts will 
be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the 
end of their scheduled study period. 
7.2.  Records Retention.  All study data will be de-identified and stored in secured electronic 
files and/or a locked file cabinet within a locked room.  Data including personal identifiers (i.e. 
screening data) will be kept separately in a secure, locked location. 
 
8.  Study Monitoring, Auditing, and Inspecting 


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8.1.  Study Monitoring Plan.  The PI will allocate adequate time for such monitoring activities.  
The PI will also ensure that any sponsor or other compliance or quality assurance reviewer is 
given access to all the above noted study-related documents and study related facilities (e.g. 
diagnostic laboratory), and has adequate space to conduct a monitoring visit, if requested. 
8.2.  Auditing and Inspecting.  The PI will permit study-related monitoring, audits, and 
inspections by the IRB, the sponsor, government regulatory bodies, and compliance and quality 
assurance groups of all study related documents (e.g. source documents, regulatory documents, 
data collection instruments, study data etc.).  The PI will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.).   
9.  Ethical Considerations 
This protocol and any amendments will be submitted to the IRB, in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the IRB concerning the 
conduct of the study will be made in writing to the investigator and a copy of this decision will 
be provided to the sponsor before commencement of this study.  All subjects for this study will 
be provided a consent form describing this study and providing sufficient information for 
subjects to make an informed decision about their participation in this study.  The formal consent 
of a subject, using the IRB-approved consent form, must be obtained before that subject is 
submitted to any study procedure.  This consent form must be signed by the subject or legally 
acceptable surrogate, and the investigator-designated research professional obtaining the consent.  
 
10.  Study Finances 
10.1.  Funding Source.  This study is financed by the American Diabetes Association (Grant 4-
14-CKD-20) and supplies are furnished by Medtronic. 
10.2.  Conflict of Interest.  Any investigator who has a conflict of interest with this study 
(patent ownership, royalties, or financial gain greater than the minimum allowable by their 
institution, etc.) must have the conflict reviewed by a properly constituted Conflict of Interest 
Committee with a Committee-sanctioned conflict management plan that has been reviewed and 
approved by the study sponsor prior to participation in this study.  All investigators will follow 
the Institutional conflict of interest policy. 
10.3.  Subject Payments.  Participants will be compensated $25 for each main study visit (study 
visits 1-5), for a total of $125 if all study visits are completed. 
10.4.  Publication Plan.  Funding sources will be acknowledged in publications, but funding 
sources will not be involved in decisions regarding what or how to publish study results in any 
way.


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