Conditions: Prediabetes Type 2 Diabetes
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 267
Healthy volunteers: yes

Brief summary:
The RISE Adult Medication Study is a 4-arm, 3-center, clinical trial of adults with prediabetes and early type 2 diabetes to address the hypothesis that aggressive glucose lowering will lead to recovery of beta-cell function that will be sustained after withdrawal of treatment. Adult participants (ages 20-65) will be randomized to one of the following treatment regimens: (1) blinded placebo, (2) blinded metformin alone, (3) early intensive insulin treatment with basal insulin glargine followed by open-label metformin, (4) the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide plus open-label metformin.

The primary clinical question RISE will address is: Are improvements in ß-cell function following 12 months of active treatment maintained for 3 months following the withdrawal of therapy? Secondary outcomes will assess durability of glucose tolerance following withdrawal of therapy, and whether biomarkers obtained in the fasting state predict parameters of ß-cell function, insulin sensitivity and glucose tolerance and the response to an intervention.

Detailed description:

Arms:
arm 1: Metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day). Participants randomized to the metformin-alone arm will be blinded to treatment. arm 2: Basal insulin glargine for 3 months titrated to achieve a morning fasting blood glucose of 80-90 mg/dl, followed by open-label metformin (titrated up to 2000 mg/day) for 9 months. arm 3: Placebo - masked to metformin-alone. Placebo will be titrated to the maximum number of tablets equivalent to maximum dose of metformin. arm 4: Liraglutide + open-label Metformin. Liraglutide will be titrated to the maximum dose tolerated (up to 1.8 mg/day) after which metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day).

Interventions: intervention 1: Metformin intervention 2: Liraglutide intervention 3: Glargine intervention 4: Placebo
Intervention descriptions: intervention 1: Titrated to 1000 mg BID intervention 2: Titrated to 1.8 mg/day intervention 3: Titrated to target fasting glucose \<90 mg/dl intervention 4: Matching to metformin 1000 mg BI

Protocol document:
Prot_000.pdf: 
 
 
PROTOCOL 
The Restoring Insulin Secretion (RISE) Study 
RISE Adult Medication Study 
 
 
 
 
 
RISE Study Group 
Date: August 19, 2016 
Version 1.6 
 
Distributed by 
RISE Study Data Coordinating Center 
Biostatistics Center 
George Washington University 
6110 Executive Boulevard 
Rockville, Maryland 20852 
 
 
 
 


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CONFIDENTIAL 
TABLE OF CONTENTS 
1 
Executive Summary ............................................................................................................................... 7 
1.1 
Specific Aims and Objectives ........................................................................................................ 8 
1.2 
Overall Design and Study Interventions ....................................................................................... 9 
2 
Background and Significance .............................................................................................................. 10 
2.1 
Prediabetes and Type 2 Diabetes: Epidemiology, Natural History and Pathogenesis ................ 10 
2.2 
Obstructive Sleep Apnea (OSA) and Diabetes Risk ..................................................................... 11 
2.3 
Results of Type 2 Diabetes Prevention Studies .......................................................................... 11 
2.4 
Long Term Intervention Studies in Patients with Early Type 2 Diabetes .................................... 12 
2.5 
Metformin ................................................................................................................................... 14 
2.6 
Insulin Glargine ........................................................................................................................... 15 
2.7 
Liraglutide ................................................................................................................................... 15 
2.8 
Approaches to Measuring ß-cell Function, -cell Function, Insulin Sensitivity and Glucose 
Tolerance ................................................................................................................................................ 16 
2.8.1 
Intravenous Tests of ß- and -cell Function and Insulin Sensitivity ....................................... 16 
2.8.2 
Oral Tests of ß- and -cell Function and Insulin Sensitivity .................................................... 18 
2.9 
Biomarkers of ß-cell Function, -cell Function, Insulin Sensitivity and Glucose Tolerance ...... 18 
2.9.1 
Putative Diabetes Biomarkers ................................................................................................. 19 
3 
STUDY DESIGN..................................................................................................................................... 19 
3.1 
Overview and Rationale .............................................................................................................. 19 
3.2 
Primary Outcomes ...................................................................................................................... 21 
3.3 
Secondary Outcomes .................................................................................................................. 21 
3.3.1 
ß-cell Function and Glucose Tolerance ............................................................................... 22 
3.3.2 
-cell Function .................................................................................................................... 23 


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3.3.3 
Insulin Sensitivity ................................................................................................................ 23 
3.3.4 
Blood and Urine Biomarkers ............................................................................................... 23 
3.3.5 
Physical and Body Composition Measures ......................................................................... 23 
3.4 
Treatments .................................................................................................................................. 24 
3.4.1 
Three-week Placebo Run-in Phase ...................................................................................... 24 
3.4.2 
Twelve-month Active Treatment Phase .............................................................................. 24 
3.4.3 
Metformin ........................................................................................................................... 24 
3.4.4 
Liraglutide plus Metformin ................................................................................................. 25 
3.4.5 
Insulin Glargine Followed by Metformin ............................................................................ 25 
3.4.6 
Placebo ................................................................................................................................ 25 
3.4.7 
Medication Wash-out and Post-treatment Follow Up ....................................................... 25 
3.4.8 
Rescue ................................................................................................................................. 26 
3.5 
Inclusion Criteria ......................................................................................................................... 26 
3.6 
Exclusion criteria ......................................................................................................................... 26 
3.7 
Randomization ............................................................................................................................ 28 
3.8 
Masking ....................................................................................................................................... 28 
4 
RECRUITMENT ..................................................................................................................................... 28 
4.1 
Recruitment ................................................................................................................................ 28 
4.2 
Description/Justification of the Target Study Population ........................................................... 29 
4.3 
Informed Consent ....................................................................................................................... 30 
4.4 
Staged Screening and Randomization ........................................................................................ 30 
5 
PATIENT MANAGEMENT ..................................................................................................................... 32 
5.1 
Description of RISE Research Facility Treatment(s) .................................................................... 32 
5.2 
Drug Distribution ......................................................................................................................... 32 
5.3 
Adherence Measures .................................................................................................................. 33 


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5.3.1 
Placebo Run-in .................................................................................................................... 33 
5.3.2 
Liraglutide ........................................................................................................................... 33 
5.3.3 
Insulin .................................................................................................................................. 34 
5.3.4 
Metformin/Placebo ............................................................................................................. 34 
5.4 
Retention .................................................................................................................................... 34 
6 
DATA COLLECTION .............................................................................................................................. 35 
6.1 
Main Study Procedures ............................................................................................................... 35 
6.1.1 
Fasting Blood and Urine Samples........................................................................................ 35 
6.1.2 
Oral Glucose Tolerance Test (OGTT) ................................................................................... 35 
6.1.3 
Hyperglycemic Clamp .......................................................................................................... 35 
6.2 
Eligibility Screening Measurements ............................................................................................ 36 
6.3 
Baseline and Post-Randomization Measures .............................................................................. 37 
6.3.1 
Physical Measures ............................................................................................................... 38 
6.3.2 
Sleep Assessments .............................................................................................................. 39 
6.3.3 
Safety Measures .................................................................................................................. 39 
6.3.4 
Participant Protocol Adherence .......................................................................................... 39 
6.4 
Visit Windows ............................................................................................................................. 39 
7 
SAFETY / HUMAN SUBJECTS PROTECTION ......................................................................................... 39 
7.1 
Data and Safety Monitoring Board (DSMB) ................................................................................ 40 
7.2 
Data and Safety Monitoring Plan ................................................................................................ 40 
7.2.1 
Informed Consent ............................................................................................................... 40 
7.2.2 
Safety Review Plan and Monitoring .................................................................................... 40 
7.2.3 
Confidentiality ..................................................................................................................... 41 
7.3 
Expected Side Effects .................................................................................................................. 41 
7.4 
Risk Management ....................................................................................................................... 42 


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7.5 
Potential Benefits ........................................................................................................................ 45 
7.6 
HIPAA – Protection of Patient Information................................................................................. 45 
8 
ADVERSE EVENT REPORTING .............................................................................................................. 45 
8.1 
Definition of Serious Adverse Events .......................................................................................... 46 
8.2 
Non-serious Adverse Events ....................................................................................................... 46 
8.3 
Reporting Adverse Events ........................................................................................................... 46 
8.4 
Tracking Adverse Events ............................................................................................................. 47 
8.5 
Emergency Unmasking ................................................................................................................ 47 
9 
STATISTICAL CONSIDERATIONS ........................................................................................................... 47 
9.1 
Primary Outcome and Analyses .................................................................................................. 48 
9.2 
Secondary Outcomes and Analyses ............................................................................................ 48 
9.3 
Sample Size/Power Calculations ................................................................................................. 49 
9.4 
Interim Analysis Plans ................................................................................................................. 50 
9.5 
Stopping Rules............................................................................................................................. 50 
9.6 
Handling of Missing Data ............................................................................................................ 50 
10 
DATA PROCESSING AND MANAGEMENT ........................................................................................ 50 
10.1 
Data Management System .......................................................................................................... 50 
10.2 
Data Transfer .............................................................................................................................. 51 
10.3 
Quality Control ............................................................................................................................ 51 
10.4 
Back-up, Data Security and Confidentiality ................................................................................ 51 
10.5 
Tracking Study Progress .............................................................................................................. 51 
10.6 
Archiving and Study Close-out .................................................................................................... 52 
11 
STUDY ADMINISTRATION ................................................................................................................ 52 
11.1 
Organization ................................................................................................................................ 52 
11.2 
Central Laboratories and Reading Centers ................................................................................. 53 


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11.3 
Training and Certification............................................................................................................ 54 
11.4 
Site Visits ..................................................................................................................................... 54 
11.5 
Study Website ............................................................................................................................. 55 
11.6 
Conflict of Interest Policy ............................................................................................................ 55 
11.7 
Publications and Presentations Policy ........................................................................................ 56 
11.8 
Ancillary Studies Policy ............................................................................................................... 56 
11.9 
Protocol Amendments ................................................................................................................ 57 
11.10 
Repository for Storage and Distribution of RISE Data and Samples ....................................... 57 
12 
STUDY TIMELINE ............................................................................................................................. 57 
13 
LITERATURE CITED .......................................................................................................................... 58 
 
 
 


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1 Executive Summary 
A core defect in the pathogenesis of type 2 diabetes involves the ß-cell, which has been shown 
to be dysfunctional in both prediabetes, a high risk state that is antecedent to type 2 diabetes, 
and established type 2 diabetes [1]. In addition to ß-cell failure, insulin resistance and -cell 
dysfunction are prominent features of the disease leading to diabetes onset [1, 2].  
The possibility that improvements in ß-cell function in type 2 diabetes can be achieved and 
maintained for a period of time after withdrawal of a dietary or pharmacological intervention 
has been suggested by results from small studies in patients with varying degrees of 
hyperglycemia treated aggressively with insulin, oral hypoglycemic drugs and diet [3-5]. 
However, it is unclear whether any beneficial effect on ß-cell function can be maintained and 
the natural history of progressive loss of ß-cell function altered. Further, while these studies 
focused on the ß-cell, they did not consider the possibility that producing a sustained 
improvement in -cell function may also be important in slowing progression of glucose 
intolerance. 
Numerous medications, acting by different mechanisms, are available to treat type 2 diabetes 
and lower blood glucose. Metformin is thought to reduce hepatic glucose production and 
improve insulin resistance; it has been shown to prevent progression of prediabetes to diabetes 
[6]. Insulin lowers glucose while providing ß-cell “rest”. Insulin sensitizers may improve ß-cell 
function indirectly by reducing ß-cell stress [7, 8]. Sulfonylureas initially improve ß-cell function 
but may accelerate secondary failure [7, 8]. Glucagon-like peptide-1 receptor agonists (GLP-
1RA) and other incretin-based therapies improve islet function [9, 10], but their ability to 
prevent diabetes and slow its progression is unknown. 
The RISE (Restoring Insulin Secretion) Study consortium is comprised of seven clinical centers. 
Investigators at these centers will conduct three different protocols to assess the feasibility of 
different interventions in adults and children to preserve or improve ß-cell function in 
individuals with prediabetes or recent-onset type 2 diabetes.  Three adult centers (the topic of 
research supported by this protocol) will together perform a randomized, partially blinded, 
placebo-controlled trial comparing three treatment regimens versus placebo. The three 
treatment regimens are: (1) metformin alone, (2) early intensive insulin treatment with insulin 
glargine (Lantus®) followed by metformin, or (3) the GLP-1RA liraglutide (Victoza®) plus 
metformin. These adult centers are located at the VA Puget Sound Health Care System / 
University of Washington, University of Chicago / Jesse Brown VA Medical Center, and Indiana 
University. In addition to this 3-center adult study, four centers will participate in a pediatric 
study performing a randomized trial comparing metformin with insulin glargine (Lantus®) 
followed by metformin. These centers are located at the University of Colorado, University of 


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Pittsburgh, Yale University and Indiana University. One additional adult center at the University 
of Southern California will perform a randomized trial comparing the effects of gastric band 
obesity surgery to metformin on ß-cell function. The three protocols will use many of the same 
inclusion and exclusion criteria, study procedures, timeline and outcome measures to allow for 
comparisons among groups and interventions. The overall goal of each active intervention is to 
reduce glucose levels to near normal during a 12-month treatment period and determine 
whether this slows deterioration or induces recovery of ß- and -cell function and produces a 
prolonged remission, i.e. sustained improvement in islet function that is associated with 
improved glycemia after the intervention has been discontinued. 
This protocol describes the study that will be performed at three centers in adults. 
1.1 Specific Aims and Objectives 
The primary objective of the RISE Adult Medication Study is to compare in a preliminary proof-
of-principle trial the efficacy of three treatment strategies versus placebo on measures of ß-cell 
function after 3-months of post-treatment washout that will follow 12-months of active 
treatment. Participants will have prediabetes or untreated, recent-onset type 2 diabetes, 
defined by elevations in 2-hour post-challenge glucose levels along with elevations in 
hemoglobin A1c and/or fasting glucose concentrations. The hypothesis is that, in participants 
with prediabetes or recent-onset type 2 diabetes, one or more of the strategies aimed at 
lowering glucose will lead to preservation or recovery of islet function that will be sustained 
after withdrawal of treatment. To address this hypothesis, we have identified the following 
primary and secondary specific aims. 
The primary specific aim is to determine whether: 
 Functional improvements in ß-cell function following 12 months of active treatment 
with (1) metformin alone for 12 months, (2) insulin glargine short term (3 months) 
followed by metformin for 9 months, or (3) the combination of liraglutide plus 
metformin for 12 months can be maintained for at least 3 months following the 
withdrawal of therapy, compared to placebo. 
The secondary specific aims are to determine in this same cohort whether: 
 Treatment with the intervention therapies for 12 months improves ß-cell function 
compared to placebo,  
 Functional improvements in ß-cell function are maintained for 9 months following the 
withdrawal of therapy, compared to placebo, 


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 Treatment with the intervention therapies for 12 months improves -cell function 
compared to placebo, and whether this improvement is maintained after withdrawal of 
therapy,  
 Measures of ß- and -cell function from an oral glucose tolerance test (OGTT) and 
fasting samples made on and off therapy are sufficiently well correlated with more 
robust and technically demanding assessments, validating use of the simpler measures 
in large clinical trials, and 
 Biomarkers obtained at baseline can predict parameters of ß- and -cell function, insulin 
sensitivity and glucose tolerance and the response to an intervention. 
1.2 Overall Design and Study Interventions 
The RISE Adult Medication Study is a preliminary proof-of-principle, four-arm, partially double-
blind study in which volunteers with prediabetes or drug-naïve, recent onset type 2 diabetes 
(HbA1c ≤7%, fasting glucose 95-125 mg/dl, and 2-hour glucose ≥140 mg/dl post 75 gram oral 
glucose challenge) are randomized to: (1) metformin alone, (2) short-duration insulin glargine 
followed by metformin, (3) liraglutide plus metformin, or (4) metformin placebo. The study will 
recruit participants over a three-year period and follow them for a total of 21 months from 
randomization. The primary outcome measure is ß-cell function as determined in two ways, 
defined below. The anticipated duration of the RISE Study is five years, including pre-trial 
planning and post-trial analysis and reporting. 
ß-cell function, -cell function, insulin sensitivity and glucose tolerance will be assessed using 
intravenous and oral tests. Both intravenous and oral tests will be obtained at baseline, after 12 
months of therapy and at 15 months (3 months after treatment has been stopped). In addition, 
oral tests will be done at 6 months on therapy, and 9 months off treatment. From these 
intravenous and oral tests as well as fasting measures, we will assess the sustainability of 
induced improvements and determine how well simpler measures of ß-cell function, -cell 
function and insulin sensitivity correlate with more sophisticated measures. Finally, a series of 
biomarkers will be measured to determine whether they predict ß- and -cell function, insulin 
sensitivity and glucose tolerance, and/or well as the response to therapy.  
This study will provide critical information about the ability of early aggressive treatment 
approaches to lead to sustained recovery of islet function, and whether such approaches 
should be studied in larger clinical trials. Further, this study will provide valuable information 
regarding the potential use of simpler measures of glucose metabolism as well as biomarkers 
that can be used in future clinical studies and, ultimately, in routine clinical care. 


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2 Background and Significance 
2.1 Prediabetes and Type 2 Diabetes: Epidemiology, Natural 
History and Pathogenesis  
The increasing prevalence of obesity has been associated with a relentless rise in the 
prevalence of diabetes and prediabetes (impaired glucose tolerance [IGT] and/or impaired 
fasting glucose [IFG]). In the United States, there are currently nearly 26 million people, or 
11.3% of the population aged 20 years or older, with diabetes; the incidence is estimated at 1.9 
million new cases annually [11]. Over 90 percent of these cases are due to type 2 diabetes. In 
addition, approximately 79 million, or 35% of the same age group, have prediabetes [11]. While 
both diabetes and prediabetes are defined by differing levels of fasting and/or 2-hour plasma 
glucose [12] or HbA1c [13], one can consider the disorders a continuum of progressive 
dysglycemia. Individuals with prediabetes are at very high risk of developing diabetes [6, 14-16], 
while those with established diabetes exhibit a progressive loss of glucose control [17].  
The pathogenesis of diabetes and prediabetes involves two major defects: insulin resistance 
and ß-cell dysfunction [1, 18]. Although improvements in insulin sensitivity can slow 
progression of both disorders, ultimately, progressive ß-cell dysfunction is critical for both the 
development [19] and progression [8] of type 2 diabetes. The ß-cell abnormality has been 
demonstrated to comprise abnormalities in both insulin release in response to glucose and non-
glucose secretagogues, as well as a defect in the ability of the ß cell to efficiently process 
proinsulin to insulin [1, 20]. 
The progressive loss of the ability to release insulin determines the deterioration of glycemia 
[18, 21, 22], and thereby sets up a vicious cycle in which the metabolic derangements 
(“glucolipotoxicity”) associated with type 2 diabetes beget further ß-cell dysfunction [23]. In 
addition to ß-cell dysfunction, ß-cell volume (“mass”) is reduced in type 2 diabetes and possibly 
in those with prediabetes [24-26]. This loss of ß-cells may result from or be accelerated by 
glucolipotoxicity [23] and other abnormalities such as amyloid deposition that impact the islet 
[27]. 
Aside from the ß-cell lesion, a functional abnormality of the islet -cell also contributes to 
hyperglycemia in type 2 diabetes [2, 28, 29]. While fasting glucagon levels may or may not be 
elevated [2], normal suppression of glucagon following oral nutrient ingestion does not occur; 
rather a paradoxical increase in glucagon levels can occur [2, 28, 29]. Further, during 
hyperglycemic clamps, glucagon release is greater in patients with type 2 diabetes than in 
healthy subjects [30]. Finally, -cell dysfunction is present in subjects with IGT [31, 32] and first-


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degree relatives of individuals with type 2 diabetes [33], both groups at increased risk of 
developing type 2 diabetes. Thus, -cell dysregulation appears to also be an early feature of the 
islet lesion in patients with type 2 diabetes and those at high risk.  
2.2 Obstructive Sleep Apnea (OSA) and Diabetes Risk 
The alarming increase in overweight and obesity plays a pivotal role in the rise in diabetes 
prevalence. The obesity epidemic has in turn resulted in an increased prevalence of OSA, a 
treatable sleep disorder involving shallow and fragmented sleep as well as intermittent hypoxia. 
OSA is a well-documented risk factor for glucose intolerance, insulin resistance and diabetes, 
independently of body mass index [34, 35]. Further, studies have shown that OSA is a frequent 
co-morbidity of diabetes with a prevalence averaging 68% [36-38]. To date, however, clinical 
trials in individuals with prediabetes or diabetes have not taken the presence and severity of 
this co-morbidity into account. Thus, we will make assessments of sleep by questionnaire and 
examine whether disturbed sleep determines the progression of ß- and/or -cell function over 
time or the impact of the glucose-lowering intervention. 
2.3 Results of Type 2 Diabetes Prevention Studies  
A number of studies have demonstrated the ability to slow the progression from prediabetes to 
diabetes. Overall, the greatest success has been achieved with the three thiazolidinediones 
(TZDs) which in TRIPOD (Troglitazone In the Prevention of Diabetes), DPP (Diabetes Prevention 
Program), DREAM (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication) 
and ACT NOW (Actos Now for Prevention of Diabetes) reduced the short-to-intermediate risk of 
deterioration in glycemic control by 55-72% [15, 39-41], rates similar to or greater than the 58% 
risk reduction observed with lifestyle interventions in the DPP and FDS (Finnish Diabetes 
Prevention Study) [6, 14, 39]. The DPP also demonstrated that metformin reduced the risk of 
progression to diabetes by 31% over three years [39]. Other large studies examining the effects 
of medications showed that acarbose in STOP-NIDDM decreased the risk by 25% [42], but the 
ß-cell secretagogue nateglinide did not reduce the risk of progression to diabetes in 
NAVIGATOR (Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research) 
[43]. The ORIGIN (Outcome Reduction With Initial Glargine Intervention) study showed that 
insulin glargine reduced the risk of developing diabetes by 28% while participants were on 
therapy, and by 20% 100 days after withdrawal of therapy [44]. 
Medication combinations have had variable effects, with low dose rosiglitazone plus metformin 
in CANOE (Canadian Normoglycemia Outcomes Evaluation) producing a comparable effect to 
that reported in other studies where larger doses of a TZD were used [45]. Of relevance to RISE, 
no studies of diabetes prevention have yet been reported with incretin-related medications 


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alone or in combination with other approaches. 
Follow up after discontinuation of the intervention, with the aim of assessing the durability of 
the intervention effects has only been undertaken in a few instances. In the FDS, withdrawal of 
the lifestyle intervention was associated with continued risk reduction three years later [46]. In 
DREAM On, after withdrawal of rosiglitazone, the annual incidence of diabetes was similar in 
those who were or were not randomized to receive the medication, while the cumulative 
incidence in those previously exposed to active medication remained lower; this observation 
suggests a delay but not a reversal of the underlying disease process [39, 47, 48]. To date there 
has not been a systematic evaluation to determine whether interventions can slow the 
progression to diabetes by changing the underlying pathophysiology, particularly that of decline 
in ß-cell function. 
2.4 Long Term Intervention Studies in Patients with Early Type 2 
Diabetes 
Registration studies have examined the glucose-lowering effects of new medications for 
treating type 2 diabetes. These studies have been relatively short in duration (6-12 months) and 
follow up has typically been in the form of an open label extension lacking an active 
comparator. Importantly, with the exception of the UKPDS (United Kingdom Prospective 
Diabetes Study) and ADOPT (A Diabetes Outcome Progression Trial), long-term effects of 
diabetes treatments on ß-cell function have not been determined. 
In the UKPDS, patients with recently diagnosed diabetes received “intensive” treatment with a 
sulfonylurea, insulin [17] or metformin [49] for an average of 10 years. After the first year, 
fasting glucose and HbA1c increased at similar rates in both the “intensive” and “conventional” 
treatment groups, firmly establishing the progressive nature of the disease [17, 49]. This 
deterioration in both groups was shown to be due to relentless ß-cell failure [50]. Why insulin 
did not prevent progression of ß-cell dysfunction is unclear, but may be because HbA1c was not 
reduced to near normal levels, reaching a nadir of about 6.4% at the end of the first year of 
treatment. 
The findings in the UKPDS contrast with those of other studies in which short-term treatment 
with multiple daily insulin injections (MDI) or continuous subcutaneous insulin infusion (CSII) 
improved ß-cell function after fasting glucose was normalized [3-5]. The largest of these studies 
was performed in 382 Chinese adults with fasting plasma glucose levels of >126 mg/dl who 
were randomly assigned to therapy with insulin (MDI or CSII) or oral glucose-lowering 
medications in order to rapidly correct the elevated glucose and maintain it in the normal range 
for two weeks. Patients were subsequently prescribed diet and exercise alone and followed for 


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a year. More subjects in the two insulin groups achieved the target glycemic level and did so in 
less time than those using oral agents. Remission rates after one year were significantly higher 
in the insulin groups (51.1% in CSII and 44.9% in MDI) than in the group taking oral glucose 
lowering therapy (26.7%; p=0.0012). ß-cell function in the remission group, determined by 
HOMA B (homeostatic model assessment ß-cell index) and the acute insulin response to 
glucose, improved significantly after the intensive interventions, and was better sustained in 
the insulin groups after one year. 
ADOPT compared rosiglitazone, metformin and glyburide in patients with recently diagnosed 
(<3 years) diabetes [7]. Over a median of four years, rosiglitazone reduced the progression of 
hyperglycemia more effectively than did glyburide, with metformin being intermediate in its 
effect. The glyburide-induced increase in secretory output was associated with a more rapid 
loss of ß-cell function than “resting” the ß-cell by decreasing secretory demand with 
rosiglitazone [7, 8]. Importantly, patients who progressed to monotherapy failure had higher 
fasting glucose and HbA1c levels and lower ß-cell function at baseline, and demonstrated the 
most marked decline in ß-cell function irrespective of treatment assignment [8]. The use of 
rosiglitazone has since been severely restricted by the U.S. Food and Drug Administration (FDA) 
because of concerns about associated cardiovascular events. The other TZD, pioglitazone, 
remains available but has been associated with bladder cancer [51, 52]. In addition, this class of 
drugs has been associated with weight gain, edema and fractures [7], side effects that further 
limit the attractiveness of these drugs in individuals early in the course of disease. 
Incretin-based therapies hold new promise for promoting recovery and preservation of islet 
function. They not only increase insulin secretion and decrease glucagon release, but also 
preserve the morphology of cultured human islets [53] and increase ß-cell mass following 
partial pancreatectomy in rodents [54]. In humans, long-term intervention studies with these 
agents are limited. The only study examining the potential for durability compared the effect of 
three years of treatment with the GLP-1RA exenatide to insulin glargine in a small number of 
patients who were also taking metformin. HbA1c (7.4-7.6% at baseline) was reduced similarly in 
both groups to 6.7-6.8% after one year of therapy in 69 participants, with the exenatide group 
demonstrating improved ß-cell function while the insulin glargine group showed no change. 
Following one month of washout, ß-cell function was similar to pretreatment values in both 
groups [55]. Thereafter, therapy was restarted in a subgroup, and was continued to three years 
in 36 participants, at which point medication was withdrawn for one month. Better ß-cell 
function was observed in those treated with exenatide, in keeping with a benefit beyond the 
period of exposure [56]. The magnitude of improvement was small, however, and It is unclear 
whether the need for prolonged therapy to demonstrate a benefit was because subjects had 
reasonably long standing diabetes with poor ß-cell function at baseline and/or the attained 


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glucose level on therapy was not close enough to normal initially. 
It may be that the greatest potential to induce prolonged remission will be with aggressive 
glucose lowering and in those with earlier disease and milder defects, possibly by reducing ß-
cell burden to produce and release insulin. This is supported by the observations that (a) in 
ADOPT those who did not progress to monotherapy failure had lower glucose levels and better 
ß-cell function at baseline, (b) the greatest success in slowing progression in those with 
prediabetes and early diabetes occurred with TZDs, which reduce ß-cell secretory demand, and 
(c) the beneficial effect of exenatide was observed after prolonged therapy in individuals with 
well established diabetes in whom glucose levels were not near normal at baseline or during 
therapy. 
Thus, we propose to study subjects with prediabetes or early diabetes who at baseline will have 
better ß-cell function than those with a longer duration of diabetes. We will use therapeutic 
approaches that aim to lower glucose to levels that are close to normal using approaches that 
will either increase ß-cell responsiveness or decrease secretory demand on the ß-cell and 
compare them to placebo. 
2.5 Metformin   
Metformin is a glucose lowering medication of the biguanide class that has been used in the 
management of type 2 diabetes for over 50 years. It reduces the excess hepatic glucose 
production that characterizes type 2 diabetes without increasing insulin secretion. In fact, in the 
DPP it was documented that the improvement in insulin sensitivity associated with metformin 
treatment resulted in a decrease in secretory demand and, thus, insulin release by the ß-cell 
[19]. In addition to its glucose lowering action, an added potential benefit of metformin is a 
modest weight loss, and some protection from weight gain with other diabetes treatments 
including insulin [57, 58]. Metformin is not currently approved for use in the prevention of type 
2 diabetes. However, the DPP demonstrated that metformin is effective in persons with 
impaired glucose tolerance, reducing the development of diabetes by 31% [6]. 
The most common side effects associated with metformin are gastrointestinal. As many as 30% 
of persons report diarrhea, nausea, metallic taste, abdominal bloating, flatulence or anorexia. 
These symptoms are generally transient, resolve spontaneously and can be avoided by gradual 
escalation of dosage. About 4% of participants were unable to continue metformin in U.S. 
clinical trials. Metformin is not associated with hypoglycemia unless used in conjunction with 
other glucose-lowering medications (sulfonylurea or insulin). Metformin has been found to 
rarely cause lactic acidosis (about 0.03 cases per 1,000 person years), and then only when used 


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in persons with renal or hepatic insufficiency or during episodes of hypoxia or circulatory failure 
[57].  
2.6 Insulin Glargine 
Insulin glargine is a recombinant human insulin analogue that in most subjects is administered 
once daily, as it forms subcutaneous microprecipitates from which small amounts of this 
analogue are released, resulting in a relatively constant profile over 24 hours. It has been used 
since 2000 to treat patients with type 2 diabetes and has recently been reported to reduce the 
risk of developing type 2 diabetes in individuals with prediabetes by 28% [44]. Insulin glargine 
administered at night lowers plasma glucose by decreasing hepatic glucose production [59] and 
can be titrated in individuals with prediabetes and established diabetes to achieve fasting 
glucose concentrations of <95 mg/dl without a marked increase in recurrent or severe 
hypoglycemia [44]. 
The most common side effects observed with insulin glargine are hypoglycemia and weight 
gain. This insulin has been reported in some non-randomized, epidemiological studies to be 
associated with an increased risk of cancer [60]. However, ORIGIN, a randomized trial in which 
over 6,000 participants received insulin glargine for a median of 6.2 years, did not observe an 
association between insulin glargine and cancer [44]. 
2.7 Liraglutide 
Liraglutide is an acylated human GLP-1RA with 97% amino acid sequence homology to the 
endogenous form of GLP-1(7-37). It was approved for use in type 2 diabetes in 2009. 
Liraglutide, like other GLP-1RAs, increases intracellular cyclic AMP in ß-cells leading to insulin 
release in the presence of elevated glucose concentrations; thus, insulin secretion subsides as 
blood glucose decreases and approaches euglycemia [10]. The clinical implication of this is that 
hypoglycemia is infrequent when liraglutide is combined with agents other than sulfonylureas 
or insulin. Liraglutide also decreases glucagon secretion in a glucose-dependent manner, but 
does not limit the -cell’s response to hypoglycemia. The mechanism of blood glucose lowering 
may also involve a delay in gastric emptying. Unlike native GLP-1, liraglutide is stable against 
metabolic degradation by dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidases. 
ß-cell function in patients with type 2 diabetes is enhanced by liraglutide therapy either alone 
or in combination with other glucose lowering agents [61]. In animal studies, beneficial effects 
on ß-cell mass have also been observed, but such an effect in humans has not been 
demonstrated. Liraglutide is also associated with reductions in body weight. 


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Liraglutide is associated with upper gastrointestinal side effects including nausea and vomiting, 
which frequently subside with continued treatment and can be reduced in severity by dose 
titration. GLP-1 based therapies, which would include liraglutide, have been reported to be 
associated with an increased risk of pancreatitis, the mechanism for which is unclear [62]. This 
adverse effect occurs on a background of an increased risk of pancreatitis in patients with type 
2 diabetes [63]. In rodent studies, liraglutide has been found to cause thyroid C-cell tumors; 
however, it has not been established that this occurs in humans [62]. Given the above, 
liraglutide should not be used in patients with a history of pancreatitis, a personal or family 
history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia 
syndrome type 2.  
2.8 Approaches to Measuring ß-cell Function, -cell Function, 
Insulin Sensitivity and Glucose Tolerance 
Glucose homeostasis is physiologically modulated under fasting and prandial conditions by a 
number of regulatory factors, most prominently insulin and glucagon. Measurements made 
under fasting conditions are generally proportional to direct measures of the dynamic 
responses, but the most rigorous measurement of ß-cell function (insulin and/or C-peptide 
responses to physiologic stimuli) comes from evaluation of dynamic tests. Dynamic testing can 
be accomplished with oral intake of glucose or mixed meals, or with intravenous infusion of 
glucose or other ß-cell stimulators. In RISE, the hyperglycemic clamp technique will be used to 
examine insulin sensitivity and ß-cell function, and the OGTT will be used as a complementary 
measure that more closely reflects the integrated physiologic response to ingested stimuli, 
including incretins. 
2.8.1 Intravenous Tests of ß- and -cell Function and Insulin Sensitivity 
Glucose tolerance is dependent on ß-cell function and insulin sensitivity, and both of these can 
be quantified using the hyperglycemic clamp [64]. The role of -cell function in determining 
glucose tolerance is less well defined. 
The acute insulin (C-peptide) response to intravenous glucose (AIRg or first phase insulin 
response) occurs within the first ten minutes following bolus glucose administration and is a 
sensitive marker of ß-cell function that decreases as the fasting glucose level rises. A potential 
“drawback” of this measure is that the first phase response drops sharply as the fasting glucose 
level approaches 115 mg/dl [65]. Above that level, the first-phase response is markedly 
diminished and frequently absent. Although this early response may respond to treatment 
interventions aimed at restoring or preserving ß-cell function in some patients, this defect, in 
the absence of medication, appears particularly resistant to reversal. The response is possibly 


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related to the type of intervention used to bring about improvement in ß-cell function. These 
difficulties with measuring early responses at baseline limit our ability to depend on this 
measure of ß-cell function as a primary outcome in RISE. 
The second phase insulin response to intravenous glucose begins at the time of glucose 
administration and continues for as long as the glucose level remains elevated. It is frequently 
quantified as part of a hyperglycemic clamp. Unlike the acute insulin response to glucose, the 
second phase response persists and is measurable even when the fasting glucose concentration 
exceeds 115 mg/dl [66]. Moreover, it is proportional to overall ß-cell secretory capacity and can 
be measurably improved with treatment interventions targeting ß-cell function [67]. 
ß-cells also respond to non-glucose secretagogues, such as peptides and amino acids. The 
prevailing glucose level modulates the ß-cell secretory response to non-glucose secretagogues. 
By performing hyperglycemic clamps with the addition of a bolus intravenous arginine injection, 
it is possible to quantify the maximum insulin response (AIRmax), which provides an estimate of 
the maximum ß-cell secretory capacity at a given point in time. In the absence of techniques 
that provide a direct measure of ß-cell mass in living humans, this measure of maximal 
secretory capacity is currently taken as an indirect measure of ß-cell mass. AIRmax is decreased 
in patients with type 2 diabetes [30] and in those at risk of developing the disorder [68]. Again, 
unlike the first phase response, AIRmax responses are present and readily quantified in 
individuals with higher fasting glucose levels (>115 mg/dl). Effects of treatment interventions 
on AIRmax have not been extensively evaluated but are beginning to be studied [56]. 
ß-cell responses also are modulated by the prevailing insulin sensitivity. Therefore, expressing 
ß-cell function relative to insulin sensitivity provides a better estimate of how well the ß-cell is 
performing [69]. This approach of accounting for the effect of insulin sensitivity has been used 
extensively with AIRg derived from frequently sampled IV glucose tolerance tests, where the 
intravenous glucose tolerance test (IVGTT)-derived measure of insulin sensitivity (SI) is used to 
produce the ‘disposition index’ (SI x AIRg) [69]. This approach can also be applied to adjust 
other measures of ß-cell function, providing that the underlying assumption of a hyperbolic 
relationship between the insulin sensitivity variable and the ß-cell function variable is true. 
Likewise, AIRmax can be adjusted for insulin sensitivity (e.g. SI x AIRmax; [69]). Insulin 
sensitivity-adjusted ß-cell function measures derived from second phase responses and AIRmax 
responses measured with hyperglycemic clamp methods have been selected as the primary 
outcome measurements for RISE. 
The reciprocal of glucose’s ability to potentiate the ß-cell response is its ability to suppress 
glucagon secretion from the -cell. This function can also be measured using hyperglycemic 
clamps along with arginine [30, 70]. The ability of glucose to suppress the acute glucagon 


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response is impaired in people with type 2 diabetes and in those with prediabetes, indicative of 
impaired -cell regulation [30, 71]. This parameter will be quantified using the hyperglycemic 
clamp with arginine injection (AGRmin, minimum acute glucagon response) and, if funding is 
available, will be analyzed as a secondary outcome in RISE. 
2.8.2 Oral Tests of ß- and -cell Function and Insulin Sensitivity 
The OGTT provides measures of islet function and has been used in large clinical trials for this 
purpose. The early insulin response (insulinogenic index) is an important determinant of 
glucose tolerance [18]. This response, when used in combination with a fasting measure of 
insulin sensitivity (1/fasting insulin, HOMA, or QUICKI) provides another estimate of ß-cell 
function termed the “oral disposition index” (DIo) [22, 72]. However, the accuracy of HOMA in 
assessing changes in insulin sensitivity over time may not be as reproducible and accurate as 
clamp techniques [73]. Using modeling approaches such as those developed by Mari et al. [74] 
and Cobelli et al. [75], it is possible to obtain a number of additional parameters of ß-cell 
function and insulin sensitivity from the OGTT. In addition, using C-peptide levels and de-
convolution techniques, insulin secretion rates can be calculated from the OGTT [74-76] . 
Finally, overall glucose tolerance can be calculated from the glucose excursion during the test 
[77], providing a measure that is directly interpretable and applicable in the clinical setting. 
Physiological glucagon suppression during an OGTT is an important determinant of glucose 
tolerance and provides an estimate of -cell function. In individuals with type 2 diabetes, 
glucagon suppression is impaired [2, 28, 29], an abnormality that is improved with incretin-
based therapy [10]. However, whether this change persists after withdrawal of therapy is 
unknown. 
These OGTT-based measures will be performed in the study and their relationship with 
intravenous test-based measurements will be determined, both at baseline and following drug 
interventions.  
2.9 Biomarkers of ß-cell Function, -cell Function, Insulin 
Sensitivity and Glucose Tolerance  
It is often the case that biologic phenomena of interest are both difficult and costly to measure 
directly. This can be true of physiologic states such as ß-cell function, but it is also true for time-
dependent changes such as rates of progression to overt diabetes. In these instances we turn to 
biomarkers. An optimal biomarker is measured from a single biological sample (e.g., blood or 
urine) and is less costly, less labor intensive and highly correlated with the result from the 
process under evaluation. However, a biomarker might be the result of combinations of blood 


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tests, or measurements from other body fluids, or even measurements of other biological 
substances [78].  
In RISE, treatments aimed at restoring or preserving ß-cell function are being implemented and 
their effects determined using dynamic measures of ß-cell function discussed above. This 
provides the opportunity to concurrently attempt to identify biomarkers to assess islet function 
in relation to the systemic metabolic state, and to predict how these change over time. The 
identification of such biomarkers is an important ancillary goal of the project since a practical 
application of strategies learned from this study will ultimately require a screening test to 
identify likely responders to the interventions. 
2.9.1 Putative Diabetes Biomarkers 
The detailed measures of β-cell function that we will be making provide an opportunity to 
identify biomarkers that can predict deterioration of β-cell function and/or response to 
interventions that can mitigate such deterioration. The identification of such biomarkers is an 
important ancillary goal of the RISE Consortium. Because of budget constraints, the focus 
during this stage of the project will be on collecting patient specimens that can used in the 
future for identification of biomarkers once the main outcomes of the study are known. We will 
collect samples that can be used to examine previously described peptide markers of diabetes 
risk (e.g., adiponectin, ferritin, ApoB, C-reactive protein, IL-2 receptor A [79-82]) and evolving 
markers of ß-cell mass regulation (e.g., prolactin, DNA fragments and methylation, GLP-1, 
glucose-dependent insulinotropic peptide [GIP], HSP90nucleic acids [83-87]). We will also 
collect serum samples that can be analyzed using genomic, micro-RNA, proteomic and 
metabolomics approaches comparing for example responders to non-responders to the study 
interventions.   
3 STUDY DESIGN 
3.1 Overview and Rationale 
This document is specific for the RISE Adult Medication Protocol that three centers are 
performing together in individuals with prediabetes or recent onset type 2 diabetes. This 
preliminary proof-of-principle study is a randomized, partially blinded, placebo-controlled trial 
comparing metformin alone, insulin glargine followed by metformin, or liraglutide plus 
metformin to placebo. The primary outcome is ß-cell function, measured as defined below.  
The RISE Adult Medication Protocol will involve 255 adults age 20-65 years old. Volunteers will 
be men and women with prediabetes or with drug-naïve, recent onset, mild type 2 diabetes 
who meet the following glucose-based parameters: HbA1c ≤7.0%, plus an OGTT fasting plasma 


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glucose 95-125 mg/dl and a 2-hour post challenge glucose ≥140 mg/dl. Participants will be 
randomized to: (1) metformin alone for 12 months, (2) 3-months basal insulin glargine titrated 
to normalize fasting glucose followed by 9 months metformin, (3) liraglutide plus metformin for 
12 months, or (4) placebo for 12 months. Volunteers will be recruited over a three-year period 
and followed for a total of 21 months following randomization. After baseline assessments and 
the run-in period, participants will be treated with active medication or placebo for 12 months. 
To determine if treatment has persistent benefits on ß-cell function, subjects will be followed 
after discontinuation of treatment for a minimum of 3 months and up to 9 months if possible. 
Primary and secondary assessments will be performed at various time intervals while 
participants are receiving therapy and after medication discontinuation. The timing of the 
study, including interventions and testing, is shown in Figure 1.  
 
Figure 1: Timing of interventions and outcomes testing for RISE Adult Medication Protocol 
The chosen interventions are intended to test whether “resting” the ß-cell (metformin alone or 
metformin following normalization of fasting glucose with long-acting insulin) or “improving” ß- 
and -cell function (liraglutide) will retard the natural progression of prediabetes and type 2 
diabetes. A placebo arm is included as a control group to determine the effects of the 
interventions relative to the natural history of the disease.  
By including a 3-month washout period after which the primary outcomes will be assessed, the 
study will examine whether a beneficial effect of treatment persists beyond the period of active 
drug intervention. While shorter initial treatment intervals may be effective, the plan is first to 
determine the efficacy and durability of 12 months of treatment as a proof of principle. If no 
sustained effect is seen after 12 months of treatment, then it is very unlikely that a shorter 
treatment period would be efficacious. Complete end-of-study measures will be performed at 
the end of the 3-month washout period (15 months on study) and used for the primary analysis 
of the study. Where possible, ß-cell function will be measured using an OGTT at 9 months post 
therapy (21 months on study) to evaluate whether treatment effects persist beyond the initial 


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3-month washout period. Full evaluation of the length of any durable response beyond these 
time points will require future studies designed specifically to address that question. 
3.2 Primary Outcomes  
The primary objective of the RISE Study is to evaluate the effects of randomized treatment on 
ß-cell function, measured by hyperglycemic clamp techniques. Given that insulin and C-peptide 
are both used in quantifying ß-cell function, each of them will be measured in certain or all tests 
in part to avoid the problem of collinearity when performing the statistical analyses. 
Two co-primary outcomes are specified:  
 ß-cell function measured as the second phase response (steady-state of the 
hyperglycemic clamp) (100-120 minutes of glucose infusion) [64]. This will be calculated 
as mean C-peptide at steady state, adjusted for insulin sensitivity using the 
hyperglycemic clamp-derived measure of insulin sensitivity (glucose disposal 
rate/insulin: GDR/I). 
 ß-cell function measured as AIRmax (arginine-induced acute insulin response at 
hyperglycemic glucose; ß-cell secretory capacity) [30]. This will be calculated as the 
incremental area under the C-peptide curve from 0-10 minutes following arginine 
injection at a plasma glucose ≥450 mg/dl, adjusted for insulin sensitivity measured by 
the hyperglycemic clamp. 
Overall, for primary and secondary outcomes we will use the insulin sensitivity measured during 
steady state of the hyperglycemic clamp (glucose disposal rate [derived from the steady state 
glucose infusion rate] divided by steady state plasma insulin concentration 100-120 min) for 
adjustment of ß-cell function measures [69]. 
The main analysis will evaluate the effect of study treatments to induce durable improvement 
in these primary outcome measures of ß-cell function, by comparing each treatment against 
placebo following a 3-month medication washout. The study will be analyzed under the 
intention-to-treat principle. 
3.3 Secondary Outcomes  
There are a number of pre-specified secondary outcomes. These include measures derived 
from the hyperglycemic clamp that are not specified as primary outcomes; measures derived 
from the OGTT; analyses related to treatment effect at the end of the 12 month active 
intervention period compared to pre-treatment baseline; and analyses related to various 
putative predictors of treatment outcome.  


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As presented in Figure 1, the timing of available secondary measures differs according to 
measurement methodology. Secondary outcomes will be evaluated by intention-to-treat 
analyses when evaluating effects of randomized study treatments. 
3.3.1 ß-cell Function and Glucose Tolerance 
(i) Hyperglycemic clamp-derived ß-cell measures:  
a. First phase insulin response (incremental insulin area from 0-10 minutes after initial 
glucose bolus) 
b. First phase C-peptide response (incremental C-peptide area from 0-10 minutes after 
initial glucose bolus) 
c. Disposition index derived from a and b, adjusting for insulin sensitivity using the 
hyperglycemic clamp-derived measure of insulin sensitivity (glucose disposal 
rate/insulin: GDR/I)  
d. Second phase insulin response, with adjustment for insulin sensitivity using non-
clamp-derived surrogate measures 
e. AIRmax response to arginine calculated using insulin concentrations and adjusted for 
insulin sensitivity 
(ii) OGTT-derived ß-cell measures:  
a. Early insulin response to oral glucose (insulinogenic index: ∆ insulin from 0-30 
minutes/∆ glucose from 0-30 minutes [∆I/∆G])  
b. Early C-peptide response to oral glucose (parallel to (a)) 
c. Oral disposition index (DIo; insulinogenic index adjusted for insulin sensitivity) 
d. Modeled parameters of ß-cell function (ß-cell glucose sensitivity, rate sensitivity and 
potentiation factor; static, dynamic, and total ß-cell glucose sensitivity) 
e. Ratios of incremental insulin/glucose (iAUCins/iAUCg) and C-peptide/glucose (iAUCc-
p/iAUCg) responses from 0-120 minutes  
f. Incremental glucose (iAUCg) response as a measure of glucose tolerance  
g. 2-hour glucose 
h. GLP-1 total and incremental response to oral glucose load (samples will be collected, 
and measured for this analysis if funding allows) 
(iii) Fasting measures:  
a. Glucose  
b. Proinsulin/insulin ratio 
c. HOMA %B (using the Oxford calculator) 
d. HbA1c 


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3.3.2  -cell Function (contingent on funding) 
A. Hyperglycemic clamp-derived measures:  
a. Glucagon suppression in response to sustained hyperglycemia during the clamp (the 
decrement in glucagon concentration from baseline to nadir value at 100-120 
minutes) 
b. Acute glucagon response to arginine (the incremental increase in glucagon 
concentration from pre-arginine baseline for the 10 minutes after the arginine 
injection) 
B. OGTT-derived measures: integrated glucagon response from 0-120 minutes 
C. Fasting measures: glucagon 
3.3.3  Insulin Sensitivity 
(i) Hyperglycemic clamp-derived measures: glucose disposal rate at steady state (100-120 
minutes) divided by ambient insulin concentrations 
(ii) OGTT-derived measures:  
a. Matsuda index  
b. Model-derived insulin sensitivity  
(iii) Fasting measures:  
a. 1/fasting insulin,  
b. HOMA-S (using the Oxford calculator),  
c. QUICKI 
3.3.4  Blood and Urine Biomarkers  
(i) Glycemic control: HbA1c (baseline predictor, and as a time-dependent treatment       
outcome) 
(ii) Adipokines/inflammatory markers: adiponectin; others contingent on funding (see list 
above in Section 2.8.1) 
(iii) Non-esterified fatty acids 
(iv) Renal/vascular: urinary albumin/creatinine ratio at baseline (contingent on funding) 
3.3.5 Physical Measures 
(i) Physical measures: blood pressure, body weight, body mass index, waist and hip 
circumference 


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3.4 Treatments 
3.4.1 Three-week Placebo Run-in Phase 
Prior to randomization, eligible volunteers will participate in a 3-week run-in period. They will 
be instructed by study staff in proper injection technique and will receive three weeks of both 
placebo injections and tablets. At the end of the placebo-run in period, they will return any 
unused medication which will be counted to assess adherence. Participants taking <80% of the 
medication will be excluded from further participation. 
Those who have been compliant with medication use (≥80%) will be eligible to participate and 
will undergo the baseline study procedures. Once these are completed, and if willing to 
undergo these tests repeatedly as required by the study, they will be randomized to one of the 
treatment arms and will enter the active treatment phase. In addition, after completing the first 
set of study procedures, they will receive instruction in lifestyle modification, including 
individualized instruction on weight loss, exercise and diet. 
3.4.2 Twelve-month Active Treatment Phase 
Participants will be randomized to one of the four interventions. Participants will be seen every 
three months throughout the study and will be given three months of medication at a time 
during the active treatment phase. Study staff will monitor compliance by auditing returned 
medication every three months. Participants randomized to insulin will be required to perform 
home blood glucose monitoring.  
Participants randomized to metformin monotherapy will not know whether they have been 
assigned to metformin or placebo. Double blinding of these two groups will be done to 
minimize dropout of those participants assigned to placebo. 
The two groups receiving injectables (i.e., liraglutide and insulin glargine) will not be masked to 
the intervention. 
All medications used in RISE are approved for treating type 2 diabetes and will be used 
according to the label; Investigational New Drug (IND) applications will be obtained for use of 
all medications in individuals with prediabetes. For study procedures performed during the 
active phase of treatment, study medications will be withheld on the morning of testing. 
3.4.3 Metformin  
Initiation and determination of maintenance dosing for metformin will be the same in all 
treatment groups, although the timing of undertaking these steps differs by treatment group. 


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To minimize non-compliance due to gastrointestinal side effects, participants will be titrated 
over four weeks from a starting dose of 500 mg once daily to a maximum dose of 1000 mg bid. 
Participants will remain on the maximum tolerated dose of metformin throughout the study. If 
participants are unable to tolerate metformin they will continue in the study but will not take 
the medication. 
3.4.4 Liraglutide plus Metformin 
Liraglutide will be started at a dose of 0.6 mg subcutaneously, once daily. This dose will be 
continued for one week, after which subjects will increase the daily dose to 1.2 mg if they have 
tolerated the 0.6 mg daily dose. Likewise, after one week at 1.2 mg daily, the dose will be 
increased to 1.8 mg daily, the maximal recommended daily dose in the treatment of diabetes. If 
participants cannot tolerate the higher dose, they will revert back to the previously tolerated 
dose and will remain on that maximal tolerated daily dose for the duration of the study. Once 
the maximal dose of liraglutide has been reached and is tolerated, metformin will be initiated 
and titrated as described above. If the combination of the medications produces intolerable 
adverse effects, liraglutide treatment will be retained in preference to metformin. 
3.4.5 Insulin Glargine Followed by Metformin 
Insulin will be titrated over a period of one month based on self blood glucose monitoring to 
achieve a fasting blood glucose of 80-90 mg/dl without hypoglycemia, and then continued with 
dose adjustment to maintain the fasting glucose in this range. Insulin glargine has been shown 
to be titratable in individuals with prediabetes and established diabetes to achieve fasting 
glucose concentrations of <95 mg/dl without a marked increase in recurrent or severe 
hypoglycemia [44]. Following 3-months of insulin treatment, insulin glargine will be 
discontinued and metformin will be commenced and titrated as above. 
3.4.6 Placebo 
Matching metformin placebo will be titrated equivalently to the active metformin. Adverse 
effects and final dosing achieved will be recorded in parallel with active metformin. 
3.4.7 Medication Wash-out and Post-treatment Follow Up  
Following the completion of the intensive re-assessments (hyperglycemic clamp and OGTT) 
after 12 months of the intervention, study medications will be stopped and the participants will 
continue to be followed off medications, for a minimum of 3 months and up to 9 months, 
depending on the time of randomization within the 5-year study period. At the end of the first 3 
months off treatment (i.e., 15 months after randomization), the hyperglycemic clamp and OGTT 
will be repeated to determine the durability of the effects of the active interventions on ß- and 


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-cell function. Although it is unlikely in this study population, participants may experience 
deterioration in ß-cell function during this 3-month wash out period, and require rescue 
therapy. Criteria for rescue, and protocol-specified rescue therapy, are described below (see 
Section 7.4). Participants who do not require rescue will undergo the final clamp and OGTT 
procedures at the end of the 3-month washout period. They will then continue to remain off 
study medications and retesting will occur 9-months following discontinuation of the 
intervention (i.e., 21 months after randomization). The rescue protocol will be utilized, as 
needed, during this last 6-month follow-up period. Following the complete 9-month washout 
period, patients will be referred to their primary care provider for further follow up. 
3.4.8 Rescue 
The approach to rescuing a participant with severe hyperglycemia is described in Section 7.4. 
3.5 Inclusion Criteria 
1. Fasting plasma glucose 95-125 mg/dl plus 2-hour glucose ≥140 mg/dl on 75 gm OGTT 
plus HbA1c ≤7.0%. There is no upper limit for the 2-hour glucose on OGTT.  
2. Age 20-65 years 
3. Body mass index (BMI) ≥25 kg/m2 (≥23 kg/m2 in Asian Americans) but ≤50 kg/m2 
4. Self-reported diabetes <1 year in duration 
5. Drug naïve (no prior to oral glucose lowering agent(s), insulin or other injectable 
glucose lowering agents) 
3.6 Exclusion criteria  
1. Underlying disease likely to limit life span and/or increase risk of intervention or an 
underlying condition that is likely to limit ability to participate in outcomes assessment 
2. An underlying disease that affects glucose metabolism other than type 2 diabetes 
3. Taking medications that affect glucose metabolism, or has an underlying condition that 
is likely to require such medications 
4. Active infections 
5. Renal disease (eGFR <45 mL/minute/1.73 m) 
6. Anemia (hemoglobin <11 g/dl in women, <12 g/dl in men) or known coagulopathy 


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7. Cardiovascular disease, including uncontrolled hypertension. Participants must be able 
to safely tolerate administration of intravenous fluids required during clamp studies. 
8. History of conditions that may be precipitated or exacerbated by a study drug: 
a. 
Pancreatitis 
b. 
Serum ALT more than 3 times the upper limit of normal 
c. 
Excessive alcohol intake 
d. 
Suboptimally treated thyroid disease 
e. 
Medullary carcinoma of the thyroid or MEN-2 (in participant or a family history) 
f. 
Hypertriglyceridemia (>400 mg/dl despite treatment) 
9. Conditions or behaviors likely to affect the conduct of the RISE Study 
a. 
Unable or unwilling to give informed consent 
b. 
Unable to adequately communicate with clinic staff 
c. 
Another household member is a participant or staff member in RISE 
d. 
Current, recent or anticipated participation in another intervention research 
project that would interfere with any of the interventions/outcomes in RISE 
e. 
Weight loss of >5% in past three months for any reason other than post-partum 
weight loss. Participants taking weight loss drugs or using preparations taken for 
intended weight loss are excluded. 
f. 
Likely to move away from participating clinics in next two years 
g. 
Women of childbearing potential who are unwilling to use adequate 
contraception 
h. 
Current (or anticipated) pregnancy and lactation. 
i. 
Major psychiatric disorder that, in the opinion of clinic staff, would impede the 
conduct of RISE 
10. Additional conditions may serve as criteria for exclusion at the discretion of the local 
site. 
Further details pertaining to exclusion criteria are specified in the Manual of Procedures. 


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3.7 Randomization  
Randomization is stratified by clinical center and by prediabetes vs. diabetes status to ensure 
balance among the treatment groups with respect to anticipated differences in the participant 
populations. For each clinical center, the Coordinating Center (CoC) will generate two 
randomization schemes using a permuted block design. In this way, sample sizes across the four 
treatment arms will remain relatively equivalent as the trial progresses. The clinical center staff 
will use a computer-based system to input eligibility data and receive a random treatment 
assignment. 
3.8 Masking  
During the run-in period, participants will take metformin placebo and inject saline to assess 
compliance with possible study medications. After randomization, the metformin and placebo 
medications will be masked through a metformin-matched placebo. The insulin followed by 
metformin and liraglutide plus metformin arms will be unmasked.  
Because the primary outcomes are based on a single set of measurements taken 3-months 
following medication withdrawal, the outcome measurements are inherently masked to both 
participants and investigators. Participants and clinical center staff will be masked to study 
results until after the final outcome measurements are complete.  
4 RECRUITMENT 
4.1 Recruitment  
The primary source of participants for the RISE Study is the active patient population of the 
study sites and their usual referral sources. Participants will be recruited over a three year 
period. Recruitment techniques include notices placed on bulletin boards at the medical 
centers, newspaper and radio advertisements and public service announcements, and referral 
from colleagues. Prescreening of electronic and clinical medical records is strongly encouraged 
to reduce available screen failure rates. Selection is based solely on the participant's ability to 
meet the criteria stated in the protocol and his/her willingness to participate in the study. Site-
specific recruitment strategies are developed by each local study team. 
The performance of the clinical centers in recruiting and retaining eligible RISE participants will 
be monitored by the CoC and the Recruitment and Retention Committee. Monthly recruitment 
summaries will be issued throughout the recruitment and randomization period detailing the 
number of potential participants screened, number randomized, and reasons for ineligibility or 
of refusal to participate by clinical center. The reasons for ineligibility or refusal to participate 


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will be compared among the clinical centers, and if large differences are found, explanations for 
these differences will be sought. If the randomization rate falls below the desired number of 
participants per month, data on reasons for ineligibility and refusal will be used to try to 
identify strategies that would increase the randomization rate. Site visits may be needed and 
assistance will be offered to clinical centers struggling with recruitment efforts. 
4.2 Description/Justification of the Target Study Population 
Preliminary screening will be done to enrich the yield of individuals who have prediabetes or 
type 2 diabetes. These individuals will be invited for initial field testing using HbA1c criteria. This 
testing will be performed on individuals who are highly predisposed to develop type 2 diabetes 
including, but not limited to, those with one or more of the following features: 
 Known impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) 
 Overweight or obesity (BMI ≥25 kg/m2 (≥23 kg/m2 in Asian Americans) but ≤50 kg/m2) 
 Age >45 years 
 First degree relative with type 2 diabetes  
 Sedentary lifestyle 
 Those with low HDL cholesterol or high triglycerides, hypertension (i.e., “the metabolic 
syndrome”) 
 Certain racial and ethnic groups (e.g., Non-Hispanic Blacks, Hispanic/Latino Americans, 
Asian Americans and Pacific Islanders, and American Indians and Alaska Natives) 
 Women who had gestational diabetes, or who have had a baby weighing 9 pounds or 
more at birth 
 Women with polycystic ovary syndrome (PCOS) 
 
The lifetime risk for type 2 diabetes among these groups is substantially higher than that seen 
in the general population. Further, the presence of more than one of these factors enhances 
the likelihood of development of type 2 diabetes to an even greater degree than does the 
presence of any single factor noted above. A recent evaluation of diabetes risk attempted to 
quantify the value of well known diabetes-associated risk factors [88]. 
The presence of risk factors/characteristics noted above will prompt screening these persons 
with a POC HbA1C; those who have a value of ≤7.2% will be asked to undergo a standard 75 gm 
OGTT along with a lab-based HPLC HbA1c. In this way, the proportion of subjects who will 
undergo an OGTT will be at high likelihood of having IGT or newly diagnosed type 2 diabetes by 
virtue of their risk status and elevated POC HbA1C. This approach is designed to increase the 


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yield of detecting IGT and type 2 diabetes while simultaneously maximizing the use of resources 
(both in terms of effort of personnel and use of testing supplies). 
This strategy will yield individuals who will be identified as being at high risk for ß-cell 
dysfunction (risk group plus POC HbA1C ≤7.2%). Of those who undergo a 75 gram OGTT and the 
lab-based HPLC HbA1c, we project that approximately one-third of individuals will meet study 
enrollment criteria, i.e., will have a fasting plasma glucose 95-125 mg/dl plus a 2-hour glucose 
≥140 mg/dl plus a laboratory-based HbA1c ≤7.0%. There is no upper limit for the 2-hour glucose 
on OGTT. 
4.3 Informed Consent  
The informed consent process will be performed in a quiet setting prior to the initiation of any 
study procedures. The subject will be provided adequate time to read and understand the 
written consent and ask questions as necessary. If they choose, they may take additional time 
to discuss the study with family and/or physicians outside the clinic setting. Consent documents 
are not signed until volunteers demonstrate adequate understanding of all aspects of the study 
and consent process. A copy of the consent will be given to the subject. There will be two 
consent forms – one for the Screening stage and one for the Intervention stage. Model consent 
forms are provided in Appendix A. Written informed consent will be obtained prior to initiation 
of any study-related activities. 
In the event that a significant protocol change occurs, the informed consent documents will be 
adjusted appropriately and sites will submit the revised documents to their Institutional Review 
Board (IRB) for approval. Local IRBs will determine whether it is necessary to re-consent 
participants. 
Sites will submit to the CoC stamped IRB approval letters and current copies of all consent 
forms prior to study initiation, and annually thereafter. These records will be maintained by the 
CoC as a central archive.  
4.4 Staged Screening and Randomization 
Screening for enrollment in RISE will be conducted in a stepwise manner involving completion 
of an initial screening encounter, an OGTT screening visit and a 3-week run-in period at the end 
of which baseline measurements, including the OGTT and hyperglycemic clamp, will be 
performed. Screening proceeds from least invasive, most easily obtained criteria to the most 
demanding procedures. Once a participant is determined to be ineligible, the screening process 
stops. 


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The staged screening process is intended to accomplish the following: 
 identify potentially eligible participants for RISE,  
 verify eligibility of participants,  
 accomplish the objectives of the informed consent process,  
 complete a run-in period,  
 establish a research cohort likely to complete the study and adhere to the medication 
schedule and the complex testing of ß-cell function and related measures, and 
 randomize participants into RISE. 
Complete definitions and procedures are in the Manual of Procedures. 
All steps below will be conducted if and only if the individual provides written informed consent 
for participation in RISE. If for any reason the participant wishes not to participate in any of the 
activities and experimental procedures outlined in the informed consent, the consent form will 
not be signed and no further data collection or biological testing will be conducted. If the 
participant agrees to participate in RISE, he/she will provide written documentation by signing 
the consent form. If for any reason the participant wishes to withdraw from the study at any 
time, there will be no pressure upon the participant to continue and withdrawal will be 
documented.  
Staged screening and enrollment includes the following steps: 
1. Initial Contact: This contact aims to identify individuals who are predisposed to develop 
type 2 diabetes by virtue of having one or more risk factors (Section 4.2). Potential 
participants are seen and given detailed information about RISE, including research 
interventions, randomization, masking, test procedures, risks and benefits, and the 
eligibility process. If they give oral and/or written consent, they are first interviewed and 
records are reviewed for personal and medical history. If they pass these completely 
noninvasive eligibility criteria, they will have a POC HbA1c measurement. Should their 
value be ≤7.2%, they will be invited to attend the clinic for a full screening visit where a 
complete history will be taken and lab tests performed. 
2. Screening: If the participant meets initial inclusion criteria, he/she will return for a 
physical examination, full eligibility testing, and instruction in taking medication for the 
placebo run-in phase. A fasting 75 gram OGTT will be performed. In order to qualify for 
further consideration, the fasting glucose must be between 95-125 mg/dl and the 2-
hour glucose must be ≥140 mg/dl and the laboratory-based HbA1c must be≤7.0%. 
3. Run-in: If the above criteria are met, the participant will be asked to undergo a 3-week 
run-in period. The run-in period (described in Section 3.4.1) allows staff to evaluate a 
patient’s suitability for RISE. At the end of the run-in, clinic staff will assess the patient’s 


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adherence to medication taking, assess final eligibility criteria, and determine whether 
the patient should be randomized to RISE. 
4. Final screening visit and randomization: If the participant is eligible, informed consent is 
obtained, baseline data are collected and the OGTT and hyperglycemic clamp are 
performed. If after completion of these studies the participant is willing to be 
randomized, the participant is randomly assigned to a treatment group. 
If during the screening process the participant is deemed ineligible, but his/her condition 
changes during the recruitment period (e.g., the participant has uncontrolled hypertension that 
becomes adequately treated or an active infection that has resolved), he/she may be 
reconsidered for inclusion if he/she maintains eligibility for three months. Screening procedures 
are re-initiated and the participant must meet all eligibility criteria at the time of re-enrollment.  
A minimal amount of data is recorded on participants who fail screening (such as age group, 
gender, race/ethnicity, diabetes duration) for purposes of comparing participants versus 
nonparticipants. 
5 PATIENT MANAGEMENT  
5.1  
Description of RISE Research Facility Treatment(s) 
Study treatment interventions are described in detail above (Section 3.4). Glucose management 
(including study medications) will be provided free of charge to RISE participants. In accordance 
with standards of care, HbA1c will be monitored every 3 months. Procedures to be followed for 
rising HbA1c levels are described in Section 7.4. Beyond the treatment of the glucose-aspect of 
prediabetes and diabetes care, the research study will not assume responsibility for the medical 
care of the participant. Non-glucose aspects of diabetes care (e.g., blood pressure, lipids, 
obstructive sleep apnea) and non-diabetes related medical problems will be referred to the 
participant’s primary care provider. When a potential treatment could affect the study’s 
outcome(s), the RISE physician may discuss the choices with the participant’s primary care 
provider. RISE Study labs will be shared with the provider, with the participant’s permission. For 
those participants who do not have a primary care provider, the study staff will help find 
appropriate medical care. 
5.2  
Drug Distribution 
Study medications will be distributed directly to individual study centers. Individual centers will 
organize and maintain inventory, in cooperation with their investigational or research 
pharmacy. Sites will ensure that sufficient medication is always on hand to allow medication 


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distribution for the next three month period. This includes medications required for the next 12 
randomized enrollees (i.e., on average three initial distributions for each of the four treatment 
arms) plus all of the upcoming distributions to enrolled participants who will be returning 
within three months. Expiration dates of all medications will be double checked and 
documented on arrival at the study center and at the time of distribution to participants to 
ensure that the provided supplies will not expire during the current treatment interval.  
Except for the placebos (metformin and liraglutide) distributed during the 3-week run-in period, 
medication will be dispensed to participants in 3-month quantities, and 
bottles/boxes/containers will be collected from participants at the quarterly visits to allow 
compliance assessment by pill counting or residual volume estimation for liquid medications. 
Subsequent treatment supplies will be provided with each quarterly visit.  
Non-study medications will not be provided through the RISE study clinical centers.  
5.3  
Adherence Measures 
Adherence will be documented, monitored, and addressed as part of participant care and 
management and to monitor whether procedures are being implemented and followed 
equivalently across all sites. Adherence refers to all study procedures – not only taking the 
prescribed amount of study drug, but also attending scheduled study visits and completing 
procedures at those visits. The goal is to maintain high levels of adherence in all participants 
and across all sites. Primary adherence measures will address visit attendance and completion 
of study procedures, medication adherence, and adherence to recommended home glucose 
monitoring. Medication adherence will be assessed on a quarterly basis, by pill counting or by 
residual volume estimation of insulin glargine and liraglutide. Participants will be instructed to 
bring all study medications (including empty bottles/vials/pens) to study visits. 
5.3.1 Placebo Run-in 
Metformin placebo compliance will be assessed by pill counting. Liraglutide placebo compliance 
will be assessed by residual volume assessment. 
5.3.2 Liraglutide 
Liraglutide will not be blinded in RISE. Liraglutide pens contain 3 ml, and the amount that each 
participant should use is readily calculated based on their study dosing during and after 
titration. The expected amount consumed will be calculated and compared to residual amounts 
in the currently active pen, and in any residual unused pens. 


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5.3.3 Insulin 
Insulin will not be blinded in RISE. Insulin use will be prescribed to assigned participants only for 
the first 3 months of their participation. The projected volume consumed cannot be 
generalized, but will need to be calculated for each participant based on their recorded dosing 
titration and their final dosing. The dosing administration record will be used to assess 
compliance, and confirmed with a residual volume assessment as with liraglutide pens. 
5.3.4 Metformin/Placebo 
Active or placebo metformin compliance will be assessed by counting of dispensed and 
returned tablets.  
5.4  
Retention  
Retention refers to efforts to prevent participant dropout or withdrawal from the study. It is 
critically important to successfully engage and retain participation over the course of the trial. 
For purposes of sample size estimation, we have predicted withdrawal rates of 10% during the 
15-months of primary data collection and have adjusted sample size to meet study 
requirements. However, lower rates of attrition are desirable.  
The Study Coordinator at each site is primarily responsible for monitoring participant attrition 
and initiating team conferences for retention strategies or dropout recovery rates. Individual 
sites will develop strategies to enhance retention specific to their locale and specific 
population. Activities at both the national and local level will be coordinated to maximize 
retention and minimize attrition. Subjects missing scheduled visits will be contacted within 24 
hours of the scheduled visit to reschedule and discuss strategies to improve compliance. If the 
site is unable to contact the subject, the site will send a certified letter to the participant to 
encourage continuation in the trial even if they no longer wish to take the study medication. At 
the local level, study staff will implement efforts to personalize the study (mailing out personal 
notes, birthday cards, etc.). 
Attrition is monitored regularly by the CoC and the Recruitment and Retention Committee. An 
attempt is made to collect data on the reason for leaving the study in the case of a participant 
who withdraws. Assistance is offered to any site with a higher than average attrition rate. Sites 
will also be encouraged to share their ideas and experiences via regular communication and 
conference calls for Study Coordinators. The CoC will prepare monthly reports on visit 
completion, compliance with the RISE Study protocol and participants on inactive follow-up.  


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6 DATA COLLECTION 
6.1  Main Study Procedures  
The timing of major study procedures during the different phases of the study is illustrated in 
Figure 1. Outcomes using hyperglycemic clamp procedures will be obtained at baseline, at the 
end of 12 months of treatment, and after a 3-month washout period (i.e., 15 months post 
randomization). Additional outcomes will be obtained from the OGTT concurrent with the 
hyperglycemic clamp procedures, and also at additional time points -- at 6 months on therapy, 
and at 9 months after stopping therapy (i.e., 21 months post randomization). Blood and urine 
samples for planned measures will be collected at these visits, along with extra blood and urine 
samples that will be stored for future analyses. Further details on these measures are provided 
below, and are summarized in Figure 1 above. All procedures and measures will be conducted 
by centrally trained and certified staff. 
6.1.1 Fasting Blood and Urine Samples 
HbA1c will be measured and fasting blood and urine samples will be collected at each 3-
monthly study visit. Aliquots of fasting blood and urine will be stored for subsequent 
measurement of biomarkers. A blood sample for DNA will be collected at randomization for 
subsequent genetic analysis should funding become available. Routine chemistries for safety 
(examples include complete blood count, liver function tests, pregnancy tests) will be done at 
screening and at six months.  
6.1.2  Oral Glucose Tolerance Test (OGTT) 
Participants will come to the clinical research testing facility in the morning following a 10-12 
hour overnight fast. They will drink 75 grams of an oral glucose solution (centrally provided 
from a single manufacturer) over ≤5 minutes. Blood samples will be obtained 10, 20, 30, 60, 90, 
120, 150 and 180 min after the glucose ingestion. OGTT procedures will be performed at 
baseline, at 6 and 12 months on active treatment, and 3 and 9 months after stopping 
treatment, i.e., 15 and 21 months after randomization. 
6.1.3  Hyperglycemic Clamp 
Hyperglycemic clamps (goal steady state glucose levels of 200 mg/dl and >450 mg/dl) will be 
performed at baseline, 12 months post randomization while on active treatment, and 15 
months post randomization (i.e., after 3 months of washout). Participants will return to the 
testing facility to undergo the clamp after a 10-12 hour overnight fast. The clamp will be 
performed on a day separate from the OGTT. 


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The clamp procedure will incorporate 3 main sets of blood sampling for the planned outcome 
measures: first phase (0-10 minutes); second phase (100-120 minutes); and maximal stimulated 
responses (from 10 minutes before arginine until 10 minutes after arginine). To guide the 
clamp, a small volume of arterialized venous blood will be obtained at 5-min intervals 
throughout for clamp for measurement of plasma glucose concentration and titration of the 
dextrose infusion. 
For the OGTT and clamp measures, participants will be asked to refrain from vigorous exercise 
and tobacco use for 24 hours before the baseline measures. Study medications will be withheld 
the morning of testing. 
6.2  Eligibility Screening Measurements 
Screening and run-in procedures are listed in Table 1. 
Prescreening (initial contact):  Prescreening for potential eligibility will be done using a single 
random capillary (fingerstick) blood sample for measurement of HbA1C with a POC instrument. 
Participants are eligible to continue screening procedures if the POC HbA1C is ≤7.2%% and 
screening questionnaire that includes a focused medical history, anthropometric and blood 
pressure measures indicate that they meet initial eligibility criteria. Subjects who are discovered 
to have HbA1c >7.2% will be excluded from participation and referred for formal diabetes 
assessment and treatment through their regular health care provider(s).  
Screening: Participants who meet pre-screening eligibility criteria will present to the study 
center for formal screening to undergo a standard 2-hour 75 gram OGTT, with samples 
analyzed in the central laboratory. Only fasting and 2 hour post-load samples will be obtained 
(a laboratory-based HbA1c must be ≤7.0%, fasting glucose must be 95-125 mg/dl and 2 hour 
glucose must be 140 mg/dl for eligibility in RISE). Eligibility lab tests will also be performed, 
including electrolytes, TSH†(when clinically indicated), triglycerides, creatinine, ALT, 
hemoglobin, and pregnancy test. 
Placebo run-in: Participants meeting eligibility criteria will be instructed to begin the 3-week 
placebo run-in. Participants who have <80% adherence with study medications during this run-
in phase will be withdrawn from the study and no further study procedures will be performed. 
Participants who are adherent with ≥80% of study medication during run-in will proceed to 
baseline study measurements. Participants will be asked demographic and medical history 
information.  


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Table 1: Data Collection During Screening and Run-In Procedures 
STEP 
TEST / PROCEDURE 
COMMENTS 
1) Pre-screening 
Screening HbA1C (POC) 
Continue screening if ≤7.2%  
Screening questionnaire 
Initial review of eligibility  
Height, weight and BP 
Initial screening for eligibility 
2)  Screening 
HbA1c, 75 gram OGTT (central lab); 
glucose at 0 and 120 min 
Eligibility HbA1c ≤7.0%, fasting 
glucose 95-125 mg/dl; 2-h 
glucose 140 mg/dl 
Eligibility labs*  
Laboratory eligibility criteria 
Demographics, medical history, 
medications and physical 
examination 
Eligibility evaluation 
3) Run-in  
Placebo dispensed 
Initiate run-in 
Evaluate  
Determine eligibility for 
randomization 
*Eligibility labs: electrolytes, TSH†, triglycerides, creatinine, ALT, hemoglobin  
†TSH should be assessed as part of trial screening procedures in the following settings: 1) reported use of anti-
thyroid medication, 2) reported use of thyroid hormone, 3) reported history of thyroid disease or 4) clinical 
suspicion of thyroid disease on history and physical. 
 
6.3  Baseline and Post-Randomization Measures  
Measurements to evaluate safety, adherence, and outcomes are summarized in Table 2. The 
outcomes, derived from hyperglycemic clamp procedures, will be measured at baseline, 12 
months (end of treatment), and 15 months post randomization (end of washout). OGTT 
outcomes measurements and blood sampling for other outcomes will be performed at 
baseline, 6 and 12 months following randomization (on treatment) and then at 15 and 21 
months (off treatment). Hyperglycemic clamp and OGTT outcomes measures are described in 
detail above. Other measurements are discussed below. 
Table 2: Timeline of Outcomes, Safety Testing, and Adherence Measures 
 
Baseline/
Pre 
random-
ization 
Post Randomization 
Month 
 
 
3  
6  
9  
12  15  18  
21  
Physical  
 
 
 
 
 
 
 
 
Height 
x 
 
 
 
 
 
 
 


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Baseline/
Pre 
random-
ization 
Post Randomization 
Month 
 
 
3  
6  
9  
12  15  18  
21  
Weight 
x 
x 
x 
x 
x 
x 
x 
x 
Waist / Hip circumference 
x 
 
 
 
x 
x 
 
x 
Blood pressure 
x 
x 
x 
x 
x 
x 
x 
x 
Outcomes 
 
 
 
 
 
 
 
 
Hyperglycemic clamp & AIRmax 
x 
 
 
 
x 
x 
 
 
OGTT 
x 
 
x 
 
x 
x 
 
x 
HbA1C 
x 
x 
x 
x 
x 
x 
x 
x 
Questionnaires 
x 
 
 
 
 
 
 
 
Sleep  
(Pittsburgh Sleep 
Questionnaire, Epworth 
Sleepiness Scale, Berlin 
Questionnaire) 
x 
 
 
 
 
 
 
 
Biomarkers 
x 
 
x 
 
x 
x 
 
x 
Stored Specimens 
 
 
 
 
 
 
 
 
DNA 
x 
 
 
 
 
 
 
 
Plasma / Serum 
x 
 
x 
 
x 
x 
 
x 
Urine 
x 
 
x 
 
x 
x 
 
x 
Safety 
 
 
 
 
 
 
 
 
SMBG for those on insulin 
x 
x 
 
 
 
 
 
 
Hemoglobin or Hematocrit 
x 
 
x 
 
x 
 
 
 
Blood chemistries** 
x 
 
x 
 
 
 
 
 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test (local measure) 
x 
x 
x 
x 
x 
x 
x 
x 
Medication adherence 
x 
x 
x 
x 
x 
 
 
 
** fasting serum ALT and creatinine; pregnancy tests as needed based on symptoms and 
menstrual history 
6.3.1  Physical Measures 
Height will be measured with a stadiometer. Weight will be measured with a calibrated 
electronic scale. Waist and hip circumferences will be measured at the mid-point between the 
iliac crest and the lowest rib (waist), and at the top of the femur (hip) with the participant 
standing upright.  


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6.3.2  Sleep Assessments  
During screening, participants will complete the Pittsburgh Sleep Questionnaire, Epworth 
Sleepiness Scale and Berlin Questionnaire for analysis of self-reported sleep-related measures 
as potential predictors of response to treatment. 
6.3.3  Safety Measures 
Acute treatment effects will be assessed using home glucose monitoring for those assigned to 
insulin therapy, plus scheduled clinic visits and telephone contact. The study will provide blood 
glucose monitors and strips to participants assigned to the insulin arm for use for the first 3 
months of the intervention (baseline to 3 months). During the insulin treatment phase, 
participants will record fasting blood glucose once daily, in the morning, to guide dose 
adjustment for the insulin. Routine chemistries consisting of hemoglobin or hematocrit (local 
lab), serum liver enzymes (ALT) and creatinine will be collected for evaluation of liver and 
kidney function at screening and at six months during treatment. Adverse events (AE) will be 
surveyed at each visit using a standardized questionnaire. Pregnancy tests (local lab) will be 
performed in women with child-bearing potential prior to study procedures at each visit. 
6.3.4  Participant Protocol Adherence 
Pill counts will be performed at each visit from run-in to the end of the treatment period. 
Similarly, insulin or liraglutide pen residual volume will be determined. Participants will be 
asked to bring all medications to all visits. Self-monitoring blood glucose (SMBG) data will be 
reviewed at the 3 month study visit for subjects assigned to insulin treatment.  
6.4  
Visit Windows 
Participants will be encouraged to complete visits within a 1-2 week window before or after the 
scheduled study visit. All participants will have a visit calendar generated at the time of 
randomization to assist in keeping visits scheduled as required.  
7 SAFETY / HUMAN SUBJECTS PROTECTION 
This trial will be conducted in compliance with the protocol and all applicable regulatory 
requirements. All participating clinical sites must have a Federal-wide Assurance with the Office 
for Human Research Protections. All sites will follow HIPAA regulations. 
Prior to study initiation, the protocol and the informed consent documents will be reviewed 
and approved by the IRB at each participating clinical site and by an independent Data and 
Safety Monitoring Board (DSMB). Any amendments to the protocol or consent materials must 
be approved by the DSMB and the IRBs before implementation. 


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7.1  Data and Safety Monitoring Board (DSMB)  
A DSMB comprised of appropriately qualified and conflict-free independent experts is 
appointed by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and 
provides input to the Institute. Board members are chosen by the NIDDK without consultation 
with the study investigators. The purpose of the Board is to assure independent review as to 
whether study participants are exposed to any unreasonable risk because of study 
participation, and to monitor study progress and integrity. In addition to safety monitoring, the 
Board can review unblinded study data and make recommendations for early termination of 
studies for achieving an end point or for futility. Before any of the RISE studies can begin, the 
DSMB, in addition to the local IRBs, must approve the protocol. Any subsequent major changes 
to the protocol must also be approved by the DSMB and IRBs. 
Following each DSMB meeting, a summary of DSMB recommendations is provided to the IRB of 
each participating clinical center and other institutional monitoring committees/boards as 
needed. 
7.2  Data and Safety Monitoring Plan  
7.2.1  Informed Consent 
The informed consent process will be conducted by qualified study personnel. All participants 
must read, sign and date a consent form prior to participation in any stage of the study. The 
informed consent will be revised and participants re-consented whenever there is new, 
clinically significant information regarding the safety of the interventions, when a relevant 
protocol amendment is approved, or when any new information becomes available that may 
affect an individual’s participation in the study. At any time during the study, participants will 
have the option to withdraw from participation without repercussion. In the event that a 
participant withdraws, study medication will no longer be provided but the arm to which the 
participant was randomized will remain blinded, as the analysis will be one of intention-to-
treat. 
7.2.2  Safety Review Plan and Monitoring 
A. Justification of Sample Size – See Section 9.3. 
B. Stopping Rules – The DSMB may suggest terminating a study arm at any time for safety 
or efficacy reasons. Details of interim analysis plans and stopping rules can be found in 
Sections 9.4 and 9.5.  


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C. Safety Monitoring Committee and Safety Review Officer – The study will appoint an 
internal Safety Monitoring Committee (SMC) which will review AEs or other safety-
related problems sent to them from the field. The RISE SMC will review AEs in a blinded 
manner. An external Safety Review Officer will evaluate any serious adverse events 
(SAE) where the SMC is not in agreement about whether the event is related to study 
drug as well as certain specified SAEs of concern (e.g., pancreatitis). The Safety Review 
Officer will not be blinded to study intervention. 
D. Safety Review Plan – The DSMB will meet at least twice yearly either in person or by 
conference call to review study progress and safety as described in Section 7.1. 
7.2.3  Confidentiality 
A. Protection of subject privacy – Participants are identified within the study only by their 
RISE Participant ID. No confidential identifiers are used in any data collection. 
B. Database Protection – All files are stored in a locked cabinet at the clinical centers, and 
data are entered into a secure, password-protected website maintained by the CoC. The 
CoC holds no personal identifiers and stores the data on its enterprise server accessible 
only by approved staff. At the end of the study, all records will be kept in a secure locale 
for a period dictated by local IRB and Institutional policies as well as federal regulations, 
whichever is longest. 
C. Confidentiality During AE Reporting – AEs and SAEs are recorded on data collection 
forms and reported to the CoC without personal identifiers. Identifiers on accompanying 
documents (such as medical records) are removed before submission to the CoC and 
any subsequent transfer to the Safety Monitoring Committee and/or Safety Review 
Officer.  
7.3  Expected Side Effects 
The RISE Study will use the following medications: metformin, insulin glargine and liraglutide.  
Metformin: Known adverse effects associated with metformin are primarily gastrointestinal 
(diarrhea, nausea, vomiting, abdominal bloating, flatulence, anorexia), hematologic (reduced 
vitamin B12 levels and, rarely, megaloblastic anemia), and the rare possibility of lactic acidosis. 
The risk of lactic acidosis associated with metformin use will be minimized by (1) monitoring 
liver transaminases, (2) monitoring renal function, and (3) temporary discontinuation of 
metformin before radiologic studies involving the injection of contrast dye, surgical procedures 
requiring reduced fluid intake, and serious illness that might be associated with hypoxia, 
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Insulin glargine: The side effects of insulin glargine include hypoglycemia and weight gain. The 
occurrence of hypoglycemia will lead to insulin dose adjustment at the discretion of the 
investigator. Participants will be counseled about the possibility of weight gain while on insulin 
therapy and given dietary counseling and resources. Participants on insulin will perform SMBG 
to minimize the risk of hypoglycemia. 
Liraglutide: The most common adverse effects associated with liraglutide are gastrointestinal 
and include nausea, vomiting, and diarrhea. An increased risk of pancreatitis has also been 
reported. A history of previous pancreatitis is an exclusion criterion and an absolute 
contraindication to continuing liraglutide. In addition, increased levels of calcitonin, which are 
associated with medullary thyroid carcinoma, a rare form of thyroid cancer, have been reported 
in some animal and human studies. A history of medullary thyroid cancer or a family history of 
MEN-2 is an exclusion criterion in RISE. 
7.4  Risk Management 
Glucose management (including study medications) will be provided free of charge to RISE 
Study participants while participating in the study. Participants will receive training about the 
proper use of hypoglycemic medications as well as education about the symptoms, causes and 
response to episodes of hyper- and hypoglycemia. Participants who develop symptomatic hypo- 
or hyperglycemia, or experience any side effects of medications or study procedures will be 
instructed to call the clinical site. The following procedures will be implemented to minimize 
risk to participants: 
 Hyperglycemia: Participants will be instructed regarding the signs and symptoms of 
hyperglycemia and are to call the clinic with any concerns. To minimize the risk of 
symptomatic hyperglycemia, the following procedures will be followed: 
 If HbA1c >7% at any routine quarterly visit, therapy will be invigorated by frequent 
telephone contact and/or visits to encourage optimal medication adherence and 
lifestyle choices. HbA1c will be obtained at the next quarterly visit. If HbA1c remains 
>7% but <8%, frequent contact will be maintained. 
 If HbA1c >8.0% at any routine quarterly visit, therapy will be invigorated and HbA1c will 
be repeated after 6 weeks. If it remains >8.0%, outcome assessment will be scheduled in 
2 weeks (i.e., regardless of time since randomization).  
 If at any time – either a routine visit or when a participant is brought in due to 
symptoms – the HbA1c >9%, the HbA1c will be repeated within 2 weeks and, if 
confirmed, the participant will be scheduled for immediate outcome measurement. 


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 Metabolic decompensation:  In the unlikely event that a study subject develops 
metabolic decompensation, defined as hyperglycemia (plasma glucose >300 mg/dl) 
accompanied by significant symptoms (e.g., vomiting, dehydration, lethargy) and/or 
moderate or large urinary ketones, the participant will be evaluated to determine if 
temporary use of insulin therapy is required. Once insulin is started, the site will attempt 
to wean insulin within 4 weeks. If insulin cannot be weaned off within 4 weeks, the 
patient will be censored at that time. 
 If outcome measurements are performed prior to the scheduled time points of 12 or 15 
months, once completed the participant will be referred back to their primary care 
provider for further care.  
 Gastrointestinal (GI) symptoms are a common occurrence with metformin and liraglutide. 
However, these symptoms more commonly occur early in the course of treatment. All 
eligible participants will be slowly titrated to the maximal tolerated doses of metformin or 
liraglutide, in order to minimize gastrointestinal side effects. For metformin, the dose will 
be started at 500 mg daily and titrated slowly to 1000 mg bid. If GI side effects develop and 
are mild, the patient will be encouraged to remain on the study medication. If GI side 
effects are moderate or difficult to tolerate, metformin will be reduced to the next lowest 
dose (for example, 1000 mg bid to 1000 mg + 500 mg; 1000 mg + 500 mg to 500 mg bid; 
etc.). If symptoms persist, metformin will be reduced to the next step. If GI symptoms 
resolve, metformin will be re-escalated by 500 mg per day each week until reaching the 
previously tolerated dose. The participant will continue on the maximum tolerated dose. A 
similar procedure will be followed for liraglutide, with the relevant doses being 0.6, 1.2 and 
1.8 mg daily. 
 Anemia may be an adverse effect of metformin. It is defined as a hematocrit <30.0%, a 
hemoglobin <10 gm/dl, a decline in hematocrit by 4% from study entry, or a decline in 
hemoglobin by 2 gm/dl from study entry. If anemia persists for more than six months 
despite appropriate therapy, consideration will be given to discontinuing study medication.  
 Renal insufficiency increases the risk of lactic acidosis associated with metformin. To asses 
renal insufficiency, serum creatinine and estimated GFR (eGFR) will be calculated using the 
CKD-Epi equation (ref . Ann Intern Med. 2009;150(9):604-612.) at screening and after six 
months on therapy.  Participants must have an eGFR of 45 mL/minute/1.73 m2 or higher to 
be eligible.  Metformin will be discontinued if eGFR is below 30 mL/minute/1.73 m2 at the 
Month 6 visit. If eGFR ≥30 and <45 mL/minute/1.73 m2 then the RISE Safety Committee will 
review the case to assess the benefits and risks of continuing treatment, and make a 


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recommendation to the clinical center investigators about whether to continue the 
participant on metformin. 
 Mild hypoglycemia is common in subjects with prediabetes or diabetes being treated with 
medications to lower glucose levels into or near the normal range. Participants will be 
educated to recognize and treat mild hypoglycemic episodes and to contact study staff to 
report hypoglycemic episodes or receive advice. Adjustments to study medication will be 
made when appropriate. 
 Severe hypoglycemia is defined by the need to be treated with glucagon, the need for a 
third party to resolve a hypoglycemic episode, or loss of consciousness or seizure. Study 
medications will be adjusted downward as appropriate. 
 Metformin and its placebo are temporarily discontinued 24 hours before, during, and for 48 
hours after any of the following events to reduce the risk of lactic acidosis: 1) procedure 
involving the injection of contrast dye; 2) surgery or other procedure requiring general 
anesthesia; 3) any illness that could be associated with hypoxia, circulatory failure, or 
dehydration; 4) hospitalization. Serum creatinine will be rechecked no sooner than 48 hours 
after the conclusion of the event and study medication recommenced if appropriate.  
 Other indications for temporary or permanent discontinuation of study medication include: 
 Pregnancy:  Study medications will be discontinued if a participant becomes pregnant. 
The participant will be referred to a high risk obstetrics clinic for further care. Study 
medications will not be administered if a participant plans to become pregnant. 
 Lactation:  No study medication will be administered to women who are nursing a baby. 
 Lactic acidosis:  Any study participant who experiences a bout of lactic acidosis will have 
metformin and metformin placebo permanently discontinued.  
 Dermatological problems:  Any study participant who experiences severe dermatological 
problems, such as urticaria, bullous rashes, exfoliative dermatitis, Stevens-Johnson 
syndrome, thought to be related to study medication will have study medication 
permanently discontinued. 
 Pancreatitis: Any study participant who is diagnosed with pancreatitis during the study 
will have liraglutide permanently discontinued. 
 Medullary thyroid carcinoma: Any study participant who is diagnosed with medullary 
thyroid carcinoma during the study will have liraglutide permanently discontinued. 
 Adverse effects of the study procedures may occur very rarely and include: 
o Glucose injection and infusion:  Irritation of a vein resulting in phlebitis can occur with 
administration of concentrated glucose solutions. The risk will be decreased by 


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minimizing the use of concentrated solutions and selecting large veins for infusion of 
solutions. 
o Arginine:  Overdosage, especially in children, can be fatal. To reduce this risk, the dose 
of arginine will be weight based (0.07 gm/kg in children) with a maximum dose of 5 gm 
per dose in both adults and children. 
7.5 Potential Benefits 
There is potential benefit of participation by individuals with either prediabetes or type 2 
diabetes. Prediabetic participants are at increased risk of developing diabetes and may benefit 
from the frequent monitoring and testing that will allow earlier recognition should their 
condition progress; treatment is also predicted to slow progression from prediabetes to type 2 
diabetes. Participants with type 2 diabetes will benefit through the close monitoring and the 
improvement in glucose control that should occur in all subjects. In addition, they have the 
potential to receive insulin or liraglutide that should further improve glucose control in them 
and potentially slow progression of their disease. Further, liraglutide could help with weight 
loss. As all subjects have a condition that is becoming more prevalent and carries with it the risk 
of additional complications, participation will also benefit the individual, the researchers and 
society through the gaining of new knowledge. 
7.6  HIPAA – Protection of Patient Information 
All data collected in the process of pre-screening, screening, and conducting the proposed 
research will be stored and maintained locally and centrally in compliance with HIPAA 
regulations. Access to study data will be secure with limited, password-protected access. Only 
study personnel who are IRB approved will have access to data collected as part of these 
studies. Data entered into the central database will be stored at the CoC on a server that is 
maintained with the highest stringency of protection. Similarly, data entered into local 
databases will be stored at the clinical center on a server that is maintained with the highest 
stringency of protection.  
8 ADVERSE EVENT REPORTING  
An adverse event is defined as any medical problem experienced by a RISE participant whether 
or not considered intervention-related by the clinical center staff. The timely and complete 
reporting of adverse events is a critical requirement in the conduct of this trial. In 2013 the FDA 
issued an IND exemption for the RISE Study. Therefore, the study group and NIDDK are not required to 
report any study adverse events to the FDA. 


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8.1  Definition of Serious Adverse Events 
a. The event results in an inpatient hospitalization (any overnight stay associated with an 
admission). 
b. The event results in the prolongation of a hospital stay. 
c. The event results in permanent or severe disability. 
d. The event results in death. 
e. A pregnancy results in a congenital anomaly. 
f. The event results from an overdose (either accidental or experimental) of the study 
medication. 
g. The event is life-threatening. 
h. Treatment is required to prevent a serious event. 
8.2  Non-serious Adverse Events  
Non-serious adverse events are all AEs which do not meet the above criteria for “serious”. 
8.3  Reporting Adverse Events 
AEs will be ascertained in an unbiased manner using standard questions that are identical and 
identically administered to participants in all treatment arms. To accomplish this, AEs will be 
reported on a standard form that is completed by the study staff at each regular study visit 
following commencement of study-related activities. Targeted non-serious AEs (e.g., abdominal 
pain) are ascertained by asking questions relating to specific events of import in prediabetic or 
diabetic participants as well as side effects that may be associated with any of the study 
treatment arms. AEs also include any significantly abnormal laboratory result obtained on the 
patient between visits or at the time of the visit. 
The clinical center staff who learn of an SAE must data enter the completed RISE Serious 
Adverse Event Report prior to the close of the following business day. Upon request, all SAEs 
will be reported within the prescribed period to the relevant pharmaceutical sponsors. 
All pregnancies occurring during the study must be reported by the clinical center staff to the 
CoC. This reporting must occur prior to the close of the business day that follows the clinical 
center becoming aware of the pregnancy. Further, the outcome of the pregnancy must be 
determined and reported by clinical center staff as soon as possible after the pregnancy is 
completed. All this information will be reported within the prescribed period to the relevant 
pharmaceutical sponsors. 


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8.4  Tracking Adverse Events 
 Serious Adverse Events: SAEs will be monitored by the RISE Safety Monitoring Committee, 
which will remain blinded to treatment arm. The external DSMB will monitor SAEs by 
treatment arm. It is important to note that all serious and unexpected AEs must be reported 
to the CoC, regardless of the drug-related assessment. For example, a patient struck by 
lightning requires a report, even though this is not likely to be a drug related event.  
 Non-serious adverse events: Non-serious AEs are tabulated by the CoC in periodic reports. 
Summaries of the AEs, tabulated by clinic, are provided to the Safety Monitoring 
Committee, which reviews this summary during one of its regularly scheduled meetings.  
 Safety Monitoring Committee: The Safety Monitoring Committee reviews AEs in a blinded 
fashion. The committee considers whether changes in the protocol (monitoring, consent 
process, etc.) are indicated based on the occurrence, frequency, or severity of AEs. The 
committee also evaluates whether there is any clustering of AEs by clinic. Any concerns on 
the part of the Safety Monitoring Committee may be referred to the Safety Review Officer 
and/or DSMB, which can review SAEs in an unmasked manner. 
 Safety Review Officer: The Safety Review Officer will review any SAEs where the SMC is not 
in agreement about whether the event is related to study drug, as well as certain specified 
SAEs of concern (e.g., pancreatitis). The Safety Review Officer will not be blinded and will 
confirm or reject the causality determination of the SAE to study intervention. As deemed 
necessary, he/she may contact the local site PI to obtain additional information about the 
SAE. Any concerns on the part of the Safety Review Officer may be referred to the DSMB.  
8.5  Emergency Unmasking 
The Safety Monitoring Committee remains blinded to treatment group. If a SAE warrants 
unblinding, an on-call member of the Safety Monitoring Committee is available for consultation 
at all times. Unblinding will be performed by a selected member of the study group in 
combination with the CoC. 
9 STATISTICAL CONSIDERATIONS  
All analyses will be conducted under the intention-to-treat principle using the treatment as 
assigned to each participant, and using all available data from all participants. Analyses of study 
data will be conducted to address the primary and secondary objectives of the trial, other 
stated objectives, and other interrelationships among elements of study data of interest to the 
investigators and of relevance to the objectives of the study.  


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9.1  Primary Outcome and Analyses 
Two primary outcomes each measuring ß-cell function after 3-months of washout will be 
assessed for this trial. In order to maintain a study-wide =0.05, a closed testing procedure will 
be used to assess the primary outcome [89].   The closed testing procedure is a method of 
hierarchical testing which tests higher-order comparisons before allowing lower-level 
comparisons, thus controlling the type I error and preserving power. First, ß-cell function will be 
compared across the four treatment groups using an analysis of covariance model adjusted for 
baseline ß-cell function.   From this model, the overall test of equality across the four treatment 
groups will be computed. If that overall test is significant at the =0.05 level, then each of the 
four possible sets of three interventions will be compared in four separate analysis of 
covariance models. The final significance testing of any set of two treatment groups is only 
undertaken if the p-values for each of the two 3-intervention tests which include a particular 
two intervention group are both p<0.05. For example, for interventions I1, I2, I3 and I4, the first 
analysis of variance test I1234 assesses whether there are any differences among the four 
groups. If the overall test across the four groups is not significant, testing concludes and no 
treatment group is declared different from any other. Alternately, if that initial 4-group test is 
significant at the =0.05 level, four separate analysis of covariance models with combinations 
I123, I124, I134 and I234 are tested. The comparison I12 is only tested if both I123 and I124 are 
significant at p<0.05 and so forth. The closed testing procedure is chosen as the primary 
outcome analysis to maintain an overall study-wide =0.05 while preserving power and 
allowing each set of interventions to be compared under pre-specified circumstances. The two 
primary outcomes will be analyzed separately with a total type I error probability of 0.05 for 
each, i.e. without an adjustment for two separate outcomes. 
 
Each ANCOVA model will employ White’s robust (information sandwich) estimate of the 
covariance matrix of the model coefficients as the basis for inference [90]. This approach 
preserves power and protects the type 1 error probability when the homoscedastic normal 
errors assumptions are violated.  
9.2  Secondary Outcomes and Analyses 
Comparisons of the primary study outcomes will be made for those with vs. without diabetes at 
study entry, by race/ethnicity and sex, by baseline HbA1c and ß-cell function, and by categorical 
groups of various biomarkers.  
Analysis of covariance will be used to compare the three intervention groups and the placebo 
group for the primary measures of ß-cell function at the end of the active intervention phase 
(12-months) and 9-months post-washout as well as for additional continuous variables of 


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interest at the end of the intervention phase (12-months) and at 3-months and 9-months post-
washout. As for the primary outcomes, all analyses will be adjusted for the baseline value of 
each outcome and will use the closed testing procedure described above to preserve an overall 
=0.05 for those outcomes as well. 
An important secondary analysis of this study is to determine whether ß- and -cell function 
from OGTT and fasting samples are sufficiently well correlated with more robust assessments of 
ß- and -cell function obtained from the hyperglycemic clamp to validate their use in large 
clinical trials. For these analyses, Pearson and non-parametric Spearman correlations of simple 
versus sophisticated measures of ß- and -cell function will be computed. Correlations will be 
assessed for measures made both on and off therapy. 
Finally, to examine biomarker associations with glucose metabolism, Pearson and non-
parametric Spearman correlations of each biomarker with ß- and - cell function, insulin 
sensitivity and glucose tolerance measures will be determined. In addition, multiple linear 
regression models will be developed to predict measures of glucose metabolism with the most 
informative biomarker sets. 
9.3 Sample Size/Power Calculations 
There is little preliminary data on the expected differences in the primary outcomes in 
previously drug-naïve patients following a washout. Several 
unpublished analyses provided ranges of possible differences 
between treated and placebo patients, as well as expected 
correlations between baseline and follow up measures. 
Therefore, sample size was based on a minimum effect size 
(i.e., absolute difference between any two groups divided by 
the standard deviation (SD)) using a two-sided significance 
level of =0.05, and a conservative correlation of 0.57 
between baseline and follow up measures. A sample size of 
56 per arm (224 total) at the end of the washout provides 
≥80% power to detect a minimum effect size of 0.60 between any two treatment groups in 
either of the primary outcome measurements (see Table 3) for the closed-testing procedure as 
described above using a baseline-adjusted analysis of covariance. A higher effect size will result 
in significantly increased power. A total of 255 participants will be recruited to allow for a 10% 
loss to follow-up over the course of the study. 
Table 3: Power for a sample size of 
224 at end of study (56/treatment 
arm) 
Minimum 
Power 
Adjusted 
Effect 
Size 
Correlation 
84% 
0.62 
0.60 
81% 
0.60 
0.57 
77% 
0.57 
0.50 


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9.4  Interim Analysis Plans 
The CoC will provide interim analyses of primary and major secondary trial outcomes to the 
DSMB on a predefined schedule. These results will not be shared with the study group unless 
the DSMB recommends early stopping of the trial. 
9.5  Stopping Rules 
The DSMB will monitor trial outcomes as they emerge for futility with specific rules outlined in 
the DSMB Monitoring Plan. This trial will not be stopped for lack of efficacy, as it is a proof-of-
principle study with small numbers of participants in each treatment arm.  
9.6  Handling of Missing Data 
It is anticipated that a small number of participants will require immediate rescue therapy and 
be unable to have the 3-month post-washout evaluation. In these cases, the primary outcome 
will be missing. A sensitivity analysis which includes these participants will use a conservative 
approach by assuming that these participants have worse function than the participants who 
were measured. This is implemented by ranking the observed function values from the 
participants who completed the washout evaluation, and assigning a lower value (or worst 
rank) to those with missing data [89]. The groups are then compared using a Wilcoxon rank 
test.  
10 DATA PROCESSING AND MANAGEMENT  
10.1  
Data Management System 
Data are entered by the clinical centers using a web data entry application that directly enters 
study data into the CoC’s study database. The web application guides the clinical site staff 
member through the data entry process. If an invalid response is entered, the website signals 
and provides a message about the error and how to solve it. At any point during entry, the staff 
member can make an electronic note concerning a particular response. Valid individual 
responses are saved as soon as they are entered. The system includes programmed skip 
patterns as required by the case report forms, and also includes quality control checks such as 
lists of valid values for multiple choice items. The system provides automated consistency 
checking so the study staff can resolve inconsistencies quickly without a lengthy communication 
with the CoC. The same checking is also run on the central database at the CoC to verify that 
centers are resolving consistency checks. 


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10.2  
Data Transfer  
Newly entered clinical center data are received by the CoC immediately upon data entry. The 
CoC merges newly received data with the accumulated data in a SAS database. Data transfer 
from central units such as the central laboratory will be through the CoC data management 
system. 
10.3 
Quality Control 
Range checks, inter-item checks, cross-table checks, and double data entry verification are used 
where appropriate to ensure accurate data entry. Specific quality control procedures are run to 
check for missing, incorrect, and questionable values immediately after they are entered. 
Reports with the necessary patient identifying information and the problem values are printed 
and sent to the clinical centers for correction or verification. When returned, corrected values 
are entered and checked again for consistency with other items. The goals are to make quality 
control a continuous process, to make the turnaround time between error detection and 
correction as short as possible, and to document any changes made to the database. 
10.4 
Back-up, Data Security and Confidentiality 
The CoC adheres to the George Washington University Biostatistics Center’s data backup and 
security policies to ensure the safety and confidentiality of the data. Backup procedures 
include: twice-weekly system backup, daily incremental backup, and off-site disaster recovery 
backup. Security procedures include: logon and link password protection, and for internet 
access, separate Web servers which use SSL and encryption algorithms. Virus and malware 
protection software is used on all computers and is updated on an hourly basis. All portable 
computers employ full disk encryption. George Washington University computing facilities 
provide support in the event of a disaster. Access to the server and databases is secured by use 
of login user accounts and passwords. Remote access is granted only to authorized users and is 
accomplished using a secure virtual private network (VPN). Appropriate filtering/firewall setup 
is used to prevent unauthorized access. 
10.5 
Tracking Study Progress 
The purpose of tracking reports is to keep the collaborative group informed of study progress, 
and to report special problems and resolutions. Reports will be produced regularly by the CoC, 
as directed by the Steering Committee. These reports will be distributed to the study group 
through the study website. 
Tracking reports include the following types of information: 


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 screening and enrollment (versus goal), by clinical center, gender, and race/ethnicity 
 tables describing adherence to the study protocol (attendance at scheduled study visits, 
study intervention compliance) 
 database inventory 
 number of data edit queries generated and outstanding, by clinical center 
 progress of analysis and manuscripts 
10.6 
Archiving and Study Close-out  
At the end of the study, after all data have been received and edited, the database will be 
archived in computer readable format, including documentation files, files of study documents 
(such as forms annotated with variable names, protocols, and manuals of procedures), data 
files in the form of SAS transport files and input statements, data dictionaries, and program 
code documenting any derived variables. After the study is complete, all data will be available 
to RISE study investigators and to investigators from outside the study in a manner consistent 
with the NIDDK’s data distribution procedures. Data will be stored at a readily accessible, 
password-protected website. 
11  STUDY ADMINISTRATION  
This randomized clinical trial is one of three studies conducted by the RISE Study Consortium. 
RISE is a collaborative study group funded by the NIDDK of the National Institutes of Health 
(NIH) under a cooperative agreement mechanism. The goal of the RISE Study is to test different 
interventions to preserve ß-cell function in separate trials, with shared procedures and data 
collection approaches allowing for the ability to compare data across studies and combine data 
from individual studies by harmonizing study outcomes and data collection. The RISE Study 
investigators will be conducting three separate clinical trials. The investigators for each trial are 
responsible for recruiting participants and implementing their respective protocols. In addition, 
the RISE Study investigators participate in consortia activities, as described below. 
11.1 
Organization  
The major organizational components and their responsibilities are described: 
 The RISE Steering Committee, comprised of the principal investigators of the clinical centers, 
the CoC, and the NIDDK project office, is the primary decision making body for the study 
with overall responsibility for the design and conduct of the common elements of the study 
protocols. 
 The NIDDK project office participates in all decision-making activities and selects and 
oversees the activities of the DSMB. 


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 The Coordinating Center (CoC) located at the George Washington University Biostatistics 
Center operates under subcontract to the Seattle Institute for Biomedical and Clinical 
Research (SIBCR). The CoC has responsibility for coordinating the study, including 
production and distribution of materials and documents, set-up and administration of the 
data management system, maintenance of the central database, analysis of primary study 
results, distribution of final study data to the clinical centers and NIDDK repository, and 
reporting of results in collaboration with the other investigators. 
 The Central Blood Laboratory (CBL) operates under subcontract to the Seattle Institute for 
Biomedical and Clinical Research. The CBL is responsible for providing procedures for the 
handling, storage, and shipment of blood specimens, for performing the tests and assays, 
for performing quality control, for providing patient-level reports to clinical centers, and for 
transferring results to the CoC. 
 The DSMB is composed of outside experts in the design and conduct of clinical trials, and in 
type 2 diabetes. The board is responsible for reviewing the study documents, monitoring 
study progress, and monitoring patient safety.  
 Working committees include Outcomes, Recruitment and Retention, Safety and Monitoring, 
Publications and Presentations, Ancillary Studies, Lab Quality Control, and Program 
Coordinators. Committees can be discontinued and additional committees can be created 
as required. 
11.2  
Central Laboratories and Reading Centers 
In collaboration with the CoC and study investigators, central laboratories and reading centers 
perform the following tasks: 
1. Establish procedures and standards for training staff involved in the measurement, 
collection, preparation, handling, transfer, and all other procedures and processes. 
2. Conduct training sessions and contribute training materials to the study manuals of 
procedures. 
3. Provide or facilitate the acquisition of equipment and materials, including specifying brands, 
sizes, and suppliers as applicable.  
4. Establish procedures for data entry and transfer of data to CoC. 
5. Develop procedures for the internal as well as external quality control, and provide periodic 
reports on the quality control surveillance. 
6. Provide long-term storage of reserve specimens or materials as directed by the Steering 
Committee and NIH policy for use in ancillary or future studies. 


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Each director represents the laboratory or center at RISE Steering Committee meetings, on 
Steering Committee conference calls, and on other conference calls where the director’s 
participation is deemed necessary. 
11.3  
Training and Certification  
During the start-up period, clinic staff will receive central training and certification at a training 
workshop held by the study group. The CoC staff and selected clinical center staff with 
expertise in various study components will provide instruction in all aspects of the study. The 
purpose of the training workshop is to provide training for study staff in order to insure that the 
study is conducted in a standardized manner across all participating centers. The training, based 
on the study manual of procedures, includes review of study design, focus on eligibility criteria, 
subject follow-up schedule and assessments, physical, metabolic measurements, processing 
and shipment of specimens, use of data entry software and electronic forms, transferring data 
to the CoC, maintaining patient and data confidentiality, and patient treatment guidelines. 
Prior to being allowed to recruit participants, each clinical center must pass certification 
criteria, including satisfactory participation in training as above, and supplying the CoC with an 
IRB approval letter and stamped informed consent forms. 
Throughout the study, new staff will be trained at the appropriate clinical center and by CoC 
staff where appropriate. Clinic staff will re-certify annually on identified procedures. Records of 
certifications and training will be maintained at the clinical sites. 
11.4  
Site Visits  
The Steering Committee will be responsible for ongoing monitoring of the performance of study 
components. 
There are two types of site visits that can be conducted (1) scheduled monitoring and (2) as 
needed to address specific problems. 
The RISE Study does not anticipate scheduled monitoring site visits. 
If necessary, site visits will be conducted to address specific problems at a clinical center. 
Depending on the specific issues, site visits will be attended by the study chair or designee, the 
NIDDK project office, the CoC, clinical center coordinators, and others as needed. Each visit will 
follow a predetermined format and site visitors will complete a checklist to record findings. The 
site visit team will review study procedures and compare data collection records to listings from 
the central database. A formal site visit report will be provided to the clinical center and to the 


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RISE Executive Committee to aid in correcting any issues found, and a follow-up site visit will be 
conducted if necessary.  
11.5  
Study Website  
The CoC maintains the study website, which is a secure site requiring a user ID and password 
combination for access. The web server utilizes the Secure Socket Layer (SSL) protocol that 
encrypts all traffic to and from the server. Investigators, coordinators, consultants, and other 
study staff who would benefit from access to the information on the website are each given a 
unique user ID and password, which identifies the user to the web server and can be used to 
restrict access to particular web pages if desired. 
The website contains study documents such as the protocol, manual of procedures, and forms, 
study calendar, directory, meeting and conference call information, links to other sites, tracking 
reports, minutes, and agendas. 
11.6  
Conflict of Interest Policy 
The RISE Study investigators have adopted a conflict of interest policy similar to that used by 
other NIDDK collaborative groups. On an annual basis or whenever there is a significant change 
in status, RISE collaborators are required to disclose any financial or related interest that could 
present an actual conflict of interest or be perceived to present a conflict of interest. Disclosure 
is required to protect each individual’s reputation and career from potentially embarrassing or 
harmful allegations of inappropriate behavior, and to protect the integrity of RISE Study 
research. Conflict of interest forms are kept on file at the CoC, and all conflicts are declared at 
each study group meeting. 
The RISE Ethics Committee (NIDDK Project Scientist, NIDDK Program Official and study group 
member) determines (1) if the disclosed interests could directly and significantly affect the 
performance of study responsibilities and (2) the actions needed for management, reduction, 
or elimination of the conflict. In addition to complying with the RISE conflict of interest policies, 
collaborators must certify to the Ethics Committee that they have complied with all of their 
local and institutional requirements regarding conflict of interest and disclosure. This is 
accomplished by supplying the CoC with copies of the local IRB letter of approval and stamped 
informed consent form(s). Should an institution make a determination regarding an 
investigator’s potential conflict of interest that could affect participation in RISE, the local clinic 
should report this to the RISE Executive Committee. 


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11.7  
Publications and Presentations Policy  
The Publications and Presentations Subcommittee (PPS) will coordinate, monitor, review, and 
assume responsibility for overseeing the preparation of all study-wide communications (press 
releases, interviews, presentations (oral and posters), and publications) relating to the scientific 
aspects of the study. There will be no publication or presentation of study plans or results, 
including ancillary studies, which have not been reviewed and approved by a majority of the 
PPS, and for some types of communications, a majority of the Steering Committee.  
With respect to publications and presentations from the RISE Study consortium, the goals of 
the PPS are to: 
1. Ensure accurate, uniform, timely, and high quality reporting of RISE activities and 
results; 
2. Preserve the scientific integrity of the study; 
3. Safeguard the rights and confidentiality of participants; 
4. Assure that the timing of publications and presentations serves the right of the public 
to know the results of the program without jeopardizing its conduct; and 
5. Ensure that appropriate credit is acknowledged for people responsible for RISE and 
the data being reported and for the funding organizations. 
Detailed policies are found in the Manual of Operations. 
11.8  
Ancillary Studies Policy  
The Ancillary Studies Subcommittee will evaluate all proposals for studies that involve RISE 
participants and/or data that are not a part of the protocol. These studies may be done in all 
RISE participants or only on a subset of participants in RISE. Ancillary studies may make use of 
data and/or samples already collected from RISE participants or may involve the collection of 
new data and/or samples. The RISE Ancillary Studies Subcommittee must review all proposed 
ancillary studies and these must receive final approval by both the Steering Committee and 
DSMB. Major factors in consideration of ancillary studies will include: 
 Clinical importance and scientific validity; 
 Compatibility of goals with those of RISE; and 
 Burden on study subjects and staff, including those at the CoC 


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Approved ancillary studies will be reviewed by the DSMB. Detailed policies are found in the 
Manual of Operations. Ancillary studies will have to obtain funding from outside the study. 
11.9  
Protocol Amendments 
Adoption of protocol amendments requires two-thirds majority approval by voting members of 
the RISE Steering Committee and approval by the DSMB. The amended protocol will be 
resubmitted to the IRB, and the participant consent will be revised appropriately. 
11.10 Repository for Storage and Distribution of RISE Data and 
Samples  
At the end of the study, de-identified research data and samples of blood and urine will be 
provided to the NIDDK Central Repositories, a research resource supported by the National 
Institutes of Health. The Repository collects, stores, and distributes biological samples and 
associated data from people with many kinds of disorders, from unaffected family members, 
and from other healthy people. The purpose of this collection is to make samples available for 
use in research for the study of obesity and diabetes and related complications after the RISE 
Study is completed. Sending samples to the Repository may give scientists valuable research 
material that can help them to develop new diagnostic tests, new treatments, and new ways to 
prevent or postpone the onset of obesity and/or diabetes.  
As a component of the informed consent process, all participants will be asked to provide 
specific informed consent for release of data and samples to the NIDDK Repositories. Before 
the RISE Study investigators send data or samples to the Repository, each sample and data 
record will be given a code number and the data will be de-identified according to HIPAA 
requirements. Participants may choose to participate in RISE but not provide consent to have 
their samples and/or data transferred to the NIDDK Repository. 
12  STUDY TIMELINE  
The study timeline allows for recruitment over the first 3 years of the study, which commences 
after all approvals have been obtained (DSMB, FDA, IRBs, CTAs or CRADAs), central study 
training has been performed and all study medications and supplies have been procured. 
Intervention and washout phases occur through the middle of year 5 and presentations and 
publications throughout the period of the study. 


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13  LITERATURE CITED 
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interacting epidemics. Chest 133: 496-506 
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impaired glucose metabolism in normal-weight and overweight/obese individuals: the Sleep 
Heart Health Study. Diabetes Care 31: 1001-1006 


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[36] 
Resnick HE, Redline S, Shahar E, et al. (2003) Diabetes and sleep disturbances: findings 
from the Sleep Heart Health Study. Diabetes Care 26: 702-709 
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patients with type 2 diabetes. Diabetes Care 32: 1017-1019 
[38] 
Aronsohn RS, Whitmore H, Van Cauter E, Tasali E (2010) Impact of untreated obstructive 
sleep apnea on glucose control in type 2 diabetes. Am J Respir Crit Care Med 181: 507-513 
[39] 
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with troglitazone in the Diabetes Prevention Program. Diabetes 54: 1150-1156 
[40] 
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prevention in impaired glucose tolerance. N Engl J Med 364: 1104-1115 
[41] 
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function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance 
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prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 359: 2072-
2077 
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The NAVIGATOR Study Group (2010) Effect of nateglinide on the incidence of diabetes 
and cardiovascular events. N Engl J Med 362: 1463-1476 
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The ORIGIN Trial Investigators (2012) Basal insulin and cardiovascular and other 
outcomes in dysglycemia. N Engl J Med 367: 319-328 
[45] 
Zinman B, Harris SB, Neuman J, et al. (2010) Low-dose combination therapy with 
rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double-blind 
randomised controlled study. Lancet 376: 103-111 
[46] 
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incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes 
Prevention Study. Lancet 368: 1673-1679 
[47] 
DREAM On Investigators (2011) Long-term effect of rosiglitazone and/or ramipril on the 
incidence of diabetes. Diabetologia 54: 487-495 
[48] 
The DREAM Trial Investigators (2011) Incidence of diabetes following ramipril or 
rosiglitazone withdrawal. Diabetes Care 34: 1265-1269 


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control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 
34). Lancet 352: 854-865 
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16. Overview of 6 years' therapy of type II diabetes: a progressive disease. Diabetes 44: 1249-
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risk of bladder cancer among diabetic patients in France: a population-based cohort study. 
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cancer in people with type 2 diabetes: nested case-control study. BMJ 344: e3645 
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apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 
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replication and neogenesis, resulting in increased ß-cell mass and improved glucose tolerance 
in diabetic rats. Diabetes 48: 2270-2276 
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SAP_001.pdf: 
RISE Primary Outcome Analysis Plan – Adult Medication Study  
Approved by RISE Steering Committee, Sept 2017  
Approved by RISE DSMB, November 2017  
  
Often the Disposition Index (DI) – insulin sensitivity * insulin response – is used as an overall 
measure of beta-cell function that appropriately accounts for the reciprocal relationship of insulin 
sensitivity and the beta-cell’s insulin response. In these analyses, the DI assumes that the product 
of the two variables is constant within an individual at a given time, such that changes in insulin 
sensitivity would be mirrored by a proportional change in the insulin response. This implies that all 
points along the line represent the same level of metabolic function. In many instances this 
relationship has been demonstrated using insulin responses to be a rectangular hyperbola (by 
definition, the slope of the log-log relationship equal to -1.0); however, in others this relationship 
has just been assumed. The power calculations for RISE were based on the DI using data provided 
by several investigators that used methodologies that differed from those used in RISE.  
During protocol development there was thus concern that relationships underlying this constant 
depend on the actual measures of peptide (insulin or C-peptide) release by the beta cell. In 
particular, the slope of the log-log relationship between secretion and sensitivity might not be 
equal to -1.0 for the C-peptide measures chosen for RISE as had been observed in prior studies 
based on insulin measures. Therefore, the protocols specifically state that the primary outcomes 
would be based on two different C-peptide responses (steady state and maximal) adjusted for 
insulin sensitivity defined as the glucose disposal rate divided by steady state insulin (aka M/I) 
during the hyperglycemic clamp. However, given the likely possibility that the relationship may not 
be a rectangular hyperbola, the protocol did not specify details of the approach to be used for the 
primary outcome analysis as a decision would be based on evaluation of the baseline data.  
During analysis of the baseline data, we found that the DI (i.e. sensitivity x secretion) is sometimes 
paradoxically lower in pediatric participants than adult participants, despite the fact that the insulin 
sensitivity vs. C-peptide curves describing the relationship between these two variables appears 
higher in children. This contradictory finding is at least in part due to the fact that the range of 
values for insulin sensitivity among children is narrow compared to that of adults, i.e., children are 
more insulin resistant than adults. Further, the log-log slopes of insulin sensitivity vs. C-peptide 
responses are not equal to -1 in children or adults (or overall). Although the untransformed data 
show a clear inverse relationship typical of a hyperbolic curve, the slopes for each of the primary 
outcome measures on the log scale is approximately -0.3 (not -1.0 as may have been expected); this 
is a hyperbola but not a square hyperbola. Thus, the approach of performing the primary outcome 
analysis comparing treatment groups after washout, with a test of difference in DI at Month 15 
adjusted for baseline, may not be appropriate and needed to be reassessed.    
Several options were considered including a simple linear regression model (on a log scale) of C-
peptide (and insulin) release as a function of insulin sensitivity, with a term for treatment group and 
adjusting for both variables at baseline. However, this was also deemed inappropriate because that 
model would estimate the difference in C-peptide (and insulin) release between groups assuming 
that there was no difference in insulin sensitivity between groups. Rather, we want to account for 
movement of both variables simultaneously without forcing a specific relationship between them. 
This can be accomplished by performing the primary outcome analysis using two separate models: 
insulin sensitivity at Month 15 vs. treatment arm (adjusted for baseline) and C-peptide (and insulin) 


release at Month 15 vs. treatment arm (adjusted for baseline), where the two models are fit 
simultaneously using Seemingly Unrelated Regression techniques1-5. This provides an estimate of 
the treatment group difference in insulin sensitivity as well as the treatment group difference in the 
release of the beta-cell peptides, while allowing for the correlation among the insulin sensitivity 
and peptide release measures. This yields an estimate of the joint covariance structure of the two 
models, and allows a joint statistical test of both variables using a 2-DF chi-square test of the 
treatment arm difference in each model. Thus, we will be able to test whether both the insulin 
sensitivity and C-peptide (and insulin) release variables are different across treatment groups at 
Month 15, adjusted for their baseline value.   
This approach will provide a clear answer to the question of whether the Month 15 result differs by 
treatment, adjusting for baseline measures. However, given that an underlying reciprocal 
relationship is expected, it is possible that a significant difference could be found between groups, 
but that this represents a proportional shift without a specific improvement in peptide release 
adjusted for sensitivity. In other words, the data points could lie on a different part of a shared 
relationship curve such that the change represents a mutually compensated change in these terms 
without a separate underlying change in beta-cell function. Therefore, if the results of the two 
model analysis are significant, further analysis will evaluate the patterns of change in either or both 
variables within each group.   
Below is sample Primary Outcome R code for this primary analysis.     
  
R code and sample output for primary outcome with Seemingly Unrelated Regression model using systemfit  
  
> fit12=systemfit(list(Eq1 = log_mi ~ Treatment + log_mi_base,                
Eq2 = log_cpeptide_steady ~ Treatment +    
  
        
log_cpeptide_steady_base),  
                method='SUR',                 
data=RISEM15)  
  
> linearHypothesis(fit12,test = "Chisq",  
                 c('Eq1_TreatmentTreat2=0','Eq2_TreatmentTreat2=0'))  
  
Hypothesis: Eq1_TreatmentTreat2 = 0    Eq2_TreatmentTreat2 = 0  
  
Model 1: restricted model  
Model 2: fit12  
  
  Res.Df   Df   Chisq     Pr(>Chisq)  
1 
xxx                       
2 
xxx-2   2    xxxx    x.xxx  pvalue for the 2-DF joint statistical test 
of both sensitivity and secretion variables of the treatment arm 
difference   
  
  
References:   
1. https://en.wikipedia.org/wiki/Seemingly_unrelated_regressions  


2. https://www.jstatsoft.org/article/view/v023i04/v23i04.pdf  
3. Zellner, Arnold. An efficient method of estimating seemingly unrelated regression equations 
and tests for aggregation bias". Journal of the American Statistical Association. 1962; 57: 348– 
368. doi:10.2307/2281644.  
4. Srivastava, Virendra K.; Giles, David E.A. (1987). Seemingly unrelated regression equations 
models: estimation and inference. New York: Marcel Dekker.   
5. Henningsen Arne, Hamann Jeff. systemfit: A Package for Estimating Systems of Simultaneous 
Equations in R. Journal of Statistical Software. 2007; 23:1-40.