Clinical trial NCT01779375
Conditions: Prediabetes Type 2 Diabetes
Keywords: Children Pediatric
Sponsor: RISE Study Group
Start date: 2013-06-16; Completion date: 2018-04-01
Enrollment: 91 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The RISE Pediatric Medication Study is a 2-arm, 4-center, clinical trial of children 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. Pediatric participants (ages 10-19) will be randomized to one of the following treatment regimens: (1) metformin alone or (2) early intensive treatment with basal insulin glargine followed by 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). arm 2: Basal insulin glargine for 3 months titrated to achieve a morning fasting blood glucose of 85-95 mg/dl, followed by metformin (titrated up to 2000 mg/day) for 9 months.
Interventions: intervention 1: Metformin intervention 2: Glargine
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
SAP_002.pdf: 
RISE Primary Outcome Analysis Plan – Pediatric 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.  

ICF_001.pdf: 
Consent Form Approval 
 
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Date: 
 
 
 
Valid for Use Through: 
 
 
Treatment Consent Form 
 
Study Title: The Restoring Insulin Secretion (RISE) Study Pediatric Protocol: 
Treatment phase consent 
 
 
Principal Investigator:  
Version Date: 05/21/2013 
 
 
 
 
You (you = you or your child) are being asked to be in a research study. This form 
provides you with information about the study. A member of the research team will 
describe this study to you and answer all of your questions. Please read the information 
below and ask questions about anything you don’t understand before deciding whether 
or not to take part.  
 
Why is this study being done? 
 
You are being asked to take part in a research study to see if medications used for the 
treatment of type 2 diabetes can help the body to make insulin or slow the progression 
of prediabetes or early type 2 diabetes in teenagers. It is currently thought that the best 
time to slow or stop diabetes is at its earliest stages. This study is called the RISE 
Pediatric Study. 
 
Metformin is a pill approved by the FDA for treating type 2 diabetes in children. Insulin 
glargine is a once a day injection approved for treating type 2 diabetes in adults, and 
type 1 diabetes in children. We received special approval from the Food and Drug 
Administration for use of glargine and metformin for this study. 
 
You are being asked to participate in the treatment phase of the RISE Pediatric Study 
because you are between the ages of 10 and 19, you have prediabetes or early type 2 
diabetes, and have completed the screening phase of the study.  
 
Other people in this study 
 
Up to 40 participants will be enrolled in this study in xx and up to 120 total at 4 pediatric 
sites across the US. The study is expected to last 5 years, but your will part will last for 
only 21 months.   
 
 
What will happen during the treatment phase? 
 


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The table at the end of this form lists all the procedures that will be done during this 
study.   
 
If you continue in the treatment phase of the RISE study, you will participate in three (3) 
long study visits, two (2) medium visits, and  three (3) shorter study visits over  21 
months. At the beginning of the RISE study, you will be placed in one of two treatment 
groups: 
 
 Group 1 will start or continue on metformin. 
 Group 2 will start insulin glargine, followed by metformin.  
 
This study will have two different groups of research subjects like you. To decide which 
group you will be in, we will use a method of chance. This method is like flipping a coin 
or rolling dice. Each group will get slightly different care. You will not know which 
treatment group you are in. Neither will your study doctor. This information needs to be 
kept secret so that the study is based on scientific results, not on peoples’ opinions.  
 
However, we can give this information out if you have an emergency. If you are in an 
emergency, make sure you tell the emergency staff about this study. They can contact 
us, and we will give them all relevant information. 
  
1. Metformin:  
If you are randomized into the metformin treatment group, and if you were on 
metformin before you entered RISE, the dose will gradually be increased to a 
maximum of 1 tablet twice daily. You will take metformin for 12 months. We will 
adjust the dose as tolerated.  
 
2. Insulin glargine followed by metformin 
Insulin glargine is a slow release, long acting form of insulin given once a day. 
This type of insulin works similarly to the way your pancreas releases insulin 
when you are not eating. You will take the glargine by injection one time per day. 
You will monitor your blood sugar using a home blood glucose monitor that will 
be provided to you. You will be trained on when and how to check your blood 
sugar levels. We will start you on a small dose of glargine and over a period of 1 
month, we will adjust your glargine dose to a fasting meter glucose level of 85-95 
mg/dl. You will continue the glargine treatment for a total of 3 months. 
 
After discontinuing the glargine, you will begin to take metformin at a dose of one 
half tablet (500 mg) per day. The metformin dose will gradually be increased over 
a month to a maximum of 1000 mg twice daily (One pill, twice a day, for a total of 
2 pills per day).The metformin treatment will last 9 months to bring the total 
duration of treatment to 12 months. 
 
RISE Study Visits 
 


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If you choose to join the RISE Study treatment phase, you will be seen every 3 months 
throughout the study for a total of 8 visits.  During the first 12 months of the study, you 
will receive treatment according to the group to which you have been assigned. The 
body’s ability to produce insulin will be measured and diabetes tests will be run at the 
beginning of the study, 6 months later (Visit 3), and 12 months later (Visit 5). Three and 
9 months after you stop taking the study medication, we will once again measure your 
body’s ability to make insulin and give you diabetes tests (Visits 6 and 8).  
 
1. Study Visit 1  -  
 
This visit will take around one and a half days and will include an overnight stay in 
the research center:  
 
 You will be asked not to eat or drink anything but water for at least 10 hours 
before the visit. 
 You will be asked to come to the research center before 8 AM in the morning.  
 We will measure your height and weight, as well as your waist and hip 
measurements using a tape measure. Blood pressure will be checked using a 
cuff that inflates around your arm. 
 You will be asked about any changes to your health and/or medications since 
your last visit. 
 We will do a brief physical exam, including an exam of your pubertal maturation.  
 If you are female and you are old enough, you will be asked to give a urine 
sample for a pregnancy test. You cannot continue to be on the study if you are 
pregnant.  
 A small plastic needle will be inserted in a vein on one of your hands or arms (we 
call this an IV) for drawing blood samples. This area will be kept warm with a 
heating pad to improve the blood circulation. If you would like, we will use 
numbing medicine before placing the IV. 
 An oral glucose tolerance test (OGTT) will be performed. Two blood samples will 
be taken from your arm to test your blood sugar and other blood tests related to 
diabetes and heart disease. You will then be asked to drink a glassful of flavored 
sugar water over 5 minutes. Blood samples will be taken from your hand IV every 
10 to 30 minutes for a total of 8 times. The test will last 3 hours. The total amount 
of blood drawn for this test will be about 8 tablespoons.   
 At the end of the test you will be given lunch.   
 You will spend the rest of the day in the research center eating meals provided 
by the study.   


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 You will be asked to fill out questionnaires related to sleep.   
 You will be asked not to eat or drink anything but water for at least 10 hours 
before the visit. 
 The next morning, a second IV will be placed on your opposite arm for a test 
called a hyperglycemic or glucose clamp which measures how well your 
pancreas produces insulin while you receive IV glucose. If the first IV is no longer 
working, there is a chance it will have to be replaced. At approximately 8:00 AM, 
the glucose clamp test will begin and last until approximately 12:00 PM.  More 
information about this test is given later in this consent form. After the clamp test, 
you will be given lunch and the IV’s removed once your blood sugar is stable. 
 You will be provided with a 3 month supply of study medications and a logbook.  
 Your blood sugars will be reviewed and any questions answered 
 You will go home after you have eaten lunch and your blood sugar is stable.  
 The study staff will be in contact with you to review blood sugars and answer any 
questions you may have after the visit.  
 
2. Study Visit 2 - 3 months after Visit 1 
This visit will last around 1 hour.  
 You will be asked to bring your meter, logbook, study medication bottles and 
cartridges. This applies to all participants in the study. 
 You will have a physical exam including height, weight and blood pressure.  
 You will be asked about changes in your health since your last visit. 
 You will have about 1 tablespoon of blood drawn to check your blood sugar level 
and a test called HbA1C which measures glucose control over the last 3 months.     
 Your blood sugars will be reviewed and your questions answered. 
 You will receive refills of your study medication. 
 If you are female and you are old enough, a urine pregnancy test will be done.  
3. Study Visit 3 - 6 months after Visit 1 
 
This visit will take around 4 hours.   
 
 You will be asked not to eat or drink anything but water for at least 10 hours 
before we see you. 
 
 You will be asked to bring your meter, logbook, study medication bottles and 
cartridges. This applies to all participants. 


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 You will have a physical exam including height, weight and blood pressure.  
 You will be asked about changes in your health since your last visit. 
 Your blood sugars will be reviewed and your questions answered 
 You will receive refills of your study medication. 
 If you are female and you are old enough, a urine pregnancy test will be done.  
 A small plastic needle will be inserted in a vein on one of your hands or arms (we 
call this an IV) for drawing blood samples. This area will be kept warm with a heating 
pad to improve the blood circulation. If you would like, we will use numbing medicine 
before placing the IV. An OGTT will be performed exactly as described in visit one. 
The total amount of blood drawn for this test will be about 8 tablespoons.   
 At the end of the test, you will be given lunch.  
 You will go home after you have eaten and your blood sugar is stable. 
 
4.  Study Visit 4 - 9 months after Visit 1  
 
This visit will be exactly like Visit 2 
 
5.  Study Visit 5 – 12 months after Visit 1  
 
This visit will be exactly like Visit 1 
 
 You will return your pill bottles and study medication will be stopped after 
completion of the final visit.  
 You will be asked about any changes to your health and/or medications since 
your last visit. 
 
 Your blood sugars will be reviewed and any questions answered 
6.  Study Visit 6 – 15 months after Visit 1  
 
This visit will be exactly like Visit 1 
 
7.  Study Visit 7 – 18 months after Visit 1  
 
This visit will be exactly like Visit 2 except that you will not return or receive medications.  
 
 
8.  Study Visit 8 – 21 months after Visit 1  
 
This visit will be exactly like Visit 3 


Consent Form Approval 
 
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Management of your blood sugars 
 
After each visit the RISE study team will be told if your HbA1c test is within the target 
range and the study team will discuss this result with you. If your HbA1c was not in the 
target range, the study team will tell you what to do. For example, if your HbA1c is too 
high while on study medications, it will be repeated and if it stays too high, you will be 
scheduled to do Visit 5 early and will then be finished with your involvement in the 
study. 
 
If your HbA1c stays too high after you have come off study medications (after visit 5), 
you will have your next scheduled visit as soon as possible and will then be finished 
with your involvement in the study. After you have finished in RISE, you will return to 
your primary health provider for further care. We will provide all the information we 
learned about you during RISE to you and your provider.  
 
Diabetes Related Problems and the Treatment of These Problems 
 
As part of the RISE study visits, we will be testing for other problems sometimes found 
in people with prediabetes and diabetes. Testing for these problems and treating them 
is part of caring for children with prediabetes and diabetes. These three problems are: 
 high blood pressure, 
 protein in the urine (a sign that the diabetes is affecting  the kidney) 
 high levels of fats (cholesterol or triglycerides).   
If we find any of these problems while you are in the RISE study, we will inform you and 
discuss treatment recommendations with you and your primary health care provider. 
 
Detailed procedure description 
Laboratory tests 
Blood will be drawn from a vein in your hand or arm to measure how the pancreas 
produces  insulin, diabetes control, and tests for inflammation and blood fat. A urine 
sample will also be obtained and tested to see how the kidneys are functioning and, if you are 
female, to be sure that you are not pregnant. 
Physical exam 
You will have a physical exam done by trained medical staff.  This is similar to having a 
routine doctor’s visit and includes measuring your height, weight, heart rate, blood 
pressure, general physical exam and a puberty exam.   
 
Questionnaires 


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You will be asked to fill out questionnaires (surveys) about your sleep habits, mood, 
energy level, and appetite. These questionnaires will take approximately 15 minutes to 
complete and have been used and validated in previous studies.  
Hyperglycemic Clamp 
This test will be performed in the Clinical Research Center (CTRC) after you have 
fasted overnight (nothing to eat or drink from the night before except water). This test 
will last approximately 3½ hours during which we will increase your blood sugar by 
infusing sugar water and arginine in the vein, to test how well the pancreas produces 
insulin. Arginine is an amino acid (protein) that is present in our body and in foods we 
eat. For this test you will need two IV lines, one for the infusion and the other on the 
opposite hand or arm to obtain blood every 5-15 minutes to measure blood sugar and 
hormone levels. Before starting the IV’s, we will numb the skin. The hand or arm that is 
used for blood samples will be kept warm in a heating pad. During this test you will lay 
in a bed either watching TV or asleep. For the first two and a half hours, we will keep 
your blood sugar level at approximately 180-200 mg/dl. This level is commonly found in 
people with mild diabetes after they eat. For the final hour, we will raise your glucose 
level to approximately 450 mg/dl and then give the arginine. We will collect additional 
blood samples and end the test. The total amount of blood drawn during the 
hyperglycemic clamp will be about 15 tablespoons. 
 
At the end of the 3½ hour infusion period, we will stop all the infusions, give you lunch, 
and watch you for approximately one hour to be sure that you do not develop a 
temporary low blood sugar level. If your blood sugar starts to decrease too much, we 
will give you additional glucose by IV or by mouth to prevent a low blood sugar and 
continue to observe you until your blood sugar levels stabilize. When your blood sugar 
levels are stable, we will take out the IVs.  
Timeline of Study Procedures 
Study 
Visit 
Months after 
Randomization 
Procedures 
Approximate 
Length of 
Visit 
Visit 1 
0 months 
(Baseline) 
 Height, weight, waist and hip 
circumference, blood pressure 
 Medical history 
 Hyperglycemic clamp 
 Oral glucose tolerance test (OGTT) 
 Questionnaires 
 Collection of DNA, blood and urine 
for storage * 
 Blood and urine tests (HbA1c, 
biomarkers, CBC, blood chemistries, 
pregnancy test) 
 Review pill and injection taking 
 Begin study medications 
36 hours 
(overnight) 
Visit 2 
3 months 
 Medical history 
1 hour 


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 Weight, blood pressure 
 Blood and urine tests (HbA1c, 
pregnancy) 
 Review pill and injection taking 
 Give drug supply 
Visit 3 
6 months 
 Medical history 
 Weight, blood pressure 
 Oral glucose tolerance test (OGTT) 
 Blood and urine tests (HbA1c, 
biomarkers, CBC, blood chemistries, 
pregnancy test) 
 Collection of blood and urine for 
storage * 
 Review pill and injection taking 
 Give drug Supply 
4 hours 
Visit 4 
9 months 
 Medical history 
 Weight, blood pressure 
 Blood and urine tests (HbA1c, 
pregnancy test if applicable) 
 Review pill and injection taking 
 Give drug supply 
1 hour 
Visit 5 
12 months 
 Medical History 
 Weight, waist and hip circumference, 
blood pressure 
 Hyperglycemic clamp 
 Oral glucose tolerance test (OGTT) 
 Collection of blood and urine for 
storage * 
 Blood and urine tests (HbA1c, 
biomarkers, CBC, blood chemistries, 
pregnancy) 
 Collect pills and injections. 
 Discontinue study medications 
36 hours 
(overnight) 
Visit 6 
15 months 
 Weight, waist and hip circumference, 
blood pressure 
 Hyperglycemic clamp 
 Oral glucose tolerance test (OGTT) 
 Collection of blood and urine for 
storage * 
 Blood and urine tests (HbA1c, 
biomarkers, pregnancy test) 
 
36 hours 
(overnight) 
Visit 7 
18 months 
 Medical history 
1 hour 


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 Weight, blood pressure 
 Blood and urine tests (HbA1c, 
pregnancy test if applicable) 
Visit 8 
21 months 
 Medical history 
 Weight, blood pressure 
 Oral glucose tolerance test (OGTT) 
 Blood and urine tests (HbA1c, 
biomarkers, CBC, blood chemistries, 
pregnancy test) 
 Collection of blood and urine for 
storage * 
4 hours 
 * Only collected if consent is given for these procedures. 
 
What are the possible discomforts or risks? 
 
Risk of Feeling Uncomfortable: Even when there is no ill intention on the part of the 
person asking questions, some people become embarrassed when asked detailed 
questions.  Some people get upset when they have a physical examination.  You do not 
have to do anything that upsets you or makes you uncomfortable. 
 
Risk of Drawing Blood: There is minor risk of infection associated with having your 
blood drawn. A child may faint or become sick to the stomach at the sight of a needle or 
when blood is drawn. There can be some discomfort or bruising at the site of the blood 
draw, but it will go away within a few days.  
 
Risk of Drinking Sugar Water: About one out of ten people have mild nausea or an 
upset stomach with the glucose (sugar) drink that is given during the oral glucose test. 
Rarely some people may experience a mild low blood sugar reaction (symptoms like 
nervousness or sweating) at the end of the test. You will be given a snack to guard 
against this. 
Increasing the blood sugar level rapidly may cause a warm sensation all over, lasting a 
few seconds. Very occasionally, a vein will become irritated or inflamed (about 1%–2% 
of the time) after a glucose injection. This problem is treated with Tylenol or ibuprofen 
and goes away on its own over a few days.  
Risk of Giving Arginine by IV:  This can cause flushing, nausea, vomiting, headache, 
and allergic reaction.  As with other IV solutions, it can cause irritation of the vein and 
surrounding tissues which will be reduced by using a large vein for infusion. 
 
Risks Associated with Metformin  
 
The FDA has approved metformin for treating diabetes in adults and children but not in 
prediabetes. We obtained special permission from the FDA to use metformin for this 
protocol. There are risks associated with metformin that you should be aware of. If you 
have kidney or liver problems or if you are allergic to metformin, you should inform the 
RISE study doctor. You should talk to the study doctor before you undergo any surgery 


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or undergo any x-ray procedures that use any type of injection of contrast (such as a 
dye to make the x-ray easier to see).  We strongly discourage the use of alcohol in all 
teenagers.  In addition, alcohol should not be used while taking metformin.   
 
The most common side effects from metformin include nausea, diarrhea, vomiting, 
bloating, excessive gas, loss of appetite, and an unpleasant taste in the mouth. These 
are more common when the drug is first started and often disappear over time. About 
30% (30 out of 100 people) experience symptoms. Other effects include lower than 
normal vitamin B12 levels in the blood which can lead to anemia (low blood count), 
hypoglycemia (low blood sugar) when metformin is taken with other diabetes medicines. 
 
In rare instances (3 in 100,000 people), a condition called lactic acidosis has been 
reported in patients using metformin. It is usually associated with certain medical or 
surgical problems (including those given above). You must notify your RISE study 
doctor if you experience a general feeling of uneasiness or discomfort, muscle 
tenderness or pain, breathing problems, unusual sleepiness or stomach discomfort, or 
any other unexplained symptom(s). Other signs may be low body temperature 
(hypothermia), decreased blood pressure (hypotension), and a slowed heartbeat 
(bradycardia). If ignored or untreated, lactic acidosis can lead to serious effects 
progressing to coma or death.  
 
Risks Associated with Insulin Glargine  
 
The FDA has approved insulin glargine for treating type 2 diabetes in adults and type 1 
diabetes in children. We obtained special permission from the Food and Drug 
Administration to use glargine in this study. The side effects of insulin glargine include 
hypoglycemia (low blood sugar) and slight weight gain. If you are assigned to take 
insulin glargine you will be counseled about the possibility of weight gain while on 
insulin therapy and given dietary counseling and resources. You will also perform self-
monitoring of blood glucose to minimize the risk of low blood sugar. 
 
The symptoms of low blood sugar include feeling hungry, tired, nervous, shaky, sweaty, 
nauseated, confused, or having a rapid heartbeat or personality changes. If a person 
drinks or eats sugar-containing food right away, the symptoms will usually stop. In the 
most severe cases, low blood sugar can cause unconsciousness and seizures. If you 
have these symptoms, you will need to check your blood sugar to be sure that these 
feelings are actually caused by low sugar. As part of the education, we will teach you 
about the signs and symptoms of low blood sugar and what to do. 
 
Risks of Stopping, Starting, or Changing Medications 
 
Any time that a diabetes medication is started, stopped, or changed, there is a risk that 
you may have more high sugars (hyperglycemia) or low sugars (hypoglycemia as 
described above).   
The symptoms of high blood sugar include drowsiness, thirst, excessive urination, blurry 
vision, and loss of appetite. If you begin to go to the bathroom much more often or start 


Consent Form Approval 
 
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wetting the bed after the medicine is changed, you will need to check your blood sugar 
more often and also check the urine for ketones. As part of the education we will teach 
you about the signs and symptoms of high blood sugar and what to do. It is important 
that you call RISE study staff whenever you suspect you have high blood sugar levels. 
 
Risks if You Become Pregnant 
 
Effects of the study medicines on how an unborn baby grows and develops are not 
known. Birth defects, including physical deformities, mental retardation, premature birth, 
or other problems, are known risks of some drugs. Because we do not know the effects 
of the RISE medicines on a baby before it is born, it is important that you not become 
pregnant during the study. However, metformin and insulin glargine are often used 
during pregnancy; therefore it is very unlikely to harm a fetus. In addition, the study 
medications may improve the health of a woman’s ovaries, and increase the likelihood 
of getting pregnant. Therefore, it is very important for girls in the study to avoid getting 
pregnant.  
 
Teenage girls have the legal right to keep birth control and pregnancy information 
private, even from their parents. All girls in the RISE study will receive private birth 
control counseling. For teenagers, we strongly encourage abstinence. However, if you 
say that you are going to be sexually active or there is any chance that you could 
become pregnant, you must use one of the allowed birth control methods for at least 
1 month before screening, for the entire time that you are in the RISE study, and for at 
least 30 days after the RISE study is over. This is required by the RISE study. The RISE 
study doctor or nurse can explain the allowed birth control methods and help you decide 
which might be best for you. The study doctor can also suggest where you can get more 
information and advice. We will not tell parents whether their daughter is on any type of 
birth control unless she gives us permission. 
 
We will do a pregnancy test at every study visit. If you suspect that you are pregnant or 
are concerned that you may have become pregnant, you should advise the RISE study 
doctor immediately.  If you become pregnant during the treatment phase of the RISE 
study, you will be withdrawn from the study. We will refer you for medical care to a 
doctor who specializes in taking care of pregnant women who have diabetes.  
 
Unforeseen Risks 
The study may include risks that are unknown at this time. Your participation may be 
ended if any adverse reactions occur. 
What are the possible benefits of the study? 
 
This study is being done to see if medications used for the treatment of type 2 diabetes 
can help the body to make insulin or slow the progression of prediabetes or early type 2 
diabetes in teenagers. There is no guarantee your health will improve by participating in 
this study. Also, there may be risks, as discussed in the section describing discomforts 
or risks. 
 


Consent Form Approval 
 
                                                                                                                 Initials ______  
12 of 19 
Alternative Treatments 
The alternative treatment for type 2 diabetes is the standard of care, which includes 
metformin, insulin and daily blood sugar testing. The alternative treatment for 
prediabetes is diet and exercise.  
 
Who is paying for this study?  
National Institute of Diabetes, Digestive Disease and Kidney (NIDDK). 
Will I be paid for being in the study?  
We know that RISE study activities require a lot of effort on your part.  Because of this, 
we will pay you $xx for visits 2, 4, and 7; $xx for visits 3 and 8; $xx for visit 1; $xx for 
visit 5; and $xx for visit 6. This is a total of $xx if you complete all of the study visits. It is 
important to know that payment for participation in a study is taxable income.  
We will also pay you back for costs related to getting to your study visits.  For example, 
we will be able to pay for the costs of parking or bus fare.  Please feel free to discuss 
this with the RISE staff.   
Will I have to pay for anything? 
It will not cost you anything to be in the study. 
Is my participation voluntary? 
Taking part in this study is voluntary. You have the right to choose not to take part in 
this study. If you choose to take part, you have the right to stop at any time. If you 
refuse or decide to withdraw later, you will not lose any benefits or rights to which you 
are entitled.  
Can I be removed from this study?  
The study doctor may decide to stop your participation without your permission if the 
study doctor thinks that being in the study may cause you harm, if you become 
pregnant, or for any other reason. Also, the sponsor may stop the study at any time.  
What happens if I am injured or hurt during the study?  
If you have an injury while you are in this study, you should call Dr. xxx  immediately.  
Her phone number is xx. We will arrange to get you medical care if you have an injury 
that is caused by this research.  However, you or your insurance company will have to 
pay for that care. 
 
Who do I call if I have questions? 


Consent Form Approval 
 
                                                                                                                 Initials ______  
13 of 19 
The researcher carrying out this study is xxx, MD. You may ask any questions you have 
now. If you have questions later, you may call the research coordinator xxx, at xxx.  You 
will be given a copy of this form to keep.   
You may have questions about your rights as someone in this study. You can call xxx, 
Research Coordinator, with questions.  You can also call the Institutional Review Board 
at xxx.  
 
You can also talk to a Subject Advocate at the Clinical and Translational Research 
Center (CTRC).  The phone number there is xxx. 
 
Who will see my research information?  
The xxx and the hospital(s) it works with have rules to protect information about you.  
Federal and state laws including the Health Insurance Portability and Accountability Act 
(HIPAA) also protect your privacy. This part of the consent form tells you what 
information about you may be collected in this study and who might see or use it.  
  
The institutions involved in this study include: 
 
 xxx 
 xxx 
We cannot do this study without your permission to see, use and give out your 
information.  You do not have to give us this permission.  If you do not, then you may 
not join this study.   
 
We will see, use and disclose your information only as described in this form and in our 
Notice of Privacy Practices; however, people outside the xxx and its affiliate hospitals 
may not be covered by this promise. 
 
We will do everything we can to keep your records a secret.  It cannot be guaranteed.  
 
The use and disclosure of your information has no time limit.  You can cancel your 
permission to use and disclose your information at any time by writing to the study’s 
Primary Investigator, at the name and address listed below.  If you do cancel your 
permission to use and disclose your information, your part in this study will end and no 
further information about you will be collected.  Your cancellation would not affect 
information already collected in this study.   
 
 
 
xxx 
 
Both the research records that identify you and the consent form signed by you may be 
looked at by others who have a legal right to see that information.   
 Federal offices such as the Food and Drug Administration (FDA) that protect 
research subjects like you. 


Consent Form Approval 
 
                                                                                                                 Initials ______  
14 of 19 
 People at the Institutional Review Board 
 The study doctor and the rest of the study team. 
 NIH/NIDDK, who is the company paying for this research study. 
 Officials at the institution where the research is being conducted and officials at 
other institutions involved in this study who are in charge of making sure that we 
follow all of the rules for research 
We might talk about this research study at meetings.  We might also print the results of 
this research study in relevant journals.  But we will always keep the names of the 
research subjects, like you, private.  
 
You have the right to request access to your personal health information from the 
Investigator. 
 
We respect your right to privacy.  But there are some things we cannot keep private.  If 
you give us information about child neglect or abuse, we have to report that to Social 
Services.  If you give us information about someone hurting someone else, we have to 
report that to the police.   
 
To help us further protect your privacy, the investigators have obtained a Confidentiality 
Certificate from the Department of Health and Human Services (DHHS).  
With this Certificate, the investigators cannot be forced (for example by court subpoena) 
to disclose research information that may identify you in any Federal, State, or local 
civil, criminal, administrative, legislative, or other proceedings. Disclosure will be 
necessary, however, upon request of DHHS for audit or program evaluation purposes.  
You should understand that a Confidentiality Certificate does not prevent you or a 
member of your family from voluntarily releasing information about yourself or your 
involvement in this research. Note however, that if an insurer or employer learns about 
your participation, and obtains your consent to receive research information, then the 
investigator may not use the Certificate of Confidentiality to withhold this information. 
This means that you and your family must also actively protect your own privacy.  
Finally, you should understand that the investigator is not prevented from taking steps, 
including reporting to authorities, to prevent serious harm to yourself or others.  
Information about you that will be seen, collected, used and disclosed in this 
study: 
 
 Name and Demographic Information (age, sex, ethnicity, address, phone 
number, etc. 


Consent Form Approval 
 
                                                                                                                 Initials ______  
15 of 19 
 Portions of my previous and current Medical Records that are relevant to this 
study, including but not limited to Diagnosis(es), History and Physical, laboratory 
or tissue studies, radiology studies, procedure results 
 Research Visit and Research Test records 
What happens to Data, Blood and Specimens that are collected in this study?  
 
Scientists at the xxx and the hospitals involved in this study work to find the causes and 
cures of disease.  The data, blood and specimens collected from you during this study 
are important to this study and to future research.  If you join this study: 
  
We are asking you (or your child) to provide samples of blood and urine, which will be 
sent 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 diabetes, after the current 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 diseases.  
 
The Repository will take measures to protect your privacy, although no guarantee of 
confidentiality can be absolute. Before the researchers in this study send samples to the 
Repository, each sample will be given a code number. Your name, or your child's name, 
and all personal identifying information, such as address, social security number, and 
date of birth, will be removed. Therefore, the Repository will not be able to give out your 
name, or other information that identifies you or your child, to the scientists who receive 
the samples. However, the Repository and scientists will have some data about you, 
such as age, sex, diagnosis, race, and outcomes of the initial study. 
 
You will not receive any direct benefit or payment for participating, but your sample may 
benefit the future health of the community at large or some particular group. Because 
other researchers will not have access to your identity, neither you nor your physician 
will get the eventual results of studies that might be performed using your sample. It is 
possible that data resulting from use of your sample may eventually be used in a 
research publication. In that event, your name or other identifying information will not be 
included, as this information will not be available to the researchers.  
 
It is important for you to understand that there is a small chance that some research 
may yield results that may indirectly have a negative impact on insurability, 
employability, and/or family relationships of some individuals or groups of people. 
Sometimes, research results in findings or inventions that have value if they are made 
or sold. These findings or inventions may be patented or licensed, which could give a 
company the sole right to make and sell products or offer testing based on the 
discovery. Some of the profits from this may be paid back to the researchers and the 
organizations doing this study, but you will not receive any financial benefits.  


Consent Form Approval 
 
                                                                                                                 Initials ______  
16 of 19 
Your donation is voluntary, and if you choose not to participate there will be no penalty 
or loss of benefits to which you are entitled.  
 
If you agree to have your sample(s) stored in the Repository, you can change your mind 
up until the end of the RISE study. When study researchers receive written instructions 
from you, they will destroy your sample and all information that identifies you. After the 
RISE study ends, you will not be able to withdraw your sample because the Repository 
will not know which one is yours. The sample will stay in the Repository indefinitely. 
 
Additional Information Resulting From Trial 
 
You will be notified of any significant findings that develop during the course of the 
research study which may affect your ability or willingness to continue participation in 
this study.  
 
Additionally, a summary of the research results may be available to you after the results 
have been analyzed.  A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law.  This Web site will not include 
information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time. 
 
Agreement to be in this study 
 
I have read this paper about the study or it was read to me. I understand the possible 
risks and benefits of this study. I know that being in this study is voluntary. I choose to 
be in this study. I will get a copy of this consent form. 
 
 
Signature of Subject: 
 
 
 
 
 
 
Date:___________ 
(Age 13 or older) 
 
Print Name:  
 
 
 
 
 
 
 
 
Signature of Parent:  
 
 
 
 
 
 
Date:___________ 
(If subject is under age 18) 
 
Print Name:  
 
 
 
 
 
 
 
 
 
Consent form explained by: 
 
 
 
 
 
Date:  
 
 
 
 
Print Name:  
 
 
 
 
 
 
 
 
 
Investigator:  
 
 
 
 
 
 
 
Date:  
 
 


Consent Form Approval 
 
                                                                                                                 Initials ______  
17 of 19 
 
 
Witness: ________________________________________    
Date: ___________ 
(Only if using short form) 
 
Optional Consent for Data and Specimen Banking for Future Research 
 
Dr. xxx would like to keep some of the data and blood that is taken during the study but 
is not used for other tests. If you agree, the data and samples will be kept and may be 
used in future research to learn more about diabetes. The research that is done with 
your data and samples is not designed to specifically help you. It might help people who 
have diabetes and other diseases in the future. Reports about research done with your 
data and samples will not be given to you or your doctor. These reports will not be put in 
your health records. The research using your data and samples will not affect your care. 
 
The choice to let Dr. xxx keep the data and samples for future research is up to you. No 
matter what you decide to do, it will not affect the care that you will receive as part of the 
study. If you decide now that your data and samples can be kept for research, you can 
change your mind at any time and contact your study doctor to let him or her know that 
you do not want Dr. xxx to use your data and samples any longer and they will no 
longer be used for research. Otherwise, they may be kept until they are used up, or until 
Dr. xxx decides to destroy them. You can write to Dr. xxx to request removal from the 
study. 
 
xxxx 
 
When your data and samples are given to other researchers in the future, Dr. xxx will 
not give them your name, address, phone number or any other information that will let 
the researchers know who you are.  
 
Sometimes data and samples are used for genetic research (about diseases that are 
passed on in families). Even if your data and samples are used for this kind of research, 
the results will not be told to you and will not be put in your health records. Your data 
and samples will only be used for research and will not be sold. The research done with 
your data and samples may help to develop new products in the future, but there is no 
plan for you to be paid. 
 
The possible benefits of research from your data and samples include learning more 
about what causes diabetes and other diseases, how to prevent them and how to treat 
them. The greatest risk to you is the release of your private information. Dr. xxx will 
protect your records so that your name, address and phone number will be kept private. 
The chance that this information will be given to someone else is very small. There will 
be no cost to you for any data or sample collection and storage by Dr. xxx. 
 
Please read each sentence below and think about your choice. After reading each 
sentence, circle “yes” or “no.” If you have questions, please talk to your doctor or nurse. 


Consent Form Approval 
 
                                                                                                                 Initials ______  
18 of 19 
Remember, no matter what you decide to do about the storage and future use of your 
data and samples, you may still take part in the study. 
 
I give permission for my blood and urine to be stored in a central bank (currently stored 
at the xxx) for future use by RISE investigators in studies of diabetes, related 
complications, and heart disease: 
 
 
________  YES 
 
________  NO 
 
________  INITIALS 
 
I give permission for my research data to be sent to the NIDDK Central Repository for 
future use by NIH approved investigators in studies of diabetes, related complications, 
and heart disease: 
 
________  YES 
 
________  NO 
 
________  INITIALS 
 
I give permission for my blood and urine to be sent to the NIDDK Central Repository for 
future use by NIH approved investigators in studies of diabetes, related complications, 
and heart disease: 
 
________  YES 
 
________  NO 
 
________  INITIALS 
 
Permission to store genetic information (DNA) 
 
If you do agree to having a sample for DNA collected, then in the future, investigators 
may perform DNA analysis on your blood sample to help better understand diabetes, 
metabolic disorders, obesity, or other health problems.  You will not be notified of the 
purpose of these studies.  This research may include technology or techniques that are 
not known today.  Upon doing this the researchers may discover that you have a risk 
factor for a specific disease(s) or abnormal chromosome pattern.  You usually will not 
be told of the results, however, in rare cases, if the researchers do find something 
wrong that can make a significant difference in your life, then attempts may be made to 
contact you with the results. 
 
I give permission for my blood to be sent to the NIDDK Central Repository for future use 
by NIH approved investigators in DNA studies. 
 
________  YES 
 
________  NO 
 
________  INITIALS 
 
Permission to be re-contacted for future studies 
 
It is possible that future studies will come as a result of the findings from the RISE 
study. If you agree to be re-contacted, we will store your contact information in a locked 
file in a secure place and if such studies arise in the future, we may re-contact you to 
see if you are interested in such studies.  
 


Consent Form Approval 
 
                                                                                                                 Initials ______  
19 of 19 
I give permission to be re-contacted by the investigators of this study regarding future 
studies of diabetes, related complications, and heart disease: 
 
________  YES 
 
________  NO 
 
________  INITIALS 
 
I have read this description about the storage of my data and specimens or it was read 
to me.  I understand the possible risks and benefits of this storage. I agree to take part 
in the storage and future research use of my data and blood as indicated above. 
 
 
Signature____________________________   
Date___________ 
 
 

Prot_000.pdf: 
 
 
PROTOCOL 
The Restoring Insulin Secretion (RISE) Study 
RISE Pediatric Medication Study 
 
 
 
 
 
RISE Study Group 
Date: May 1, 2016 
Version 1.3 
 
Distributed by 
RISE Study Data Coordinating Center 
Biostatistics Center 
George Washington University 
6110 Executive Boulevard 
Rockville, Maryland 20852 
 
CONFIDENTIAL 
 
 


RISE Pediatric Medication Protocol  
 
Page 2 
 
 
 
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 ..................................................................... 12 
2.3 
Results of Type 2 Diabetes Prevention Studies .......................................................................... 12 
2.4 
Long Term Intervention Studies in Patients with Early Type 2 Diabetes .................................... 13 
2.5 
Metformin ................................................................................................................................... 16 
2.6 
Insulin Glargine ........................................................................................................................... 17 
2.7 
Approaches to Measuring ß-cell Function, -cell Function, Insulin Sensitivity and Glucose 
Tolerance ................................................................................................................................................ 17 
2.7.1 
Intravenous Tests of ß- and -cell Function and Insulin Sensitivity ................................... 18 
2.7.2 
Oral Tests of ß- and -cell Function and Insulin Sensitivity ............................................... 19 
2.8 
Biomarkers of ß-cell Function, -cell Function, Insulin Sensitivity and Glucose Tolerance ...... 20 
2.8.1 
Putative Diabetes Biomarkers ............................................................................................. 20 
3 
STUDY DESIGN..................................................................................................................................... 21 
3.1 
Overview and Rationale .............................................................................................................. 21 
3.2 
Primary Outcomes ...................................................................................................................... 22 
3.3 
Secondary Outcomes .................................................................................................................. 23 
3.3.1 
ß-cell Function and Glucose Tolerance ............................................................................... 23 
3.3.2 
-cell Function .................................................................................................................... 24 
3.3.3 
Insulin Sensitivity ................................................................................................................ 25 


RISE Pediatric Medication Protocol  
 
Page 3 
 
 
 
3.3.4 
Blood and Urine Biomarkers ............................................................................................... 25 
3.3.5 
Physical and Body Composition Measures ......................................................................... 25 
3.4 
Treatments .................................................................................................................................. 25 
3.4.1 
Three-week Placebo Run-in Phase ...................................................................................... 25 
3.4.2 
Twelve-month Active Treatment Phase .............................................................................. 26 
3.4.3 
Metformin ........................................................................................................................... 26 
3.4.4 
Insulin Glargine Followed by Metformin ............................................................................ 26 
3.4.5 
Medication Wash-out and Post-treatment Follow Up ....................................................... 27 
3.4.6 
Rescue ................................................................................................................................. 27 
3.5 
Inclusion Criteria ......................................................................................................................... 27 
3.6 
Exclusion criteria ......................................................................................................................... 28 
3.7 
Randomization ............................................................................................................................ 29 
3.8 
Masking ....................................................................................................................................... 29 
4 
RECRUITMENT ..................................................................................................................................... 30 
4.1 
Recruitment ................................................................................................................................ 30 
4.2 
Description/Justification of the Target Study Population ........................................................... 30 
4.3 
Informed Consent ....................................................................................................................... 31 
4.4 
Staged Screening and Randomization ........................................................................................ 32 
5 
PATIENT MANAGEMENT ..................................................................................................................... 34 
5.1 
Description of RISE Research Facility Treatment(s) .................................................................... 34 
5.2 
Drug Distribution ......................................................................................................................... 34 
5.3 
Adherence Measures .................................................................................................................. 34 
5.3.1 
Placebo Run-in .................................................................................................................... 35 
5.3.2 
Insulin .................................................................................................................................. 35 
5.4 
Retention .................................................................................................................................... 35 


RISE Pediatric Medication Protocol  
 
Page 4 
 
 
 
6 
DATA COLLECTION .............................................................................................................................. 36 
6.1 
Main Study Procedures ............................................................................................................... 36 
6.1.1 
Fasting Blood and Urine Samples........................................................................................ 36 
6.1.2 
Oral Glucose Tolerance Test (OGTT) ................................................................................... 36 
6.1.3 
Hyperglycemic Clamp .......................................................................................................... 37 
6.2 
Eligibility Screening Measurements ............................................................................................ 37 
6.3 
Baseline and Post-Randomization Measures .............................................................................. 39 
6.3.1 
Physical Measures ............................................................................................................... 41 
6.3.2 
Sleep Assessments .............................................................................................................. 42 
6.3.3 
Safety Measures .................................................................................................................. 42 
6.3.4 
Participant Protocol Adherence .......................................................................................... 42 
6.4 
Visit Windows ............................................................................................................................. 42 
7 
SAFETY / HUMAN SUBJECTS PROTECTION ......................................................................................... 43 
7.1 
Data and Safety Monitoring Board (DSMB) ................................................................................ 43 
7.2 
Data and Safety Monitoring Plan ................................................................................................ 43 
7.2.1 
Informed Consent ............................................................................................................... 43 
7.2.2 
Safety Review Plan and Monitoring .................................................................................... 44 
7.2.3 
Confidentiality ..................................................................................................................... 44 
7.3 
Expected Side Effects .................................................................................................................. 45 
7.4 
Risk Management ....................................................................................................................... 45 
7.5 
Potential Benefits ........................................................................................................................ 49 
7.6 
HIPAA – Protection of Patient Information................................................................................. 49 
8 
ADVERSE EVENT REPORTING .............................................................................................................. 50 
8.1 
Definition of Serious Adverse Events .......................................................................................... 50 
8.2 
Non-serious Adverse Events ....................................................................................................... 50 


RISE Pediatric Medication Protocol  
 
Page 5 
 
 
 
8.3 
Reporting Adverse Events ........................................................................................................... 50 
8.4 
Tracking Adverse Events ............................................................................................................. 51 
8.5 
Emergency Unmasking ................................................................................................................ 51 
9 
STATISTICAL CONSIDERATIONS ........................................................................................................... 51 
9.1 
Primary Outcome and Analyses .................................................................................................. 52 
9.2 
Secondary Outcomes and Analyses ............................................................................................ 52 
9.2.1 
Measures of ß- and -cell Function and Glucose Tolerance .............................................. 52 
9.3 
Sample Size/Power Calculations ................................................................................................. 53 
9.4 
Interim Analysis Plans ................................................................................................................. 53 
9.5 
Stopping Rules............................................................................................................................. 53 
9.6 
Handling of Missing Data ............................................................................................................ 54 
10 
DATA PROCESSING AND MANAGEMENT ........................................................................................ 54 
10.1 
Data Management System .......................................................................................................... 54 
10.2 
Data Transfer .............................................................................................................................. 54 
10.3 
Quality Control ............................................................................................................................ 54 
10.4 
Back-up, Data Security and Confidentiality ................................................................................ 55 
10.5 
Tracking Study Progress .............................................................................................................. 55 
10.6 
Archiving and Study Close-out .................................................................................................... 55 
11 
STUDY ADMINISTRATION ................................................................................................................ 56 
11.1 
Organization ................................................................................................................................ 56 
11.2 
Central Laboratories and Reading Centers ................................................................................. 57 
11.3 
Training and Certification............................................................................................................ 57 
11.4 
Site Visits ..................................................................................................................................... 58 
11.5 
Study Website ............................................................................................................................. 58 
11.6 
Conflict of Interest Policy ............................................................................................................ 59 


RISE Pediatric Medication Protocol  
 
Page 6 
 
 
 
11.7 
Publications and Presentations Policy ........................................................................................ 59 
11.8 
Ancillary Studies Policy ............................................................................................................... 60 
11.9 
Protocol Amendments ................................................................................................................ 60 
11.10 
Repository for Storage and Distribution of RISE Data and Samples ....................................... 61 
12 
STUDY TIMELINE ............................................................................................................................. 61 
13 
LITERATURE CITED .......................................................................................................................... 61 
 
 
 


RISE Pediatric Medication Protocol  
 
Page 7 
 
 
 
1 Executive Summary 
Type 2 diabetes in youth is associated with the onset of multiple diabetes-related complications 
in the teenage and early adult years, such as microalbuminuria, retinopathy, hypertension, 
cardiac hypertrophy, dyslipidemia and nonalcoholic fatty liver disease.  In adults with type 2 
diabetes, these complications are usually not seen until well into the course of the disease; 
therefore, their onset in adolescence is concerning and predicts very early morbidity and 
mortality for youth with type 2 diabetes.  In addition, the recent Treatment Options for Type 2 
Diabetes in Adolescents and Youth (TODAY) study found that approximately 50% of youth failed 
treatment with metformin within 2 years, a much more rapid failure rate than in adults, and 
while rosiglitazone was more effective, it is no longer used in youth due to safety concerns [1]. 
Therefore, since metformin was not effective in early diabetes in TODAY, intervening earlier at 
the stage of prediabetes may be of more benefit. In addition, new interventions that can 
interrupt this disease process at an early stage of diabetes are a critical need in youth. 
A core defect in the pathogenesis of type 2 diabetes involves the ß-cell, which has been shown 
to be dysfunctional in youth with prediabetes, a high risk state that is antecedent to type 2 
diabetes, as well as in established type 2 diabetes [2]. In addition to ß-cell failure, insulin 
resistance and -cell dysfunction are prominent features leading to type 2 diabetes onset [2-4]. 
Defects in both insulin sensitivity and beta cell dysfunction are present long before the 
diagnosis of diabetes in obese youth, arguing for early intervention [5-13]. 
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 adults with varying degrees of 
hyperglycemia treated aggressively with insulin, oral hypoglycemic drugs and diet [14-16]. 
These studies demonstrate that, at least for some patients, ß-cell function can be improved.    
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, especially among youth, in 
whom the progression of ß-cell failure appears more rapid than adults [1]. 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 
in adults.  All lower blood glucose. Metformin, which has been approved for use in the pediatric 
population, is thought to reduce hepatic glucose production and improve insulin resistance; it 
has been shown to prevent progression of prediabetes to diabetes in adults [17]. Insulin lowers 
glucose while providing ß-cell “rest”, and reducing the effects of gluco/lipotoxitcity. Insulin 


RISE Pediatric Medication Protocol  
 
Page 8 
 
 
 
sensitizers may also improve ß-cell function indirectly by reducing ß-cell stress [18, 19]. 
Sulfonylureas initially improve ß-cell function but may accelerate secondary failure [18, 19]. 
Glucagon-like peptide-1 receptor agonists (GLP-1RA) and other incretin-based therapies 
improve islet function [20, 21], but their ability to prevent diabetes and/or 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. Four centers who are very 
experienced in studies of insulin insensitivity and secretion in youth [5-13, 22-24] (the topic of 
research supported by this protocol) will participate in a pediatric study performing a 
randomized trial comparing early intensive insulin treatment with insulin glargine (Lantus®) 
followed by metformin,  with metformin treatment alone. These centers are located at the 
University of Colorado, University of Pittsburgh, Yale University and Indiana University. In 
addition, three adult centers 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) liraglutide plus metformin. These adult centers are 
located at the VA Puget Sound Health Care System / University of Washington, University of 
Chicago 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.  Achieving sustainable remissions will be 
a step in developing new treatments for prediabetes and early type 2 diabetes that can delay 
development or slow progression of the disease. 
This protocol describes the study that will be performed at four centers in a pediatric 
population with type 2 diabetes or pre-diabetes. 
1.1 Specific Aims and Objectives 
The primary objective of the RISE Pediatric Medication Study is to compare, in a preliminary 
proof-of-principle trial, the efficacy of two treatment strategies on measures of ß-cell function 


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after 3-months of post-treatment washout that will follow 12 months of active treatment. 
Participants will have prediabetes or 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, initial aggressive glucose lowering with insulin glargine (Lantus®) for three 
months followed by metformin will lead to preservation or recovery of islet function that will be 
sustained off treatment when compared to metformin alone. To address this hypothesis, we 
have identified the following primary and secondary specific aims. 
The primary specific aim is to determine whether: 
 Improvements in ß-cell function following 12 months of active treatment with  initial 
insulin glargine (Lantus®) (three months) followed by metformin ( 9 months)  will be 
maintained for at least 3 months after  the withdrawal of therapy, more effectively than 
treatment with metformin alone. 
The secondary specific aims are to determine whether: 
 Treatment with initial insulin glargine (Lantus®) followed by metformin for 12 months 
improves ß-cell function compared to metformin alone at 12 months,  
 Improvements in ß-cell function are maintained for 9 months after withdrawal of initial 
insulin glargine (Lantus®) followed by metformin, compared to metformin alone. 
 Treatment with initial insulin glargine (Lantus®) followed by metformin  for 12 months 
improves -cell function compared to metformin alone, 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 Pediatric Medication Study is a preliminary proof-of-principle, two-arm open-label 
study in which volunteers with prediabetes or recent onset type 2 diabetes (HbA1c levels  
≤8.0% if treatment naïve, ≤7.5% if on metformin for <3 months and ≤7.0% if on metformin for 


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3-6 months, fasting glucose ≥90 mg/dl and 2-hour glucose ≥140 mg/dl post 75 gram oral 
glucose challenge) are randomized to: (1) metformin alone, or (2) initial insulin glargine 
(Lantus®) for three months followed by metformin. 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, as 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 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 samples, 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, 
as well as the response to therapy.   Since preliminary data suggest that not all patients with 
diabetes respond, predictive biomarkers will be valuable for determining those individuals with 
the best chance of responding to intensified early treatments.   
This study will provide critical information about the ability of early aggressive treatment 
approaches to lead to sustained recovery of islet function in youth, 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 in youth, as 
well as biomarkers that can be used in future clinical studies and, ultimately, in patient care.  
2 Background and Significance 
2.1 Prediabetes and Type 2 Diabetes: Epidemiology, Natural 
History and Pathogenesis 
The increasing prevalence of obesity in youth and adults has been associated with a relentless 
rise in the prevalence of type 2 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 [25]. Over 90 percent of these cases are type 2 
diabetes. In addition, approximately 79 million, or 35% of the same age group, have 
prediabetes [25]. In the United States during the period 2002-2005, 3,600 youth were newly 


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diagnosed with type 2 diabetes annually. The estimated rate of new cases of type 2 diabetes in 
youth aged <10 years was 0.4 per 100,000 per years, with the rate increasing in those 10-19 
years of age to 8.5 per 100,000 per year [26]. Of note, the rate was greater in children and 
adolescents from minority groups [26]. Amongst adolescents, the 2005-2006 National Health 
and Nutrition Examination Survey (NHANES) estimated the prevalence of prediabetes to be 
16.1% [27]. 
While both diabetes and prediabetes are defined by levels of fasting and/or 2-hour plasma 
glucose [28] or HbA1c [29], the disorders are a continuum. Individuals with prediabetes are at 
very high risk of developing diabetes [17, 30-32], while those with established diabetes exhibit a 
progressive loss of glucose control [33]. Since data indicate that beta cell function declines with 
duration of sustained hyperglycemia, early interventions may be essential to achieve the best 
results. 
The pathogenesis of diabetes and prediabetes involves two major defects: insulin resistance 
and ß-cell dysfunction [2, 34]. Although improvements in insulin sensitivity can slow 
progression of both disorders, ultimately, progressive ß-cell dysfunction is critical for both the 
development [35] and progression [19] 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 [2, 36]. In obese youth, defects in both insulin sensitivity and beta cell 
dysfunction are present long before the diagnosis of diabetes [5]. The decline in ß-cell function 
may also be more rapid than in adults [37, 38], but also potentially more reversible due to the 
recent onset, and therefore may involve unique pathophysiology. Therefore, studies in youth 
separate from adults are required. 
The progressive loss of the ability to release insulin determines the deterioration of glycemia 
[34, 39, 40], and thereby sets up a vicious cycle in which the metabolic derangements 
(“glucolipotoxicity”) associated with type 2 diabetes beget further ß-cell dysfunction [41]. In 
addition to ß-cell dysfunction, ß-cell volume (“mass”) is reduced in type 2 diabetes and possibly 
in those with prediabetes [42-44]. This loss of ß-cells may result from or be accelerated by 
glucolipotoxicity [41] and other abnormalities such as amyloid deposition that impact the islet 
[45]. 
Aside from the ß-cell lesion, a functional abnormality of the islet -cell also contributes to 
hyperglycemia in type 2 diabetes [3, 46, 47]. While fasting glucagon levels may or may not be 
elevated [3], normal suppression of glucagon following oral nutrient ingestion does not occur, 
but rather a paradoxical increase in glucagon levels can occur [3, 46, 47]. Further, during 
hyperglycemic clamps, glucagon release is greater in patients with type 2 diabetes than in 


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healthy subjects [48]. Finally, -cell dysfunction is present in subjects with IGT [49, 50] and first-
degree relatives of individuals with type 2 diabetes [51], 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. 
In adults OSA is a well-documented risk factor for glucose intolerance, insulin resistance and 
diabetes, independently of body mass index [52, 53], while in youth it has been shown to be 
associated with markers of diabetes risk including visceral adiposity and insulin resistance [54, 
55]. Further, studies have shown that OSA is a frequent co-morbidity of diabetes in adults with 
a prevalence averaging 68% [56-58]. To date, however, clinical trials in youth or adults 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 impacts the progression of ß- and -cell function over time and the impact of 
the glucose-lowering intervention. 
2.3 Results of Type 2 Diabetes Prevention Studies  
A number of studies have established the ability to slow the progression from prediabetes to 
diabetes in adults. 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% [31, 59-61], rates 
similar to or greater than the 58% risk reduction observed with lifestyle interventions in the 
DPP and FDS (Finnish Diabetes Prevention Study) [17, 30, 59]. The DPP also demonstrated that 
metformin reduced the risk of progression to diabetes by 31% over three years in adults [59]. 
Other large studies examining the effects of medications showed that acarbose in STOP-NIDDM 
decreased the risk by 25% [62], 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) [63]. 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 importantly, by 20% 100 days after withdrawal of 
therapy [64]. Therefore long-term glargine may have durable effect on reducing diabetes risk in 
adults. Shorter duration of insulin therapy, and insulin’s impact on actual beta or alpha cell 


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function have not been tested yet, in adults or youth.  
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 [65].  
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 [66]. 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 [59, 67, 68]. 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 ß-cell 
function. 
While studies in the pediatric literature exist regarding risk factors for type 2 diabetes (obesity, 
insulin resistance, inactivity, etc.), there are no published type 2 diabetes prevention studies 
targeting youth or studies in youth with early type 2 diabetes.  There is a study underway, but 
not yet completed, examining dietary interventions in adolescents with insulin resistance 
and/or prediabetes [69].  
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 in adults. These studies frequently 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 on ß-cell function have not been determined. 
In the UKPDS, patients with recently diagnosed diabetes received “intensive” treatment with a 
sulfonylurea, insulin [33] or metformin [70] 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 [33, 70]. This 
deterioration in both groups was shown to be due to relentless ß-cell failure [71]. Why insulin 
did not prevent progression of ß-cell dysfunction is unclear, but, if our current hypothesis is 


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correct,  may be because HbA1c was not reduced to normal or 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 in 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 [14-16]. 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 
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 [18]. 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 [18, 19]. Importantly, patients who failed monotherapy 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 [19]. 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 [72, 73]. In addition, this class of drugs 
has been associated with weight gain, edema and fractures [18], side effects that further limit 
the attractiveness of these drugs in individuals early in the course of disease. 
The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study examined 
whether metformin plus rosiglitazone, or metformin plus a lifestyle intervention were superior 
to metformin alone in maintaining glycemic control when initiated early in the course of youth-
onset type 2 diabetes [1]. In participants aged 10 to 17 years, the study demonstrated that 
monotherapy with metformin was ineffective in maintaining glycemic control in half of the 
adolescents with type 2 diabetes, a failure rate much higher than expected from adult studies 


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with the medication. Addition of rosiglitazone, but not intensive lifestyle, was superior to 
metformin alone. Insulin sensitivity improved significantly at 6 months with metformin plus 
rosiglitazone, but not with the other two interventions. There was also a significant 
improvement in ß-cell function with metformin plus rosiglitazone, while with metformin alone 
and metformin plus lifestyle ß-cell function deteriorated. Importantly, a higher HbA1c at 
baseline was predictive of ß-cell decline. Given the safety concerns regarding rosiglitazone, this 
medication is no longer suitable for use in youth.  Alternative approaches to preserving beta 
cell function are needed. 
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 [74] and increase ß-cell mass following 
partial pancreatectomy in rodents [75]. 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 [76]. Thereafter, therapy was restarted in a subgroup, and was continued to three years 
in 36 participants, at which time one month of medication withdrawal was associated with 
better ß-cell function in the exenatide group, in keeping with a benefit beyond the period of 
exposure [77]. 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 long 
standing diabetes with poor ß-cell function at baseline and/or the attained glucose level on 
therapy was not close enough to normal to achieve optimal effects during the initial treatment 
period. Incretin-based therapies such as liraglutide are associated with nausea, an increased 
risk of pancreatitis, and possibly an increased risk of thyroid cancer. Therefore, due to this risk 
profile and the lack of safety data in youth, the incretin family is not currently considered ideal 
for youth.   
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 failed monotherapy and those who failed oral therapy in TODAY had higher 
glucose levels and worse 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 


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therapy in individuals with well-established diabetes in whom glucose levels were not near 
normal at baseline or during therapy. In addition, the defects in both insulin sensitivity and beta 
cell dysfunction leading to diabetes are present long before the diagnosis of the disease in 
obese youth. While in youth type 2 diabetes beta cell function relative to insulin sensitivity, DI,  
is 80% impaired, in obese youth with IFG and/or IGT it is ~ 45% impaired compared with equally 
obese youth with normal glucose tolerance [78]. Indeed, even prior to the development of 
impaired glucose tolerance, reductions in insulin sensitivity and early phase insulin secretion 
are present and are indistinguishable from those seen in the presence of established IGT [5]. 
Thus, we propose to study subjects with prediabetes or early type 2 diabetes who at baseline 
will have better ß-cell function than those with a longer duration of diabetes. We will use 
therapeutic approaches acceptable for youth that aim to lower glucose to levels that are close 
to normal using metformin and insulin, that will decrease secretory demand on the ß-cell. 
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 
[35]. 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 [79, 80]. 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% [17]. 
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 
in persons with renal or hepatic insufficiency or during episodes of hypoxia or circulatory failure 
[79]. In youth, metformin has been well tolerated both in the treatment of type 2 diabetes and 
for weight loss [1, 81].  


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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, is FDA-approved for use in adults with type 2 
diabetes and youth with type 1 diabetes, and has recently been reported to reduce the risk of 
developing type 2 diabetes in individuals with prediabetes by 28% [64]. Insulin glargine 
administered at night lowers plasma glucose by decreasing hepatic glucose production [82] 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 [64]. Glargine activity does not peak, unlike NPH insulin, and thus there is much 
less risk of hypoglycemia, especially overnight. In addition, due to its lack of a peak, subjects can 
safely skip meals or fast with glargine. 
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 [83]. However, type 2 diabetes itself is associated 
with increased cancer risks, which is a likely confounder. In addition, ORIGIN, a randomized trial 
in which over 6,000 participants received insulin glargine for a median of 6.2 years, had minimal 
hypoglycemia and weight gain and did not observe an association between insulin glargine and 
cancer, nor with increased cardiovascular disease [64]. 
2.7 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 frequently 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 studies, 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. 


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2.7.1 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 [84]. 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 [85]. Above that level, the first-phase response is markedly 
diminished and frequently absent in adults, although less is known about it in youth. 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 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 in adults [86], but additional data is required in adolescents. Moreover, it is 
proportional to overall ß-cell secretory capacity and can be measurably improved with 
treatment interventions targeting ß-cell function [87]. Over time, once diabetes has developed, 
the overall insulin response to increased glucose levels becomes progressively blunted. 
In addition to changes in glucose levels, ß-cells also respond to non-glucose secretagogues, such 
as peptides and amino acids, and these responses can persist even after severe blunting of the 
glucose-induced response. 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 under 
preexisting metabolic conditions at a given point in time. In the absence of techniques that 
provide a direct measure of ß-cell mass in living humans, this secretory capacity is currently 
taken as an indirect measure of ß-cell mass. AIRmax is decreased in patients with type 2 
diabetes [48] and in those at risk of developing the disorder [88]. Again, unlike the first phase 
response, AIRmax responses are present and readily quantified in individuals with higher fasting 


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glucose levels (>115 mg/dl). However, little is known about this component of ß-cell secretory 
capacity in youth, arguing for the need for assessment of this measure in youth in the proposed 
studies. Effects of treatment interventions on AIRmax have not been extensively evaluated but 
are beginning to be studied [77]. 
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 [89]. 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) [89]. 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; [89]). 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 [48, 90]. The ability of glucose to suppress the acute glucagon 
response is impaired in adults with type 2 diabetes and in those with prediabetes, indicative of 
impaired -cell regulation [48, 91]. Knowledge in youth about the ability of glucose to suppress 
the  cell is lacking. This parameter will be quantified using the hyperglycemic clamp with 
arginine injection (AGRmin, minimum acute glucagon response) and will be analyzed as a 
secondary outcome in RISE. 
2.7.2 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 [34]. 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) [40, 92]. However, the accuracy of HOMA in 
assessing changes in insulin sensitivity over time may not be as good as clamp techniques [93]. 
Using modeling approaches such as those developed by Mari et al. [94] and Cobelli et al. [95], it 
is possible to obtain a number of additional parameters of ß-cell function and insulin sensitivity. 
In addition, using C-peptide levels and de-convolution techniques, insulin secretion rates can be 
calculated from the OGTT [94-96]. Finally, overall glucose tolerance can be calculated from the 


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glucose excursion during the test [97], 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 [3, 46, 47], an abnormality that is improved with incretin-
based therapy [21]. 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 in adults and youth. Previously we demonstrated that in obese youth, oral DI 
mirrors the DI calculated from two clamp experiments and is a simple surrogate estimate of 
beta cell function relative to insulin sensitivity [98].   
2.8 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, labor intensive and highly correlated with the result from the process 
under evaluation. However, a biomarker might be the result of combinations of blood tests, or 
measurements from other body fluids, or even measurements of other biological substances 
[99].  
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. 
2.8.1 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 


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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 [100-103]) and evolving 
markers of ß-cell mass regulation (e.g., prolactin, DNA fragments and methylation, GLP-1, 
glucose-dependent insulinotropic peptide [GIP], HSP90nucleic acids [104-108]). 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 Pediatric Medication Protocol that three pediatric 
centers, with a contribution from the adult center at Indiana University, are performing 
together in youth with prediabetes or recent onset type 2 diabetes. This preliminary proof-of-
principle study is a randomized trial comparing metformin alone to initial insulin glargine 
followed by metformin. The primary outcome is ß-cell function, measured as defined below.  
The RISE Pediatric Medication Protocol will involve 90 adolescents, age 10-19 years old, Tanner 
stage >1 as defined by breast stage >1 in girls, and testes >3 ccs in boys. Volunteers will have 
prediabetes or recent onset (<6 months) type 2 diabetes and meet the following glucose-based 
parameters: HbA1c ≤8.0% if treatment naïve, OGTT-based fasting plasma glucose ≥90 mg/dl 
and a 2-hour post challenge glucose ≥140 mg/dl. Youth receiving metformin will be included if 
their HbA1c is ≤7.5% if on metformin for <3 months and ≤7.0% if on metformin for 3-6 months. 
Participants will be randomized to: (1) metformin alone for 12 months, or (2) initial insulin 
glargine for 3 months followed by metformin for 9 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 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.  


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Figure 1: Timing of interventions and outcomes testing for RISE Pediatric Medication Protocol 
The chosen interventions are intended to test whether “resting” the ß-cell (metformin alone) or 
further resting the ß-cell (addition of insulin glargine) will retard the natural progression of 
prediabetes and type 2 diabetes by reducing secretory demand on the ß-cell.  
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 
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 co-linearity 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) [84]. This will be calculated 


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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) [48]. 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 [89]. 
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 glargine followed by 
metformin against metformin alone 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.  
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 


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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 
3.3.2  -cell Function 
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 


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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 (measures at other time 
points contingent on funding) 
3.3.5 Physical Measures 
(i) Physical measures: blood pressure, body weight, body mass index, waist and hip 
circumference. 
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  placebo 
tablets. Participants already on metformin will be provided metformin at their entering dose 
while treatment naïve patients will receive placebo capsules. 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, and if 
they were previously on metformin, returned to their home metformin medication. 
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 


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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 two 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 who have diabetes will be required to perform 
home blood glucose monitoring.  
Participants randomized to metformin monotherapy or initial insulin glargine followed by 
metformin will not be masked to the intervention. 
Metformin is approved for treating type 2 diabetes in youth and will be used according to the 
label. Investigational New Drug (IND) applications have been ruled exempt for the use of 
metformin in youth with prediabetes and for the use of insulin glargine in youth with 
prediabetes and type 2 diabetes. For study procedures performed during the active phase of 
treatment, study medications will be withheld on the morning of testing. 
3.4.3 Metformin  
Metformin use is the same in all treatment groups that use it. To minimize non-compliance due 
to gastrointestinal side effects, patients who are not already on metformin will be titrated over 
a maximum of eight weeks from a starting dose of 500 mg once daily to a maximum dose of 
1000 mg bid. Participants already on metformin will have their dose titrated similarly 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 Insulin Glargine Followed by Metformin 
Insulin will be titrated over a period of one month based on daily self-blood glucose monitoring 
to achieve a fasting blood glucose of 80-90 mg/dl without hypoglycemia, and then continued 
with dose adjustments to maintain the fasting glucose in this range. 
Insulin glargine has been shown to be safely titratable in adults  with prediabetes and 
established type 2 diabetes to achieve fasting glucose concentrations of <95 mg/dl without a 
clinically significant increase in recurrent or severe hypoglycemia [64].  Following 3-months of 


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insulin treatment, insulin glargine will be discontinued and metformin will be commenced and 
titrated as above. 
3.4.5 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 
-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 as determined by elevation 
in HbA1c, development of urinary ketones or symptoms of hyperglycemia, 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 and 
decisions regarding appropriate treatment. 
3.4.6 Rescue 
The approach to rescuing a participant with severe hyperglycemia is described in Section 7.4. 
3.5 Inclusion Criteria 
1. Fasting plasma glucose ≥90 mg/dl plus 2-hour glucose ≥140 mg/dl on 75 gm OGTT plus 
laboratory-based HbA1c ≤8.0% if treatment naïve. There is no upper limit for the 2-
hour glucose on OGTT. In those taking metformin laboratory-based HbA1c must be 
≤7.5% if on metformin for <3 months and ≤7.0% if on metformin for 3-6 months. 
2. Age 10-19 years 
3. Pubertal development Tanner stage >1 as defined by breast stage >1 in girls, and testes 
>3 cc’s in boys. 
4. Body mass index (BMI) ≥85th percentile but <50 kg/m2  


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5. Self-reported diabetes <6 months in duration 
6. Treatment with metformin for <6 months preceding screening 
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 
mellitus 
3. Taking medications that affect glucose metabolism, or has an underlying condition that 
is likely to require such medications 
4. Treatment with insulin for >1 week preceding screening 
5. Active infections 
6. Renal disease (serum creatinine >1.2 mg/dl) or serum potassium abnormality (<3.4 or 
>5.5 mmol/l) 
7. Anemia (hemoglobin <11 g/dl in girls, <12 g/dl in boys) or known coagulopathy 
8. Cardiovascular disease, including uncontrolled hypertension defined as average systolic 
or diastolic blood pressure > 99 percentile for age or >135/90, despite adequately 
prescribed antihypertensive medications. Participants must be able to safely tolerate 
administration of intravenous fluids required during clamp studies. 
9. History of conditions that may be precipitated or exacerbated by a study drug: 
a. 
Serum ALT more than 3 times the upper limit of normal 
b. 
Excessive alcohol intake 
c. 
Sub-optimally treated thyroid disease 
d. 
Treated or untreated seizure disorder 
10. Conditions or behaviors likely to affect the conduct of the RISE Study 
a. 
Participant and/or parents unable or unwilling to give informed consent 
b. 
Participant and/or parents unable to adequately communicate with clinic staff 
c. 
Another household member is a participant or staff member in RISE 


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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% of body weight in the past 3 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 2 years 
g. 
Current (or anticipated) pregnancy and lactation. 
h. 
A pregnancy that was completed less than 6 months prior to screening.  
i. 
Breast feeding within 6 months prior to screening.  
j. 
Women of childbearing potential who are unwilling to use adequate 
contraception 
k. 
Major psychiatric disorder that, in the opinion of clinic staff, would impede the 
conduct of RISE 
11. 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. 
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 two 
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 who are drug-naive will take metformin placebo. All 
participants will be taught how to perform injections  to assess compliance with possible study 
medications. Placebo injections will not be used during the active treatment phase – i.e., the 
treatment assignment will not be blinded. 


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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, referral from 
colleagues, and screening from the investigators’ clinics. 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, his/her 
willingness to participate in the study, and his/her parents’ willingness to have their child 
participate. 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 
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 clinical, HbA1c 
and/or OGTT criteria. Youth who are highly predisposed to develop type 2 diabetes include, but 
are not limited to, those with: 
 Known impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) 
 Overweight or obesity (BMI ≥85th percentile) 
 Age ≥10 years 
 First degree relative with type 2 diabetes  
 Sedentary lifestyle 
 Those with low HDL cholesterol or high triglycerides, hypertension (i.e., “the metabolic 
syndrome”) 


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 Certain racial and ethnic groups (e.g., Non-Hispanic Blacks, Hispanic/Latino Americans, 
Asian Americans and Pacific Islanders, and American Indians and Alaska Natives) 
 Teenage women who had gestational diabetes, or who have had a baby weighing 9 
pounds or more at birth 
 Offspring of mothers who had diabetes while pregnant, including gestational diabetes 
 Adolescent girls 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 [109]. 
 
Patients who are in these high risk categories will be invited for a screening visit during which 
they will undergo a 75 gram glucose tolerance test and have HbA1c measured.  Of those who 
undergo a 75 gram OGTT and the lab-based HPLC HbA1c, we expect that approximately one-
third of individuals will meet study enrollment criteria, i.e., will have a fasting plasma glucose 
≥90 mg/dl plus a 2-hour glucose ≥140 mg/dl plus a laboratory-based HbA1c ≤8.0% if treatment 
naïve [in those taking metformin, HbA1c must be ≤7.5% if on metformin for <3 months and 
≤7.0% if on metformin for 3-6 months]. There is no upper limit for the 2-hour glucose on OGTT. 
4.3 Informed Consent  
Written informed consent will be obtained prior to initiation of any study-related activities. The 
informed consent process will be performed in a quiet setting prior to the initiation of any study 
procedures. The subject and his/her parents 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. 
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 


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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, annually thereafter, and at the time of any protocol changes. 
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 a 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. 
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 parents of the participating minor and/or the 
participating individual provides written informed consent for participation in RISE. If for any 
reason the participant and his/her parents wish 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 and 
his/her parent agree 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 


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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/assent, they are first 
interviewed and records are reviewed for personal and medical history. If they pass 
these eligibility criteria, 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 ≥90 mg/dl, 2-hour glucose must be 
≥140 mg/dl and the laboratory-based HbA1c must be ≤8.0% if treatment naïve [in those 
taking metformin, HbA1c must be ≤7.5% if on metformin for <3 months and ≤7.0% if on 
metformin for 3-6 months]. 
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 
adherence to medication taking, assess final eligibility criteria which will include a 
repeat POC HbA1c that must meet the same criteria as at the initial contact, and 
determine whether the patient should be randomized to RISE. 
4. Final screening visit and randomization: If the participant is eligible, informed 
consent/assent is obtained, baseline data including at laboratory HbA1c 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. 


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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. With the participant’s permission, RISE Study lab results will be shared with the 
provider. 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 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 
distribution for the next 3 month period. This includes medications required for the next 6 
randomized enrollees (i.e., on average 3 initial distributions for each of the 2 treatment arms) 
plus all of the upcoming distributions to enrolled participants who will be returning within 3 
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 placebo (metformin) distributed during the 3-week run-in period, medication will 
be dispensed to participants in 3 month quantities, and bottles/boxes/containers/syringes 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 clinical centers.  
5.3  
Adherence Measures 
Adherence will be documented, monitored, and addressed as part of participant care and 


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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 glargine. Participants will be instructed to bring all study 
medications (including empty bottles/vials/pens/syringes) to study visits. 
5.3.1 Placebo Run-in 
Metformin/placebo compliance will be assessed by pill counting as a percentage of the 
expected pills that were taken. Active metformin will be provided to subjects already on 
metformin at the dose they were currently taking, and compliance assessed by pill counting as 
a percentage of the provided expected pills that were taken.  
5.3.2 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 and assessment of syringes 
remaining. 
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 


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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. 
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. A hemoglobin and urine 
pregnancy test will be performed at baseline, 12 and 15 months to rule out anemia and 
pregnancy prior to each clamp procedure; ALT and creatinine will be measured at baseline and 
6 months. Pregnancy tests will also be done at any time if pregnancy is suspected.  
6.1.2  Oral Glucose Tolerance Test (OGTT) 
Participants will come to the clinical research testing facility in the morning following a 10-12 


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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 at -10, -5, 10, 20, 
30, 60, 90, 120, 150 and 180 min relative to 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. The clamp can be performed on the day 
immediately following the OGTT, but the OGTT will not be performed on the day immediately 
following the clamp.  
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 can be done using a single 
random capillary (finger stick) blood sample for measurement of HbA1C with a POC instrument 
or a lab HbA1c as a guide to help decide who to screen. In addition, a screening questionnaire 
that includes a focused medical history, anthropometric and blood pressure measures must 
also indicate that they meet initial eligibility criteria. 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 ≤8.0% if 
treatment naïve [in those taking metformin, HbA1c must be ≤7.5% if on metformin for <3 


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months and ≤7.0% if on metformin for 3-6 months], fasting glucose must be ≥90 mg/dl and 2-
hour glucose 140 mg/dl for eligibility in RISE. Eligibility lab tests will also be performed, 
including electrolytes, TSH (when clinically indicated), triglycerides, creatinine, ALT, GAD and 
ICA-512 antibodies, hemoglobin, and urine 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 
Optional Screening HbA1C (POC or 
recent lab value) 
Continue screening if ≤8.2% if 
treatment naïve, ≤7.7% if on 
metformin for <3 months and 
≤7.2% if on metformin for 3-6 
months 
Screening questionnaire 
Initial review of eligibility  
Height, weight and BP 
Initial screening for eligibility 
2)  Screening 
HbA1c (central lab), 75 gram OGTT 
(central lab); glucose at 0 and 120 
min 
Eligibility HbA1c ≤8.0% if 
treatment naïve, ≤7.5% if on 
metformin for <3 months and 
≤7.0% if on metformin for 3-6 
months fasting glucose ≥90 
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, GAD and ICA512 antibodies, 
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, provided that HbA1c levels remain within the acceptable range while 
off treatment). Hyperglycemic clamp and OGTT outcomes measures are described in detail 


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above. Other measurements are discussed below. 


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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 
x 
x 
x 
x 
x 
x 
x 
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  
(Cleveland Adolescent 
Sleepiness Questionnaire, Sleep 
Disturbance Scale for Children) 
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 with diabetes 
x 
x 
x 
x 
x 
x 
x 
x 
Hemoglobin (local measure) 
x 
 
 
 
x 
x 
 
 
Blood chemistries**(local 
measure) 
x 
 
x 
 
 
 
 
 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test (local measure) 
x 
 
 
 
x 
x 
 
 
Medication adherence 
x 
x 
x 
x 
x 
 
 
 
** fasting serum ALT and creatinine +pregnancy tests can also be done 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 


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iliac crest and the lowest rib (waist), and at the top of the femur (hip) with the participant 
standing upright.  
6.3.2  Sleep Assessments  
During screening, participants will complete the Cleveland Adolescent Sleepiness Questionnaire 
and the Sleep Disturbance Scale for Children for analysis of self-reported sleep-related 
measures as potential predictors of response to treatment.  
6.3.3  Safety Measures 
The study will provide blood glucose monitors and strips for use during the study. Participants 
with diabetes will be instructed to monitor and record fasting blood glucose daily, in the 
morning, and as otherwise instructed for safety monitoring. Routine local laboratory studies 
consisting of a hemoglobin or hematocrit, serum ALT and creatinine, and a urine pregnancy test 
will be collected for evaluation of anemia and liver and kidney function and to rule out 
pregnancy at baseline; serum ALT and creatinine will be repeated at 6 months during 
treatment, and a hemoglobin or hematocrit and urine pregnancy will be repeated at 12 and 15 
months to rule out anemia or pregnancy before the insulin clamp. Adverse events (AE) will be 
surveyed at each visit using a standardized questionnaire.  
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, glargine pen residual volume will be determined. Participants will be asked to bring all 
medications to all visits. For participants with diabetes and for those on glargine, self 
monitoring blood glucose (SMBG) data will be reviewed at each visit (every 3 months) or more 
frequently if needed.  
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. The specific actions 
recommended when a visit window is missed will be described in the MOP. 
 


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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. 
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 
Written informed consent will be obtained prior to initiation of any study-related activities. The 
informed consent process will be conducted by qualified study personnel. All participants must 
read, sign and date a consent/assent form as appropriate (consent for participants age 18 and 
above, assent signed by participants/consent signed by parents for participants under age 18) 
prior to participation in any stage of the study. The informed consent/assent 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 


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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. 
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.  
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 (details in the MOP). 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 personal 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 FDA 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.  


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7.3  Expected Side Effects 
The RISE Pediatric Study will use the following medications: metformin and insulin glargine.  
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, 
dehydration, or shock. In the TODAY study, among approximately 230 youth on metformin 
alone, there was no severe hypoglycemia (unpublished data).  
Insulin glargine: The side effects of insulin glargine include hypoglycemia and slight weight gain. 
Participants will be counseled about the possibility of weight gain while on insulin therapy and 
given dietary counseling and resources. In addition, the metformin phase following the insulin 
should also help decrease weight gain. The occurrence of hypoglycemia will lead to insulin dose 
adjustment at the discretion of the investigator. Glargine does not peak, unlike NPH insulin, and 
therefore has much lower risk of hypoglycemia, especially overnight. In addition, due to its lack 
of a peak, subjects can safely skip meals or fast with glargine. Participants on insulin will 
perform SMBG to minimize the risk of hypoglycemia. In the ORIGIN trial, weight gain in the 
glargine group was on average only 1.6 kg after a mean glargine use of 6.2 years, and 
hypoglycemia was minimal [64]. In the TODAY study, of 699 pediatric subjects where much 
higher doses of insulin were used, there was only 1 episode of severe hypoglycemia which had 
no sequelae (unpublished data).  
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: 


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 If HbA1c ≥8% at any routine quarterly visit, therapy will be invigorated by frequent 
telephone contact and/or visits to encourage optimal medication adherence and 
lifestyle choices. Participants with diabetes will be asked to perform self monitoring of 
blood glucose twice a day and whenever they have symptoms of hyperglycemia or feel 
ill for any reason. They will be asked to report persistent readings above 200 mg/dl to 
the clinic staff, who will request that the patient check ketones and determine from the 
presence of symptoms and/or ketones whether the participant needs to be brought to 
the research clinic for interim assessment. HbA1c will be obtained at the next quarterly 
visit. If HbA1c remains ≥8% but <8.5% frequent contact will be maintained. 
 If HbA1c ≥8.5% at any routine quarterly visit, therapy will be invigorated (see MOP for 
details) and HbA1c is repeated after 6 weeks. The daily self care and reporting will be 
the same as for participants with a HbA1c ≥8%. If the HbA1c remains ≥8.5%, 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%, therapy will be invigorated (see MOP for details), the 
HbA1c will be repeated within 2 weeks and, if confirmed, the participant will be 
scheduled for immediate outcome measurement. Once outcome measures are 
completed, the participant is started on insulin glargine, 0.5 units per kilogram given in 
the evening and transferred back to their primary care provider for ongoing care. 
 Temporary use of insulin: Some patients may require temporary suspension of study 
drug and use of insulin for temporary medical conditions such as hospitalization for 
injury, surgery or other intercurrent illness. Any type or dose of insulin can be used at 
the discretion of the treatment team. In such cases, an attempt is made to withdraw 
insulin once the acute event has resolved and study drugs are resumed. If insulin cannot 
be weaned off within 4 weeks, the patient is censored at that time. 
 Self monitoring of blood glucose: Participants with diabetes will be asked to monitor 
their fasting blood glucose each morning, and as needed based on clinical status. During 
temporary insulin therapy, patients are asked to increase their monitoring to twice a 
day (fasting in the morning and 2 hours after the largest meal). The target for the fasting 
glucose will be 70-150 mg/dl, and the target for post-meal glucose will be 100-200 
mg/dl. 
 Metabolic decompensation is 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. All patients are educated to contact the 
study coordinator if they experience metabolic decompensation. This education is 
reinforced at study visits. Once insulin is started, the site will attempt to wean insulin 


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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. 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, 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. 
 Anemia may be an adverse effect of metformin. It is defined as hemoglobin <10 gm/dl, 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 assess 
renal insufficiency, serum creatinine and estimated GFR (eGFR) will be calculated using the 
CKD-Epi equation 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 m2at 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 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. 


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 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. Severe hypoglycemia is not 
expected in the population of youth being studied (obese, insulin resistant youth with 
prediabetes and type 2 diabetes) with the type and the low dose of insulin being proposed. 
In support of the safety of glargine, the recent ORIGIN trial studied a similar population 
(subjects with prediabetes defined as impaired fasting glucose or impaired glucose 
tolerance and subjects with type 2 diabetes). In ORIGIN, 12,537 subjects with were 
randomized to receive glargine (with a target fasting blood glucose level of ≤95 mg/dL) or 
standard care [64] for a mean duration of 6.2 years. Hypoglycemia in ORIGIN was minimal 
despite the very large sample size and long duration of treatment. In the ORIGIN study, 
there was also less hypoglycemia in subjects with prediabetes than diabetes. Hypoglycemia 
will also be minimized by frequent blood glucose monitoring during the glargine portion of 
the study. In addition, the mean BMI in the adult ORIGIN study was 29.85 kg/m2, whereas in 
the pediatric TODAY study the mean BMI was 34.5 kg/m2 [1]. As a result, we would expect 
our pediatric patients to be more insulin resistant and less susceptible to hypoglycemia than 
in adults.  
 Metformin is 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 and protocol visits will be discontinued if a participant 
becomes pregnant. The participant will be discontinued from the study and 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 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. 
 Adverse effects of the study procedures may occur very rarely and include: 


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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 
minimizing the use of concentrated solutions, monitoring the veins closely during the 
infusion 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) with a maximum dose of 5 gm per dose. 
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.  The DPP also demonstrated that metformin reduced the risk of progression 
to diabetes by 31% over three years in adults with prediabetes; metformin has also been shown 
to lower blood sugar, improve elevated liver enzymes and in girls, improve ovarian dysfunction 
[59]. Insulin glargine treatment is also predicted to slow progression from prediabetes to type 2 
diabetes, potentially by resting the beta cell. 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 that should further improve 
glucose control and potentially slow progression of their disease by resting the beta cell. In 
particular, results of the ORIGIN  study showed that not only did glucose control improve in 
adults with prediabetes and type 2 diabetes while on glargine, but his effect persisted off 
medication. Participants with prediabetes at the start of the trial (n=1456) were followed-up 
approximately 3 months after glargine discontinuation. In this group, subjects who received 
glargine had a 28% reduction in the development of diabetes at the 3 month follow-up after 
discontinuation of glargine, likely from improved beta cell function.   Finally, as all of our 
proposed subjects have prediabetes or type 2 diabetes, conditions that are becoming more 
prevalent and carry with them 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 


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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. This trial will be 
conducted under an IND and will comply with all FDA reporting requirements and those of the 
pharmaceutical sponsors. 
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. 
In order to facilitate timely reporting of SAEs to the FDA by the NIDDK, the clinical center staff 
who learn of an SAE must data enter the completed RISE Serious Adverse Event Report prior to 


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the close of the following business day. Upon request, all SAEs will be reported within the 
prescribed period to the relevant pharmaceutical sponsors. 
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 Safety 
Monitoring Committee does not agree about relatedness in an unblinded fashion, 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 


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stated objectives, and other interrelationships among elements of study data of interest to the 
investigators and of relevance to the objectives of the study. 
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. Analysis of covariance will be used to compare the two intervention 
groups after the washout. All analyses will be adjusted for the baseline value of each outcome.  
Because we are only interested in improvements in ß-cell function in youth treated with 
glargine + metformin vs. metformin alone, analyses will be tested using a one-tailed test at the 
=0.05 level to detect a benefit of glargine + metformin. The two primary outcomes will be 
analyzed separately with a total type I error probability of 0.05 for each, one-sided, i.e. without 
an adjustment for two separate outcomes. 
9.2  Secondary Outcomes and Analyses 
9.2.1  Measures of ß- and -cell Function and Glucose Tolerance 
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 two intervention groups 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 interest at both 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. 
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. 


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9.3  Sample Size/Power Calculations 
As this is a proof-of-principle trial, we have chosen 2 measures 
of ß-cell function as co-primary outcomes. They measure 
different components of ß-cell function, and we have no basis 
of determining whether one or the other is likely to change 
following the interventions. There is little preliminary data on 
the expected differences in either of the primary outcomes 
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 equal to the difference between the two 
groups divided by the standard deviation (SD) of 0.57 in favor of the glargine + metformin group 
at a power of 80%. A one-sided significance level of =0.05 to detect a benefit of glargine + 
metformin was used for each comparison, and a conservative correlation of 0.5 between 
baseline and follow up measures. A sample size of 39 per arm (78 total) at the end of the 
washout provides ≥80% power to detect a minimum effect size of 0.57 favoring glargine + 
metformin for either of the primary outcome measurements (see Table 3) using a t-test from a 
baseline-adjusted analysis of covariance. A higher effect size will result in significantly increased 
power. A total of 90 participants will be recruited to allow for a 10% loss to follow-up over the 
course of the study. 
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. 
Table 3: Power for a sample 
size of 78 at end of study 
(39/treatment arm) 
Actual Power 
Effect Size 
90.8% 
0.68 
87.7% 
0.64 
84.5% 
0.61 
81.1% 
0.58 
77.6% 
0.55 


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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 [110]. 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. 
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 


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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 back-up, 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: 
 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 
 Drop-out or loss to follow-up 
10.6 
Archiving and Study Close-out  
At the end of the study, after all data have been received and edited, the database is archived 
in computer readable format, including documentation files, files of study documents (such as 


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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. 
 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 


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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 for use in ancillary or future studies. 
 
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 


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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, 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, supplying the CoC with an IRB 
approval letter and stamped informed consent forms. Details of certification are provided in 
the MOP.  
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 
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 


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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 including any 
newly acquired, are declared at each study group meeting. 
The RISE Ethics Committee (NIDDK Project Scientist, NIDDK Program Official and study group 
member) determine (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. 
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. The PPS 
may also help to identify publication opportunities in areas where productivity is lacking or low. 


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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 
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 is resubmitted 
to the IRB, and the participant consent is revised appropriately. 


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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. 
13  LITERATURE CITED 
1. 
The TODAY Study Group, A clinical trial to maintain glycemic control in youth with type 2 
diabetes. N Engl J Med, 2012. 366(24): p. 2247-56. 
2. 
Kahn, S.E., R.L. Hull, and K.M. Utzschneider, Mechanisms linking obesity to insulin 
resistance and type 2 diabetes. Nature, 2006. 444(7121): p. 840-846. 
3. 
Dunning, B.E. and J.E. Gerich, The role of α-cell dysregulation in fasting and postprandial 
hyperglycemia in type 2 diabetes and therapeutic implications. Endocr Rev, 2007. 28(3): p. 253-
83. 


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4. 
Bacha, F., et al., Progressive deterioration of beta-cell function in obese youth with type 
2 diabetes. Pediatr Diabetes, 2012. 
5. 
Giannini, C., et al., Evidence for early defects in insulin sensitivity and secretion before 
the onset of glucose dysregulation in obese youths: a longitudinal study. Diabetes, 2012. 61(3): 
p. 606-14. 
6. 
Sjaarda, L.A., et al., HbA1c Diagnostic Categories and beta-Cell Function Relative to 
Insulin Sensitivity in Overweight/Obese Adolescents. Diabetes Care, 2012. 
7. 
Michaliszyn, S.F., et al., Metabolomic Profiling of Amino Acids and beta-Cell Function 
Relative to Insulin Sensitivity in Youth. J Clin Endocrinol Metab, 2012. 97(11): p. E2119-24. 
8. 
Sjaarda, L.G., et al., Oral disposition index in obese youth from normal to prediabetes to 
diabetes: relationship to clamp disposition index. J Pediatr, 2012. 161(1): p. 51-7. 
9. 
Burns, S.F., et al., Declining beta-cell function relative to insulin sensitivity with 
escalating OGTT 2-h glucose concentrations in the nondiabetic through the diabetic range in 
overweight youth. Diabetes Care, 2011. 34(9): p. 2033-40. 
10. 
Tfayli, H., S. Lee, and S. Arslanian, Declining beta-cell function relative to insulin 
sensitivity with increasing fasting glucose levels in the nondiabetic range in children. Diabetes 
Care, 2010. 33(9): p. 2024-30. 
11. 
Giannini, C. and S. Caprio, Islet function in obese adolescents. Diabetes Obes Metab, 
2012. 14 Suppl 3: p. 40-5. 
12. 
Bacha, F., et al., Determinants of glycemic control in youth with type 2 diabetes at 
randomization in the TODAY study. Pediatr Diabetes. 13(5): p. 376-83. 
13. 
Kester, L.M., H. Hey, and T.S. Hannon, Using hemoglobin A1c for prediabetes and 
diabetes diagnosis in adolescents: can adult recommendations be upheld for pediatric use? J 
Adolesc Health. 50(4): p. 321-3. 
14. 
Garvey, W.T., et al., The effect of insulin treatment on insulin secretion and insulin 
action in type II diabetes mellitus. Diabetes, 1985. 34: p. 222-234. 
15. 
Ilkova, H., et al., Induction of long-term glycemic control in newly diagnosed type 2 
diabetic patients by transient intensive insulin treatment. Diabetes Care, 1997. 20(9): p. 1353-6. 


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16. 
Weng, J., et al., Effect of intensive insulin therapy on beta-cell function and glycaemic 
control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-
group trial. Lancet, 2008. 371(9626): p. 1753-60. 
17. 
The Diabetes Prevention Program Research Group, Reduction in the incidence of type 2 
diabetes with lifestyle intervention or metformin. N Engl J Med, 2002. 346: p. 393-403. 
18. 
Kahn, S.E., et al., Glycemic durability of rosiglitazone, metformin, or glyburide 
monotherapy. N Engl J Med, 2006. 355: p. 2427-2443. 
19. 
Kahn, S.E., et al., Effects of rosiglitazone, glyburide and metformin on ß-cell function and 
insulin sensitivity in ADOPT. Diabetes, 2011. 60: p. 1552-1560. 
20. 
Fehse, F., et al., Exenatide augments first- and second-phase insulin secretion in 
response to intravenous glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab, 2005. 
90: p. 5991-5997. 
21. 
Drucker, D.J. and M.A. Nauck, The incretin system: glucagon-like peptide-1 receptor 
agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet, 2006. 368: p. 1696-
1705. 
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