Detemir Versus NPH for Type 2 Diabetes Mellitus in Pregnancy: a Comparative-effectiveness, Open Label, Randomized Controlled Trial
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
Sponsor: The University of Texas Health Science Center, Houston

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IRB NUMBER: HSC-MS-18-0575 
IRB APPROVAL DATE: 07/31/2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Detemir versus NPH for type 2 diabetes mellitus in pregnancy: 
a comparative-effectiveness, open label, randomized controlled trial 
 
NCT03620890 
 
Version Date: 07/31/2018 
 
 

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IRB NUMBER: HSC-MS-18-0575 
IRB APPROVAL DATE: 07/31/2018 
 
Detemir versus NPH for type 2 diabetes mellitus in pregnancy: 
a comparative-effectiveness, open label, randomized controlled trial 
 
 
STUDY PROTOCOL 
Principal Investigator: Michal Fishel Bartal M.D. 
 
 
Co-investigators: 
Jerrie Refuerzo M.D 
Clara Ward M.D 
Joycelyn Cornthwaite, CDE 
Sunbola Ashimi, PhD 
Baha M. Sibai, M.D 
 
 
 
Division of Maternal Fetal Medicine 
Department of Obstetrics, Gynecology and Reproductive science 
The University of Texas Health Science Center at Houston 

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IRB NUMBER: HSC-MS-18-0575 
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1. Background 
Pre-gestational diabetes affects 0.7-1.5% of pregnancies, while the prevalence 
continues to increase, with a reported increase of 27.7% from 1999 to 2005. 1-3 
Pre-gestational diabetes refers to type 1 and type 2 diabetes, while Type 2 diabetes 
mellitus is the common major form of diabetes and account for about 90% of all diabetic 
cases worldwide. Type 2 diabetes mellitus is associated with a decrease in insulin 
secretion and elevated insulin resistant and has several risk factors including: weight, 
race, inactivity and family history and the number of adults with diabetes is increasing 
from year to year globally.4 
Women with diabetes mellitus remain at increased risk of adverse pregnancy outcomes 
during pregnancy and birth, with a higher risk for pregnancy loss, gestational 
hypertension, macrosomia and cesarean delivery compared to women 
without diabetes mellitus. 5 Glucose control during pregnancy decreases the risk of 
complications such as fetal demise, birth injuries and macrosomia.6,7 
Insulin is the preferred agent for management of both type 1 diabetes and type 2 
diabetes in pregnancy because it does not cross the placenta and oral agents are 
generally insufficient to overcome the insulin resistance in type 2 diabetes and are 
ineffective in type 1 diabetes.8-10 However, currently there is insufficient data to 
determine what type of insulin achieves the best glycemic control during 
pregnancy with minimum adverse events such as hypoglycemia.11 
Basal insulins suppress uncontrolled hepatic glucose production and therefore have to 
be relatively long acting, usually injected once or twice daily. Basal insulin includes 
neutral protamine hagedron (NPH, isophane insulin) and the modern insulin analogs- 
insulin glargine and insulin detemir. 
The main difference between NPH and insulin analog is the pharmacodynamics; NPH 
will peak between 4-12 hours after injection with a duration of action around 14 hours. 
Whereas both glargine and detemir are characterized by a gentle rise and fall with a 
longer duration of action (18-20 hours) in most patients.12 NPH is often the initial choice 
of insulin treatment in patients with diabetes mellitus during pregnancy but because of 
its duration of action fails to mimic the physiologic profile of insulin release, it may 
require multiple injections during the day and has been associated with increased risk 
for hypoglycemia.13 
Outside of pregnancy, clinical trials comparing efficiency outcomes with basal insulin 
analogs found that insulin analogs are mostly non-inferior or better than other insulins, 
while reducing the incidence of hypoglycemia and weight gain- two main adverse 
effects that are of concern for the patient and the physician. 14-17 Switching patients with 
diabetes mellitus type 2, who were inadequately controlled on NPH, to basal insulin was 
associated with significant improvement of glycemic control and reduction of the 
hypoglycemic events during treatment with basal analogs.18 A recent registry based 
study regarding the long term effect of basal insulin treatment on cardiovascular 

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mortality found substantially higher mortality rates among users of NPH insulin as 
compared to insulin analogs; detemir or glargine.19 
Over the past years, there has been an increase in the use of long acting basal insulin 
in the treatment of patients with diabetes mellitus type 2. The American Diabetes 
Association (ADA) 2018 guidelines on pharmacological approaches to glycemic control 
10 recommend that when basal insulin is added to anti hyperglycemic agents in patients 
with type 2 diabetes, long-acting basal analogs (U-100 glargine or detemir) can be used 
instead of NPH to reduce the risk of symptomatic and nocturnal hypoglycemia. 
According to the American Association of Clinical Endocrinologists and American 
College of Endocrinology (AACE/ACE) 2018 consensus statement on the management 
of patients with diabetes mellitus, basal insulin analogs are preferred over NPH because 
a single basal analog dose provides a relatively flat serum insulin concentration for 24 
hours or longer. Basal insulin analogs and NPH were equally effective in reducing 
HBA1C in clinical trials; however, insulin analogs caused significantly less 
hypoglycemia. 20 
Basal insulin in pregnancy: NPH was the first basal insulin that have shown to be 
safe during pregnancy. In the past years, many doctors prefer to prescribe long acting 
basal insulin for different reasons including: patients that have difficulty controlling their 
blood glucose levels using NPH due to its shorter duration of action, use of insulin 
analogs prior to pregnancy and the higher risk for hypoglycemic events reported with 
NPH. 
While some doctors believe that detemir is safe and effective in women with type 2 
diabetes during pregnancy, the American College of Obstetricians and Gynecologists 
(ACOG) acknowledge that women with type 2 diabetes in pregnancy should be treated 
with basal insulin but do not specify which type of insulin is recommended.21 
A few studies evaluated the use of long acting insulin analog in pregnancy. In a meta- 
analyses of 8 studies evaluating glargine, which included only observational and 
retrospective studies, a total of 702 women with pre-gestational or gestational diabetes 
treated with either glargine or NPH, there were no significant differences in the maternal 
and neonatal outcomes between NPH and glargine 22 . One prospective study 
examined maternal and neonatal outcomes in 138 women with preexisting diabetes and 
gestational diabetes treated with glargine or NPH and found that maternal outcomes 
were significantly worse in the pre-gestational group receiving NPH insulin compared to 
insulin glargine 23. Maternal hypoglycemia occurred significantly more likely in the NPH 
insulin group compared to insulin glargine. 
In recent years, insulin detemir has become a preferred agent of treatment of diabetes 
in pregnancy. In contrast to insulin glargine, in 2012, insulin detemir received US Food 
and Drug Administration approval for reclassification to pregnancy category B from 
pregnancy category C. This was based on a randomized control trial comparing insulin 
detemir and NPH in 310 pregnant women with diabetes mellitus type 124. Results 
demonstrated that detemir was non-inferior to NPH in both glycemic control and 
hypoglycemia events. 

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Since then, there have been a few studies evaluating the use of detemir in pregnancy 
(Table 1). In all of them, detemir was comparable to NPH in achieving glucose control 
as well as maternal and neonatal outcomes. Only one randomized controlled study,25 
has investigated detemir in the setting of pregnant women with gestational diabetes and 
diabetes mellitus type 2. In this study, only 7 (17%) patients that received detemir and 7 
(16%) patients that received NPH, had diabetes mellitus type 2 and all the other 
patients in the study had gestational diabetes. The result of this study indicated that 
detemir was not inferior to NPH for the treatment of GDM and T2DM in pregnancy. Of 
note, there were more hypoglycemic events per patient in the NPH group. 
The recent Cochrane review (2017)11 regarding different insulin types and 
regimens for pregnant women with pre-existing diabetes concluded that at 
present, insufficient data exists to allow the review authors to make any 
substantial or concrete conclusions about the effectiveness of one insulin type or 
regimen over another in pregnant women with pre-existing type 1 or type 2 
diabetes. 
Until now, no study has compared neonatal and maternal outcomes in patients with 
diabetes mellitus type 2 treated with detemir versus NPH. We hypothesize that 
treatment with detemir in patients with diabetes mellitus type 2 during pregnancy will 
reduce adverse neonatal outcome and reduce the number of hypoglycemic events 
during pregnancy compared to patients treated with NPH. To prove this hypothesis, we 
propose a comparative- effectiveness, open label, randomized controlled trial for 
treatment of Type 2 diabetes in pregnancy with long acting insulin detemir versus NPH. 

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Table 1: Human studies on the use of insulin detemir in pregnancy 
 
Author 
Year 
Design 
Insulin 
N 
Type 
of 
diabet 
es 
Primary 
outcome 
Differe 
nce in 
the 
mean 
basal 
glucos 
e 
Differenc 
e in the 
mean 
fasting 
glucose 
Lapolla 
et al. 
2009 
Report 
Detemir 
10 
T1DM 
Glycemic 
control 
Shenov 
et al. 
2012 
Retrospectiv 
e 
Detemir 
18 
T1DM 
+T2D 
M 
Maternal and 
neonatal 
outcome 
Mathies 
en et al. 
2012 
RCT 
Detemir 
vs NPH 
310 T1DM 
HBA1C at 36 
weeks of 
gestation 
125.1 
vs 
132.8 
mg/dL 
(P=0.0 
03) 
96.8 vs 
113.8 
mg/dL 
(P=0.01 
2) 
Callesen 
et al. 
2013 
Retrospectiv 
e 
Detemir 
vs 
glargine 
113 T1DM 
Glycemic 
control 
estimated by 
HBA1C 
Hod et 
al. 
2014 
RCT 
Detemir 
vs NPH 
313 T1DM 
HBA1C at 36 
weeks of 
gestation 
Herrera 
et al. 
2015 
RCT 
Detemir 
vs NPH 
87 
GDM 
and 
T2DM 
Overall 
mean blood 
glucose 
2.1 
mg/dL 
(P=.29 
3) 
Koren et 
al. 
2016 
Retrospectiv 
e 
Detemir 
vs 
Glyburide 
91 
GDM 
Good 
glycemic 
control 
91.8 vs 
91.8 
(P=0.91) 

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2. Methods 
2.1 Study objectives 
2.1.1 Objective 
To determine whether use of detemir compared to NPH decreases rates 
of composite neonatal outcome and maternal hypoglycemia events in 
women with T2DM 
2.1.2 Rationale 
Treatment with Basal insulin analogs improve glycemic control in patients 
with uncontrolled diabetes. They have been associated with fewer events 
of hypoglycemia in non-pregnant and pregnant women. Many women of 
childbearing age are now receiving insulin analogs and would prefer to 
continue using them during pregnancy and their efficiency in pregnancy 
requires further study. 
2.1.3 Primary outcome 
Composite adverse neonatal outcome: 
 Neonatal intensive care unit (NICU) admission or 
 Neonatal hypoglycemia (<40 mg/dL in the first 24 hours of life and 
less than 50 mg/dL after) or requiring medical therapy or 
 Respiratory distress (need for at least 4 hours of respiratory support 
with supplemental oxygen, continuous positive airway pressure or 
ventilation at the first 24 hours of life or 
 Shoulder dystocia - defined as the need for any extra maneuvers, 
other than gentle downward traction of the fetal head in order to 
deliver the fetal body after the fetal head has been delivered or 
 Large for gestational age (LGA) -weight over 90th percentile of the 
expected value according to gestational age or 
 Macrosomia- Fetal weight above 4000g 
2.1.4 Secondary outcome measures; Maternal 
 Mean fasting glucose 
 Mean post prandial glucose 
 Hypoglycemia events (<60 mg/dl) 
 Maternal weight gain 
 Gestational hypertension 
 Preeclampsia 
 Cesarean delivery 
 Operative vaginal delivery 
2.1.5 Secondary outcome measures; Neonatal 
 Gestational age at delivery 
 Small for gestational age (SGA) 
 Neonatal intensive care unit (NICU) length of stay 
 5-minute Apgar score ≤ 5 
 Neonatal jaundice requiring therapy 

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2.1.6 Ancillary Studies 
2.1.6.1 Medication adherence survey: Medication non- adherence is an 
important public health issue that clinicians encounter. Approximately 
78% of e-prescriptions are actually filled; only 72% of new prescriptions 
are filled.26 Non-compliance is most common among new prescriptions for 
chronic conditions including diabetes (31.4%). Diabetes is a common 
chronic condition. Adherence to medications can be affected by a variety 
of factors in patients with diabetes; perception that medications are only 
needed when glucose levels are high, concerns regarding adverse effects 
and lack of self-confidence in their self-treatment.27 Medications are 
commonly used in pregnancy with at least 81.2-96.9% of women using at 
least one medication, either prescribed or over-the-counter.28,29 The 
attitudes regarding drug use in pregnancy and ability to obtain drug 
information plays an important role in medication adherence30,31. The 
MMAS-8 validated survey (attached as Figure 1 ) will be given to women 
to complete during their routine prenatal visit if they meet study criteria 
and agree to the study. This is a copyrighted survey and for this particular 
study, we have permission to use the MMAS-8. This survey will be 
supplemented with other questions collecting information on 
demographics and challenges with prescription error and pick up 
problems. It takes approximately 10 minutes to complete. The answers 
will not be available to the managing health care provider, but will be kept 
in the locked research office until after the delivery of subject. Based on 
the scores of the survey, the subject will be divided into groups based on 
high, medium and low adherence. Maternal demographics, antepartum 
course, pregnancy outcomes and neonatal outcomes will be collected 
from prenatal/office and hospital chart. Outcomes between groups will be 
compared.31-34 
 
2.1.6.2 Social determinants of health (SDH) Survey (SDH)- while our 
approach to clinical care is rooted in biology, an increasingly 
interdisciplinary approach is being employed that acknowledges SDH, i.e 
the social and structural aspects of a patient’s life that can influence 
health. Social determinants of health (SDH) include but are not limited to 
basic resources, educational opportunities and economic stability, access 
to health care, community resources, literacy, socioeconomics, and 
safety.35 By understanding SDH, interventions can be pursued that can 
improve individual and population health. For patients living with diabetes, 
there is a correlation between social determinants of health and glycemic 
control.36 Many obstetrical conditions are also impacted by SDH. 37 Using 
this broader context to understand patients’ health care decision-making 
and health literacy facilitates recognizes the intersections of social identity 
and their associated patterns of structural oppression, and fosters a 
creative approach to overcoming potential barriers. The PRAPARE 
Assessment (The Protocol for Responding to and Assessing Patients’ 

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Assets, Risks, and Experiences) is an established tool to briefly assess 
SDH. Core measures of this tool include race, ethnicity, education, 
employment, insurance, income, material security, transportation, social 
integration and support, stress and migrant, veteran and housing status. It 
will provide insight by which we can understand correlations between SDH 
and health care outcomes in our population as a springboard to improving 
both the outcomes and the pathways leading to them. The brevity of 
questions covering numerous social domains can help target particular 
social features that may be correlated with glycemic control as well as 
target resource referrals and utilization, thereby translating into actionable 
items. 
 
2.1.6.3 Physician empathy survey- Physician empathy represents 
understanding of patient concerns, experiences, and perspectives that is 
communicated to the patient, which within a therapeutic relationship, 
includes an intention to help. (8) Regardless of intention, empathy must be 
conveyed and therefore perceived by the patient.38 The perception of 
empathy has been associated with patient compliance with physician 
recommendations, thereby linking outcomes to to physician engagement 
and empathetic care. 39 The Jefferson scale of patient perception (JSPPE) 
of physician empathy has 5-items rated on a 7-point scale that can be 
answered to assess the patient’s perception physician empathy.40,41 
Patients will be will be instructed to fill the scale and to hand them back to 
the researcher in a closed envelope. All forms will be anonymized. The 
questionnaires will be returned directly to the researchers in closed 
envelopes and the results will be inserted into a data system by a 
designated person. Empathy score will be the total score of JSPPPE and 
we will use this information to correlate perceptions of empathy with 
compliance as well as maternal and neonatal outcomes. 
 
1.1 Design summary 
This is a comparative-effectiveness, open label, randomized controlled trial for 
the treatment of pregnant women with diabetes mellitus type 2 with insulin 
detemir versus NPH 
1.2 Inclusion criteria 
 Preexisting type 2 diabetes mellitus requiring medical treatment or 
 overt diabetes diagnosed prior to 20 weeks of gestation using either 
HBA1C ≥ 6.5 or fasting glucose ≥126 mg/dl or random blood glucose ≥ 
200 mg/dl or two step method ( 50g GCT >135 mg/dl followed by 100 
GCT with at least 2 values above thresholds: FBG >90, 1 hr >180, 2 hr > 
155, 3 hr > 140 mg/dl). 
 Gestational age ≤20 weeks 
 Willing to start insulin therapy or to continue insulin treatment during 
pregnancy 
 Singleton or twin pregnancy 

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1.3 Exclusion criteria 
 Known allergy/prior adverse reaction to NPH/detemir 
 Patients <18y 
 Known major fetal anomalies 
 Diabetic nephropathy (Cr≥1.5) 
 Diabetic proliferative retinopathy 
 Patients with Type 1 diabetes or gestational diabetes 
1.4 Recruitment and feasibility 
Recruitment will occur at the outpatient obstetric clinics at: 
1. UT MFM clinic at Texas Medical center 
2. UT Women center at Bellaire 
3. Memorial Hermann Memorial city MFM clinic 
4. Memorial Hermann Sugar land MFM clinic 
5. Memorial Hermann Greater Heights MFM clinic 
6. LBJ MFM clinic 
7. St. Joseph MFM clinic 
8. Memorial Hermann Katy MFM clinic 
9. Cypress Fairbanks MFM clinic 
10. Memorial Hermann Pearland MFM clinic 
11. Women’s Hospital of Texas MFM clinic 
12. Memorial Hermann Cypress Hospital 
1.5 Randomization 
Randomization will be achieved by computer-generated random sequences that 
will be created by a non-clinical member of the research team. A permuted block 
randomization with a random fashion will be used to prevent imbalances between 
groups. The medication based on the computer-generated list will be typed out 
on a piece of paper with the medication regimen according to the below 
regimens. The piece of paper will be placed in an opaque envelope and 
numbered according to the computer-generated list. Envelopes will be kept 
secured at the outpatient obstetrics clinic and will be managed by the research 
team. 
Intervention and procedures 
Women that meet the inclusion and exclusion criteria will be approached by the 
research staff/MFM physician at their first outpatient visit. An informed consent 
will be obtained and a copy will be given to the subject. Women will be 
randomized to insulin detemir or insulin NPH as the basal insulin treatment 
during pregnancy. Group 1 will be composed of women allocated to detemir 
treatment. Group 2 will be composed of women allocated to NPH treatment. 
Detemir and NPH will be administrated subcutaneously at the same time. In both 
groups short acting Insulin (aspart/lispro/regular) will be administered as needed 
before each meal (0-30 minutes) according to the physician preference. Current 
weight will be obtained at the visit and the initial daily total insulin dose will be 
determined based on the patient weight and trimester according to the 
recommended guidelines for treatment during pregnancy. In the first trimester the 
patient weight will be multiplied by 0.7, in the second trimester by 0.8, and in the 
third trimester by 0.9 for the total daily units of insulin. 42,43 

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In-group 1 the total daily dose of insulin will be divided into 50% detemir insulin 
and 50% short acting insulin. Detemir dose can be divided in half, injected in the 
morning and in the evening, 12 hours apart. Short acting insulin will be divided 
with one third each being injected with breakfast, lunch and dinner meals. In- 
group 2, approximately 60% of the daily insulin NPH dose is given in the morning 
and 40% in the evening. Of the morning dose, two third will be the NPH and one- 
third the short acting insulin. The evening insulin dose will be divided in 2: half 
will be short acting insulin the other half will be NPH at bed-time. 
 
Patients that have been treated with previous diabetic medications will continue 
treatment with the new insulin after randomization as suggested by our 
department protocol and is determined by the medications half time (Table 2, 
Table 3): 
 
1. Patients treated with metformin will continue metformin or stop it depends on 
the physician decision. They will start insulin on the same day without need 
for washout. 
2. Patients treated with Glyburide or a combination of glyburide and metformin, 
according to our standard of care and due to the risk of hypoglycemia will 
stop the glyburide and will only start insulin on the next day. Metformin will 
be prescribed at the discretion of treating physician. 
3. Patients treated with Glargine (Lantus) prior to randomization, will start 
NPH/detemir 24 hours after stopping glargine due to his longer half time. 
4. Patients treated with NPH/Detemir that are randomized to the same 
medication can continue the new treatment on the same day in the next 
scheduled injection (am/pm). 
5. Patients treated with NPH/detemir that are randomized to a different type of 
insulin can also continue the new treatment on the same day in the next 
scheduled injection (am/pm). 
 
 
 
Table 2: Action profile of the commonly used oral diabetic medications in 
pregnancy 
 
Type 
Time to Peak of 
plasma 
concentration 
(hours) 
Elimination half 
time in plasma 
(hours) 
Undetectable in 
blood plasma 
Metformin 
1-3 hours 
6.2 hours 
24 hours 
Glyburide 
2-3 hours 
4 hours 
24 hours 
 
Modified from the medication insert information sheet. 

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TABLE 3: Action profile of the commonly used insulin in pregnancy 
 
Type 
Onset of action 
Peak of action 
(Hours) 
Duration of action 
(Hours) 
Insulin NPH 
2-4 hours 
4-10 hours 
10-18 hours 
Insulin Detemir 
2-3 hours 
6-8 hours 
6-23.2 
Insulin Glargine 
4-6 hours 
none 
24 hours 
 
Modified from the medication insert information sheet. 
 
Follow up: Patient will be asked to continue follow up as standard and to check 
glucose levels at fasting, 1 hour pre-prandial and/or 1 or 2 hours postprandial, as 
recommended by their treating physician. Each patient will have a meeting with a 
registered nurse and diabetic educator in order to learn how to self-administer 
insulin. Patient will be followed every 1-2 weeks, as necessary, determined by 
their glucose control, until delivery. Of note, these visits do not constitute an extra 
burden for the patient, as this is the regular interval that patients with diabetes 
mellitus type 2 would have been followed even if they were not enrolled in the 
study. 
A release of records form will be signed at randomization, so that in case that the 
patient delivers at another center, we can still obtain records from her delivery. 
The research team will collect participant data including demographic 
characteristics, medical history, obstetric history, labor course and outcomes. At 
each visit, patient weight, blood pressure, compliance, side effects and fetal 
ultrasound parameters will be evaluated. Glucose levels will be recorded at each 
visit to determine the mean overall glucose, mean fasting glucose, mean 
postprandial glucose, percentage of values below, within and above target 
values. 
The treating physician will adjust insulin dose to maintain good glucose control 
based on targets: 
 fasting glucose <95 mg/dl 
 2-hour postprandial values < 120 mg/dl, overall mean glucose < 100 mg/dl 
Subjects that fail the therapy assigned by randomization will continued to be 
followed until delivery, regardless of the regimen that their provider chooses for 
glycemic control. 
 Every participant will be invited to answer a 10 min Medication adherence 
survey once during pregnancy. 

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 Every participant will be invited to answer a 10 min PRAPARE 
Assessment survey (The Protocol for Responding to and Assessing 
Patients’ Assets, Risks, and Experiences) once during pregnancy. 
 Every participant will be invited to answer a 5 min JSPPE empathy survey 
(The Jefferson scale of patient perception of physician empathy) at 3 
clinical visits during pregnancy: at the first visit, in the second trimester 
and in the third trimester of pregnancy. 
1.6 Safety assessment 
1.6.1 Risk associated with NPH/Detemir 
Insulin treatment including detemir and NPH has reported possible risks 
and discomfort including: 
1. Hypoglycemia is the most commonly observed adverse reaction in patients using 
insulin, including detemir and NPH. The rates of hypoglycemia in the detemir 
clinical trials (32%) were mostly comparable between detemir-treated patients 
and NPH-treated patients. Some studies have shown a lower risk for 
hypoglycemic events with detemir compared to NPH. Severe hypoglycemia is 
defined as an event with symptoms consistent with hypoglycemia requiring 
assistance of another person and associated with blood glucose below 50 mg/dL 
has been reported to occur in 0.4 of patients treated with detemir and 1.5% in 
patients treated with NPH. 
2. Severe, life-threatening, generalized allergy, including anaphylaxis, can occur 
with insulin products, including detemir and NPH. Local allergy in the injection 
site reported in 0.25% of patients with detemir and 0.12% of patients with NPH. 
3. Long-term use of insulin can cause lipodystrophy at the site of repeated insulin 
injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) 
and lipoatrophy (thinning of adipose tissue), and may affect insulin adsorption. 
Rotate insulin injection sites within the same region to reduce the risk of 
lipodystrophy. 
4. Weight gain can occur with insulin therapy and has been associated to detemir 
and NPH, it has been attributed to the anabolic effects of insulin and the 
decrease in glycosuria. 
5. Insulin, including detemir and NPH, may cause sodium retention and edema, 
particularly if previously poor metabolic control is improved by intensified insulin 
therapy. 
NPH and detemir have been used in pregnancy and is not believed to cause birth 
defects or any problem in the developing fetus or newborn. REPROTOX®, an 
information system developed by the Reproductive Toxicology Center, is a 
database on the reproductive effects of chemical, medications, physical agents, 
and biologics. REPROTOX® lists insulin detemir use during pregnancy has been 
associated with outcomes similar to those with NPH insulin. The FDA lists 
detemir as a category B drug. REPROTOX® information regarding NPH is that 
poorly controlled diabetes mellitus during pregnancy is a cause of fetal 

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complications, including congenital anomalies. Insulin therapy can reduce the 
risk of those complications. The FDA lists NPH as a category B drug. 
 
Using of Insulin during pregnancy does not appear to affect your chances of 
breastfeeding, or the length of time the participate can breastfeed. Insulin is 
transported into human milk at comparable concentrations to serum insulin. 
Mothers using insulin to treat diabetes may nurse their infants. 
 
1.6.2 Specification of safety parametersbe 
Both of the intervention proposed are done in routine clinical care and 
have been tested in previous studies. The medications are not new in 
pregnancy, they do not cross the placenta and not associated with 
congenital anomalies. Therefore, the establishment of safety data 
monitoring board is not necessary. The principal investigator and mentor 
will monitor the progress of study and determine the safety parameters. 
1.6.3 Management of adverse events 
Any adverse event will be reported to the committee for the Protection of 
Human Subjects (CPHS). Due to the use of medications that have been 
used in pregnancy in the past, there is no increased anticipation of severe 
adverse events. 
1.6.4 Procedures in the event of abnormal clinical finding 
In the event of an abnormal clinical finding, the health care provider caring 
for the participant will be notified to allow treatment in the usual clinical 
manner. 
1.7 Statistical considerations 
1.7.1 Sample size 
Retrospective data collected from Memorial Hermann Hospital showed 
that 43.6% of women with type 2 diabetes would have composite adverse 
neonatal outcome. 44 
In order to detect a 40% reduction in this rate between the groups with 
80% power and a Bayesian posterior probability of 75% (of any 
reduction),108 (54 per group) women need to be randomized. 
A total of 216 women would need to be approached for consent, to 
accommodate an expected enrollment rate of 50%. 
Based on our ICD-10 consult code, there were approximately 200 type 2 
diabetic consults across the sites from March 2017 - March 2018. If we 
anticipate a 50% enrollment rate, we should be able to complete this study 
in 1.5 years. After one year, we are going to assess the feasibility for a 
period of 12 month. If recruitment was less than 40 women, we will 
conclude that the study is not feasible. 
 
Interim analysis after 50% enrollment will be performed in order to assess 
the frequency of the primary and secondary outcomes. At that point, a 
decision will be made to see if there is a need to adjust the sample size. 

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1.7.2 Statistical tests 
An intent-to-treat analysis will be conducted. Composite primary outcome 
will be evaluated with a Bayesian binomial model using a neutral 
informative prior (excluding treatment effects outside the range of 0.3-3 in 
the relative risk [RR] scale). We will report RR and 95% credible intervals 
as well as probability of reduced adverse neonatal outcome. Secondary 
outcome measures will be compared using the independent t-test for 
continuous variables and the x2 or fisher's exact test for categorical 
variables as appropriate. Mann-Whitney U test will be used for non- 
parametric comparisons. 
1.8 Ethical considerations 
1.8.1 Informed consent 
A copy of the informed consent document in both English and Spanish will 
be submitted by the PI to the Institutional Review board (IRB) for review 
and approval prior to the start of the study. A properly executed written 
informed consent shall be obtained from each patient prior to entering the 
study. All prospective study candidates will be given a full explanation of 
the consent form, allowed to read the approved form, and be provided the 
opportunity to ask any questions. Once all questions have been answered 
and the investigator is assured that the individual understands the 
requirements of the study, the subject will be asked to sign the consent. 
The investigator shall provide a copy of the signed and dated informed 
consent to the patient and the original shall be maintained in the patient's 
study files. Patients who do not sign the consent form will not be permitted 
to participate in the study. 
1.8.2 Institutional review board 
Before initiation of the study, the PI will obtain approval of the research 
protocol from the IRB. The study will be registered in www.clinicaltrials.gov 
as required by the US law for public access. 
1.8.3 Subject confidentially 
Each study's subject anonymity will be maintained throughout the study, 
prior to collection of the data a unique study number will be assigned to 
each case thus de-identifying the individual subject. In the study site, there 
will be a log of the study subject to the assigned study number. 
Research assistants are in compliance with required CITI training. When 
results of this research study are reported in medical journals or at 
scientific meetings, the subjects who take part will not be named or 
identified. The Federal Privacy Act protects the confidentiality of medical 
records and any private health information collected. Access to personal 
information will be limited to the investigators only. However, these 
individuals are required to keep all information confidential. 
1.8.4 Data handling and record keeping 
Access to source documents: 
Research personal will perform data collection manually from patient 
charts at the different sites. Please refer to attached data collection sheet 

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IRB APPROVAL DATE: 07/31/2018 
 
for detail on variables to be collected. Data will be collected from 
randomization until 6 weeks post partum. 
1.8.5 Records retention: Data will be digitally encrypted and stored in the 
UTHealth Redcap system. At the conclusion of the study, the principal 
investigator will retain copies of the approved protocol and all other 
supporting documentation related to the project. De-identified patient 
information may be used for future research projects. 
1.86 Quality control Assurance: the principal investigator and co-investigators 
Go through all the files to assure that data is reliable and complete. The 
verification will be by self assessment. 

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