Clinical trial NCT01613807
Conditions: Gestational Diabetes Mellitus
Keywords: gestational diabetes mellitus insulin analogues in pregnancy
Sponsor: Sansum Diabetes Research Institute
Start date: 2008-10-01; Completion date: 2010-10-01
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Evaluation of the Safety and Efficacy of Humalog® Mix50/50TM administered as 3 injections daily to Humalog® plus Humulin N® insulin administered as 6 separate injections daily in terms of glucose control for women with Gestational Diabetes.

Detailed description:
Controlling hyperglycemia during pregnancy decreases the risk of adverse neonatal and maternal outcomes. Not only must fasting glucose be normalized, but clinical evidence also indicates that controlling postprandial hyperglycemia will significantly reduce the risk of adverse neonatal and maternal outcomes.

Standard therapy to achieve near-normal glycemia in gestational diabetes involves combining intermediate-acting basal (NPH) insulin with rapid-acting insulin (insulin lispro), thereby requiring 6 daily injections. Premixed Humalog® Mix50/50TM has the potential advantage over combination rapid-acting plus NPH insulin because it involves fewer injections, and those injections are associated with mealtime. The potential downside to the premixed formulation is nocturnal hypoglycemia associated with the time lag between the dinner and breakfast dose. This study will evaluate the efficacy and safety of Humalog® Mix50/50TM compared to that of Humalog® plus Humulin N® insulin for the treatment of insulin-requiring patients with gestational diabetes mellitus, while monitoring glucose control, intrauterine growth and assessing pregnancy outcomes.

Arms: arm 1: Insulin LISPRO: 3 doses of Humalog® Mix50/50™ at mealtime. arm 2: Usual insulin regimen of insulin, Long-Acting and Insulin: 3 injections of Humalog(r) daily with meals; 3 injections of Humulin N (r) daily on rising, mid-afternoon, and at bedtime
Interventions: intervention 1: Insulin LISPRO intervention 2: Insulin, Long-Acting and Insulin
Intervention descriptions: intervention 1: Humalog® Mix50/50™ \[50% insulin lispro protamine suspension and 50% insulin lispro injection, (rDNA origin)\], three times daily at mealtime. Dose determined by blood glucose history. intervention 2: Usual insulin regimen: Long-acting insulin three times daily on rising, mid-afternoon, and before bed, and insulin lispro three times daily at mealtime. Doses determined by blood glucose history and carbohydrate content of the meal.

Protocol documents:
Prot_000.pdf: 
Amendment 2, 11/24/08 
PROTOCOL 
HUMALOG® MIX50/50TM FOR THE TREATMENT OF INSULIN REQUIRING 
GESTATIONAL DIABETES 
 
 
RATIONALE 
Controlling hyperglycemia during pregnancy decreases the risk of adverse neonatal and 
maternal outcomes. Not only must fasting glucose be normalized, but clinical evidence 
also indicates that controlling postprandial hyperglycemia will significantly reduce the 
risk of adverse neonatal and maternal outcomes (1-2). 
 
Standard therapy to achieve near-normal glycemia in gestational diabetes involves 
combining intermediate-acting basal (NPH) insulin with rapid-acting insulin (insulin 
lispro), thereby requiring 6 daily injections (Figure 1). Premixed Humalog® Mix50/50TM 
has the potential advantage over combination rapid-acting plus NPH insulin because it 
involves fewer injections, and those injections are associated with mealtime (Figure 2). 
The potential downside to the premixed formulation is nocturnal hypoglycemia 
associated with the time lag between the dinner and breakfast dose. This study will 
evaluate the efficacy and safety of Humalog® Mix50/50TM compared to that of 
Humalog® plus Humulin N® insulin for the treatment of insulin-requiring patients with 
gestational diabetes mellitus, while monitoring glucose control, intrauterine growth and 
assessing pregnancy outcomes. 
 
PREVIOUS WORK 
The principal investigator has established nationally-recognized protocols for the care of 
pregnant women with diabetes (3-6) and has played an active role in the field of 
gestational diabetes (7-9). Thus she is uniquely positioned to study the potential efficacy 
of new therapies for gestational diabetes. Two studies have particular relevance to the 
proposed research and are attached to this application. Jovanovic and colleagues 
studied the metabolic and immunologic effects of insulin lispro in gestational diabetes 
(10) by randomizing women to receive either regular human insulin or insulin lispro 
before consuming a test meal. The study proved the safety of insulin lispro for women 
with gestational diabetes. In a subsequent study led by Pettitt (11), postprandial 
glycemic control was demonstrated in women with gestational diabetes taking insulin 
aspart via higher insulin peak and lower demand on endogenous insulin secretion. 
 
STUDY HYPOTHESIS 
Humalog® Mix50/50TM administered as 3 injections daily is equivalent to Humalog® plus 
Humulin N® insulin administered as 6 separate injections daily in terms of glucose 
control, but may have some advantages due to increased ease of use. 
 
PRIMARY OBJECTIVE 
Compare the efficacy and safety of three daily injections of Humalog® Mix50/50TM to 
six daily injections of Humalog® and Humulin N® insulin, by fasting glucose 
measurements. 
 


Amendment 2, 11/24/08 
SECONDARY OBJECTIVES 
1. Compare incidence of maternal hypoglycemic events between the two treatment 
arms. 
2. Compare neonatal outcomes between the two treatment arms. 
3. Compare fetal fat measurements between the two treatment arms. 
4. Compare adherence rates and patient acceptability of the two injection regimens 
5. Compare A1C between groups at end of protocol and within groups at baseline 
versus end of protocol. 
 
STUDY DESIGN 
Women diagnosed with gestational diabetes receive diet and exercise education. They 
are instructed to record their pre- and post-prandial glucose measurements obtained by 
fingerstick. Following one week of diet and exercise therapy, patients with fasting glucose 
levels >90 mg/dL or postprandial glucose level >120 mg/dL will be recruited to this study. 
 
Inclusion Criteria 
• Pregnant and at least 13 weeks gestation  
• Diagnosed with gestational diabetes1  
• Failed diet therapy 
 
Exclusion Criteria 
• pregnant women <18 years old or over 45 years old 
• a urine dipstick urine with >2+ protein 
• blood pressure >140/80 mmHg; hematocrit <30% 
• refusal to take insulin 
• inability to understand instructions or to consent to participate. 
 
METHODS 
Subjects will be randomized 1:1 to receive usual insulin treatment of six injections daily 
(Humalog® injected three times daily before meals plus Humulin N® insulin injected at 
8am, 4pm and midnight) as diagrammed in Figure 1, or 3 injections of Humalog® 
Mix50/50TM (injected only before meals) as diagrammed in Figure 2. 
 
Baseline measures will include glucose tolerance test data, height, weight, and A1C by 
DCA2000+. In addition to the standard instruction to test blood glucose pre- and one-hour 
postprandial, all participants will be asked to test blood glucose levels at 3 a.m. Patients 
on the Humalog® Mix50/50TM arm of the study will be initially prescribed insulin doses of 
0.3 times their weight in kilograms to be taken before each of three meals. Those on the 
standard therapy arm will be initially prescribed insulin doses calculated at 0.15 times their 
weight in kilograms for each of their 6 injections. 
 
1 We shall use American Diabetes Association criteria for diagnosis of GDM: blood glucose 
concentration >140 mg/dL one hour after administration of a 50 gram glucose load, 
followed by an oral glucose tolerance test (OGTT) in which 2 or more of the readings are 
at or above 95 mg/dL fasting, 180 mg/dL at one hour, 155 mg/dL at 2 hours and 145 
mg/dL 3 hours after administration of a 100 gram glucose load (12). 


Amendment 2, 11/24/08 
 
Participants will be seen weekly for adjustment in dosages based on their food records, 
downloaded glucose monitor data and Al C levels. Subjects in the study group whose 
fasting glucose exceeds 90 mg/dl will be prescribed Humalog® Mix75/25TM at their 
evening meal rather than Humalog® Mix50/50TM. Subjects will be discontinued from the 
study if their 3 a.m. blood glucose concentration falls below 55 mg/dL that is unresponsive 
to a snack at bedtime or if their fasting blood .glucose is greater than 90mg/dL despite 
increasing doses of Humalog® Mix50/50T at the evening meal followed by treating with 
Humalog® Mix75/25TM at the evening meal. 
 
Maternal weight will be recorded at each visit. Participants will be asked to bring their 
supply of insulin pens to every other visit, for which they will be paid ten dollars to 
maximize cooperation with this essential aspect of the research. The insulin pens will be 
counted as measures of adherence.  
 
Consent forms of enrolled patients will be given to the hospital at prenatal enrollment and 
will be part of their hospital medical chart at the time of delivery. Delivery room nurses will 
be instructed to collect cord blood and notify the study coordinator of the birth. Data 
collected from the birth will include sex of the baby, gestational week, ethnicity, length, 
birthweight and mode of delivery. Neonates will be assessed for macrosomia and 
hypoglycemia. Maternal postpartum glucose levels will be recorded. 
 
SAMPLE SIZE 
40 women will be recruited into the study in order to achieve at least 30 evaluable subjects 
(15 in each treatment arm) over the 12 months duration of the study. Based on the 
standard deviation for fasting glucose concentrations reported from the NHANES II study, 
measurable data from 30 subjects (15 in each group)will have 80% power to find an inter-
group difference as small as 8 mg/dL at a p-value of 0.05 (13). 
 
PRIMARY EFFICACY MEASURES 
The primary measure used to substantiate the primary study objective will be maternal 
glucose control as reflected by fasting values from glucose monitor data. 
 
SECONDARY EFFICACY MEASURES 
The maternal A1C will be measured by Bayer DCA2000+ at baseline and at end of 
protocol. The 3 a.m. glucose records will be assessed for nocturnal hypoglycemia. 
Maternal weight gain will be assessed as an indicator of over-insulinization. In addition, we 
will analyze baby birth weight percentile, APGAR scores, cord blood insulin levels and 
mode of delivery as measures of fetal outcome. We will use insulin pen count data as an 
indicator of maternal adherence to the therapy regimen. 
 
STATISTICAL ANALYSIS 
Data analysis will be done using SAS for Windows version 9. Differences between groups 
in continuous variables (glucose, A1C, birth weight etc.) will be compared with t-tests and 
potential confounders (age, race/ethnicity etc.) will be controlled for with linear regression. 
Differences in categorical variables (hypoglycemic events, macrosomia, type of delivery 


Amendment 2, 11/24/08 
etc.) will be evaluated using chi-square or Fisher's tests as appropriate. Our tests will be 
testing the hypothesis that the two treatments are different and the null hypothesis will be 
equivalence. 
 
ANTICIPATED FINDINGS 
We anticipate maternal and fetal outcomes with the Humalog® Mix50/50TM will be 
equivalent or non-inferior to standard insulin therapy due to the convenience of three 
injections rather than six per day. The risk of possible increased hypoglycemia, particularly 
during the night, however, needs to be carefully assessed. 
 
REFERENCES 
 
1. Combs CA, Gunderson E, Kitzmiller JL, Gaven LA, Main EK. Relationship of fetal 
macrosomia to maternal postprandial glucose control during pregnancy. Diabetes 
Care. 15(10):1251-1257, 1992. 
2. Manderson JG, Patterson CC, Hadden DR, Traub Al, Ennis C, McCance DR. 
Preprandial versus postprandial blood glucose monitoring in type 1 diabetic 
pregnancy: 
a 
randomized 
controlled 
clinical 
trial. 
Am 
J 
Obstet 
gynecol 
189(2):507-512, 2003. 
3. Jovanovic L, Druzin M, Peterson CM. The effect of euglycemia on the outcome of 
pregnancy in insulin-dependent diabetics as compared to normal controls. Am J Med. 
71:921-927, 1981. 
4. Jovanovic L, Peterson CM: Insulin and glucose requirements during the first stage of 
labor in insulin-dependent diabetic women. Am J Med. 75:607-612, 1983. 
5. Jovanovic-Peterson L, Peterson CM, Reed G et al.: Maternal postprandial blood 
glucose levels and infant birthweight: The Diabetes in Early Pregnancy Study. Am J 
Obstet Gynecol 164:103-111, 1991. 
6. Jovanovic L, Kitzmiller JL, Peterson CM: Randomized trial of human versus animal 
species insulin in pregnancies complicated by diabetes. Am J Obstet Gynecol 
167:1325-1330, 1992. 
7. Jovanovic-Peterson L, Editor-In Chief. Medical Management of Pregnancy 
Complicated by Diabetes. American Diabetes Association, Inc., Alexandria , VA, 1993, 
revised 1995. 
8. Jovanovic L and Peterson CM. Screening for gestational diabetes. Optimum timing 
and criteria for retesting. Diabetes 34 Suppl 2: 21-23, 1985. 
9. Jovanovic L and Pettitt DJ. Gestational diabetes mellitus. JAMA 286: 2516-2518, 
2001. 
10.Jovanovic L, Ilic, S, Pettitt D, Hugo K, Gutierrez M, Bowsher R, Bastyr EJ. Metabolic 
and immunologic effects of insulin lispro in gestational diabetes. Diabetes Care 
22:1422-1427, 1999. 
11. Pettitt DJ, Ospina P, Kolaczynski JW, Jovanovic L. Comparison of an insulin analog, 
insulin aspart, and regular human insulin with no insulin in gestational diabetes 
mellitus. Diabetes Care 26:183-186, 2003. 
12. Metzger BE, Coustan DM. Summary and recommendations of the Fourth International 
Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care 21:B161-167, 
1998. 


Amendment 2, 11/24/08 
13.Rhee MK, Ziemer DC, Kolm P, Phillips LS. Postchallenge glucose rises with increasing 
age even when glucose tolerance is normal. Diab Med 23:1174-1179, 2006.