Diabetes, Pregnancy
Conditions
Keywords
Metformin, Glucophage, Riomet, Glumetza, Fortamet, Glucophage XR
Brief summary
Purpose: The objective of this proposal is to study the safety and efficacy of metformin added to insulin for treatment of type 2 diabetes mellitus (T2DM) among pregnant women. Participants: 950 pregnant women with type 2 diabetes complicating pregnancy from 10 U.S. clinical centers Procedures (methods): Pregnant women with T2DM between 10 weeks and 22 weeks 6 days and a singleton fetus will be randomized to double-blinded insulin/placebo versus insulin/metformin. Primary outcome is composite adverse neonatal outcome (clinically relevant hypoglycemia, birth trauma, hyperbilirubinemia, stillbirth/neonatal death). Study visits monthly at clinical visits; blood draw at 24-30 weeks, newborn anthropometric measurements at less than 72 hours of life. Maternal and infant outcomes will be chart abstracted.
Interventions
DRUGMetformin
1000 mg twice a day
DRUGPlacebo
Delivered to match active drug
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* Maternal age 18-45 years * Singleton pregnancy with no known fetal anomalies * Gestational age between 10weeks 0 days and 22 weeks 6 days by menstrual dating confirmed by ultrasound, or ultrasound alone * Clinical diagnosis of preexisting T2DM requiring medical treatment (oral agent or insulin) * Clinical diagnosis of diabetes diagnosed between 10 weeks and \< 20 weeks 6 days gestation * Willing to start insulin therapy and discontinue oral hypoglycemic pills other than study pills * Able to swallow pills
Exclusion criteria
* Clinical diagnosis of pre-existing renal disease, defined as creatinine \> 1.5 mg/dL * Clinical history of lactic acidosis * Known allergy to metformin * Participation in another study that could affect primary outcome * Delivery planned at non-MOMPOD study locations * Unwillingness to use insulin treatment or follow prenatal care doctor's instructions for insulin and blood glucose monitoring
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Composite Adverse Neonatal Outcome | An average of 48 hours for term infants and 30 days for preterm infants | Participants with one or more of the following: * capillary blood glucose level of \< 30 mg/dL or capillary blood glucose requiring medical treatment, or * Birth trauma (umbilical cord artery pH \< 7.0 or shoulder dystocia with brachial plexus injury), or * Hyperbilirubinemia requiring phototherapy, or * Deliver \< 37 weeks' gestation, or * Miscarry, are stillborn, experience a neonatal demise, or * Large for gestational age infant (birth weight \> 90th percentile for gestational age), or * Small for gestational age infant (birth weight \< 10th percentile for gestational age) or low birth weight (\< 2500 gm) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Maternal Side Effects | Throughout study until delivery at 40 weeks gestation | Secondary outcome of maternal side effects were defined as: * clinically relevant hypoglycemia defined as capillary blood glucose \< 60 or \< 80 with symptoms * GI side effects defined as nausea, vomiting, diarrhea |
| Mean Infant Fat Mass | Within 72 hrs of birth | Neonatal fat mass measured by skin-fold thickness (anthropometrics).The circumference of the upper limb is the circumference of the upper arm, and the circumference of the lower limb equals the mean of the circumferences measured at the midthigh and calf. The volume of the subcutaneous layer of fat covering each cylinder is estimated by multiplying the length times the circumference times the layer of fat estimated by the skinfold measures. The triceps skinfold measure is used as an estimate of the fat thickness of the limbs, and the subscapular skinfold measure approximates the fat thickness of the trunk. Total body fat is estimated by summing the volumes of fat covering each of the cylinders and multiplying by 0.9 (the density of fat). |
| Maternal Safety Based on Treatment Emergent Adverse Events | An average of 48 hours following delivery | Adverse maternal outcomes. |
| Neonatal Safety Based on Treatment Emergent Adverse Events | up to 28 days of life | Adverse neonatal outcomes |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Metformin Metformin 1000 mg twice a day | 397 |
| Placebo Placebo, identical to Metformin. Delivered to match active drug | 397 |
| Total | 794 |
Baseline characteristics
| Characteristic | Metformin | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 32.8 years STANDARD_DEVIATION 5.5 | 32.9 years STANDARD_DEVIATION 5.6 | 33.1 years STANDARD_DEVIATION 5.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 203 Participants | 412 Participants | 209 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 183 Participants | 359 Participants | 176 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 11 Participants | 23 Participants | 12 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 116 Participants | 224 Participants | 108 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 226 Participants | 458 Participants | 232 Participants |
| Race (NIH/OMB) White | 55 Participants | 112 Participants | 57 Participants |
| Region of Enrollment United States | 397 Participants | 794 Participants | 397 Participants |
| Sex: Female, Male Female | 397 Participants | 794 Participants | 397 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 397 | 10 / 397 | 1 / 376 | 1 / 397 | 10 / 397 | 2 / 370 |
| other Total, other adverse events | 54 / 397 | 0 / 397 | 151 / 376 | 57 / 397 | 0 / 397 | 151 / 370 |
| serious Total, serious adverse events | 113 / 397 | 0 / 397 | 81 / 376 | 111 / 397 | 0 / 397 | 105 / 370 |
Outcome results
Primary
Number of Participants With Composite Adverse Neonatal Outcome
Participants with one or more of the following: * capillary blood glucose level of \< 30 mg/dL or capillary blood glucose requiring medical treatment, or * Birth trauma (umbilical cord artery pH \< 7.0 or shoulder dystocia with brachial plexus injury), or * Hyperbilirubinemia requiring phototherapy, or * Deliver \< 37 weeks' gestation, or * Miscarry, are stillborn, experience a neonatal demise, or * Large for gestational age infant (birth weight \> 90th percentile for gestational age), or * Small for gestational age infant (birth weight \< 10th percentile for gestational age) or low birth weight (\< 2500 gm)
Time frame: An average of 48 hours for term infants and 30 days for preterm infants
Population: Modified intent to treat population of all participants who took at least one dose of study agent and had primary outcome data available.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Metformin | Number of Participants With Composite Adverse Neonatal Outcome | 269 Participants |
| Placebo | Number of Participants With Composite Adverse Neonatal Outcome | 277 Participants |
Comparison: The sample size gave adequate power over a range of expected primary outcome event rates, with type I error set at 0.044 (reduced from 0.05 for interim analysis), with reasonable power under a conservative scenario assuming that 20% of subjects immediately stopped taking study agent.95% CI: [0.63, 1.19]
Secondary
Maternal Safety Based on Treatment Emergent Adverse Events
Adverse maternal outcomes.
Time frame: An average of 48 hours following delivery
Population: Number of randomized participants who took at least one dose of study agent.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Metformin | Maternal Safety Based on Treatment Emergent Adverse Events | Any adverse event associated with maternal death | 2 Participants |
| Metformin | Maternal Safety Based on Treatment Emergent Adverse Events | Any maternal serious adverse event | 113 Participants |
| Metformin | Maternal Safety Based on Treatment Emergent Adverse Events | Any adverse event associated with fetal death | 10 Participants |
| Metformin | Maternal Safety Based on Treatment Emergent Adverse Events | Any maternal non-serious adverse event | 149 Participants |
| Metformin | Maternal Safety Based on Treatment Emergent Adverse Events | Any adverse event leading to early study agent discontinuation | 13 Participants |
| Placebo | Maternal Safety Based on Treatment Emergent Adverse Events | Any maternal non-serious adverse event | 157 Participants |
| Placebo | Maternal Safety Based on Treatment Emergent Adverse Events | Any adverse event leading to early study agent discontinuation | 20 Participants |
| Placebo | Maternal Safety Based on Treatment Emergent Adverse Events | Any adverse event associated with maternal death | 1 Participants |
| Placebo | Maternal Safety Based on Treatment Emergent Adverse Events | Any adverse event associated with fetal death | 10 Participants |
| Placebo | Maternal Safety Based on Treatment Emergent Adverse Events | Any maternal serious adverse event | 111 Participants |
p-value: 0.6Chi-squared
Secondary
Mean Infant Fat Mass
Neonatal fat mass measured by skin-fold thickness (anthropometrics).The circumference of the upper limb is the circumference of the upper arm, and the circumference of the lower limb equals the mean of the circumferences measured at the midthigh and calf. The volume of the subcutaneous layer of fat covering each cylinder is estimated by multiplying the length times the circumference times the layer of fat estimated by the skinfold measures. The triceps skinfold measure is used as an estimate of the fat thickness of the limbs, and the subscapular skinfold measure approximates the fat thickness of the trunk. Total body fat is estimated by summing the volumes of fat covering each of the cylinders and multiplying by 0.9 (the density of fat).
Time frame: Within 72 hrs of birth
Population: Data are reported for those infants who underwent anthropomorphic measurements.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Mean Infant Fat Mass | 0.46 kg | Standard Deviation 0.3 |
| Placebo | Mean Infant Fat Mass | 0.5 kg | Standard Deviation 0.24 |
p-value: 0.4t-test, 2 sided
Secondary
Neonatal Safety Based on Treatment Emergent Adverse Events
Adverse neonatal outcomes
Time frame: up to 28 days of life
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Metformin | Neonatal Safety Based on Treatment Emergent Adverse Events | Any neonatal serious adverse event | 81 Participants |
| Metformin | Neonatal Safety Based on Treatment Emergent Adverse Events | Any neonatal non-serious adverse event | 157 Participants |
| Placebo | Neonatal Safety Based on Treatment Emergent Adverse Events | Any neonatal serious adverse event | 105 Participants |
| Placebo | Neonatal Safety Based on Treatment Emergent Adverse Events | Any neonatal non-serious adverse event | 162 Participants |
p-value: 0.08Chi-squared
Secondary
Number of Participants With Maternal Side Effects
Secondary outcome of maternal side effects were defined as: * clinically relevant hypoglycemia defined as capillary blood glucose \< 60 or \< 80 with symptoms * GI side effects defined as nausea, vomiting, diarrhea
Time frame: Throughout study until delivery at 40 weeks gestation
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Metformin | Number of Participants With Maternal Side Effects | Clinically relevant hypoglycemia | 87 Participants |
| Metformin | Number of Participants With Maternal Side Effects | Gastrointestinal side effects | 182 Participants |
| Placebo | Number of Participants With Maternal Side Effects | Clinically relevant hypoglycemia | 85 Participants |
| Placebo | Number of Participants With Maternal Side Effects | Gastrointestinal side effects | 171 Participants |
p-value: 0.4Chi-squared