Pre-Eclampsia, Pregnancy Related
Conditions
Brief summary
Phase II Study of 2.5 gm of nicotinamide, given daily in 3 divided doses, to measure effect on maternal blood pressure in women with early onset preeclampsia and to determine peak and trough levels of nicotinamide. We will compare peak and trough levels in healthy non-pregnant and healthy pregnant participants.
Detailed description
See brief summary above
Interventions
DRUGnicotinamide
2.5 gm nicotinamide given orally in 3 divided doses: 1000 mg in morning and evening, 500 mg at noon/midday
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of North Carolina, Chapel Hill
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
All participants will receive study agent. 2.5 gm nicotinamide given orally in 3 divided doses (1000 in morning, 500 in afternoon, 1000 at bedtime).
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
Diagnosis and Inclusion Criteria * Maternal age 18-55 years * Singleton pregnancy with no known fetal anomalies * Early-onset preeclampsia OR early-onset severe gestational hypertension defined as: * Early-onset: between 24 weeks 0 days and -33 weeks 3 days, based on menstrual dating confirmed by first or second trimester ultrasound OR second trimester ultrasound if menstrual dating unavailable; * Preeclampsia: * New onset hypertension and proteinuria, with systolic BP \> 140 mm Hg and/or diastolic BP \> 90 mm Hg on two occasions 6 hours apart and \> 300 mg proteinuria on 24 hour urine collection OR urine P/C ratio \>0.3; * New onset hypertension and NO proteinuria, with systolic BP \> 140 mm Hg and/or diastolic BP \> 90 mm Hg on two occasions 6 hours apart and one or more of the following: serum creatinine \>1.1 mg/dL or doubling from baseline ,or central nervous system symptoms or visual changes * Severe preeclampsia defined as new onset systolic BP \> 160 mm Hg and/or diastolic BP \> 105 with proteinuria as above or or without proteinuria and one or more of the following criteria listed above * Candidate for expectant management for at least 48 hours * Deemed clinically stable by primary clinician and candidate for expectant management (delayed delivery) for at least 48 hours; * Maternal liver function tests \< 2x ULN * Maternal platelet count \> 100,000 mm³ * Planned expectant management * Pre-existing medical diseases such as hypertension, diabetes, endocrine disorders, gastrointestinal diseases, are well controlled * Fetal well-being established by estimated fetal weight \> 5th %tile; normal amniotic fluid volume (MVP \> 2 cm); normal Umbilical Artery (UA) Dopplers; or reactive Non Stress Test (NST) or Biophysical Profile (BPP) \> 6 * Delivery not anticipated within 48 hours of enrollment
Exclusion criteria
* Pre-existing renal disease (creatinine \> 1.5 mg/dL) * Any pre-existing medical condition that would increase risk for liver toxicity (e.g. hepatitis B or C; HIV; Isoniazid (INH) use) * Eclampsia; cerebral edema on CT/MRI; headache unrelieved by analgesics * Evidence of liver dysfunction (LFTs \> 2x ULN) * Thrombocytopenia (platelets \< 100,000 mm³) * Pulmonary edema * HELLP syndrome * Evidence of fetal compromise: Estimated Fetal Weight (EFW) \< 5th percentile; or BPP \< 6; or absent or reverse diastolic UA blood flow; or oligohydramnios (MVP \< 2 cm) * Placental abruption defined as unexplained vaginal bleeding * Preterm labor defined as regular contractions and cervical change * Any condition deemed by the investigator to be a risk to mother or fetus in completion of the study * Any condition deemed by the investigator to require delivery within 48 hours
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Arterial Blood Pressure (MAP) | Baseline, 48 hours | Blood pressure (mmHg) will be used to observe the effect of nicotinamide. The highest MAP (defined as the highest MAP within the 24 hour period prior to the administration of study agent) and the highest MAP through 24 hours after study drug administration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Aspartate Aminotransferase (AST) =/> 3x Upper Limit of Normal (ULN) | Within 24 hours of any dose, up to a maximum 4 weeks | — |
| Number of Participants With Maternal Side Effects | From initial administration of study agent until 24 hours post last dose, up to a maximum of 4 weeks | Maternal side effects are defined as: facial erythema, hives, sore mouth, dry hair, fatigue, flushing, headache, nausea, and heart burn. |
| Percentage of Women Maternal Abdominal Tenderness | From initial administration of study agent until 24 hours post last dose, up to a maximum of 4 weeks | — |
| Percentage of Women With Headache Unrelieved by Oral Analgesics | From initial administration of study agent until 24 hours post last dose, up to a maximum of 4 weeks | — |
| Percentage of Women With Hematocrit Decrease of More Than 3% | From initial administration of study agent until 24 hours post last dose, up to a maximum of 4 weeks | — |
| Number of Participants With Alanine Aminotransferase (ALT) =/> 3x Upper Limit of Normal (ULN) | Within 24 hours of any dose, up to a maximum 4 weeks | — |
| Percentage of Fetuses With Category III Non Stress Test Results | From initial administration of study agent until 24 hours post last dose, up to a maximum of 4 weeks | A Non Stress Test is a determination of the current well-being of the fetus, as measured by the fetal heart rate. Category I indicates that the fetus is in a state of well-being and is tolerating the intrauterine environment. Category II indicates a fetal heart rate that is showing some signs of distress. In this instance, obstetric providers will try to improve the intrauterine environment to allow the pregnancy to continue. Category III relates to a fetus whose well-being is compromised - usually requiring rapid intervention, ie expedient delivery. |
| Percentage of Fetuses With Biophysical Profile < 6 | From initial administration of study agent until 24 hours post last dose | — |
| Mean Peak Nicotinamide Level | at 1 hour post 1000 mg nicotinamide administration on Day 1 | The mean was calculated for each group using blood samples drawn on Day 1 at 1 hour post 1000 mg nicotinamide administration routinely given at 8 a.m. Peak nicotinamide level expected at 1 hour post dose. |
| Mean Trough Concentration Nicotinamide Administration | 8 hours after the 8 a.m. 1000 mg nicotimamide administration on Day 1 | The mean was calculated for each group for blood samples drawn on Day 1 8 hours post 1000 mg nicotinamide administration routinely given at 8 a.m. Trough nicotinamide level is measured immediately prior to the next dose. |
| Percentage of Women With Less Than 500 cc Urine Output in 24 Hours | From initial administration of study agent until 24 hours post last dose, up to a maximum of 4 weeks | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nicotinamide - Pre-eclampsia All participants will receive study agent
nicotinamide: 2.5 gm nicotinamide given orally in 3 divided doses: 1000 mg in morning and evening, 500 mg at noon/midday | 9 |
| Nicotinamide - Healthy Pregnant All participants will receive study agent 1000 mg in single dose
nicotinamide: 1000 mg nicotinamide in morning | 6 |
| Nicotinamide - Healthy Non-Pregnant All participants will receive study agent 1000 mg in single dose
nicotinamide: 1000 mg nicotinamide in morning | 6 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Delivery due to maternal condition | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Nicotinamide - Pre-eclampsia | Nicotinamide - Healthy Pregnant | Nicotinamide - Healthy Non-Pregnant | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 6 Participants | 6 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 6 Participants | 4 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 4 Participants | 6 Participants | 4 Participants | 14 Participants |
| Region of Enrollment United States | 9 Participants | 6 Participants | 6 Participants | 21 Participants |
| Sex: Female, Male Female | 9 Participants | 6 Participants | 6 Participants | 21 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 0 / 9 | 0 / 6 | 0 / 6 |
| serious Total, serious adverse events | 0 / 9 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Change in Mean Arterial Blood Pressure (MAP)
Blood pressure (mmHg) will be used to observe the effect of nicotinamide. The highest MAP (defined as the highest MAP within the 24 hour period prior to the administration of study agent) and the highest MAP through 24 hours after study drug administration.
Time frame: Baseline, 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nicotinamide - Pre-eclampsia | Change in Mean Arterial Blood Pressure (MAP) | 0 mmHg | Standard Deviation 9 |
| Nicotinamide - Healthy Pregnant | Change in Mean Arterial Blood Pressure (MAP) | 2 mmHg | Standard Deviation 9 |
| Nicotinamide - Healthy Non-Pregnant | Change in Mean Arterial Blood Pressure (MAP) | 4 mmHg | Standard Deviation 6 |
Secondary
Mean Peak Nicotinamide Level
The mean was calculated for each group using blood samples drawn on Day 1 at 1 hour post 1000 mg nicotinamide administration routinely given at 8 a.m. Peak nicotinamide level expected at 1 hour post dose.
Time frame: at 1 hour post 1000 mg nicotinamide administration on Day 1
Population: Data reported for all participants who had blood collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nicotinamide - Pre-eclampsia | Mean Peak Nicotinamide Level | 12701.7 ng/mL | Standard Deviation 6187.5 |
| Nicotinamide - Healthy Pregnant | Mean Peak Nicotinamide Level | 13279.7 ng/mL | Standard Deviation 970.7 |
| Nicotinamide - Healthy Non-Pregnant | Mean Peak Nicotinamide Level | 16314.1 ng/mL | Standard Deviation 3337.1 |
Secondary
Mean Trough Concentration Nicotinamide Administration
The mean was calculated for each group for blood samples drawn on Day 1 8 hours post 1000 mg nicotinamide administration routinely given at 8 a.m. Trough nicotinamide level is measured immediately prior to the next dose.
Time frame: 8 hours after the 8 a.m. 1000 mg nicotimamide administration on Day 1
Population: Data reported for all participants who had blood collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nicotinamide - Pre-eclampsia | Mean Trough Concentration Nicotinamide Administration | 479.2 ng/mL | Standard Deviation 967.3 |
| Nicotinamide - Healthy Pregnant | Mean Trough Concentration Nicotinamide Administration | 1490.7 ng/mL | Standard Deviation 1907.8 |
| Nicotinamide - Healthy Non-Pregnant | Mean Trough Concentration Nicotinamide Administration | 1991.2 ng/mL | Standard Deviation 2783.6 |
Secondary
Number of Participants With Alanine Aminotransferase (ALT) =/> 3x Upper Limit of Normal (ULN)
Time frame: Within 24 hours of any dose, up to a maximum 4 weeks
Population: Healthy women were not at risk for liver toxicity and therefore were not assessed for ALT.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nicotinamide - Pre-eclampsia | Number of Participants With Alanine Aminotransferase (ALT) =/> 3x Upper Limit of Normal (ULN) | 0 Participants |
Secondary
Number of Participants With Aspartate Aminotransferase (AST) =/> 3x Upper Limit of Normal (ULN)
Time frame: Within 24 hours of any dose, up to a maximum 4 weeks
Population: Healthy women were not at risk for liver toxicity and therefore were not assessed for AST.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nicotinamide - Pre-eclampsia | Number of Participants With Aspartate Aminotransferase (AST) =/> 3x Upper Limit of Normal (ULN) | 0 Participants |
Secondary
Number of Participants With Maternal Side Effects
Maternal side effects are defined as: facial erythema, hives, sore mouth, dry hair, fatigue, flushing, headache, nausea, and heart burn.
Time frame: From initial administration of study agent until 24 hours post last dose, up to a maximum of 4 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nicotinamide - Pre-eclampsia | Number of Participants With Maternal Side Effects | 0 Participants |
| Nicotinamide - Healthy Pregnant | Number of Participants With Maternal Side Effects | 0 Participants |
| Nicotinamide - Healthy Non-Pregnant | Number of Participants With Maternal Side Effects | 0 Participants |
Secondary
Percentage of Fetuses With Biophysical Profile < 6
Time frame: From initial administration of study agent until 24 hours post last dose
Population: Data only collected if indicated and performed as part of clinical care. No primary care providers felt this test was indicated.
Secondary
Percentage of Fetuses With Category III Non Stress Test Results
A Non Stress Test is a determination of the current well-being of the fetus, as measured by the fetal heart rate. Category I indicates that the fetus is in a state of well-being and is tolerating the intrauterine environment. Category II indicates a fetal heart rate that is showing some signs of distress. In this instance, obstetric providers will try to improve the intrauterine environment to allow the pregnancy to continue. Category III relates to a fetus whose well-being is compromised - usually requiring rapid intervention, ie expedient delivery.
Time frame: From initial administration of study agent until 24 hours post last dose, up to a maximum of 4 weeks
Population: Healthy women were not at risk for placental insufficiency and therefore did not have a non stress test.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nicotinamide - Pre-eclampsia | Percentage of Fetuses With Category III Non Stress Test Results | 0 percentage of fetuses |
Secondary
Percentage of Women Maternal Abdominal Tenderness
Time frame: From initial administration of study agent until 24 hours post last dose, up to a maximum of 4 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nicotinamide - Pre-eclampsia | Percentage of Women Maternal Abdominal Tenderness | 0 percentage of participants |
| Nicotinamide - Healthy Pregnant | Percentage of Women Maternal Abdominal Tenderness | 0 percentage of participants |
| Nicotinamide - Healthy Non-Pregnant | Percentage of Women Maternal Abdominal Tenderness | 0 percentage of participants |
Secondary
Percentage of Women With Headache Unrelieved by Oral Analgesics
Time frame: From initial administration of study agent until 24 hours post last dose, up to a maximum of 4 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nicotinamide - Pre-eclampsia | Percentage of Women With Headache Unrelieved by Oral Analgesics | 33 percentage of participants |
| Nicotinamide - Healthy Pregnant | Percentage of Women With Headache Unrelieved by Oral Analgesics | 0 percentage of participants |
| Nicotinamide - Healthy Non-Pregnant | Percentage of Women With Headache Unrelieved by Oral Analgesics | 0 percentage of participants |
Secondary
Percentage of Women With Hematocrit Decrease of More Than 3%
Time frame: From initial administration of study agent until 24 hours post last dose, up to a maximum of 4 weeks
Population: Healthy women were not at risk for anemia and therefore were not assessed for Hematocrit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nicotinamide - Pre-eclampsia | Percentage of Women With Hematocrit Decrease of More Than 3% | 44 percentage of participants |
Secondary
Percentage of Women With Less Than 500 cc Urine Output in 24 Hours
Time frame: From initial administration of study agent until 24 hours post last dose, up to a maximum of 4 weeks
Population: Healthy women were not at risk for oliguria and therefore were not assessed for urine output.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nicotinamide - Pre-eclampsia | Percentage of Women With Less Than 500 cc Urine Output in 24 Hours | 0 percentage of participants |