Study of Nicotinamide in Early Onset Preeclampsia

Study Overview
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Brief Summary
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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
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See brief summary above

Official Title
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Phase II Study of Nicotinamide in Early Onset Preeclampsia

Conditions
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Pre-Eclampsia, Pregnancy Related

Intervention / Treatment
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* Drug: nicotinamide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional 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).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nicotinamide - pre-eclampsia<br>All participants will receive study agent | Drug: nicotinamide<br>* 2.5 gm nicotinamide given orally in 3 divided doses: 1000 mg in morning and evening, 500 mg at noon/midday<br>* Other names: niacinamide;|
| Experimental: Nicotinamide - healthy pregnant<br>All participants will receive study agent 1000mg in single dose | Drug: nicotinamide<br>* 2.5 gm nicotinamide given orally in 3 divided doses: 1000 mg in morning and evening, 500 mg at noon/midday<br>* Other names: niacinamide;|
| Experimental: Healthy Non-Pregnant<br>All participants will receive study agent 1000mg in single dose | Drug: nicotinamide<br>* 2.5 gm nicotinamide given orally in 3 divided doses: 1000 mg in morning and evening, 500 mg at noon/midday<br>* Other names: niacinamide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | Maternal side effects are defined as: facial erythema, hives, sore mouth, dry hair, fatigue, flushing, headache, nausea, and heart burn. | From initial administration of study agent until 24 hours post last dose, up to a maximum of 4 weeks | 
| 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 | 
| 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 | 
| 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. | From initial administration of study agent until 24 hours post last dose, up to a maximum of 4 weeks | 
| Percentage of Fetuses With Biophysical Profile < 6 |  | From initial administration of study agent until 24 hours post last dose | 
| 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. | at 1 hour post 1000 mg nicotinamide administration on Day 1 | 
| 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. | 8 hours after the 8 a.m. 1000 mg nicotimamide administration on Day 1 |