Clinical trial NCT05426395: Vitamin B12 Dose Escalation Trial in Pregnancy
Official title: Single-blinded, Stratified, Multiple Ascending Dose Trial to Assess Pharmacokinetics and Identify Optimal Dose of Vitamin B12 in Pregnancy in Tanzania
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Vitamin B 12 Deficiency
Keywords: Vitamin B12
Pregnancy
Lead sponsor: George Washington University
Sponsor class: OTHER
Collaborators: name: Ifakara Health Institute
First posted: 2022-06-22
Enrollment: 50
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized Clinical Trial
Primary purpose: PREVENTION

Brief summary: Vitamin B12 is a cofactor for 2 enzymes that have essential functions in pregnancy, both for maternal health and for fetal development. However, there is currently limited data regarding the metabolic fate and optimal dose of supplemental vitamin B12 and its relationship to vitamin B12 status in pregnancy.

This is a single-blinded, stratified, dose-ranging trial of maternal vitamin B12 supplementation during pregnancy that will be conducted at the Ifakara Health Institute Bagamoyo Clinical Trial Unit in Tanzania. The investigators will enroll 40 pregnant women (gestational age 25-28 weeks) and 10 non-pregnant women (comparison group). Participants will be blinded to dosing (2.6, 10, and 50 µg) and supplementation will be given for four weeks.

With this trial, the investigators aim to enhance our understanding of vitamin B12 bioavailability during pregnancy in people with sufficient and insufficient baseline B12 status, identify priority dose regimens of vitamin B12 in pregnancy for investigation in later phase clinical trials to be conducted in populations where vitamin B12 insufficiency or deficiency is common, and identify biomarkers of vitamin B12 intake appropriate for pregnancy.


Eligibility criteria: The inclusion criteria for pregnant women are as follows:

* Pregnant female
* Has an estimated gestational age of 25 to 28 weeks at study initiation
* Is between the ages of 18 and 45 years of age
* Lives in the study area and does not plan to travel outside of the study area for the duration of the trial
* Consents to participate in the trial

The exclusion criteria for pregnant women are as follows:

* Known multiple pregnancy (e.g. twins, triplets)
* Has severe anemia (hemoglobin \<7 g/dL)
* Has pre-pregnancy or early pregnancy Body Mass Index ≥ 35 kg/m2
* Has a self-reported pre-pregnancy history of type II diabetes mellitus, hypertension, or hypercholesterolemia.
* Has currently diagnosed preeclampsia or eclampsia.
* Has currently diagnosed gestational diabetes.
* Has currently diagnosed renal, liver, autoimmune, or bleeding disorders. The investigators will also assess all women for clinical signs of liver disease including: jaundice or yellowing of skin/sclera/mucosa, right upper quadrant tenderness or pain. All women will be given a liver function test, regardless of clinical signs of liver disease. The tests include: serum Alanine aminotransferase (ALT) and serum Aspartate aminotransferase (AST). Abnormal liver function is defined as the following in this study for women who the investigators screened during the 2nd trimester (25-26 weeks), ALT below 2 or above 33 U/L, or AST below 3 or above 33 U/L; for women screened during the 3rd trimester (27-28 weeks), ALT below 2 or above 25 U/L, or AST below 4 or above 32 U/L (25). Those with liver disease or abnormal liver function will be excluded from the study and referred for treatment.
* Has currently diagnosed congestive heart failure. The investigators will first look for clinical signs of heart failure, and the investigators will focus on the following: i) Fatigue with limitation in performance of normal activities; ii) Coughing, wheezing and breathing difficulty because of lung congestion; iii) Swelling of ankles, feet and legs; and iv) Shortness of breath especially when lying flat. The investigators will only perform lab testing for those who have clinical manifestation, and refer them to appropriate and timely care.
* Has a history of significant gastrointestinal surgeries, such as bariatric surgery, cholecystectomy, or other surgical procedures affecting the stomach, liver, bile ducts and/or small intestine that may disrupt enterohepatic recycling of vitamin B12.
* Has a condition requiring the use of the following medications: H2 blockers, proton pump inhibitors, or prokinetic agents.
* Reports regular use of an over-the-counter, high dose vitamin B12 supplementation. (This criteria does not refer to normal prenatal vitamin supplements which typically include approximately 1 RDA of vitamin B12 or 2.6 ug of vitamin B12. Women using multiple micronutrient supplements, or MMS, are eligible for the study).
* Reports cigarette smoking or tobacco chewing
* Reports heavy alcohol use (\>3 drinks per day, or \>7 drinks per week)
* Current malaria infection (per rapid diagnostic)
* HIV/AIDS infection (due to potential interaction between first-line antiretroviral dolutegravir and multivitamins that has been shown to decrease dolutegravir exposure by about 33%).
* Has a known allergy to corn or hydroxyethyl starch (HES).

The inclusion criteria for non-pregnant women are as follows:

* Is between the ages of 18 and 45 years of age.
* Lives in the study area and does not plan to travel outside of the study area for the duration of the trial
* Consents to participate in the trial

The exclusion criteria for non-pregnant women are as follows:

* Has severe anemia (hemoglobin \<8 g/dL)
* Has Body Mass Index ≥ 35 kg/m2
* Has a self-reported diagnosis of type II diabetes mellitus, hypertension, or hypercholesterolemia.
* Has currently diagnosed renal, liver, autoimmune, or bleeding disorders. The investigators will also assess all women for clinical signs of liver disease including: jaundice or yellowing of skin/sclera/mucosa, right upper quadrant tenderness or pain. Any woman with clinical signs of liver disease will be given a liver function test including: ALT, AST (26,27). Those with liver disease will be excluded from the study and referred for treatment.
* Has currently diagnosed congestive heart failure.
* Has a history of significant gastrointestinal surgeries, such as bariatric surgery, cholecystectomy, or other surgical procedures affecting the stomach, liver, bile ducts and/or small intestine that may disrupt enterohepatic recycling of vitamin B12.
* Has a condition requiring the use of the following medications: H2 blockers, proton pump inhibitors, or prokinetic agents.
* Reports regular use of an over-the-counter, high dose vitamin B12 supplementation.
* Reports cigarette smoking or tobacco chewing
* Reports heavy alcohol use (\>3 drinks per day, or \>7 drinks per week)
* Current malaria infection (per rapid diagnostic)
* HIV/AIDS infection (due to potential interaction between first-line antiretroviral dolutegravir and multivitamins that has been shown to decrease dolutegravir exposure by about 33%).
* Has a known allergy to corn or hydroxyethyl starch (HES).

Primary outcomes:
measure: Assessing the steady state pharmacokinetics of B12 upon oral administration in pregnant women.
timeFrame: Over 4 weeks
measure: Assessing the steady state pharmacokinetics of B12 upon oral administration in pregnant women.
timeFrame: Over 4 weeks
measure: Assessing the steady state pharmacokinetics of B12 upon oral administration in pregnant women.
timeFrame: Over 4 weeks
Secondary outcomes:
measure: Assessing serum methylmalonic acid (MMA)
timeFrame: On Day 29
measure: Assessing serum and urinary homocysteine
timeFrame: On Day 29
measure: Assessing hematological response: hemoglobin
timeFrame: On Day 29
measure: Assessing hematological response: hematocrit
timeFrame: On Day 29
measure: Assessing hematological response: erythrocyte count
timeFrame: On Day 29
measure: Assessing hematological response: mean cell volume
timeFrame: On Day 29
measure: Assessing hematological response: reticulocyte number
timeFrame: On Day 29
Other outcomes:
Locations:
city: Bagamoyo
country: Tanzania
facility: Ifakara Health Institute Bagamoyo Clinical Trial Unit (BCTU)
Study officials:
References: