Non-inferiority of Lower Dose Calcium Supplementation During Pregnancy

Demonstrating Non-inferiority of Lower Dose Calcium Supplementation During Pregnancy for Reducing Preeclampsia and Neonatal Outcomes

The World Health Organization currently recommends that pregnant women in populations with low calcium intake receive daily calcium supplementation (1500 - 2000 mg) divided into three doses which are preferably taken at mealtimes, in addition to daily iron folic-acid supplements. Despite proven efficacy and the WHO recommendation, calcium supplementation in pregnancy is not standard of care in the vast majority of low-income and middle-income countries. Two important barriers to implementation are the cost of the supplements and complexity of the suggested calcium dosing schedule. A lower dose of calcium (500 mg) administered as a single dose has been shown to be beneficial in several trials, and if found to be as effective as the 1500 mg supplementation regimen, it may help overcome these barriers and increase individual and health system adoption.

The Investigators will conduct two parallel, individually randomized, double blind non-inferiority trials in India and Tanzania. Participating pregnant woman will be randomized to either 1500 mg or 500 mg calcium supplementation. The India and Tanzania trials are independently powered for the primary outcomes of i) preeclampsia and ii) preterm birth. The India and Tanzania sites will each enroll 11,000 participants.

Study Overview

• Status: Completed
• Conditions: Pregnancy Related
• Intervention / Treatment: Dietary supplement: Daily 500 mg elemental calcium as calcium carbonate; Dietary supplement: Daily1500 mg elemental calcium as calcium carbonate

• Study Type: Interventional
• Enrollment (Actual): 22000
• Phase: Phase 3

Contacts and Locations

Study Locations

• India
  • Bangalore, India
    • St. John's Research Institute
• Tanzania
  • Dar Es Salaam, Tanzania
    • Ifakara Health Institute
  • Dar Es Salaam, Tanzania
    • Africa Academy for Public Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Nulliparous
• Attending first ANC visit at study clinics
• Pregnant women <20 weeks
• ≥ 18 years old
• Intending to stay in study area until 6 weeks post delivery
• Provides informed consent

Exclusion Criteria:

• History or signs and/or symptoms of nephrolithiasis
• Prior diagnosis of parathyroid disorder or thyroidectomy
• Diseases that require digoxin, phenytoin, or tetracycline therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Daily 500 mg Calcium	Dietary supplement: Daily 500 mg elemental calcium as calcium carbonate; Pregnant women in this arm will be provided and counselled to take three tablets, one containing 500 mg elemental calcium as calcium carbonate and 2 placebo supplements daily (total of 500 mg daily). The supplements in India will also contain 83.3 IU each of vitamin D3, for a total of 250 IU daily. No vitamin D3 will be given in Tanzania.
Active Comparator: Daily1500 mg Calcium (Standard dose)	Dietary supplement: Daily1500 mg elemental calcium as calcium carbonate; Pregnant women in this arm will be provided and counselled to take three tablets each containing 500 mg elemental calcium as calcium carbonate daily (total of 1500 mg daily) as currently recommended by the World Health Organization. The supplements in India will also contain 83.3 IU each of vitamin D3, for a total of 250 IU daily. No vitamin D3 will be given in Tanzania.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of pregnant women with incident preeclampsia	Gestational week 20 to Delivery
Proportion of preterm birth	Birth

Collaborators and Investigators

• Sponsor: Harvard School of Public Health (HSPH)
• Collaborators: Ifakara Health Institute; St. John's Research Institute; Africa Academy for Public Health
• Investigators: Principal Investigator: Wafaie W Fawzi, MBBS, DrPH, Harvard School of Public Health (HSPH)

Publications and helpful links

General Publications

• Dwarkanath P, Muhihi A, Sudfeld CR, Rani S, Duggan CP, Sando MM, Wylie BJ, Fernandez R, Kinyogoli S, Munk C, Perumal N, Raj JM, Buggi N, Swai N, Thomas T, Wang M, Kurpad AV, Masanja H, Pembe AB, Fawzi WW. Non-inferiority of low-dose compared to standard high-dose calcium supplementation in pregnancy: study protocol for two randomized, parallel group, non-inferiority trials in India and Tanzania. Trials. 2021 Nov 24;22(1):838. doi: 10.1186/s13063-021-05811-7.

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2018
• Primary Completion (Actual): November 3, 2022
• Study Completion (Actual): December 16, 2022

Study Registration Dates

• First Submitted: November 19, 2017
• First Submitted That Met QC Criteria: November 19, 2017
• First Posted (Actual): November 22, 2017

Study Record Updates

• Last Update Posted (Actual): October 16, 2023
• Last Update Submitted That Met QC Criteria: October 13, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Antacids; Calcium; Calcium, Dietary; Calcium Carbonate
• Other Study ID Numbers: OPP1172660

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No