Non-inferiority of Lower Dose Calcium Supplementation During Pregnancy

NCT03350516 | Completed Phase 3 DMC

• 1 other identifier: OPP1172660
• Study Type: interventional
• Target: 22,000
• Locations: 2 countries
• Sites: 3

Brief Summary

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.

Conditions

Pregnancy Related

Outcome Measures

Primary Outcomes (2)

• Proportion of pregnant women with incident preeclampsia

  Gestational week 20 to Delivery

• Proportion of preterm birth

  Birth

Study Arms (2)

Daily 500 mg Calcium

EXPERIMENTAL

Dietary Supplement: Daily 500 mg elemental calcium as calcium carbonate

Daily1500 mg Calcium (Standard dose)

ACTIVE COMPARATOR

Dietary Supplement: Daily1500 mg elemental calcium as calcium carbonate

Interventions

Daily 500 mg elemental calcium as calcium carbonate DIETARY_SUPPLEMENT

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.

Daily 500 mg Calcium

Daily1500 mg elemental calcium as calcium carbonate DIETARY_SUPPLEMENT

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.

Daily1500 mg Calcium (Standard dose)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

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

Sponsors & Collaborators

• Harvard School of Public Health (HSPH): lead
• St. John's Research Institute: collaborator
• Ifakara Health Institute: collaborator
• Africa Academy for Public Health: collaborator

Study Sites (3)

St. John's Research Institute

Bangalore, India

Location

Africa Academy for Public Health

Dar es Salaam, Tanzania

Location

Ifakara Health Institute

Dar es Salaam, Tanzania

Location

Related Publications (3)

• Dwarkanath P, Muhihi A, Sudfeld CR, Wylie BJ, Wang M, Perumal N, Thomas T, Kinyogoli SM, Bakari M, Fernandez R, Raj JM, Swai NO, Buggi N, Shobha R, Sando MM, Duggan CP, Masanja HM, Kurpad AV, Pembe AB, Fawzi WW. Two Randomized Trials of Low-Dose Calcium Supplementation in Pregnancy. N Engl J Med. 2024 Jan 11;390(2):143-153. doi: 10.1056/NEJMoa2307212.

  PMID: 38197817 RESULT

• Pembe AB, Dwarkanath P, Kikula A, Raj JM, Perumal N, Paulo HA, M R, Duggan CP, Masanja HM, Chopra N, Sando MM, Thomas T, Yelverton CA, Muhihi A, Kurpad AV, Fawzi WW, Wylie BJ, Sudfeld CR. Hypertensive disorders of pregnancy and perinatal outcomes: two prospective cohort studies of nulliparous women in India and Tanzania. BMJ Glob Health. 2025 Jul 10;10(7):e016339. doi: 10.1136/bmjgh-2024-016339.

  PMID: 40639854 DERIVED

• 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.

  PMID: 34819147 DERIVED

MeSH Terms

Interventions

Calcium; Calcium Carbonate

Intervention Hierarchy (Ancestors)

Metals, Alkaline Earth; Elements; Inorganic Chemicals; Metals; Blood Coagulation Factors; Biological Factors; Calcium Compounds; Carbonates; Carbonic Acid; Carbon Compounds, Inorganic; Minerals

Study Officials

• Wafaie W Fawzi, MBBS, DrPH

  Harvard School of Public Health (HSPH)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Richard Saltonstall Professor of Population Sciences, Professor of Nutrition, Epidemiology, and Global Health, Chair of the Department of Global Health and Population

Study Record Dates

• First Submitted: November 19, 2017
• First Posted: November 22, 2017
• Study Start: November 30, 2018
• Primary Completion: November 3, 2022
• Study Completion: December 16, 2022
• Last Updated: December 24, 2024

Record last verified: 2024-12

Locations

IN (1); TA (2)