Calcium Aspirin Multiple Micronutrients (CAMMS) to Reduce Preterm Birth (CAMMS)

Calcium Aspirin Multiple Micronutrients (CAMMS) or Iron-folic Acid (IFA) to Reduce Preterm Birth

This trial will evaluate the impact of an integrated intervention of daily maternal calcium, aspirin, and multiple micronutrients (CAMMS) compared to iron-folic acid (IFA) during pregnancy on preterm birth and other adverse birth outcomes. Both interventions will be delivered through existing antenatal service platforms using context-specific strategies informed by formative research incorporating human-centered design processes to achieve high acceptability and high adherence, in three low-income countries with diverse contexts: Burkina Faso, Pakistan, and Zimbabwe.

Study Overview

• Status: Withdrawn
• Conditions: Low Birth Weight; Preterm Labor; Neonatal Death; Small for Gestational Age at Delivery; Hypertensive Disorder of Pregnancy
• Intervention / Treatment: Combination product: Calcium aspirin multiple micronutrients; Dietary supplement: Iron-folic Acid

Detailed Description

The CAMMS trial is an individually randomized, unblinded, phase III trial comparing aspirin, calcium and multiple micronutrients (intervention) versus iron-folic acid (control) among 10,000 pregnant women. The primary outcome is total preterm birth, stratified by spontaneous and indicated. Eligible pregnant women will be enrolled from antenatal clinics in three study populations in Burkina Faso, Pakistan, and Zimbabwe following written informed consent.

All women attending antenatal care (ANC) who are positive on a urine pregnancy test and have a fetal ultrasound examination confirming fetal heartbeat, intrauterine pregnancy, and gestational age 6<20 weeks' will be eligible for enrollment. Women who are <6 weeks will be rescheduled for 2-3 weeks later. Baseline data and clinical assessments will be conducted, and women will be randomized to daily ingestion of CAMMS or IFA until delivery. In Burkina Faso, for women randomized to CAMMS, the aspirin will be withheld until 13 weeks' gestation when it can be initiated concurrently with sulfadoxine-pyrimethamine. Women will receive context-specific adherence promotion interventions designed during formative research incorporating Human-Centered Design (HCD) processes in each country. Mothers will be followed up at 4-weekly intervals throughout pregnancy plus an additional study contact (by visit, phone call, WhatsApp, or text message) at 1-2 weeks after starting the study drug to check for tolerance and adherence. Women may also be seen at closer intervals in the third trimester by the Ministry of Health clinics. Women will be encouraged to deliver in a health institution.

Between baseline and delivery, research procedures will be undertaken by research staff based at antenatal clinics during mothers' routine antenatal visits to reduce time burden on participants. Depending on gestational age at recruitment, women will receive 7-11 research visits. One additional visit or contact by text-message (SMS) or phone call will occur one-two weeks after randomization to check that the women is tolerating and correctly taking the interventions.

At delivery, infant weight and gestational age will be measured/determined by research staff based at delivery clinics or, for home deliveries, during home visits conducted within 72 hours of delivery. For infants born outside the study area or who are not reached by research staff within 72 hours, date of birth and birth weight will be transcribed from the infant's health record with source of information noted. In unusual situations where the mother and infant cannot be reached in person before 180 days postpartum but can be reached by telephone, WhatsApp, or Text message, maternal report of data of birth and birth weight will be recorded with the source of information noted. For all infants reached by a research staff member within 72 hours of birth, birth length and head circumference will be measured by standardized research staff with high quality equipment (length measured to nearest 0.1cm with infant length board and Shorr insert-tape (Weigh & Measure LLC., Olney, MD, USA). Mothers and infants will be followed to 42 days post-partum for vital status and post-partum maternal Adverse Events (AEs) and Serious Adverse Events (SAEs). This visit may be conducted in person, by telephone, WhatsApp or text message with the source of information recorded.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Woman, confirmed pregnant by urinary pregnancy test
• 6<20 weeks' gestation determined by fetal ultrasound exam;
• Pregnancy must be intrauterine; multiple fetus pregnancies are eligible.
• Women must be willing and able to give informed consent;
• willing to receive antenatal visits at one of the study clinics.
• In Burkina Faso, women must be willing to take monthly sulfadoxine-pyrimethamine.

Exclusion Criteria:

• Pregnant women who are currently taking aspirin, calcium, or MMS;
• have a history of peptic ulcer or have any other contraindications to any of the study drugs;
• have acute or chronic condition that might interfere with the study as judged by the research clinician including severe anemia defined as Hb<5 g/dL;
• have other reasons which, at the study research physician's discretion, mean that receipt of the study drugs or participation in the trial would not be advisable.

NOTE: Women who have been started on IFA by MoH or private health care provider but are willing discontinue the IFA dispensed by MoH and to be randomized to IFA or CAMMS will not be excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Iron folic acid; 60 mg iron + 400 μg folic acid given as a combined tablet	Dietary supplement: Iron-folic Acid; Women randomized to IFA will receive monthly (28-day) blister cards containing containing 1 combined IFA tablet to be taken each day. 1 4-weekly blister card will be packaged in one unit box.; Other Names: IFA
Experimental: Calcium aspirin multiple micronutrients; 500 mg elemental calcium (as 1250 mg calcium carbonate) 81 mg aspirin 1 tablet United Nations International Multiple Micronutrient Antenatal Preparation (UNIMMAP) formula, which is a Multiple Micronutrient Supplement (MMS) for pregnant women	Combination product: Calcium aspirin multiple micronutrients; Women randomized to CAMMS will receive weekly blister cards containing all 3 components: 1 81 mg aspirin tablet, 1 UNIMMAP MMS, and 1 500-mg elemental calcium tablets. Blister packages will be labeled with times of day and days of week when tablets are to be taken. 4 weekly blister cards will be packaged in one unit box.; Other Names: CAMMS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total preterm birth	Gestational age at birth < 37 weeks, stratified by spontaneous and indicated.	At birth

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total very early preterm birth	gestational age at birth ≥20 and <28 weeks, stratified by spontaneous and indicated.	At birth
Total early preterm birth	gestational age ≥28 and <34 weeks, stratified by spontaneous and indicated.	At birth
Low birth weight	<2500 g	At birth
Very low birth weigh	<1500 g	At birth
Small for gestational age	<10th percentile weight for gestational age using INTERGROWTH 21st Reference standards	At birth
Stillbirth	fetal loss > 20 gestational weeks	Day of fetal loss from > 20 weeks gestation to birth
Neonatal death	death of a live-born infant <28 completed days of life	Day of death, between birth and <28 completed days of life
Miscarriage	fetal loss <20 gestational weeks	Day of fetal loss, up to < 20 weeks gestation
Live-or-stillbirth-preterm-deliveries	stillbirths delivered <37 weeks' gestation + preterm births	Day of fetal loss or birth, up to < 37 weeks gestation
Perinatal mortality	Stillbirths + neonatal deaths	fetal loss or infant death <28 days of completed life
Birth weight	infant weight (g) ≤ 72 h of birth	At birth
Gestational age at birth	Completed days of gestation at birth	At birth
Weight-for-gestational-age-Z-score at birth	WAZ, using INTERGROWTH 21st Reference standards	At birth
Hypertensive disorder of pregnancy	Maternal Systolic BP>140 and/or Diastolic BP>90 between enrollment and 42 days postpartum	From enrollment at 6<20 weeks gestation through 42 days postpartum
Maternal anemia	Hb<110 g/L during the third trimester of pregnancy	30 weeks' gestation
Maternal death	death of a woman between enrollment at 6<20 weeks gestation and 42 days postpartum	day of woman's death between enrollment at 6<20 weeks gestation up to 42 days postpartum

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Infant birth length and birth head circumference	Among infants assessed <72 hours after birth by research staff	birth
Tolerance of CAMMS compared to IFA	Rates of Grade 1 or 2 nausea, vomiting, rash/hives, diarrhea, constipation, and vaginal bleeding from initiation of the interventions through 42 days post-partum	Up to 42 days post-partum
Safety of CAMMS compared to IFA	Rates of SAEs, Grade 3 or 4 nausea, vomiting, rash/hives, diarrhea, constipation, and vaginal bleeding, stratified by relatedness to the intervention from initiation of the interventions through 42 days post-partum	Up to 42 days post-partum

Collaborators and Investigators

• Sponsor: Johns Hopkins Bloomberg School of Public Health
• Collaborators: Columbia University; Christiana Care Health Services; Aga Khan University; Institut Africain de Sante Publique; Zvitambo Institute for Maternal and Child Health Research
• Investigators: Principal Investigator: Jean Humphrey, ScD, Johns Hopkins University

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: November 3, 2022
• First Submitted That Met QC Criteria: November 9, 2022
• First Posted (Actual): November 14, 2022

Study Record Updates

• Last Update Posted (Actual): April 23, 2024
• Last Update Submitted That Met QC Criteria: April 22, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Infections; Body Weight; Pregnancy Complications; Obstetric Labor Complications; Death; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Toxemia; Hypertension; Premature Birth; Birth Weight; Obstetric Labor, Premature; Perinatal Death; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Vitamins; Calcium-Regulating Hormones and Agents; Vitamin B Complex; Hematinics; Aspirin; Calcium; Micronutrients; Trace Elements; Folic Acid
• Other Study ID Numbers: INV-036663

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will deposit anonymized data in an existing repository after publication of the primary and key secondary findings. (
• IPD Sharing Time Frame: About 2 years after the end of the trial when primary and secondary outcomes have been reported in the peer reviewed literature.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

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