Research Protocol Development October 9, 2019 Christopher Sudfeld, - PowerPoint PPT Presentation

Research Protocol Development October 9, 2019 Christopher Sudfeld, ScD Assistant Professor of Global Health and Nutrition Harvard T.H. Chan School of Public Health

What is the Purpose of a Research Protocol? Document the background, rationale, objectives, design, methodology, analysis and organization of your research protocol Describe (in advance) all aspects of the planned study Required by IRB (often shorter format) Very useful for Manuscript Writing

Chan A-W, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža - Jerić K, Hróbjartsson A, Mann H, Dickersin K, Berlin J, Doré C, Parulekar W, Summerskill W, Groves T, Schulz K, Sox H, Rockhold FW, Rennie D, Moher D. SPIRIT 2013 Statement: Defining standard protocol items for clinical trials. Ann Intern Med 2013;158:200-207.

Other Checklists STROBE: Strengthening the Reporting of Observational Studies in Epidemiology CONSORT: Consolidated Standards of Reporting Trials (either RCT or cRCT) COREQ: Consolidated Criteria for Reporting Qualitative Research STARD: Standards for Reporting Diagnostic Accuracy

Global Calcium Intake 8

\

Calcium Supplementation on Maternal/Child Outcomes 10

WHO Calcium Recommendations

Calcium Supplementation as Public Health Program • Vast majority of LMICs do not have a routine calcium supplementation program Why? 1) High pill burden (3 x 500 mg tablets at opposite times of iron) 2) Weight/Storage (20 week regimen weighs 1 kg per woman) 3) Cost ~$13 USD per woman as compared to Iron-Folic Acid ~2$ 4) IFA coverage poor….why spend more? 12

Non-Inferiority Trial of Calcium Supplementation in Pregnancy Trial Population: i) 11,000 pregnant women Bangalore, India ii) 11,000 pregnant women Dar es Salaam, Tanzania Regimen: a) 500 mg calcium / day b) 1,500 mg calcium / day Primary Outcomes: 1) Preeclampsia 2) Preterm birth Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03350516 13

Study Design Tanzania India Randomized Randomized Trial Trial Arm B Arm A Arm B Arm A Low Dose Standard Dose Low Dose Standard Dose 500mg Ca 1500mg Ca 500mg Ca 1500mg Ca N = 5,500 N = 5,500 N = 5,500 N = 5,500

Calcium Trial Eligibility Criteria Inclusion Criteria: Nulliparous 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

Figure 2. Description of calcium supplementation Individually Randomized Arm A Arm B 1500 mg Ca 500 mg Ca Daily Daily Morning Tablet 1 => 500 mg Morning Tablet 1 => 500 mg Midday Tablet 2 => 500 mg Midday Tablet 2 => 0 mg Evening Tablet 3 => 500 mg Evening Tablet 3 => 0 mg (a) Low dose oral supplements containing a total of 500mg calcium carbonate, taken three times daily from randomization until delivery. The first daily tablet contains 500mg of calcium while the remaining two daily tablets are placebo (a) Standard dose oral supplements containing a total of 1500mg calcium carbonate, taken three times daily from randomization until delivery. All three daily tablets contain 500mg of calcium

Primary Efficacy Endpoints: Primary Outcome #1- Preeclampsia : De novo hypertension plus new-onset proteinuria, both after gestational week 20. Hypertension is defined as either 1) a systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg on >2 occasions 4 hours to one week apart or 2) a systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥110 mm Hg on >2 occasions measured several minutes to one week apart . Proteinuria is defined as >1+ by dipstick at a study visit. Primary Outcome #2 – Preterm birth : Preterm birth will be defined as birth before 37 completed weeks’ gestation. For all women, gestational age will be based the best obstetric estimate (combining LMP and ultrasound measurements)

The total trial duration for preparation, implementation, and dissemination is 42 months. Close Out Study Preparation Enrollment and Follow Up Results 2017 2018 2019 2020 2021 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Protocol development (4 mo) x x Supplement procurement (9 mo) x x x IRB, local approvals (9 mo) x x x Hiring field staff (2 mo) x Training field staff / clinics (4 mo) x x Enrollment (21 mo) x x x x x x x Follow up (27 mo) x x x x x x x x x Data cleaning & close out (6 mo) x x Data analysis (6 mo) x x Dissemination (3 mo) x

Calcium Trial Visits Monthly ANC Postnatal 1 2 3 4 5 6 7 8 9 10 Screening x Consent x Enrollment x Maternal anthropometry x x x x x x x x x Clinical assessment x x x x x x x x x Blood pressure assessment x x x x x x x x x x Proteinuria assessment x x x x x x x x Pill count x x x x x x x Hemoglobin assessment x x x Food frequency questionnaire x Ultrasound x Delivery assessment* x Postnatal assessment* x *Maternal and infant assessments

Summary • SPIRIT and other checklists serve as a guide to develop your protocol. • Protocols and statistical analysis plans are ‘living documents’ because studies can change. *Document and provide a rationale for these changes* • Protocols for Trials and Systematic Reviews should be registered

Summary

HBNU Fellow Updates