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Clinical Research Coordinator Analysis

Drug Titration Logistics

Finding: The protocol (Section 5.1.2) specifies an initial dose up-titration of Losartan/placebo "after 10-14 days" from initiation (Day 1). This period falls between scheduled visits (Visit 2 Day 1; Visit 3 Day 30±7). While tolerability assessment for dose *modification* is described (Section 7.3.2), the protocol lacks explicit operational guidance for the *method* (e.g., phone call, unscheduled brief visit) of proactively assessing tolerability for this first planned up-titration, who performs it, and the specific documentation requirements for this interim contact and Principal Investigator (PI) decision. Recommendation: Develop a study-specific guidance document or worksheet for the 10-14 day post-randomization tolerability check and up-titration decision. This should outline:

1. Responsible personnel for participant/parental contact (e.g., CRC, Study Nurse).

2. Method and target window for contact (e.g., scheduled phone call between Day 10 and Day 14 post-Visit 2).

3. Standardized questions/checklist to assess tolerability (e.g., querying for symptoms of hypotension such as dizziness or lightheadedness, any new adverse events, and any changes in concomitant medications since Day 1).

4. Process for PI review of tolerability information and documented approval for proceeding with the up-titration.

5. Clear instructions for documenting the contact, assessment findings, and PI decision in the participant's source notes and any designated CRF/eCRF field.

Rationale: Standardizing this interim procedure ensures consistent execution of this critical early treatment adjustment, enhances participant safety monitoring during the initial titration phase, minimizes the risk of protocol deviations related to dose titration, and ensures robust documentation for PI oversight and overall trial integrity.