KEMRI, though CMRG-C, Kilifi, will take on the role of database management for active and passive case detection and monitoring of laboratory and field studies. However, SAEs will be reported to the Data Safety Monitoring Board (see below).

**xii) Data Safety Monitoring Board (DSMB)** An independent committee consisting of experts in malaria, epidemiology, statistics and other appropriate disciplines has been appointed to oversee ethical and safety aspects of the study conduct. A quorum of 3 members is required at scheduled meetings.

The role of the DSMB includes the review of the implementation and progress of the study. It provides initial, regular, and closing advice on safety-related issues to the study sponsor. Its advice is based on the interpretation of study data with reference to the study protocol. The DSMB may, if deemed necessary, convene a meeting with, or request further information from the Principal Investigators and Local Safety Monitors at any stage of the study. The DSMB is empowered to suspend the enrollment to the trial and/or drug treatment on the trial pending review of potential safety issues arising in this trial or other relevant trials of the same drug product. The process will be described in study-specific SOPs. The DSMB will be informed of:

- All SAEs.

- All withdrawals of study subjects by the Principal Investigator or the parent(s)/guardian(s) of a subject due to adverse events.

- New information that may affect adversely the safety of the subjects or the conduct of the study.

- All subsequent protocol amendments, informed consent changes or revisions of other documents originally submitted for review.

- All subsequent protocol modifications (for information).

The final analysis will be conducted by the investigators, but the analysis plan will be discussed with and approved by the DSMB before it is implemented.

# **xiii) Local Safety Monitor (LSM)**

The overall role of the Local Safety Monitors (LSM), who are experienced clinicians based in-country and based in Kilifi or Nairobi, will be to support the clinical investigators and to act as a link between the investigators and the DSMB. The LSM's role will include:

- Acting as the study volunteer's advocate.

-

- Promptly communicating relevant safety information to the DSMB.

- Providing advice to the investigators on whether a set of clinical circumstances in a study warrants formal notification to the DSMB.

- Conduct a site visit to investigate every report of a SAE

- Unblinding a subject if deemed necessary to allow for adequate treatment.

- Liaising closely with the chair of the DSMB throughout the course of the trial.

The relevant LSM will be informed by the investigator on an 'as received' basis of:

-

All SAEs.

- All withdrawals of study subjects by the Principal Investigator or the parent(s)/ guardian(s) of a subject due to adverse events.

**xiv) Adverse event monitoring**

An adverse event (AE) is defined as "any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment" (ICH Guidelines E2A). An adverse event can further be broadly defined as any untoward deviation from baseline health which includes:

- Worsening of conditions present at the onset of the study.

- Deterioration due to the primary disease.

- Intercurrent illness.

- Events related or possibly related to concomitant medications.

A serious adverse event (SAE) is defined as an experience that results in any of the following outcomes:

-

-

# Death during the period of study follow-up.

- Life-threatening experience (one that puts a participant at immediate risk of death at the time of the event).

- Inpatient hospitalization during the period of study follow-up.

- Persistent or significant disability or incapacity.

- Specific medical or surgical intervention to prevent one of the other serious outcomes listed in the definition.

# _Identification of adverse events_

On days 2 and 3 of treatment, study clinicians will assess children according to a standardized clinical record form (Appendix <u>8). Children absent from school on these days will be traced at home using information collected from parents during the</u> consenting procedure.

Adverse events will be monitored for a further 28 days using a passive surveillance system in schools and local health centers. Travel costs will be reimbursed and treatment charges waived. Any new event, or an event present at baseline that 62