Table 4 List of amendment until to date

1

V 1.1

• Amendments in response to OXTREC, HREC comments

2

V 2.1 and V 2.2

• Updated visit schedule

3

V 2.11 to V2.15

• Maximum number of symptomatic recurrences limited to 4 then supervised open PQ will be given

• Primaquine also to be given supervised for 14 days at the appropriate dose to all participants with at least 1 symptomatic or asymptomatic relapse at the end of the study

• Option for telephoning subjects to run though symptom checklist

• Patients can be enrolled into the study on the basis of a positive RDT for malaria, as per site local practice

• Amend haematological warning signs & management of acute haemolysis

4

V 2.16

• Inclusion of flow cytometry in addition to the currently proposed G6PD tests

5

V 2.16-3.0

• Removal of taking a drug with antimalarial activity during the study as reason to withdraw patient

• Add exclusion criterion – cannot be enrolled in IMPROV twice

• Exclusion criteria removed: women planning to become pregnant & previous use of antimalarial drugs

• G6PD status to be decided on basis of spot test only

• Methaemoglobin to be measured at selected sites only and rotated

• Assent form amended to include weekly PQ regimen

• HemoCue sampling increased in both arms

• Maximum number of symptomatic recurrences in Vietnam – 3 within first 6 months – added to the consent form but will be for Vietnam only

• Adjustment to dosing table for those weighing 17 kg

6

V 4.0

• Addition of Ethiopia

• G6PD substudy with consent form added as an appendix

• Study schedule amended accordingly to accommodate additional G6PD testing

• Clarity added on PK sampling on D7 & 14 – now to be done pre & post dose

7

V 5.0

• Update list of investigator and affiliations

• Remove site in Pakistan and add the 2^nd site in Ethiopia

• Revise AE reporting to grades 3 and 4 only

• Revise management of patients with anemia related adverse events & management of acute haemolysis