Table 1.
Characteristics of induced blood-stage malaria studies considered and summary of findings for any participant with grade ≥ 2 levels of alanine or aspartate aminotransferase
| Study name | Clinical trial ID* | Test compound | Dose (mg) | N | Inoculum (parasites/mL blood) | Treatment day (inoculum D0) | Participants with increased ALT and/or AST (grade ≥ 2): participant, grade, day of peak value (peak value) | ALT:AST ratio | |
|---|---|---|---|---|---|---|---|---|---|
| ALT | AST | ||||||||
| QP13C05 | ACTRN12613000565741 | Piperaquine | 960 (n = 5), 640 (n = 7), and 480 (n = 12) | 24 | 1,800 | D7 or D8 | R019, grade 2, day 18 (3.7 × ULN) | R019, grade 1, day 18 (2.3 × ULN) | 1.6 |
| QP13C14 | ACTRN12613001040752 | Ferroquine | 800 | 8 | 1,800 | D8 | R101(A), grade 4, day 28 (11.6 × ULN) | R101(A), grade 3, day 28 (5.9 × ULN) | 1.7 |
| R104, grade 4, day 12 (13.4 × ULN) | R104, grade 4, day 12 (17.3 × ULN) | 0.8 | |||||||
| R105, grade 4, day 13 (11.2 × ULN) | R105, grade 3, day 13 (6.3 × ULN) | 1.8 | |||||||
| QP14C02 | NCT02223871 | ACT-451840 | 500 | 8 | 1,800 | D7 | 007, grade 2, day 15 (3.3 × ULN) | 007, grade 1, day 10 (1.5 × ULN) | 2.1 |
| QP14C11 | NCT02281344 | MMV390048 | 20 | 6 | 1,800 | D7 | None | None | – |
| QP14C12 | NCT02389348 | OZ439 + DSM265 | 200+100 (n = 8) and 200+50 (n = 5) | 13 | 1,800 | D7 | R201, grade 3, day 23 (5.3 × ULN) | R201, grade 2, day 23 (3.1 × ULN) | 1.7 |
| R204, grade 2, day 12 (3.7 × ULN) | R204, grade 2, day 12 (3.9 × ULN) | 0.8 | |||||||
| R103, grade 2, day 28 (3.6 × ULN) | R103, grade 4, day 28 (10.9 × ULN) | 0.3 | |||||||
| QP14C21 | NCT02431637 | Piperaquine | 480 | 6 | 2,800 | D7 | None | None | – |
| QP15C01 | NCT02543086 | Cipargamin + piperaquine | 10 on D8 960 on D11–15 | 8 | 1,800 | D8 | 5108, grade 4, day 20 (24.1 × ULN) | 5108, grade 4, day 20 (11.1 × ULN) | 2.2 |
| 5101, grade 3, day 15 (5.2 × ULN) | 5101, grade 1, day 15 (2.2 × ULN) | 2.4 | |||||||
| 5103, grade 2, day 16 (4.7 × ULN) | 5103, grade 2, day 16 (2.7 × ULN) | 1.8 | |||||||
| QP15C05 | NCT02431650 | Piperaquine + OZ439 or primaquine† | 480 | 11 | 2,800 | D7 | R110, grade 3, day 15 (9.3 × ULN) | R110, grade 3, day 15 (5.7 × ULN) | 1.6 |
| R109, grade 2, day 17 (4.2 × ULN) | R109, grade 1, day 10 (2.3 × ULN) | 1.8 | |||||||
| QP15C20 | NCT02867059 | SJ733 | 150 (n = 7) and 600 (n = 10)‡ | 15 | 2,800, Cohort 1 | D8 | R101(G), grade 4, day 15 (14.6 × ULN) | R101(G), grade 3, day 15 (8.3 × ULN) | 1.8 |
| 2,300, Cohort 2 | R102, grade 3, day 16 (6.3 × ULN) | R102, grade 2, day 16 (3.0 × ULN) | 2.1 | ||||||
| R107, grade 2, day 20 (4.2 × ULN) | R107, normal (1.0 × ULN) | 4.0 | |||||||
| R208, grade 2, day 10 (3.0 × ULN) | R208, grade 1, day 10 (1.6 × ULN) | 1.9 | |||||||
| QP16C04 | NCT02783833 | MMV390048 | 40 (n = 7) and 80 (n = 8) | 15 | 2,800 | D8 | R502, grade 4, day 13 (13.0 × ULN) | R502, grade 3, day 13 (8.0 × ULN) | 1.6 |
| R503, grade 2, day 10 (4.4 × ULN) | R503, grade 2, day 9 (2.9 × ULN) | 1.5 | |||||||
| R505, grade 2, day 17 (2.9 × ULN) | R505, normal (1.2 × ULN) | 2.4 | |||||||
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal. The WHO severity grading was used for ALT and AST: grade 1, 1.25–2.5 × ULN (mild); grade 2, 2.5–5 × ULN (moderate); grade 3, 5.1–10 × ULN (severe); and grade 4, > 10 × ULN (very severe).
The trials described in this study are registered at ClinicalTrials.gov, with identifiers beginning with NCT or at http://www.anzctr.org.au with identifiers beginning with ACTRN. Cipargamin was previously known as KAE609.
Participant R110 did not receive primaquine or OZ439, only piperaquine; R109 received piperaquine and then primaquine.
Two participants did not receive SJ733 and were not included in the analysis.