Table 1. Schedule of events table.
| Day 1 | Wk 1 | Wk 2 | Wk 3 | Wk 4 | Wk 5 | Wk 6 | Wk 7 | Wk 8 | Wk 9 | Wk 10 | Wk11 | Wk 12 | Wk 13 | Wk 14 | Wk 15 | Wk 16 | Wk 17 | Wk 18 | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cryptococcal meningitis
diagnosed |
X | ||||||||||||||||||
| Commence anti-fungals 1 | X | ||||||||||||||||||
| Inpatient TB screening
package 2 |
X | X | X | ||||||||||||||||
| IMPROVE 1HP RCT
enrolment |
X | X | |||||||||||||||||
| Randomisation 3 | X | ||||||||||||||||||
| 1HP initiation (early
inpatient arm) 4 |
X | ||||||||||||||||||
| Hospital discharge | X | X | |||||||||||||||||
| Follow-up 5 | X | X | X | X | X | X | X | X | |||||||||||
| Clinical review | X | X | X | X | X | ||||||||||||||
| Pill counts 6 | X | X | X | X | X | ||||||||||||||
| Liver function tests 7 | X | X | X | X | X | ||||||||||||||
| Safety monitoring blood
tests 8 |
X | X | X | X | X | ||||||||||||||
| PK sampling 9 | X | X | X | ||||||||||||||||
| 1HP initiation (late
outpatient arm) |
X | ||||||||||||||||||
| ART initiation / switch 10 | X | X | X | ||||||||||||||||
| Primary outcome 11 | X | ||||||||||||||||||
| Trial completion | X |
1. Participants will receive antifungal for 1–2 weeks as induction therapy for cryptococcal meningitis. Following completion of induction therapy, patients will step down to 800mg Fluconazole (continuation phase) to complete total 10-week course.
2. Clinical samples will be stored for future research
3. In cases, where the participant remains an inpatient for ≥14 days, randomisation will occur on day 14 rather than on the planned day of discharge.
4. 1HP = Rifapentine 600mg daily plus Isoniazid 300mg daily (plus pyridoxine)
5. Follow-up will occur on alternate weeks until week-18.
6. Self-reported adherence will be assessed, and pill counts conducted.
7. Alternate week liver function tests (LFTs) will be performed to screen for drug-induced liver injury for the duration of 1HP.
8. Safety monitoring blood tests will be taken including alternate week full blood count and renal function blood tests for the duration of 1HP. Blood will also be stored for future research studies.
9. Rifapentine / fluconazole / dolutegravir PK sampling will be conducted for 15 participants.
10. We anticipate that ~1/3 of participants will be ART naïve, these patients will start ART at week 4–6, ~1/3 of participants will be on ART but have clinical/immunological/virological failure, these patients will switch ART at week 4–6. Patients newly started on ART (<3-months prior to their cryptococcosis diagnosis) i.e. those with unmasking cryptococcal-IRIS will continue their ART.
11. Treatment completion is defined as participant reported adherence to >90% of the study medications, to be completed within 6-weeks of treatment initiation. TB-disease free is defined as not receiving a diagnosis of active TB disease for the duration of the trial.