5 results
Search Results
Now showing 1 - 5 of 5
Item Metadata only How do study participants want to be informed about study results: Findings from a malaria trial in Cambodia, Ethiopia, Pakistan and Indonesia(2025-01-01) Bamboro S.A.; Jabbar F.A.; Bagita-Vangana M.; Hasibuan N.; Degaga T.S.; Ghanchi N.; Beg M.A.; Tripura R.; Pasaribu Pitaloka A.; Tego T.T.; Safitri W.; Yulita; Cassidy-Seyoum S.; Mwaura M.; Mnjala H.; Lee G.; Dysoley L.; Von Seidlein L.; Price R.N.; Unger H.W.; Adhikari B.; Thriemer K.; Bamboro S.A.; Mahidol UniversityBackground. Researchers acknowledge the need to share study results with the patients and their communities, but this is not done consistently due to a plethora of barriers, including a paucity of data to guide best practice approaches in different populations. Methods. This study was nested within a large multi-centre randomized controlled trial of antimalaria treatment. Data on dissemination preferences were collected at the third month follow-up visit using a short questionnaire. Data were analysed using descriptive statistics and subsequently fed into an iterative process with key stakeholders, to develop suitable strategies for result dissemination. Results. A total of 960 patients were enrolled in the trial, of whom 84.0% participated in the nested survey. A total of 601 (74.6%) participants indicated interest in receiving trial results. There was significant heterogeneity by study country, with 33.3% (58/174) of patients indicating being interested in Cambodia, 100% (334/334) in Ethiopia, 97.7% (209/214) in Pakistan, but none (0/85) in Indonesia. The preferred method of dissemination varied by site, with community meetings favoured in Ethiopia (79.0%, 264/334) and individualised communication such as a letter (27.6%, 16/58) or phone calls (37.9%, 22/58) in Cambodia. Dissemination strategies were designed with key stakeholders and based on patient preferences but required adaptation to accommodate local logistical challenges. Conclusion. The varying preferences observed across different sites underscore that a onesize- fits-all approach is inadequate. Strategies can be tailored to patient preference but require adaptation to accommodate logistical challenges.Item Metadata only Methaemoglobin as a surrogate marker of primaquine antihypnozoite activity in Plasmodium vivax malaria: A systematic review and individual patient data meta-analysis(2024-09-01) Fadilah I.; Commons R.J.; Chau N.H.; Chu C.S.; Day N.P.J.; Koh G.C.K.W.; Green J.A.; Lacerda M.V.G.; Llanos-Cuentas A.; Nelwan E.J.; Nosten F.; Pasaribu A.P.; Sutanto I.; Taylor W.R.J.; Thriemer K.; Price R.N.; White N.J.; Baird J.K.; Watson J.A.; Fadilah I.; Mahidol UniversityBackground The:8-aminoquinolines, primaquine and tafenoquine, are the: only available drugs for the radical cure of Plasmodium vivax hypnozoites. Previous evidence suggests that there is dose-dependent 8-aminoquinoline induced methaemoglobinaemia and that higher methaemoglobin concentrations are associated with a lower risk of P. vivax recurrence. We undertook a systematic review and individual patient data meta-analysis to examine the utility of methaemoglobin as a population-level surrogate endpoint for 8-aminoquinoline antihypnozoite activity to prevent P. vivax recurrence. Methods and findings We conducted a systematic search of Medline, Embase, Web of Science, and the Cochrane Library, from 1 January 2000 to 29 September 2022, inclusive, of prospective clinical efficacy studies of acute, uncomplicated P. vivax malaria mono-infections treated with radical curative doses of primaquine. The day 7 methaemoglobin concentration was the primary surrogate outcome of interest. The primary clinical outcome was the time to first P. vivax recurrence between day 7 and day 120 after enrolment. We used multivariable Cox proportional-hazards regression with site random-effects to characterise the time to first recurrence as a function of the day 7 methaemoglobin percentage (log base 2 transformed), adjusted for the partner schizonticidal drug, the primaquine regimen duration as a proxy for the total primaquine dose (mg base/kg), the daily primaquine dose (mg/kg), and other factors. The systematic review protocol was registered with PROSPERO (CRD42023345956). We identified 219 P. vivax efficacy studies, of which 8 provided relevant individual-level data from patients treated with primaquine; all were randomised, parallel arm clinical trials assessed as having low or moderate risk of bias. In the primary analysis data set, there were 1,747 patients with normal glucose-6-phosphate dehydrogenase (G6PD) activity enrolled from 24 study sites across 8 different countries (Indonesia, Brazil, Vietnam, Thailand, Peru, Colombia, Ethiopia, and India). We observed an increasing dose-response relationship between the daily weight-adjusted primaquine dose and day 7 methaemoglobin level. For a given primaquine dose regimen, an observed doubling in day 7 methaemoglobin percentage was associated with an estimated 30% reduction in the risk of P. vivax recurrence (adjusted hazard ratio = 0.70; 95% confidence interval [CI] [0.57, 0.86]; p = 0.0005). These pooled estimates were largely consistent across the study sites. Using day 7 methaemoglobin as a surrogate endpoint for recurrence would reduce required sample sizes by approximately 40%. Study limitations include the inability to distinguish between recrudescence, reinfection, and relapse in P. vivax recurrences. Conclusions For a given primaquine regimen, higher methaemoglobin on day 7 was associated with a reduced risk of P. vivax recurrence. Under our proposed causal model, this justifies the use of methaemoglobin as a population-level surrogate endpoint for primaquine antihypnozoite activity in patients with P. vivax malaria who have normal G6PD activity.Item Metadata only High daily dose Short COurse PrimaquinE after G6PD testing for the radical cure of Plasmodium vivax malaria in Indonesia and Papua New Guinea: the SCOPE implementation study protocol(2025-12-01) Price R.N.; Robinson L.J.; Duparc S.; Wansom T.; Jambert E.; Demarest H.; Huegel H.; Do T.; Brown K.; Simpson J.A.; Abraham P.; Devine A.; Ley B.; Lee G.; Adella J.; Sakalidis V.S.; Rahmalia A.; Curry E.; Mannion K.; Douglas N.M.; Farquhar R.; Daly P.; Rosens E.; Makita L.; Amdara Y.; Ronkentuo S.; Pukai I.; Abegini C.; Malai M.; Ome-Kaius M.; Pomat W.; Theodora M.; Satyagraha A.W.; Putri A.; Angeline S.; Hutagalung A.P.; Ainur F.; Jimanto V.; Burdam F.H.; Kenangalem E.; Fransisca L.; Nelwan E.; Sutanto I.; Pasaribu A.P.; Laman M.; Poespoprodjo J.R.; Price R.N.; Mahidol UniversityBackground: Plasmodium vivax malaria remains an important threat to the public in the Asia Pacific region. Preventing P. vivax relapses is crucial for reducing morbidity from malaria and ultimately controlling and eliminating this species. Primaquine is the only widely available drug with antirelapse activity against dormant stages of P. vivax. Its widespread use in clinical practice is limited by its potential to cause severe haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Methods: The primary aims of this staged, binational, multicentre, before-and-after implementation study are to determine the safety, feasibility, and cost-effectiveness of a revised package of case management interventions for improved P. vivax radical cure. The interventions include: i) pre-treatment testing of patients for G6PD deficiency using a semi-quantitative point-of-care device from SDBiosensor (ROK); ii) prescription of high dose primaquine (7mg/kg total dose) either over 7 days for G6PD normal patients (≥ 70% activity) or 14 days for intermediate patients (30- < 70% activity), or lower dose weekly primaquine over 8 weeks for deficient patients (< 30% activity); iii) improved patient education processes; iv) routine community-based review on day 3 (and day 7 for Stage 1) and v) enhanced malariometric surveillance and community pharmacovigilance. Stage 1 of the study (800 patients) will be implemented at 4 community clinics across Indonesia and Papua New Guinea (PNG) and will focus on analysis of treatment safety. If safety of the intervention is confirmed during Stage 1, the study will proceed to Stage 2, in which patient recruitment will be expanded to 10 clinics across Indonesia and PNG, and the feasibility of the similar intervention package will be assessed, but with a single community-based review on day 3. Stage 2 will run for 12 months and recruit approximately 11,410 patients. Mixed methods analyses of Stage 2 data will focus on the operational feasibility and cost-effectiveness of the revised case management package, with effectiveness determined through analysis of individual-level risk of P. vivax recurrence and population-level changes in incidence (with comparison to the pre-implementation period). Feasibility will be assessed via qualitative observations, in-depth interviews and focus groups of health care workers and participants. Discussion: The intervention package will provide critical information on the safety, feasibility and cost-effectiveness of achieving radical cure with G6PD testing prior to high dose primaquine treatment and community-based follow-up. The study results will inform national malaria programs aiming to eliminate P. vivax in Indonesia and PNG by 2030. Trial registration: The study was registered on clinicaltrials.gov for Indonesia: NCT05879224 on the 18th May 2023 and PNG: NCT05874271 on the 16th May 2023.Item Metadata only High-dose, short-course primaquine after point-of-care G6PD testing for the radical cure of Plasmodium vivax malaria: a safety study in Papua New Guinea and Indonesia(2026-06-01) Fransisca L.; Ome-Kaius M.; Laman M.; Poespoprodjo J.R.; Pasaribu A.P.; Sutanto I.; Malai M.; Nelwan E.; Adella J.; Abegini C.; Ainur F.; Amdara Y.; Angeline S.; Brown K.; Burdam F.H.; Curry E.; Daimen M.; Daly P.; Do T.; Dori A.; Douglas N.M.; Huegel H.; Hutagalung A.P.; Jambert E.; Jimanto V.; Karo V.; Kenangalem E.; Kelebi T.; Kisomb J.; Laksono I.; Lee G.; Ley B.; Mannion K.; Plinduo J.; Pukai I.; Putri A.; Rajasekhar M.; Ronkentou S.; Rosens E.; Sakalidis V.S.; Satyagraha A.; Simpson J.A.; Theodora M.; Ubra R.; Vakore N.; Wansom T.; Duparc S.; Robinson L.J.; Price R.N.; Fransisca L.; Mahidol UniversityBackground: High total dose primaquine (PQ 7 mg/kg) over 7 days can improve treatment adherence and reduce Plasmodium vivax malaria recurrences. We evaluated the safety of pre-treatment glucose-6-phosphate dehydrogenase (G6PD) testing followed by high-dose primaquine for P. vivax malaria in Indonesia and Papua New Guinea. Methods: Patients with P. vivax malaria presenting to four community health clinics were screened for G6PD deficiency using the STANDARD G6PD (SD Biosensor, Republic of Korea) and treated with PQ7 (1 mg/kg/day, 7 days) if G6PD normal, PQ14 (0.5 mg/kg/day, 14 days) if G6PD intermediate, and PQ8W (0.75 mg/kg/week, 8 weeks) if G6PD deficient. Safety and tolerability were assessed through community-based follow-up by study teams on days 3 and 7. Findings: Between October 2023 and September 2024, 800 patients were enrolled: 626 (78.3%) received PQ7, 148 (18.5%) PQ14, and 26 (3.3%) PQ8W. Of those patients who did not withdraw, 97.8% (773/790) were followed up on day 3 and 97.7% (765/783) on day 7. A total of 27 adverse events of special interest (AESIs) were reported in 26 patients; the risk of an AESI was 2.7% (17/626) of patients treated with PQ7, 4.1% (6/148) of patients treated with PQ14 and 11.5% (3/26) of patients treated with PQ8W. Overall, 24 AESIs (88.9%) were related to haemolysis, with the majority (n = 21) due to a fall in haemoglobin >3 g/dL, all without clinical compromise. Serious adverse events (SAEs) occurred in 16 (2.0%) patients, mostly gastrointestinal intolerance (68.8%; 11/16) in patients receiving PQ7. Of the 626 patients treated with PQ7, 9 (1.4%) experienced SAEs that were probably or possibly related to primaquine. Interpretation: The implementation of G6PD testing to guide primaquine treatment of patients with P. vivax malaria was feasible and the primaquine regimens had acceptable safety profiles. The study paves the way for large scale implementation studies of the intervention. Funding: UNITAID and Australian National Health and Medical Research Council.Item Metadata only Effectiveness and safety of 7-day high-dose primaquine and single-dose tafenoquine versus 14-day low-dose primaquine in patients with Plasmodium vivax malaria (EFFORT): a multicentre, open-label, randomised, controlled, superiority trial(2026-01-01) Degaga T.S.; Pasaribu A.P.; Tripura R.; Ghanchi N.; Rajasekhar M.; Adhikari B.; Ley B.; Bamboro S.A.; Jabbar F.A.; Hasibuan N.; Tego T.T.; Zehra S.; Qurashi B.; Mnjala H.; Lee G.; Li P.; Kazi A.M.; Safitri W.; Yulita Y.; Siagian D.S.P.; Syahputra D.; Hadi H.; Muhammad T.; Ibrahim A.; Syed N.; Dost K.; Puspitrasari A.M.; Kariodimedjo P.P.; Rai A.; Rumaseb A.; Sutanto E.; Ean M.; Khan A.; Sokha M.; Commons R.J.; Weston S.; Noviyanti R.; Peto T.; Callery J.J.; Ali U.; Mehmood T.; Dondorp A.; Devine A.; Setiawan E.; Mwaura M.; Cassidy-Seyoum S.; Temesgen R.; Abate D.T.; Erjabo E.B.; Gessa G.G.; Kiros F.G.; Usmani M.I.; Raza A.; Woyessa A.; Hailu A.; Simpson J.A.; Karahalios A.; Beg M.A.; von Seidlein L.; Dysoley L.; Auburn S.; Price R.N.; Thriemer K.; Degaga T.S.; Mahidol UniversityBackground: Shorter courses of primaquine and single-dose tafenoquine have potential to improve the prevention of recurrent Plasmodium vivax infections, but there are few data on their comparative effectiveness when provided unsupervised. We aimed to assess the effectiveness and safety of these new treatment options. Methods: We conducted a multicentre, open-label, randomised, controlled, superiority trial in Ethiopia, Pakistan, Indonesia, and Cambodia. Adult patients (aged ≥18 years, or aged ≥16 years in Indonesia) with uncomplicated P vivax infection and glucose-6-phosphate dehydrogenase (G6PD) activity of 70% or greater were eligible for enrolment. Patients were treated with blood schizonticidal drugs (chloroquine in Ethiopia and Pakistan, dihydroartemisinin–piperaquine in Indonesia, and artesunate–pyronaridine in Cambodia) and randomly assigned (1:1:1) by an independent statistician using randomly permuted blocks of varying sizes to receive 7 days of unsupervised high-dose primaquine (total dose 7 mg/kg), single-dose tafenoquine (300 mg), or 14 days of low-dose primaquine (total dose 3·5 mg/kg). Randomisation was stratified by site. The primary endpoint, assessed in the modified intention-to-treat population (ie, patients who received allocated treatment, and were not lost to follow-up before day 15), was the cumulative incidence of any P vivax parasitaemia within 6 months compared between the primaquine groups, with the comparison of cumulative incidence between the tafenoquine group and the 14-day low-dose primaquine group a secondary endpoint. Key safety outcomes included the numbers of adverse and serious adverse events, including the number of gastrointestinal symptoms as well as the risk of anaemia. Safety outcomes were assessed in all patients who received any doses of study drug. The study is registered at ClinicalTrials.gov, NCT04411836, and is complete. Findings: Between April 25, 2021 and Sept 13, 2024, 4850 patients were screened for eligibility, of whom 960 patients (672 [70·0%] were male and 288 [30·0%] were female) were enrolled and randomly assigned (320 patients per group). The modified intention-to-treat population of 295 patients allocated to the 7-day high-dose primaquine group, 305 patients allocated to the tafenoquine group, and 301 patients allocated to the 14-day low-dose primaquine group were considered at risk of P vivax recurrence from day 15 onwards. The cumulative incidence of P vivax recurrence at 6 months was 13·0% (97·55% CI 9·0–18·5) in the 7-day high-dose primaquine group and 18·5% (13·8–24·6) in the 14-day low-dose primaquine group (hazard ratio [HR] 0·66 [97·55% CI 0·40–1·09], p=0·063). The corresponding incidence in the tafenoquine group was 12·6% (97·55% CI 8·8–18·0), with an HR of 0·64 (97·55% CI 0·39–1·05, p=0·041) compared with the 14-day low-dose primaquine group. Of the adverse events occurring before day 42, 24 (42·9%) of 56 were considered drug related in the 7-day high-dose primaquine group, compared with 16 (22·2%) of 72 in the tafenoquine group and 13 (34·2%) of 38 in the 14-day low-dose primaquine group. Four serious adverse events occurred, of which two (gastrointestinal symptoms in two patients in the 7-day high-dose primaquine group) were considered probably related to study drug. One study drug unrelated death occurred in the 14-day low-dose primaquine group. Interpretation: Both unsupervised 7-day high-dose primaquine and single-dose tafenoquine were well tolerated in patients with normal G6PD activity and they had a lower risk of P vivax recurrence compared with those in the 14-day low-dose primaquine group, albeit with uncertain magnitude. Our findings support the effectiveness and operational feasibility of shorter radical cure regimens across diverse malaria-endemic settings. Funding: National Health and Medical Research Council of Australia and Bill and Melinda Gates Foundation.