SEADOT: Southeast Asia Dose Optimization of Tafenoquine
Study Details
Study Description
Brief Summary
Tafenoquine was recently approved by regulatory authorities in the USA and Australia. Tafenoquine is an alternative radical curative treatment to primaquine acting against the dormant liver stage of Plasmodium vivax (the hypnozoite). Tafenoquine (an 8-aminoquinoline) has the substantial advantage of single dosing as compared to a 14-day course of primaquine to achieve radical cure. The recommended tafenoquine dose is 300 mg, which was shown to be significantly worse in radical curative efficacy to a total primaquine dose of 3.5 mg/kg in Southeast Asia. The cure rate of tafenoquine 300 mg in Southeast Asian study sites was only 74%. The comparator 3.5 mg/kg total primaquine dose is the standard and most commonly used dose globally, but in Southeast Asia and the Western Pacific, higher doses of primaquine are needed for radical cure. This study aims to determine the optimal dose of tafenoquine in Southeast Asia.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
Detailed Description
Study design
A total of 600 participants will be enrolled and randomised to one of three arms: low mg/kg single dose tafenoquine (5 mg/kg); medium mg/kg single dose tafenoquine (9 mg/kg); and high mg/kg dose tafenoquine (12.5 mg/kg). Due to tablet packaging, doses will be weight dependent and equal to 200, 300, 400, or 600 mg given as a single dose for the description of the study treatment arms). Each arm will have 200 participants (~120 participants per country). The schizonticidal agent used will be determined by the study site for description of schizonticidal treatment). Tafenoquine will be given concomitantly with the schizonticidal agent on the day of enrolment. The participant will be followed daily until the malaria smear is negative for asexual parasites or until the schizonticidal treatment is completed, whichever occurs last. Follow up will continue on day 7, 14, 21, and 28 then every month until month 6. Participants will be instructed to follow up in between visits if they are feeling unwell. This is an open label randomised trial and neither participants nor clinical study staff will be blinded to the treatment allocation.
Recruitment
Potential participants will be recruited from the outpatient setting at the following sites:
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Mahidol Oxford Tropical Medicine Research Unit (MORU), Cambodia
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Lao Oxford Mahosot Hospital Wellcome Trust Research Unit (LOMWRU), Lao PDR
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Myanmar Oxford Clinical Research Unit (MOCRU), Myanmar
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Mahidol Vivax Research Unit (MVRU), Thailand
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Shoklo Malaria Research Unit (SMRU), Thailand
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Oxford University Clinical Research Unit (OUCRU), Vietnam
Screening and Enrolment
Patients presenting with fever or history of fever and have asexual P. vivax parasitaemia by microscopy will be approached for informed consent. After written informed consent has been provided, study staff who have been trained in phlebotomy will draw approximately 7.19 mL of blood. Medical history, participant weight, vital signs and physical examination, point of care haemoglobin, quantitative glucose-6-phosphate dehydrogenase testing, and urine pregnancy testing will be performed to determine if the volunteer can be enrolled.
Randomisation
Randomisation will be done by sequentially numbered sealed envelopes. The randomized arms will be low (5 mg/kg), medium (9 mg/kg) or high (12.5 mg/kg) single dose tafenoquine. The doses will be provided in a dosing table in the protocol.
There will be no control arm per se (i.e. with primaquine, the current standard of care) as the study is designed to evaluate the relationship of the tafenoquine dose (drug exposure) with the therapeutic response (P. vivax recurrence within 6 months).
Direct Observation of Drug Administration
In order to ensure complete adherence to the prescribed drug regimens, all drug administration will be directly observed by study staff. Study staff will provide the participant with the appropriate dosing of the drug for that day and observe the participant taking the drug.
The following procedures are to be performed for each direct observation of drug administration subsequent to the first dosing:
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Record adverse events as reported by participant or observed by study staff
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Record vital signs
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Record the date and time of study drug administration
Study staff will review any available laboratory findings prior to drug administration. The investigator will determine if any adverse event requires discontinuation of the study medication or results in inability to continue to comply with study procedures.
Follow-up Visits
Participants will be followed daily until the malaria smear is negative once or when the schizonticidal treatment is completed, whichever is later. Follow up will continue on days 7, 14, 21, and 28, then months 2, 3, 4, 5, and 6 (total of 12 visits depending on parasite clearance time).
Daily visits must occur on the exact day scheduled. The visit windows for the day 7, 14, and 21 visits are +/- 3 days, for the day 28 visit + 2 weeks/- 3 days, and for the months 2, 3, 4, 5 and 6 visits are +/- 2 weeks.
The following procedures are to be performed for each visit:
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Medication history and concomitant medication use
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Record adverse events as reported by participant or observed by study staff
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Record vital signs and physical examination
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Collect blood samples for laboratory tests
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Review all available laboratory results
At study exit on month 6, any participant with ongoing, unresolved adverse events will be referred to care for appropriate clinical follow-up in the outpatient department. If the participant has a P. vivax recurrence, they will be treated as per the randomisation arm and study activities (blood sampling and follow up) will restart as episode 2, day 0. The total study duration will remain the same. This means that the study completion date is 6 months from the date of enrolment for all participants regardless of the number of P. vivax episodes.
Missed Visits
In case of a no-show at the clinic for a scheduled study visit, study personnel (or community engagement) will call the participant if the participant has a phone. Study personnel (or community engagement) may visit the participant's home to remind the participant of the study visit. Maximum efforts will be made to ensure complete follow-up in the trial, including routine education for participants on follow-up schedules. For participants who do not complete a scheduled visit within the visit window, that visit will be documented as "missed" and follow up will continue.
Participant Withdrawal or Termination
Each participant has the right to withdraw consent for study at any time. In addition, the investigator may discontinue a participant from the study at any time if the investigator considers it necessary for any reason including:
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Ineligibility (either arising during the study or retrospective having been overlooked at screening)
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Significant non-compliance with treatment regimen or study requirements
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An adverse event which requires discontinuation of the study medication or results in inability to continue to comply with study procedures
The reason for withdrawal will be recorded in the case report form (CRF). If the participant is withdrawn due to an adverse event, the investigator will arrange for follow-up visits or telephone calls until the adverse event has resolved or stabilized. Participants who have been withdrawn or terminated from the study will not be replaced.
Sample Size
The trial hypothesis is that radical curative efficacy is determined by the total drug exposure, approximated by the total area under the whole blood tafenoquine concentration-time curve. This trial aims to characterise the dose-efficacy relationship of single-dose tafenoquine by randomising patients to receive target doses close to 5, 9 and 12.5 mg/kg (corresponding approximately to the previously tested Southeast Asian adult doses of 300, 450, or 600 mg, constrained by available tablet sizes). The clinically relevant primary efficacy endpoint (which for a single dose regimen is the equal to the effectiveness) is the occurrence of a microscopy detectable recurrent vivax malaria after treatment. The investigators have used previous data from the study sites on infection rates, P. vivax relapse rates, and a published model of tafenoquine population pharmacokinetics to construct a simulation model which allows for approximate determination of the sample size required to characterise the exposure-response curve for the hypnozoiticidal activity of tafenoquine. The population pharmacokinetic model of tafenoquine was used to generate area under curve exposure values as a function of the randomised doses and simulated patient weights. In addition, the investigators used estimates from the phase 2 studies of the area under curve - hypnozoiticidal efficacy relationship (pharmacodynamic model) to generate plausible estimates for the dose-response curve. The resulting pharmacokinetic-pharmacodynamic simulation model, adapted to Southeast Asia (where higher doses of 8-aminoquinoline treatment are needed), accounting for inter-site variability, estimated that 200 patients per arm (approximately 120 per country) were needed to provide 90% power to characterise the dose-response relationship (Figure 7). Sparse pharmacokinetic sampling, with 4 blood samples in the first week and additional samples at 14 and 28 days, will allow for subsequent determination of individual patient area under curve values, and an accurate characterisation of the population dose-efficacy curve.
DATA HANDLING AND RECORD KEEPING
Data Collection All study data will be recorded on standard paper Case Report Forms (CRFs). Data will be entered on a secure database in accordance with standard operating procedures (SOPs). A study-specific data management plan will detail procedures for collection, curation and storage of study data.
Source documents are original documents, data, and records from which participants' CRF data are obtained. These include, but are not limited to, hospital records (from which medical history and previous and concurrent medication may be summarized into the CRF), clinical charts, laboratory, correspondence, log books, and CRFs. For most variables, the CRF will be considered the source document.
All documents will be stored safely in confidential conditions. On all study-specific documents, other than the signed consent and screening logbook, the participant will be referred to by the study participant number/code, not by name.
Data Access
The participants will be identified by a study identification number in the study database. The name and any other identifying detail will NOT be included in any study data electronic file. The database linking the volunteer's clinical identification number (ie. hospital number) to the study identification number will be kept by the individual study sites and the data analysis team will not have access to this information. All records will be kept locked and all databases will be password protected such that clinic staff and study staff will have access to their respective databases.
Direct access will be granted to authorized representatives from the sponsor, host institutions and the regulatory authorities to permit trial-related monitoring, audits and inspections.
Data Storage
Each study site will maintain, and store securely, complete, accurate and current study records throughout the study. In accordance with the University of Oxford's policy, research data and records should be retained for five years for adults, and for children until the youngest child participating in the trial reaches 21, or in accordance with the local/in-country regulation. Applicable records include source documents, site registration documents and reports, informed consent forms, and notations of all contacts with participants.
Data Sharing
Participant's data and results from blood analyses stored in the database may be shared according to the terms defined in the MORU data sharing policy or other researchers to use in the future. All personal information will be anonymised so that no individual can be identified from their treatment records.
Quality Control and Quality Assurance
The study will be conducted in accordance with the current approved protocol, International Conference on Harmonisation (ICH) Good Clinical Practice (GCP), relevant regulations, standard operating procedures, and the General Data Protection Regulation (GDPR). The Clinical Trials Support Group (CTSG) at MORU will provide study oversight, quality management, and study monitoring.
Statistical Analysis
Baseline participant characteristics will be compared across study arms using standard descriptive statistics. To assess the primary and secondary endpoints of microscopy and sub-microscopic P. vivax recurrence, respectively, logistic regression will be used to compare rates of P. vivax infection between study arms and determine whether age or other demographic factors, mg/kg tafenoquine dose, tafenoquine area under curve or CYP2D6 status are predictive of recurrence. Logistic regression will also be used to analyse the presence of gastrointestinal adverse effects associated with use of concomitant medication, drug exposure, and CYP2D6 status. Methaemoglobin levels and association with tafenoquine area under curve will be analysed using linear regression. The estimated tafenoquine area under curve model will be based on previous work on primaquine pharmacokinetic-pharmacodynamic analysis using nonlinear mixed-effects modelling.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Low dose tafenoquine (5mg/kg) with a fixed weight dependent dose The doses are as follows; Weight range Low dose >21-25 kg 200 mg 26-40 kg 200 mg 41-50 kg 300 mg 51-60 kg 400 mg 61-80 kg 400 mg Tafenoquine will be given as 100 mg coated tablets. Whole tablets will be given, and dosing will be based on weight bands. |
Drug: Tafenoquine
Tafenoquine will be given as 100mg coated tablets. Whole tablets will be given based on weight bands.
Drug: Chloroquine
Chloroquine will be given as daily dose over 3 days (25mg/kg total dose divided 10/10/5mg/kg)
Drug: Artemether 20 mg-Lumefantrine 120 mg
Artemether-lumefantrine will be given twice daily over 3 days. Whole tablets will be given based on weight bands.
|
| Active Comparator: Medium dose tafenoquine (9mg/kg) with a fixed weight dependent dose The doses are as follows; Weight range Medium dose >21-25 kg 200 mg 26-40 kg 300 mg 41-50 kg 400 mg 51-60 kg 500 mg 61-80 kg 600 mg Tafenoquine will be given as 100 mg coated tablets. Whole tablets will be given, and dosing will be based on weight bands. |
Drug: Tafenoquine
Tafenoquine will be given as 100mg coated tablets. Whole tablets will be given based on weight bands.
Drug: Chloroquine
Chloroquine will be given as daily dose over 3 days (25mg/kg total dose divided 10/10/5mg/kg)
Drug: Artemether 20 mg-Lumefantrine 120 mg
Artemether-lumefantrine will be given twice daily over 3 days. Whole tablets will be given based on weight bands.
|
| Active Comparator: High dose tafenoquine (12.5mg/kg) with a fixed weight dependent dose The doses are as follows; Weight range High dose >21-25 kg 300 mg 26-40 kg 400 mg 41-50 kg 600 mg 51-60 kg 600 mg 61-80 kg 600 mg Tafenoquine will be given as 100 mg coated tablets. Whole tablets will be given, and dosing will be based on weight bands. |
Drug: Tafenoquine
Tafenoquine will be given as 100mg coated tablets. Whole tablets will be given based on weight bands.
Drug: Chloroquine
Chloroquine will be given as daily dose over 3 days (25mg/kg total dose divided 10/10/5mg/kg)
Drug: Artemether 20 mg-Lumefantrine 120 mg
Artemether-lumefantrine will be given twice daily over 3 days. Whole tablets will be given based on weight bands.
|
Outcome Measures
Primary Outcome Measures
- Microscopy positive P. vivax recurrence after radical treatment up to month 6 [At month 6]
Secondary Outcome Measures
- Sub-microscopic P. vivax recurrence after radical treatment up to month 6 [At Day 0, 7, 14, 21, and 28; Month 2, 3, 4, 5, and 6]
- The probability of treatment failure as defined by the probability of one or more of the observed recurrences within 6 months being a relapse (defined using time to event and parasite genotype) [At Day 0, 7, 14, 21, and 28; Month 2, 3, 4, 5, and 6]
- Number of P. vivax recurrences by day 28 [At Day 0, 7, 14, 21, and 28]
- Number of P. vivax recurrences by month 6 [At Day 0, 7, 14, 21, and 28; Month 2, 3, 4, 5, and 6]
- Number of adverse and serious adverse events [Six-month period]
- Number of incorrect glucose-6-phosphate dehydrogenase Biosensor test interpretations [At Day 0]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Patients with P. vivax mono-infection as diagnosed by microscopy
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Fever or history of fever in the previous 7 days
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Quantitative glucose-6-phosphate dehydrogenase activity ≥70% of the population median
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Weight > 20-80 kg
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Ability to understand the study instructions and provide written informed consent
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Willing to be followed for 6 months
Exclusion Criteria:
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Pregnancy
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Lactation
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Hb < 8 g/dL
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Severe malaria
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Blood transfusion in the last 3 months
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Any previous history of a haemolytic event
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History of allergic response to an 8-aminoquinoline or the nationally recommended schizonticide (e.g. chloroquine, artesunate-mefloquine, artemether-lumefantrine)
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Presence of any condition which in the judgement of the investigator would place the patient at undue risk or interfere with the results of the study (e.g. chronic disease, medications that potentiate or inhibit CYP2D6 or CYP2C8 isoenzyme function)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Mahidol Oxford Tropical Medicine Research Unit (MORU), Cambodia | Siem Reap | Cambodia | ||
| 2 | Lao Oxford Mahosot Hospital Wellcome Trust Research Unit (LOMWRU) | Vientiane | Lao People's Democratic Republic | ||
| 3 | Myanmar Oxford Clinical Research Unit (MOCRU) | Yangon | Myanmar | ||
| 4 | Mahidol Vivax Research Unit (MVRU) | Bangkok | Thailand | ||
| 5 | Shoklo Malaria Research Unit (SMRU) | Bangkok | Thailand | ||
| 6 | Oxford University Clinical Research Unit (OUCRU) | Binh Phuoc | Vietnam |
Sponsors and Collaborators
- University of Oxford
- PATH
Investigators
- Principal Investigator: Cindy Chu, MD, PhD, Shoklo Malaria Research Unit
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- MAL20005