Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT04704999 |
| Other study ID # |
MAL20005 |
| Secondary ID |
21-0023 |
| Status |
Not yet recruiting |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
August 1, 2024 |
| Est. completion date |
December 31, 2027 |
Study information
| Verified date |
March 2024 |
| Source |
University of Oxford |
| Contact |
Cindy Chu, MD, PhD |
| Phone |
+856 (0) 21 250 752 |
| Email |
cindy[@]tropmedres.ac |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
Description:
Study design
A total of 700 participants will be enrolled and randomized to one of two arms: the currently
recommended tafenoquine dose (TQ-current; e.g., 300mg adult dose) or a 50% higher tafenoquine
dose (TQ-higher; e.g., 450mg adult dose). Doses will be equal to 100, 150, 200, 300, or 450
mg, given as a single dose. Each arm will have 350 participants. The schizonticidal agent
used will be determined by the study site. Tafenoquine will be given concomitantly with the
schizonticidal agent on the day of enrolment. The participant will follow up 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 days 7, 14, 21, and 28 then
every month until month 4. Participants will be instructed to follow up in between visits if
they are feeling unwell. Treatment allocation will be double-blind.
Recruitment
Potential participants will be recruited from the outpatient setting at the following sites:
- Mahidol Oxford Tropical Medicine Research Unit, Cambodia
- Lao Oxford Mahosot Hospital Wellcome Trust Research Unit, Lao PDR
- Mahidol Vivax Research Unit, Thailand
- Shoklo Malaria Research Unit, Thailand
- Oxford University Clinical Research Unit, Vietnam
Screening and Enrolment
Patients presenting with fever or history of fever and have asexual P. vivax parasitemia 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 7.14 mL of
blood. Medical history, participant weight, vital signs and physical examination, point of
care hemoglobin, quantitative glucose-6-phosphate dehydrogenase testing, and urine pregnancy
testing will be performed for eligibility assessment.
Randomization
Randomization will be done by sequentially numbered sealed opaque envelopes and prepared by a
Clinical Trials Support Group (CTSG) that is not involved with study activities. The CTSG
will maintain a log of the study group allocation and control access to the log. The
randomized arms will be TQ- current (the currently recommended tafenoquine dose) and
TQ-higher (a 50% higher tafenoquine dose than currently recommended). Tafenoquine treatment
will be double blinded so all participants will take a study drug with or without matching
placebo. Participants will receive a fixed mg dose depending on their weight. The weight
bands will be provided in a dosing table. Randomization will be stratified by site.
Direct Observation of Drug Administration
To ensure complete adherence to the prescribed drug regimens, all drug administration will be
directly observed by study staff.
The following procedures are to be performed for each drug administration:
- Record adverse events as reported by participant or observed by study staff
- Record vital signs
- 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 inability to continue 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, and 4 (total of 10 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, and 4 visits are +/- 2 weeks. The following procedures are to be performed for each
visit:
- Medication history and concomitant medication use
- Record adverse events as reported by participant or observed by study staff
- Record vital signs and physical examination
- Collect blood samples for laboratory tests
- Review all available laboratory results
At study exit on month 4, any participant with ongoing, unresolved adverse events will be
referred for appropriate outpatient clinical follow-up. If the participant has a P. vivax
recurrence, they will be treated as per the randomization 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 4 months from the date of
enrolment for all participants regardless of the number of P. vivax episodes.
Missed Visits
If the participant does not show for a scheduled study visit, study personnel will call the
participant or visit their 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. If the scheduled visit is not completed within the
window period, 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 the 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:
- Ineligibility (arising during the study or retrospective having been overlooked at
screening)
- Significant non-compliance with treatment regimen or study requirements
- 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 the radical cure efficacy of TQ-higher is at least 10% greater
than TQ-current. This will be assessed by the absence of recurrent P. vivax infection by 4
months. From previous data in the pre-registration trials, TQ-current had a radical cure
efficacy of approximately 74% by 6 months. In short latency settings, over 90-95% of the
recurrences occur within 4 months thus, the 4-month endpoint should have a high sensitivity.
To detect a 10% difference between TQ-current and TQ-higher, account for 25% loss to follow
up, and achieve at least 80% power a sample size of about 350 participants in each arm is
needed. The sample size calculation as done in Stata 17 using the following command "power
twoproportions 0.74, diff(0.10)" and was then adjusted for a 25% loss to follow-up.
Significance level (alpha) will be set at 0.05 using a two-sided two-sample proportions
z-test. Therefore, a total of 700 participants will be enrolled across 5 countries (~140
participants in each country). Enrolment may be shifted to other countries if recruitment
rates in a country do not meet study timelines.
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. 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 and only 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 anonymized so that no individual can be
identified from their treatment records.
Quality Control and Quality Assurance
The study will be conducted 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 described by treatment arms as either mean and
standard deviation, median and interquartile range and/or full range, or expressed as
frequency and percentage depending on the data characteristics. We will perform an
intention-to-treat (ITT) analysis where participants will be analyzed according to the arm of
randomization irrespective of the treatment that was actually given and participant adherence
to the study drug. Multiple imputation (MI) will be used for handling missing outcome data
each missing value having 5 multiply imputed values that will be combined using Rubin's rule
[Rubin DB. 1996]. These analyses will be followed by complete case (CC) analysis. To assess
the differences in the primary and secondary endpoints (microscopy and sub-microscopic P.
vivax recurrence by month 4, respectively) between treatment arms, a generalized linear
models for the binomial family with identity link will be used to obtain risk differences and
the corresponding 95% confidence interval (CI). A multivariable mixedeffects generalized
linear models for the binomial family with identity link will be fitted for the primary
outcome. This model will include random intercepts for country and site, and explanatory
variables such as demographic factors and baseline characteristics; the schizonticidal drug
(chloroquine and artemetherlumefantrine); tafenoquine mg/kg dose, AUC, Cmax, t1/2; potential
tafenoquine metabolites; CYP2D6 status, and methemoglobin level. Survival analysis will be
used to evaluate time to microscopy positive P. vivax recurrence. For the adverse event
analysis, Fisher's exact test will be used for binary data. Hemoglobin and methemoglobin
levels and association with drug exposure will be analyzed using linear regression. The
estimated tafenoquine AUC model will be based on previous work on primaquine
pharmacokinetic-pharmacodynamic analysis using nonlinear mixed-effects modelling. A detailed
statistical analysis plan (SAP) will be developed as a separate document and will be
finalized before the database is locked and the details of analysis for the secondary
outcomes will be in the SAP.
