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Trial registered on ANZCTR


Registration number
ACTRN12617000329369
Ethics application status
Approved
Date submitted
12/01/2017
Date registered
2/03/2017
Date last updated
5/02/2019
Date data sharing statement initially provided
5/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Finding the best combination of drugs for curing vivax malaria in the Solomon Islands
Scientific title
A comparison of two artemisinin combination therapies (ACTs) in combination with primaquine for radical cure of Plasmodium vivax malaria in the Solomon Islands
Secondary ID [1] 290895 0
None
Universal Trial Number (UTN)
U1111-1191-4968
Trial acronym
ACT-Radical
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Plasmodium vivax malaria 301612 0
Condition category
Condition code
Infection 301319 301319 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
AL+PQ (Arm 1): Artemether-lumefantrine (2/12mg/kg) administered orally with milk twice daily for 3 days (3 morning doses directly observed by research worker, 3 evening doses self administered with adherence checked by packet return) + primaquine (0.25mg/kg) administered orally once daily with food (savory biscuit) for 14 days (co-administered with morning dose of artemether-lumefantrine under direct supervision of research worker on days 0, 1 and 2, administered on its own under observation of community worker on days 4, 5, 6, 8, 9, 11, 12, 13 and administered on its own under supervision of research worker on days 7, and 10. On day 14 research worker will document adherence with full 14 day course by reviewing records of community observers.
DP+PQ (Arm 2): Dihydroartemisinin-piperaquine (2.5/20mg/kg) administered orally once daily without milk in the morning (3 morning doses directly observed by research worker) + primaquine (0.25mg/kg) administered orally once daily with food (savory biscuit) for 14 days (co-administered with dose of dihydroartemisinin-piperaquine under direct supervision of research worker on days 0, 1 and 2, administered on its own under observation of community worker on days 4, 5, 6, 8, 9, 11, 12, 13 and administered on its own under supervision of research worker on days 7, and 10. On day 14 research worker will document adherence with full 14 day course by reviewing records of community observers.
Intervention code [1] 296841 0
Treatment: Drugs
Comparator / control treatment
AL alone (Arm 3): Artemether-lumefantrine (2/12mg/kg) administered orally with milk twice daily for 3 days (3 morning doses directly observed by research worker, 3 evening doses self administered with adherence checked by packet return)
Control group
Active

Outcomes
Primary outcome [1] 300727 0
Microscopically confirmed, PCR verified P.vivax infection occurring at any time during the designated 6-month follow-up period. This “microscopy endpoint” will require that the following criteria be met:

1. A finding of P.vivax parasitaemia on field-based examination of a Giemsa-stained thick and thin blood film (by a level 2 microscopist) at any scheduled or unscheduled visit between days 21 and 168, inclusive.
2. Confirmation of initial field microscopy diagnosis of P.vivax by a 2nd Level 2 microscopist,
or
3. Confirmation of a diagnosis of P.vivax by a 3rd Level 2 microscopist (only when 1st and 2nd reads are discrepant).
4. Malaria species specific PCR confirms the presence of P.vivax DNA in dried blood spot taken at the same time-point as the positive slide.

In addition, the primary endpoint includes the following circumstances:

1. Both asymptomatic and symptomatic infections.
2. Mixed infections: PCR-confirmed P.vivax infections where there is additional evidence of P.falciparum co-infection (on either PCR or microscopy).
Timepoint [1] 300727 0
21, 28, 42 56, 70, 84, 112, 140 and 168 days or on any intervening days if participant presents with febrile illness.
Secondary outcome [1] 330715 0
Parasitological/ treatment efficacy (1):
Positive species specific PCR (from a dried blood spot sample) for P.vivax (regardless of microscopy results) at any scheduled or unscheduled visit between days 14 and 168: The “PCR endpoint”.
Timepoint [1] 330715 0
21, 28, 42 56, 70, 84, 112, 140 and 168 days or on any intervening days if participant presents with febrile illness.
Secondary outcome [2] 330716 0
Parasitological/ treatment efficacy (2):
P.vivax recurrent parasitaemia during the follow-up period, genotypically corrected for reinfections (based on PCR from dried blood spot samples). Following genotyping of baseline-recurrent PCR positive paired samples, those with discrepant genotypes (suggesting re-infection) will be censored, leaving only those recurrences with identical genotypes as meeting this endpoint: The “Genotypically-corrected PCR endpoint”.
Timepoint [2] 330716 0
21, 28, 42 56, 70, 84, 112, 140 and 168 days or on any intervening days if participant presents with febrile illness.
Secondary outcome [3] 330717 0
Pharmacokinetic indices and surrogates of drug exposure (1)
Population pharmacokinetic model-derived per-treatment group estimate of primaquine AUC (0-24hours) following 7th primaquine dose (168 hours). Primaquine measured in serum samples and in red cell pellet.
Timepoint [3] 330717 0
Pre dose (-0.5), +0.5, +1.5, +2.0, +3.0, +4.0, +8.0, +18.0, +24.0 hours in relation to 7th daily dose of primaquine.
Secondary outcome [4] 330720 0
Pharmacokinetic indices and surrogates of active drug exposure (2):
Methaemoglobin levels (% hemoglobin saturation) measured non-invasively by Massimo Rad57 portable spectrophotometer (pulse oximetry machine) from a finger probe applied to the finger.
Timepoint [4] 330720 0
a) Day 3
b) Day 7
c) Day 14
d) As total AUC from day 0-28, calculated by linear trapezoidal interpolation of measurements at day 0, 1, 2, 3, 7, 10, 14, 21 and 28.
Secondary outcome [5] 330721 0
Safety and toxicity (1)
1. Subjective side effects reported and defined as:
a) Absent (=0)
b) Minor (=1: not bad enough to interfere with daily activity)
c) Moderate (=2: bad enough to interfere with daily activity)
d) Severe or life-threatening (=3: requiring hospitalization or associated with risk of death)

Possible adverse events include symptoms of abdominal pain or cramping, vomiting and pruritus (most likely due to primaquine). These will be assessed by research nurse using a structured side effect questionnaire and graded in severity from a) to d) as above according to assessment by research nurse.
Timepoint [5] 330721 0
Days 0 (pre-dose baseline) and days 1, 2, 3, 7, 14 and 28days from first dose.
Secondary outcome [6] 330722 0
Safety and toxicity (2)
Likely drug-induced haemolytic anaemia – defined as >25% reduction in Hb from baseline any time from day 1-28, together with evidence of haemoglobinuria (on urinary dipstick) or jaundice.
Timepoint [6] 330722 0
Urinary dipstick and hemoglobin measurement at day 0 (pre-dose baseline), 1, 2, 3, 7 and 14 from first dose.
Secondary outcome [7] 330723 0
Safety and toxicity (3)
Haemoglobin concentrations (g/dL):

Timepoint [7] 330723 0
a) Day 2 (usual post-treatment nadir)
b) Day 14 (final primaquine dose)
c) Day 28 (recovery)

Eligibility
Key inclusion criteria
1. Age over 12 months
2. Weight greater than or equal to 10kg
3. Melanesian background and living in local area
4. Microscopically (based on field microscopy) or RDT confirmed P.vivax regardless of parasite density. Mixed infections (P.falciparum-P.vivax) can be included.
Minimum age
12 Months
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Any signs of severe malaria (see WHO definitions) including: impaired consciousness, respiratory distress, severe anaemia (Hb<5), multiple seizures, frequent vomiting/ inability to swallow tablets, prostration, jaundice, hypotension, abnormal bleeding or hypoglycaemia.
2. Clinical evidence of non-malarial illness (such as pneumonia or otitis media)
3. Severe malnutrition (weight-for-age nutritional Z score [WAZ] <60th percentile)
4. Permanent disability, which prevents or impedes study participation.
5. Treatment with PQ in the previous 14 days
6. Residence or planned travel outside the study area during the follow-up period (precluding supervised treatment and follow-up procedures)
7. Known or suspected pregnancy
8. Currently breastfeeding
9. A positive rapid test for G6PD deficiency (Binax (Trademark) or Carestart (Trademark) RDT)

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
A single centre three-arm open-label randomised controlled trial with participants allocated to Arms 1, 2 and 3 in a ratio of 2:2:1.

The study would not be strictly blinded, in that investigators and participants will be aware of which treatment dose is being administered. However treatment allocation will not be known to microscopists evaluating follow-up slides or laboratory staff performing parasite PCR. Therefore the major study outcome measures should be free of potential for bias.
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Primary endpoint therapeutic efficacy analysis:

This will compare rates of P.vivax recurrence in each treatment arm based on time-to-event analysis over the 6-month follow-up period. The following approaches will be utilized:

* The primary comparison of therapeutic efficacy (ie between the AL+PQ arm and the DP+PQ arm) will be defined as the proportional difference in the P.vivax recurrence incidence rates based on Cox-regression (assuming proportional hazard).
* P.vivax recurrence incidence rates will be calculated as the number of participants in each treatment arm with recurrent P.vivax parasitaemia divided by the total duration for which they are at risk of recurrence – with this denominator equating to the total number of person-years of follow-up.
* For each individual, the total measured duration at which they are at risk will depend on duration for which they are actively followed-up in the study. This will vary between 1 and 154 days (from the final PQ dose) and will depend on the following:
a) Any individual meeting criteria for the “microscopy endpoint” will be considered to have met the study endpoint. So no further data will be collected in any individual following a documented P.vivax recurrence. Therefore participants will effectively be removed/ censored once they reach the study endpoint (recurrence or 6 months follow-up, whichever comes first).
b) Any individual who is re-treated with PQ for reasons other than a documented P.vivax recurrence (eg inadvertent re-treatment due to initial misdiagnosis of P.falciparum) will be censored from the time of PQ treatment onwards.
c) Participants who are diagnosed and treated for P. falciparum malaria during the follow-up period will be excluded from time at risk for 3 weeks following their AL re-treatment (based on estimated period of post-treatment schizonticidal prophylaxis).
d) The approach to missing data (due to missed scheduled visits or complete loss to follow-up) will be as follows:

Primary analysis will be “per-protocol”, meaning that participants lost to follow-up will effectively be censored from the time of their last follow-up.

When one or more scheduled follow-ups are missed and followed by a successful follow-up, the microscopy result during the missed visits will be assumed to be the same as on that of the next successful follow-up. For instance for a participant who is seen on Day 56 and has a negative blood slide, then misses the Day 70 visit and is seen on Day 84 with a negative blood slide, then the assumed blood slide result on Day 70 will be negative. If the Day 84 blood slide was positive, then the Day 70 result would also be assumed to be positive.

Further sub-analyses based on the primary endpoint will include the following:

1. Intention to treat analysis based on “worst case scenario”. This assumes that any participant lost to follow-up had a P.vivax recurrence at the time of their next scheduled follow-up.
2. Intention to treat analysis based on a “best case scenario”. This assumes that any participant lost to follow-up remained free of P.vivax recurrence for the entire 6-month follow-up. Together with (1), this provides a sensitivity analysis around the per-protocol estimate. (Karunajeewa HA, Mueller I, Senn M, Lin E, Law I, et al. (2008) A trial of combination antimalarial therapies in children from Papua New Guinea. N Engl J Med 359: 2545-2557.) P.vivax recurrence incidence rates documented in the delayed PQ control arm (Arm 3) will be used to re-calculate an estimate of radical curative efficacy in Arms 1 and 2 according to the formulas:

Radical curative efficacy Arm 1= 1 – P.vivax recurrence incidence rate Arm 1/
P.vivax recurrence incidence rate Arm 3

Radical curative efficacy Arm 2= 1 – P.vivax recurrence incidence rate Arm 2/
P.vivax recurrence incidence rate Arm 3

3. Recurrence incidence rates in each treatment group will be stratified by genotypically derived activity score (AS)
4. In order to explore a range of factors that may contribute to treatment failure, binary logistic regression will be conducted, using P.vivax recurrence (yes/no) as the dependent variable and the following independent variables:
a. Genotypically-derived CYP2D6 activity score (ordinal variable 0-4)
b. Age
c. Sex
d. Treatment arm (1, 2 or 3)
e. Baseline parasite density
f. Baseline temperature
g. Baseline Hb concentration (g/dL)
h. Met-Hb level at day 7

Analyses of secondary endpoints:

1. PCR endpoint (alternative parasitological/ treatment efficacy endpoint) – will use exactly the same methods as set out for the primary efficacy analysis, except that when a participant has a negative blood slide but a positive P.vivax PCR at a given time-point, this will be regarded as a recurrence, meaning that they will be considered to have reached the study endpoint and all data from subsequent follow-ups will be censored.
2. Genotypically-corrected PCR endpoint (alternative parasitological/ treatment efficacy endpoint) – will use exactly the same methods as set out for the primary efficacy analysis, except that when a participant has recurrent P.vivax parasitaemia with genotype that is discrepant with their baseline sample (consistent with a reinfection) then for the purposes of this analysis, this result will be re-classified as a negative blood slide.
3. Met-Hb levels and Hb concentrations at specified time-points will be compared between treatment arms using either independent T tests or (if non-normally distributed data) Mann-Whitney-U tests.
4. Incidence of adverse events (including haemolytic anaemia) would be compared between the treatment arms using Chi Squared testing.
5. Per-treatment group estimates of primary and secondary pharmacokinetic parameters would be determined by applying mixed non-linear effects modelling using NONMEM population pharmacokinetic modelling method.

All non-pharmacokinetic statistical analyses will be performed using STATA.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 8567 0
Solomon Islands
State/province [1] 8567 0
Guadalcanal

Funding & Sponsors
Funding source category [1] 295324 0
Charities/Societies/Foundations
Name [1] 295324 0
Bill and Melinda Gates Foundation
Address [1] 295324 0
500 Fifth Avenue North Seattle, WA 98109
Country [1] 295324 0
United States of America
Primary sponsor type
University
Name
The Walter and Eliza Hall Institute of Medical Research
Address
1G Royal Parade, Parkville, Vic 3052
Country
Australia
Secondary sponsor category [1] 294146 0
None
Name [1] 294146 0
N/A
Address [1] 294146 0
N/A
Country [1] 294146 0
Other collaborator category [1] 279390 0
University
Name [1] 279390 0
The University of Melbourne
Address [1] 279390 0
Parkville, Vic 3052
Country [1] 279390 0
Australia
Other collaborator category [2] 279391 0
University
Name [2] 279391 0
Eijkman Institute for Molecular Biology
Address [2] 279391 0
Jl. P. Diponegoro No.69, Kompleks Rumah Sakit Cipto Mangunkusumo, RW.5, Kenari, Senen, Kota Jakarta Pusat, Daerah Khusus Ibukota Jakarta 10430, Indonesia
Country [2] 279391 0
Indonesia
Other collaborator category [3] 279392 0
Government body
Name [3] 279392 0
Ministry of Health and Medical Services: National Vector Borne Disease Control (VBDC) Division
Address [3] 279392 0
PO Box 349
Honiara
Country [3] 279392 0
Solomon Islands

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296657 0
Solomon Islands Health Research Ethics Review Board
Ethics committee address [1] 296657 0
SIHRERB Secretary
National Health Research & Training Institute
Ministry of Health & Medical Service
P O Box 349
Honiara
Solomon Islands

Ethics committee country [1] 296657 0
Solomon Islands
Date submitted for ethics approval [1] 296657 0
09/09/2016
Approval date [1] 296657 0
15/11/2016
Ethics approval number [1] 296657 0
041/16
Ethics committee name [2] 296658 0
Walter and Eliza Hall Institute of Medical Research Human Research Ethics Committee
Ethics committee address [2] 296658 0
1G Royal Parade
Parkville
Vic 3052
Ethics committee country [2] 296658 0
Australia
Date submitted for ethics approval [2] 296658 0
07/11/2016
Approval date [2] 296658 0
06/12/2016
Ethics approval number [2] 296658 0
16/08

Summary
Brief summary
This project is a clinical trial designed to answer a specific question regarding the possibility that a drug-drug interaction (DDI) between two commonly used treatments for malaria may compromise effectiveness of curing the now dominant species causing malaria in the Solomon Islands, Plasmodium vivax. This hypothesis is supported by existing knowledge regarding the biology of how these drugs work and by observations that cure rates for vivax malaria are very low in other South Pacific countries (like Vanuatu) that are using the same drug combinations as in the Solomon Islands. The research is intended to help decide on the most effective malaria treatment to use in the Solomon Islands and this question has fundamental importance to strategies for eliminating malaria in the Solomon Islands and the other malaria-endemic countries of the Melanesian South Pacific.

The research will be a randomized controlled clinical trial (RCT) of patients with clinical P.vivax infection in the Solomon Islands. It will compare the radical curative efficacy of the drug primaquine (PQ) when co-administered with the current standard treatment of malaria in the Solomons, artemether-lumevantrine (AL) versus PQ co-administered with an alternative malaria treatment (dihydroartemisinin-piperaquine (DP).

The research will be conducted in the Tetere region by enrolling patients (both adults and children) through local health centres who are sick with vivax malaria (both male and female, aged 1 and over). Inclusion criteria will include a positive diagnosis of vivax malaria. Exclusion criteria will include infancy (aged <1), pregnancy, a positive G6PD test (performed on all prospective participants – a positive test indicates susceptibility to drug side-effects) and inability or refusal to provide informed written consent.
Trial website
None
Trial related presentations / publications
None
Public notes
Attachments [1] 1360 1360 0 0
Attachments [2] 1361 1361 0 0
Attachments [3] 1362 1362 0 0
Attachments [4] 1363 1363 0 0
Attachments [5] 1364 1364 0 0
/AnzctrAttachments/372150-Appendix 2. Participant Consent form v1.0.docx (Participant information/consent)

Contacts
Principal investigator
Name 71658 0
A/Prof Harin Karunajeewa
Address 71658 0
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade
Parkville
Vic 3052
Country 71658 0
Australia
Phone 71658 0
+61 3 9345 2870
Fax 71658 0
Email 71658 0
karunajeewa.h@wehi.edu.au
Contact person for public queries
Name 71659 0
A/Prof Harin Karunajeewa
Address 71659 0
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade
Parkville
Vic 3052
Country 71659 0
Australia
Phone 71659 0
+61 3 9345 2870
Fax 71659 0
Email 71659 0
karunajeewa.h@wehi.edu.au
Contact person for scientific queries
Name 71660 0
A/Prof Harin Karunajeewa
Address 71660 0
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade
Parkville
Vic 3052
Country 71660 0
Australia
Phone 71660 0
+61 3 9345 2870
Fax 71660 0
Email 71660 0
karunajeewa.h@wehi.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Full dataset will be available.
When will data be available (start and end dates)?
Anticipated from 01-01-2020 onwards (no end date).
Available to whom?
Worldwide Antimalarial Resistance Network (WWARN).
Available for what types of analyses?
Pooled analysis of efficacy of antimalarial drugs for P.vivax.
How or where can data be obtained?
Uploaded directly to WWARN following specific requests.
What supporting documents are/will be available?
Ethical approval
How or where can supporting documents be obtained?
Type [1] 1285 0
Ethical approval
Citation [1] 1285 0
Link [1] 1285 0
Email [1] 1285 0
Other [1] 1285 0
Type [2] 1286 0
Ethical approval
Citation [2] 1286 0
Link [2] 1286 0
Email [2] 1286 0
Other [2] 1286 0
Summary results
No Results