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Trial registered on ANZCTR


Registration number
ACTRN12617001158358
Ethics application status
Approved
Date submitted
1/08/2017
Date registered
8/08/2017
Date last updated
8/08/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
Breath based diagnosis of malaria infection
Scientific title
Validation of breath biomarkers for diagnosis of malaria on Lihir Island, Papua New Guinea.
Secondary ID [1] 292563 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 304232 0
Condition category
Condition code
Infection 303580 303580 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Analysis of biomarkers indicating malaria infection (clincial infection) from patient breath samples. Patients sampled twice to check the change in biomarker levels from febrile controls (no malaria infection) or healthy non-infected controls.

Sampling process
After signing the informed consent, a small questionnaire with medical and demographic data will be collected for each participant. Blood samples for qPCR analysis and blood slide and breath sample will be collected.
We will use finger prick to collect the amount of blood needed for the study. It will be three drops of blood, two for the thick and thin film examination and one drop for the qPCR test (approximately 750 µl).
Breath sample will be collected as follows:
Participants will be asked to exhale into the one use mouthpiece of the breath sampler for as long as they can or until the operator deems the sample to be sufficient. The process is repeated until 1L of breath is collected. Breath sampler will be connected to Tenax® sorbent tubes stored at 4°C. Tenax® sorbent tubes will capture only volatile organic compounds (VOC) from the breath samples, the rest of the breath sample is returned to the atmosphere. Tenax® sorbent tubes will be shipped at 4°C to CSIRO (Canberra, Australia) at weekly intervals for analysis. All participants will be asked for VOC a second breath separated by 6-12 hours.

Dr Amalia Berna will supervise the analysis process of the breath samples in the CSIRO laboratory in Canberra and she will be in charge of the site investigators training in the sample collection, store and shipment of breath samples. Dr Livingstone Tavul will supervise the analysis process of the qPCR in the IMR Vector Borne Disease Unit in Madang. Dr Moses Laman and Dr Quique Bassat will supervise the clinical aspects of the project as well as the site investigators and young researchers work. Dr Oriol Mitja` will ensure that the recruitment tasks are properly done in Lihir Medical Centre and he will be involved in the supervision of the team on site.
Intervention code [1] 298769 0
Diagnosis / Prognosis
Intervention code [2] 298770 0
Early detection / Screening
Comparator / control treatment
Will compare the specificity and sensitivity of the breath biomarkers with the standard diagnostic for malaria diagnosis (microscope - thick and thin films).
Will compare the specificity and sensitivity of the breath biomarkers with the gold standard diagnostic for malaria diagnosis qPCR.
Control group
Active

Outcomes
Primary outcome [1] 302937 0
To compare the specificity and sensitivity of the breath biomarker 1-methylthiopropane, with the gold standard for malaria diagnosis (microscope). The performance of breath biomarkers will be determined by calculating its sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) against the reference test. Sensitivity and Specificity of 95% and a precision of 5% are the required for success. This will lead us to accept the results when the results for the sensitivity and specificity of the new test will be between 90 and 100%.
Timepoint [1] 302937 0
Immediate - quantitation of biomarkers in breath for diagnostic
Primary outcome [2] 302938 0
To compare the specificity and sensitivity of the breath biomarkers (E)-1-methylthio-1-propene with the gold standard for malaria diagnosis (microscope). The performance of breath biomarkers will be determined by calculating its sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) against the reference test.Sensitivity and Specificity of 95% and a precision of 5% are the required for success. This will lead us to accept the results when the results for the sensitivity and specificity of the new test will be between 90 and 100%.
Timepoint [2] 302938 0
Immediate - quantitation of biomarkers in breath for diagnostic
Primary outcome [3] 302971 0
To compare the specificity and sensitivity of the breath biomarkers allyl methul sulphide with the gold standard for malaria diagnosis (microscope). The performance of breath biomarkers will be determined by calculating its sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) against the reference test. Sensitivity and Specificity of 95% and a precision of 5% are the required for success. This will lead us to accept the results when the results for the sensitivity and specificity of the new test will be between 90 and 100%.
Timepoint [3] 302971 0
Immediate - quantitation of biomarkers in breath for diagnostic
Secondary outcome [1] 337593 0
To compare the specificity and sensitivity of the relative levels of all biomarkers (composite) with the gold standard for malaria diagnosis (microscope). The performance of breath biomarkers will be determined by calculating its sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) against the reference test. Sensitivity and Specificity of 95% and a precision of 5% are the required for success. This will lead us to accept the results when the results for the sensitivity and specificity of the new test will be between 90 and 100%.
Timepoint [1] 337593 0
Immediate - quantitation of biomarkers in breath for diagnostic
Secondary outcome [2] 337648 0
To compare the specificity and sensitivity of the breath biomarker (Z)-1- methylthio-1-propene , with the gold standard for malaria diagnosis (microscope). The performance of breath biomarkers will be determined by calculating its sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) against the reference test.Sensitivity and Specificity of 95% and a precision of 5% are the required for success. This will lead us to accept the results when the results for the sensitivity and specificity of the new test will be between 90 and 100%.
Timepoint [2] 337648 0
Immediate - quantitation of biomarkers in breath for diagnostic

Eligibility
Key inclusion criteria
cross sectional study to compare the breath biomarkers with microscopy:
Male or female greater than 5 years.
Febrile sickness for at least 24hours.
Attending Lihir Medical Centre (Outpatient department or Emergency Room)
Volunteers must understand the procedures involved and agree to participate
in the study by giving fully informed, written consent
Minimum age
5 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Not willing to participate in the study.
Not able to exhale through the breath sampler.
Complicated malaria cases.
Consciousness impairment.
Unable to be located during the following week in case of need.
Participants with Sulphur-containing drug intake for the last 30 days will be
excluded due to the possible presence of drug-related volatile compounds in the exhaled breath.

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
Data will be recorded in a questionnaire and entered in a Microsoft Excel database in a secure computer of the site investigator. The performance of breath biomarkers will be determined by calculating its sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) against the reference test in each of both cross sectional studies. Inter-test agreement for both results of positive and negative readings will be expressed by the percentage of overall agreement and Cohen’s Kappa coefficient (Kc) for the agreement between breath biomarkers and the reference method. The following scale will be used to determine the strength of agreement between the two tests: slight: Kc = 0.01–0.20; fair: Kc = 0.21–0.40; moderate: Kc = 0.41–0.60; substantial: Kc = 0.61–0.8; or almost perfect: Kc = 0.81–1 (13). Significance will be considered at p < 0.05. Subgroup analysis will be performed to know Sensitivity and Specificity with the different Plasmodium spp (P.falciparum, P.vivax and mixed infections). Calculations will be conducted using the Statistical Package for the Social Sciences (SPSS) v 22.0.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
28/07/2017
Date of last participant enrolment
Anticipated
31/08/2019
Actual
Date of last data collection
Anticipated
31/08/2019
Actual
Sample size
Target
740
Accrual to date
7
Final
Recruitment outside Australia
Country [1] 9117 0
Papua New Guinea
State/province [1] 9117 0
Lihir

Funding & Sponsors
Funding source category [1] 297143 0
Government body
Name [1] 297143 0
CSIRO
Country [1] 297143 0
Australia
Primary sponsor type
Government body
Name
CSIRO
Address
CSIRO Building 101 Clunies Ross St, Black Mountain, ACT, 2601
Country
Australia
Secondary sponsor category [1] 296155 0
University
Name [1] 296155 0
Universitat de Barcelona
Address [1] 296155 0
Institute for Global Health
Rosselló, 132, 7th floor
08036 Barcelona
Spain
Country [1] 296155 0
Spain
Secondary sponsor category [2] 296160 0
University
Name [2] 296160 0
Papua New Guinea Institute of Medical Research
Address [2] 296160 0
Papua New Guinea Institute of Medical Research (IMR) PO Box 60 Homate Street, Goroka, 441 Papua New Guinea.
Country [2] 296160 0
Papua New Guinea

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298312 0
Medical Research Advisory Committee (MRAC) of Papua New Guinea
Ethics committee address [1] 298312 0
PO Box 807 WAIGANI 131, NCD Papua New Guinea
Ethics committee country [1] 298312 0
Papua New Guinea
Date submitted for ethics approval [1] 298312 0
02/12/2016
Approval date [1] 298312 0
22/06/2017
Ethics approval number [1] 298312 0
MRAC No. 17.12.

Summary
Brief summary
Malaria is a major cause of mortality and morbidity worldwide and Papua New Guinea (PNG) is one of the countries of the Pacific region with a higher burden of the disease. Like other countries in the tropical area, in PNG the current malaria diagnosis relies on the use of rapid diagnostic tests or in the use of clinical skills and the direct observation of Plasmodium parasite by microscope; while diagnosis of parasite carriers by qPCR is only used for research proposals due to its complexity and cost. The Commonwealth Scientific and Industrial Research Organisation (CSIRO) has identified breath biomarkers in patients with malaria that can be used as an indirect marker for malaria infection prediction using an innovative and harmless tool. We propose a study to validate this technique as a potential diagnostic tool on the field in Lihir islands. While evaluating diagnostic tools for malaria, it is important to investigate the diagnostic capacity of the new tool not only among clinical cases, which tend to have a high parasite burden, but also among infected albeit asymptomatic carriers, which contribute importantly to maintaining transmission, albeit often carrying much smaller parasite numbers in their blood. Thus, we aim to perform two cross sectional studies, with the idea of testing breath biomarkers as a malaria diagnostic tool, by 1) recruiting febrile cases actively seeking care at the health unit (THIS STUDY), and 2) recruiting healthy individuals at the community level, some of which will be carrying malaria infections. The diagnostic capacity of the breath biomarkers will be compared against the usual diagnostic methodologies in the field (optic microscopy and/or RDT) and the gold standard molecular methods (PCR).
The validation of breath biomarkers for diagnosis of malaria may open a spectrum of possibilities related with fast and harmless diagnostic tools for the routine work in a rural setting like PNG where multiple Plasmodium species coexist with a variety of diagnostic challenges, and may provide an additional and non-invasive diagnostic tool in the efforts towards malaria elimination.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 76674 0
Dr Amalia Berna
Address 76674 0
CSIRO Health and Biosecurity Clunies Ross St, Black Mountain, 2601 ACT
Country 76674 0
Australia
Phone 76674 0
+61 2 6246 4181
Fax 76674 0
Email 76674 0
[email protected]
Contact person for public queries
Name 76675 0
Dr ALisha Anderson
Address 76675 0
CSIRO Health and Biosecurity Clunies Ross St, Black Mountain, 2601 ACT
Country 76675 0
Australia
Phone 76675 0
+61 2 6246 4181
Fax 76675 0
Email 76675 0
[email protected]
Contact person for scientific queries
Name 76676 0
Dr Alisha Anderson
Address 76676 0
CSIRO Health and Biosecurity Clunies Ross St, Black Mountain, 2601 ACT
Country 76676 0
Australia
Phone 76676 0
+61 2 6246 4181
Fax 76676 0
Email 76676 0
[email protected]

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