Vivax MalariaPhase 4CRePViCamNCT02118090
Assessment of Plasmodium Vivax Chloroquine Resistance in Cambodia:
A Phase 4 study testing Chloroquine sulfate and DHA-PP in people with Vivax Malaria, run by Institut Pasteur, Cambodia at 1 site in Cambodia.
Trial summary
The investigators propose to leverage the unique infrastructures and expertise of National Centre for Parasitology Entomology and Malaria Control and the Pasteur Institute in Cambodia and combine modern fieldwork, including a mobile laboratory fully equipped for molecular biology and culture experiments, with… Read more about this study
- Who is it for?
- Ages 15 years and older
- Conditions the study is for
- Vivax Malaria
- What is being tested?
- Chloroquine sulfate and DHA-PP
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 73 participants
- Where
- 1 siteCambodia
- Study dates
- May 2014to Mar 2015
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 15 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Being aged 15 years or more with competency to give informed consent, (ii) Being positive for P. vivax and mono-infected
Who cannot join
- Being aged 14 years or less (ii) Individuals with illness that affected competency to give informed consent, (iii) Pregnant or lactating women (iv) Having taken antimalarial drugs in the past month
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Assessing Chloroquine Resistance of Plasmodium Vivax in Malaria Endemic Area
The investigators propose to leverage the unique infrastructures and expertise of National Centre for Parasitology Entomology and Malaria Control and the Pasteur Institute in Cambodia and combine modern fieldwork, including a mobile laboratory fully equipped for molecular biology and culture experiments, with state-of-the-art genomic analyses to investigate how Plasmodium vivax parasites respond to antimalarial drugs. The investigators will focus on resistance to CQ, the choice treatment for vivax malaria in most endemic countries, for which treatment failures have been reported in Cambodia. The study will address some of the key biological mechanisms limiting the efficiency of drug therapy in P. vivax, including the identification of genetic polymorphisms underlying drug resistance in Cambodian P. vivax. The findings will provide a first unbiased perspective on the mechanisms of drug resistance in P. vivax and have the strong potential to significantly improve malaria control in Southeast Asia.
Read the detailed description
In order to assess the resistance phenotype of P. vivax to CQ, the methodology will involve the following steps:
- Inclusion of P.vivax mono-infected patients from villages in treatment failure-reported area (Ban Lung district, Rattanakiri)
- Pv diagnostic confirmation (microscopy and qPCR)
- Transfer of patients to Ban Lung hospital for a 7-days clinical follow-up
- Blood collection followed by CQ administration
- Parasite clearance and whole blood CQ concentration follow-up during 7 days.
- Parasitemia follow-up during 2 months with patients staying in Ban Lung during the entire study to make sure no re-infection occurs (Ban Lung is a no-transmission area).
- Ex vivo drug susceptibility assay of P. vivax isolates and after any recrudescence/relapse, if any.
- Genotyping analysis of parasites at Day 0 and after any recrudescence/relapse, if any.
Research design
The study will be carried out in Ban Lung district (Rattanakir province, Cambodia) between April 2014 and December 2014. This research site (Rattanakiri) is chosen on the basis of relatively high reports of treatment failures to CQ. In Ban Lung district villages, all P. vivax mono-infected adult patients seeking treatment at community level (VMW and Health centers) will be offered to participate to the study
The sample size calculation was based on addressing the primary objective of identifying a true resistance phenotype to CQ. Therefore a minimum of 50 patients is required and ideally, around 100 patients will increase the probability of detecting resistant parasites.
All eligible participants will be approached by the study staff and information about the objectives of the study will be explained. Informed consent will be obtained from each participant before inclusion.
All P. vivax mono-infected patients identified in the study sites will be included.
Staff involved in this research study will be composed from scientists and technicians from CNM and IPC. Additional collaborators (Reference hospital, Health centers and VMW staff ion Rattanakiri province) will be involved in the project.
Villages in Ban Lung district where P. vivax transmission occur will be selected. Patients seeking treatment from those villages (VMW and Health canters) will be tested for malaria infection by RDT and any non-P. falciparum infected patient will be offered to participate to the study. Falciparum malaria cases will be managed by VMW and Health centers as usually according to Cambodian National guidelines
After obtaining informed consent, the patients will be enrolled in the study and two groups will be constituted:
- a control group of patients staying in their village and
- a group transferred to Banlung hospital.
Then, 3 x 5ml-ACD tubes of venous blood will be collected prior to be given CQ to patients.
For the control group, parasitemia will be followed at Day3, D7, D14, D28 and D42 D49, D56 and D60 according to WHO protocol, using fingerprick-collected blood.
For the study group, patients will be followed by fingerprick for parasites clearance and CQ concentration measures every 8h for at least 3 days until complete parasite clearance (determined by two consecutive negative results in microscopy and qPCR). Parasitemia and CQ concentration will be determined daily using fingerprick for 7 days.
To make sure the patients will not be re-infected, they will stay in Ban Lung accommodation for 2 months with every 48h fingerpricks to detect any increase in parasitemia during the study, while the control group will stay in their village where re-infection can occur.
If recrudescence is observed, patients will then be re-admitted in Ban Lung hospital and the same protocol will be performed again.
Ex vivo drug sensitivity assay of the P. vivax isolates will be performed either directly from the blood samples or after cryopreservation. In both case, the assay will involve the invasion of freshly added reticulocytes to the P. vivax isolates.
The reticulocytes used for this work will be obtained from cord blood acquired through the gynecology/obstetric department of Calmette hospital (Pr Kruy Leang Sim), according to the agreement between IPC and Calmette hospital. Cord blood will be supplied regularly to IPC, three times a week, 5 to 7 ml per ACD-tube, 5 tubes per day, if the number of birth allows such sampling. ABO blood group, hemoglobin electrophoresis, G6PD enzyme activity and Duffy status of the blood will be determined before using reticulocytes for P. vivax invasion and culture.
Data will be entered and processed using Microsoft Excel. Parasitemia will be directly correlated to CQ concentration in blood and will allow categorizing the parasites according to the slope of their clearance time and their sensitivity to CQ.
Statistical analysis will be performed when required to detect any significant effects.
- Conditions
- Vivax Malaria
- Being tested
- Chloroquine sulfate, DHA-PP
- Keywords
- malaria, Plasmodium vivax, drug resistance, chloroquine, Cambodia
- Medical subject headings
- Malaria, Vivax, Malaria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Chloroquine sulfateDrug
Also called NIVAQUINE
Chloroquine sulfate (NIVAQUINE) - 30 mg/kg for 3 days
DHA-PPDrug
Also called Duo-Cotecxin
DHA-PIP (Duo-Cotecxin®, DHA 40 mg and PP 320 mg, Zhejiang Holley Nanhu Pharamaceutical Co. Ltd, Jiaxing, Zhejiang province, China): one tablet of DHA-PIP contains 40 mg of dihydroartemisinin (DHA) and 320 mg piperaquine (PIP). It is an oral administration, one dose a day for 3 consecutive days. An adult dose (≥40 kg to 60kg body weight or more than 15 years old) consisted of three doses of 3 tablets over consecutive days (Total dose 9 tablets). The approximate total adult dose was 2-4 mg/kg for DHA and 20mg/kg for PP.
| Study group | Role | What they receive |
|---|---|---|
| Chloroquine | Experimental | Patients treat with chloroquine sulfate (NIVAQUINE) 10 mg/kg/day - 3 days Receives: Drug: Chloroquine sulfate |
| DHA-PP | Active comparator | Patient treat with DHA 40 mg and PP 320 mg, (Duo-Cotecxin®) The approximate total adult dose is 2-4 mg/kg for DHA and 20mg/kg for PP Receives: Drug: DHA-PP |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of patients with P. vivax CQ resistant parasite
Based on parasite clearance time (slow versus fast clearers) and treatments failure (according to the CQ blood concentration)
Measured: 6 months
Secondary outcomes (1)
Number of isolates characterized by whole genome sequencing and multiple Single Nucleotide Polymorphisms Bar Code
- vivax Isolates will be characterize by SNPs barcode and whole genome sequencing. The final objective is to defined correlations between SNPs detected by whole genome sequencing or bar coding and in vivo and in vitro phenotype
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Apr 2014 (estimated)
- Study startMay 2014
- Primary completionDec 2014
- Study completionMar 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Vivax MalariaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 73 participants (actual)
Sponsor and investigators
- Lead sponsor
- Institut Pasteur, Cambodia
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Didier Menard, Institut Pasteur, Cambodia
- Investigators
- Dysoley Lek, MD, Principal investigator, National Centre for Parasitology Entomology and Malaria ControlDidier Ménard, PharmD, PhD, Principal investigator, Institut Pasteur in CambodiaJean Popovici, PhD, Principal investigator, Institut Pasteur in Cambodia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02118090
- Sponsor's protocol ID
- IPC_Pv_CQR_RTK
- Other IDs
- R01AI103228
- Acronym
- CRePViCam
- Status last verified
- Mar 2015
- First submitted
- 14 Apr 2014
- Last updated
- 24 Mar 2015
- Results posted
- No
- Data monitoring committee
- No
Publications
Popovici J, Friedrich LR, Kim S, Bin S, Run V, Lek D, Cannon MV, Menard D, Serre D. Genomic Analyses Reveal the Common Occurrence and Complexity of Plasmodium vivax Relapses in Cambodia. mBio. 2018 Jan 23;9(1):e01888-17. doi: 10.1128/mBio.01888-17.
PubMed 29362233
Study at a glance
From the registry record, last updated by the sponsor on 24 Mar 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Assessing Chloroquine Resistance of Plasmodium Vivax in Malaria Endemic Area
- ClinicalTrials.gov ID
- NCT02118090
- Acronym / sponsor ID
- CRePViCam / IPC_Pv_CQR_RTK
- Conditions
- Vivax Malaria
- Keywords
- malaria, Plasmodium vivax, drug resistance, chloroquine, Cambodia
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 73 participants (actual)
- Lead sponsor
- Institut Pasteur, CambodiaUniversity, hospital or other
- Collaborators
- National Institute of Allergy and Infectious Diseases (NIAID)
- Study start
- May 2014
- Primary completion
- Dec 2014 (actual)
- Study completion
- Mar 2015 (actual)
- First posted
- 21 Apr 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The investigators propose to leverage the unique infrastructures and expertise of National Centre for Parasitology Entomology and Malaria Control and the Pasteur Institute in Cambodia and combine modern fieldwork, including a mobile laboratory fully equipped for molecular biology and culture experiments, with state-of-the-art genomic analyses to investigate how Plasmodium vivax parasites respond to antimalarial drugs. The investigators will focus on resistance to CQ, the choice treatment for vivax malaria in most endemic countries, for which treatment failures have been reported in Cambodia. The study will address some of the key biological mechanisms limiting the efficiency of drug therapy in P. vivax, including the identification of genetic polymorphisms underlying drug resistance in Cambodian P. vivax. The findings will provide a first unbiased perspective on the mechanisms of drug resistance in P. vivax and have the strong potential to significantly improve malaria control in Southeast Asia.
Detailed description
In order to assess the resistance phenotype of P. vivax to CQ, the methodology will involve the following steps:
- Inclusion of P.vivax mono-infected patients from villages in treatment failure-reported area (Ban Lung district, Rattanakiri)
- Pv diagnostic confirmation (microscopy and qPCR)
- Transfer of patients to Ban Lung hospital for a 7-days clinical follow-up
- Blood collection followed by CQ administration
- Parasite clearance and whole blood CQ concentration follow-up during 7 days.
- Parasitemia follow-up during 2 months with patients staying in Ban Lung during the entire study to make sure no re-infection occurs (Ban Lung is a no-transmission area).
- Ex vivo drug susceptibility assay of P. vivax isolates and after any recrudescence/relapse, if any.
- Genotyping analysis of parasites at Day 0 and after any recrudescence/relapse, if any.
Research design
The study will be carried out in Ban Lung district (Rattanakir province, Cambodia) between April 2014 and December 2014. This research site (Rattanakiri) is chosen on the basis of relatively high reports of treatment failures to CQ. In Ban Lung district villages, all P. vivax mono-infected adult patients seeking treatment at community level (VMW and Health centers) will be offered to participate to the study
The sample size calculation was based on addressing the primary objective of identifying a true resistance phenotype to CQ. Therefore a minimum of 50 patients is required and ideally, around 100 patients will increase the probability of detecting resistant parasites.
All eligible participants will be approached by the study staff and information about the objectives of the study will be explained. Informed consent will be obtained from each participant before inclusion.
All P. vivax mono-infected patients identified in the study sites will be included.
Staff involved in this research study will be composed from scientists and technicians from CNM and IPC. Additional collaborators (Reference hospital, Health centers and VMW staff ion Rattanakiri province) will be involved in the project.
Villages in Ban Lung district where P. vivax transmission occur will be selected. Patients seeking treatment from those villages (VMW and Health canters) will be tested for malaria infection by RDT and any non-P. falciparum infected patient will be offered to participate to the study. Falciparum malaria cases will be managed by VMW and Health centers as usually according to Cambodian National guidelines
After obtaining informed consent, the patients will be enrolled in the study and two groups will be constituted:
- a control group of patients staying in their village and
- a group transferred to Banlung hospital.
Then, 3 x 5ml-ACD tubes of venous blood will be collected prior to be given CQ to patients.
For the control group, parasitemia will be followed at Day3, D7, D14, D28 and D42 D49, D56 and D60 according to WHO protocol, using fingerprick-collected blood.
For the study group, patients will be followed by fingerprick for parasites clearance and CQ concentration measures every 8h for at least 3 days until complete parasite clearance (determined by two consecutive negative results in microscopy and qPCR). Parasitemia and CQ concentration will be determined daily using fingerprick for 7 days.
To make sure the patients will not be re-infected, they will stay in Ban Lung accommodation for 2 months with every 48h fingerpricks to detect any increase in parasitemia during the study, while the control group will stay in their village where re-infection can occur.
If recrudescence is observed, patients will then be re-admitted in Ban Lung hospital and the same protocol will be performed again.
Ex vivo drug sensitivity assay of the P. vivax isolates will be performed either directly from the blood samples or after cryopreservation. In both case, the assay will involve the invasion of freshly added reticulocytes to the P. vivax isolates.
The reticulocytes used for this work will be obtained from cord blood acquired through the gynecology/obstetric department of Calmette hospital (Pr Kruy Leang Sim), according to the agreement between IPC and Calmette hospital. Cord blood will be supplied regularly to IPC, three times a week, 5 to 7 ml per ACD-tube, 5 tubes per day, if the number of birth allows such sampling. ABO blood group, hemoglobin electrophoresis, G6PD enzyme activity and Duffy status of the blood will be determined before using reticulocytes for P. vivax invasion and culture.
Data will be entered and processed using Microsoft Excel. Parasitemia will be directly correlated to CQ concentration in blood and will allow categorizing the parasites according to the slope of their clearance time and their sensitivity to CQ.
Statistical analysis will be performed when required to detect any significant effects.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Chloroquine | Experimental | Drug: Chloroquine sulfatePatients treat with chloroquine sulfate (NIVAQUINE) 10 mg/kg/day - 3 days |
| DHA-PP | Active comparator | Drug: DHA-PPPatient treat with DHA 40 mg and PP 320 mg, (Duo-Cotecxin®) The approximate total adult dose is 2-4 mg/kg for DHA and 20mg/kg for PP |
Who may qualify
- Ages
- 15 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (1 listed)
- Being aged 15 years or more with competency to give informed consent, (ii) Being positive for P. vivax and mono-infected
Key exclusion criteria (1 listed)
- Being aged 14 years or less (ii) Individuals with illness that affected competency to give informed consent, (iii) Pregnant or lactating women (iv) Having taken antimalarial drugs in the past month
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Chloroquine sulfateAlso: NIVAQUINEChloroquine sulfate (NIVAQUINE) - 30 mg/kg for 3 days | Drug | Chloroquine |
| DHA-PPAlso: Duo-CotecxinDHA-PIP (Duo-Cotecxin®, DHA 40 mg and PP 320 mg, Zhejiang Holley Nanhu Pharamaceutical Co. Ltd, Jiaxing, Zhejiang province, China): one tablet of DHA-PIP contains 40 mg of dihydroartemisinin (DHA) and 320 mg piperaquine (PIP). It is an oral administration, one dose a day for 3 consecutive days. An adult dose (≥40 kg to 60kg body weight or more than 15 years old) consisted of three doses of 3 tablets over consecutive days (Total dose 9 tablets). The approximate total adult dose was 2-4 mg/kg for DHA and 20mg/kg for PP. | Drug | DHA-PP |
Primary outcome
Number of patients with P. vivax CQ resistant parasite
Time frame: 6 months
Based on parasite clearance time (slow versus fast clearers) and treatments failure (according to the CQ blood concentration)
1 secondary outcome
Number of isolates characterized by whole genome sequencing and multiple Single Nucleotide Polymorphisms Bar Code
Time frame: 1 year
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Mar 2015.
- Derived from this study: PubMed 29362233Popovici J, Friedrich LR, Kim S, Bin S, Run V, Lek D, Cannon MV, Menard D, Serre D. Genomic Analyses Reveal the Common Occurrence and Complexity of Plasmodium vivax Relapses in Cambodia. mBio. 2018 Jan 23;9(1):e01888-17. doi: 10.1128/mBio.01888-17.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Dysoley Lek, MD principal investigator
National Centre for Parasitology Entomology and Malaria Control
Didier Ménard, PharmD, PhD principal investigator
Institut Pasteur in Cambodia
Jean Popovici, PhD principal investigator
Institut Pasteur in Cambodia
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Chloroquine sulfate and DHA-PP in people with Vivax Malaria, run by Institut Pasteur, Cambodia at 1 site in Cambodia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 Mar 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Cambodia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of patients with P. vivax CQ resistant parasite (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02118090, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Mar 2015.