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    Clinical Trial Results:
    Controlled Human Malaria Infection study to assess gametocytaemia and mosquito transmissibility in participants challenged with Plasmodium falciparum by sporozoite challenge to establish a model for the evaluation of transmission-blocking interventions

    Summary
    EudraCT number
    		 2016-001379-66
    Trial protocol
    		 NL  
    Global end of trial date
    29 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Mar 2018
    First version publication date
    28 Mar 2018
    Other versions
    Summary report(s)
    		 2018 eLife - Reuling et al. A randomized feasibility trial comparing four antimalarial drug regimens to induce Pf gametocytemia in CHMI

    Trial information

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    Trial identification
    Sponsor protocol code
    CHMI-trans1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02836002
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Radboud university medical center
    Sponsor organisation address
    Geert-grootplein 26, Nijmegen, Netherlands, 6500HB
    Public contact
    Center for Clinical Malaria Studies, Radboud university medical center, isaie.reuling@radboudumc.nl
    Scientific contact
    Center for Clinical Malaria Studies, Radboud university medical center, isaie.reuling@radboudumc.nl
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Jun 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    - To evaluate the safety of four different CHMI-trans protocols in healthy malaria-naïve volunteers challenged with Plasmodium falciparum by sporozoite challenge. - To determine the best CHMI-trans protocol for induction of stable gametocytaemia at densities detectable by qRT-PCR
    Protection of trial subjects
    The study represents a challenge infection by bites of 5 (3D7 P. falciparum) infected mosquitoes. After the challenge there will be a period (42 days) of intense clinical monitoring with frequent site visits (up to two times a day) and blood examinations. Depending on the group, the subjects will receive a sub-curative treatment (DT1) with either sulfadoxine-pyrimethamine or piperaquine when 18S qPCR positive at 5000 par/ml (threshold of microscopic detection). Using blood samples taken twice daily, the initial clearance of parasitaemia will be carefully monitored. After DT1, volunteers will receive a curative treatment (DT2) when a recrudescence of asexual parasitaemia occurs or on day 21 post challenge infection, whichever comes first. Recrudescence of asexual parasitaemia will be carefully monitored until parasite densities reach 1,500 par/ml by 18S qPCR, at which time participants will receive a curative dose of sulfadoxine-pyrimethamine or piperaquine (DT2) depending on the study group to provide clearance of asexual parasites. All volunteers will receive a final treatment (ET) according to national guidelines with Malarone® on day 42 to assure the radical clearance of all parasite stages. In case a volunteer remains 18S qPCR and Pfs25 qRT-PCR negative for 7 days after DT1, final treatment with Malarone® will also be initiated and end of study will apply for the volunteer. The exact number of site visits and blood examinations per volunteers depends on the time to positive 18S qPCR above 5000 parasites/ml and potential recrudescence - with a maximum number of 50 study visits and a maximum of 500 mL collected blood. In addition periodical physical examinations will be performed and the subject is asked to complete a diary. The duration of subject participation will be 64 days from day of challenge, following a screening period of up to 120 days.
    Background therapy
    		 Volunteers may be advised to take tripelennamine crème for the local treatment of mosquito bites. Volunteers are advised to take paracetamol for complaints secondary to the CHMI (fever, muscle aches, headache, etc.). Tripelennamine crème, paracetamol or any other symptomatic treatment will be supplied to the volunteers. The maximum dose of paracetamol is 4 grams a day.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    19 Sep 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 32
    Worldwide total number of subjects
    32
    EEA total number of subjects
    32
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    32
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This single centre, open-label randomised trial was conducted at the Radboud university medical center (Radboudumc), Nijmegen, the Netherlands. Healthy malaria-naive male and female participants aged 18–35 years were recruited from June until November 2016.

    Pre-assignment
    Screening details
    		 Screening included physical examination, electrocardiography (ECG), hematology and biochemistry parameters and serology for human immunodeficiency virus (HIV), hepatitis B and C, and asexual stages of P. falciparum. Informed consent was provided by all participants at screening visit.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1
    Arm description
    		 Experimental: Group 1 - SP low/SP high Group 1 will be treated with a course of subcurative sulfadoxine-pyrimethamine (SP) (SP low, 500mg/25mg) as treatment 1. As treatment 2 (SP high) volunteers will receive a treatment with sulfadoxine-pyrimethamine (1000mg/50mg). Group 1 will receive a malaria challenge infection, P. falciparum 3D7 -infected mosquito bites Final treatment with a curative regimen of atovaquone/proguanil (malarone).
    Arm type
    		 Experimental

    Investigational medicinal product name
    sulphadoxine-pyrimethamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Drug: Sulfadoxine-pyrimethamine (low dose) - subcurative regimen (500mg/25mg) Other Name: Fansidar Drug: Sulfadoxine-pyrimethamine (high dose) - curative regimen (1000mg/50mg) Other Name: Fansidar Biological: malaria challenge infection, P. falciparum 3D7 malaria challenge infection by P. falciparum 3D7-infected mosquito bites Other Name: 3D7 Plasmodium falciparum Drug: Atovaquone-proguanil - curative regimen: 1000/400 mg, for 3 days Other Name: Malarone

    Arm title
    		 Group 2
    Arm description
    		 Experimental: Group 2 - SP low/Pip high Group 2 will be treated with a course of subcurative sulfadoxine-pyrimethamine (SP) (SP low, 500mg/25mg) as treatment 1. As treatment 2 (Pip high) volunteers will receive a treatment with piperaquine (960mg). Group 2 will receive a malaria challenge infection, P. falciparum 3D7 -infected mosquito bites Final treatment with a curative regimen of atovaquone/proguanil (malarone).
    Arm type
    		 Experimental

    Investigational medicinal product name
    sulphadoxine-pyrimethamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Drug: Sulfadoxine-pyrimethamine (low dose) - subcurative regimen (500mg/25mg)

    Investigational medicinal product name
    piperaquine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Drug: Piperaquine (high dose) - curative regimen (960 mg)

    Arm title
    		 Group 3
    Arm description
    		 Experimental: Group 3 - Pip low/Pip high Group 3 will receive piperaquine (Pip) in a low-dose (Pip low, 480 mg) as treatment 1. As treatment 2 (Pip high) volunteers will receive a treatment with piperaquine (960mg). Group 3 will receive a malaria challenge infection, P. falciparum 3D7 -infected mosquito bites Final treatment with a curative regimen of atovaquone/proguanil (malarone).
    Arm type
    		 Experimental

    Investigational medicinal product name
    piperaquine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Drug: Piperaquine (high dose) - curative regimen (960 mg)

    Investigational medicinal product name
    piperaquine
    Investigational medicinal product code
    Other name
    piperaquine phosphate
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Drug: Piperaquine (low dose) - subcurative regimen (480 mg) Other Name: piperaquine phosphate

    Arm title
    		 Group 4
    Arm description
    		 Experimental: Group 4 - Pip low/SP high Group 4 will receive piperaquine (Pip) in a low-dose (Pip low, 480 mg) as treatment 1. As treatment 2 (SP high) volunteers will receive a treatment with sulfadoxine-pyrimethamine (1000mg/50mg). Group 4 will receive a malaria challenge infection, P. falciparum 3D7 -infected mosquito bites Final treatment with a curative regimen of atovaquone/proguanil (malarone).
    Arm type
    		 Experimental

    Investigational medicinal product name
    piperaquine
    Investigational medicinal product code
    Other name
    piperaquine phosphate
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Drug: Piperaquine (low dose) - subcurative regimen (480 mg) Other Name: piperaquine phosphate

    Investigational medicinal product name
    sulphadoxine-pyrimethamine
    Investigational medicinal product code
    Other name
    Fansidar
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Drug: Sulfadoxine-pyrimethamine (high dose) - curative regimen (1000mg/50mg)

    Number of subjects in period 1
    		Group 1 Group 2 Group 3 Group 4
    Started
    8
    8
    8
    8
    Completed
    4
    4
    4
    4
    Not completed
    4
    4
    4
    4
         safety assessment
    4
    4
    4
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 32 32
    Age categorical
    Healthy malaria-naive male and female partici- pants aged 18–35 years
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 23 ± 2 -
    Gender categorical
    Healthy malaria-naive male and female participants aged 18–35 years
    Units: Subjects
        Female
    		 24 24
        Male
    		 8 8

    End points

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    End points reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Experimental: Group 1 - SP low/SP high Group 1 will be treated with a course of subcurative sulfadoxine-pyrimethamine (SP) (SP low, 500mg/25mg) as treatment 1. As treatment 2 (SP high) volunteers will receive a treatment with sulfadoxine-pyrimethamine (1000mg/50mg). Group 1 will receive a malaria challenge infection, P. falciparum 3D7 -infected mosquito bites Final treatment with a curative regimen of atovaquone/proguanil (malarone).

    Reporting group title
    Group 2
    Reporting group description
    		 Experimental: Group 2 - SP low/Pip high Group 2 will be treated with a course of subcurative sulfadoxine-pyrimethamine (SP) (SP low, 500mg/25mg) as treatment 1. As treatment 2 (Pip high) volunteers will receive a treatment with piperaquine (960mg). Group 2 will receive a malaria challenge infection, P. falciparum 3D7 -infected mosquito bites Final treatment with a curative regimen of atovaquone/proguanil (malarone).

    Reporting group title
    Group 3
    Reporting group description
    		 Experimental: Group 3 - Pip low/Pip high Group 3 will receive piperaquine (Pip) in a low-dose (Pip low, 480 mg) as treatment 1. As treatment 2 (Pip high) volunteers will receive a treatment with piperaquine (960mg). Group 3 will receive a malaria challenge infection, P. falciparum 3D7 -infected mosquito bites Final treatment with a curative regimen of atovaquone/proguanil (malarone).

    Reporting group title
    Group 4
    Reporting group description
    		 Experimental: Group 4 - Pip low/SP high Group 4 will receive piperaquine (Pip) in a low-dose (Pip low, 480 mg) as treatment 1. As treatment 2 (SP high) volunteers will receive a treatment with sulfadoxine-pyrimethamine (1000mg/50mg). Group 4 will receive a malaria challenge infection, P. falciparum 3D7 -infected mosquito bites Final treatment with a curative regimen of atovaquone/proguanil (malarone).

    Primary: Frequency and magnitude of adverse events

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    End point title
    		 Frequency and magnitude of adverse events
    End point description
    End point type
    Primary
    End point timeframe
    up to day 42 after challenge infection
    End point values
    		 Group 1 Group 2 Group 3 Group 4
    Number of subjects analysed
    4
    4
    4
    4
    Units: numbers
    4
    4
    4
    4
    Attachments
    		 manuscript
    Statistical analysis title
    		 anova between groups adverse events
    Statistical analysis description
    There were no serious adverse events or significant differences in the occurrence and severity of adverse events between study arms (p=0.49 and p=0.28).
    Comparison groups
    Group 1 v Group 2 v Group 3 v Group 4
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.05 [2]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [1] - There were no serious adverse events or significant differences in the occurrence and severity of adverse events between study arms (p=0.49 and p=0.28).
    [2] - There were no serious adverse events or significant differences in the occurrence and severity of adverse events between study arms (p=0.49 and p=0.28).

    Primary: gametocyte prevalence

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    End point title
    		 gametocyte prevalence [3]
    End point description
    End point type
    Primary
    End point timeframe
    up to day 42 after challenge infection
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: all subjects had gametocytes as measured by RT-qPCR. Therefore no differences were found in prevalence between groups.
    End point values
    		 Group 1 Group 2 Group 3 Group 4
    Number of subjects analysed
    4
    4
    4
    4
    Units: numbers
    4
    4
    4
    4
    Attachments
    		 manuscript
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    up to day 42 after challenge infection
    Adverse event reporting additional description
    daily questionnaire
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 none
    Dictionary version
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Non-serious adverse events are shown in table 3 and 4 of the manuscript attached. these results are not differentiated if drug- or malaria infection related. therefore it is not specified in the adverse events section as such.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    11 Nov 2016
    After observed transient liver enzyme elevations in the first cohort, the study was temporarily put on hold and the already initiated infections in the second cohort of 13 participants were abrogated by curative treatment on day 3 post challenge. The hold was lifted after reviewing safety data. Participants from the first cohort completed all study visits, and form the basis of the study results
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29482720
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