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    Clinical Trial Results:
    Controlled Human Malaria Infection (CHMI) After Immunization With Cryopreserved Plasmodium Falciparum Sporozoites Under Chloroquine Prophylaxis

    Summary
    EudraCT number
    		 2012-000322-21
    Trial protocol
    		 NL  
    Global end of trial date
    25 Feb 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Aug 2016
    First version publication date
    16 May 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TIP5
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01728701
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sanaria Inc.
    Sponsor organisation address
    9800 Medical Center Drive, Suite A209, Rockville, MD, United States, 20850
    Public contact
    Alexander Hoffman, Sanaria Helpdesk, +1 301-339-0092, ahoffman@sanaria.com
    Scientific contact
    Alexander Hoffman, Sanaria Helpdesk, +1 301-339-0092, ahoffman@sanaria.com
    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
    02 Jul 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Nov 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to determine the safety and tolerability of ID administration of PfSPZ Challenge to volunteers taking chloroquine chemoprophylaxis (an approach called PfSPZ-CVac)
    Protection of trial subjects
    This clinical study was designed and implemented and reported in accordance with the International Conference on Harmonisation (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of Helsinki. Treatment: Malarone® 4 tablets (250 mg atovaquone / 100 mg proguanil per tablet) once daily for three days.
    Background therapy
    		 All groups received weekly chloroquine phosphate chemoprophylaxis for a period of 14 weeks (300 mg chloroquine base per dose). Groups 3 and 4 received additional weekly chloroquine phosphate chemoprophylaxis from Day 225 to 259.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Sep 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 4 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    30
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study subjects were enrolled from September 2012 to February 2014 in 1 clinic center in Netherlands.

    Pre-assignment
    Screening details
    		 From the total volunteers screened, 30 subjects who met all inclusion criteria and none of the exclusion criteria were enrolled.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor
    Blinding implementation details
    Volunteers, investigators and laboratory personnel were blinded regarding receipt of vaccine or placebo.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1: PfSPZ Challenge
    Arm description
    		 Group 1 (n=10) received weekly chloroquine (CQ) chemoprophylaxis for 14 weeks (98 days), and 6 ID injections of PfSPZ Challenge [75,000 PfSPZ (per dose) of the Pf NF54 strain] on days 8, 36 and 64. Volunteers had CHMI by the bites of five mosquitoes infected with PfSPZ of the Pf NF54 strain 33 days after the last dose of chloroquine which is day 124. Of the 10 volunteers enrolled, all 10 were challenged of which 2 volunteers were protected.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Plasmodium falciparum (Pf) Sporozoite (SPZ) Challenge
    Investigational medicinal product code
    PfSPZ Challenge
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    PfSPZ Challenge containing a total of 75,000 PfSPZ of the Pf NF54 strain in 6 injections

    Arm title
    		 Group 2: Normal Saline (NS)
    Arm description
    		 Group 2 (n=5) received weekly chloroquine (CQ) chemoprophylaxis for 14 weeks (98 days), and 6 ID injections of normal saline on days 8, 36 and 64. Volunteers had CHMI by the bites of five mosquitoes infected with PfSPZ of the Pf NF54 strain 33 days after the last dose of chloroquine which is day 124. Of the 5 control volunteers enrolled, all 5 were challenged of which none of the volunteers were protected.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Normal Saline
    Investigational medicinal product code
    NS
    Other name
    Placebo
    Pharmaceutical forms
    Injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    Six NS injections

    Arm title
    		 Group 3: PfSPZ Challenge
    Arm description
    		 Group 3 (n=10) received weekly chloroquine chemoprophylaxis for 14 weeks (98 days), and 6 ID injections of PfSPZ Challenge [75,000 PfSPZ (per dose) of the Pf NF54 strain] on days 8, 36 and 64. Eight of 10 volunteers restarted 6 weeks of CQ (days 225-259), and received 4th immunization on day 232. Four of these 8 volunteers received homologous CHMI (by bites of 5 NF54-infected mosquitoes) on day 369, and none were protected. Per protocol, if ≥75% of volunteers in group 1 were protected against homologous CHMI, groups 3 and 4 would have heterologous CHMI with mosquitoes infected with Pf NF135.C10 strain 75 days after the last dose of chloroquine. If <75% of volunteers in group 1 were protected against homologous CHMI, groups 3 and 4 would receive additional 6 weeks of CQ (starting day 225), a 4th immunization (75,000 PfSPZ Challenge or NS) on day 232 and homologous CHMI 110 days after last dose of CQ.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Plasmodium falciparum (Pf) Sporozoite (SPZ) Challenge
    Investigational medicinal product code
    PfSPZ Challenge
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    PfSPZ Challenge containing a total of 75,000 PfSPZ of the Pf NF54 strain in 6 injections

    Arm title
    		 Group 4: Normal Saline (NS)
    Arm description
    		 Group 4 (n=5) received weekly chloroquine chemoprophylaxis for 14 weeks (98 days), and 6 ID injections of normal saline on days 8, 36 and 64. All 4 volunteers restarted 6 weeks of CQ (days 225-259), and received 4th immunization on day 232. Three of these 4 volunteers received homologous CHMI (by bites of 5 NF54-infected mosquitoes) on day 369, and none were protected. Per protocol, if ≥75% of volunteers in group 1 were protected against homologous CHMI, groups 3 and 4 would have heterologous CHMI with mosquitoes infected with Pf NF135.C10 strain 75 days after the last dose of chloroquine. If <75% of volunteers in group 1 were protected against homologous CHMI, groups 3 and 4 would receive additional 6 weeks of CQ (starting day 225), a 4th immunization (75,000 PfSPZ Challenge or NS) on day 232 and homologous CHMI 110 days after last dose of CQ.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Normal Saline
    Investigational medicinal product code
    NS
    Other name
    Placebo
    Pharmaceutical forms
    Injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    Six NS injections

    Number of subjects in period 1
    		Group 1: PfSPZ Challenge Group 2: Normal Saline (NS) Group 3: PfSPZ Challenge Group 4: Normal Saline (NS)
    Started
    10
    5
    10
    5
    Completed
    10
    5
    4
    4
    Not completed
    0
    0
    6
    1
         Logistical reasons
    -
    -
    5
    1
         Tetanus vaccination
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1: PfSPZ Challenge
    Reporting group description
    		 Group 1 (n=10) received weekly chloroquine (CQ) chemoprophylaxis for 14 weeks (98 days), and 6 ID injections of PfSPZ Challenge [75,000 PfSPZ (per dose) of the Pf NF54 strain] on days 8, 36 and 64. Volunteers had CHMI by the bites of five mosquitoes infected with PfSPZ of the Pf NF54 strain 33 days after the last dose of chloroquine which is day 124. Of the 10 volunteers enrolled, all 10 were challenged of which 2 volunteers were protected.

    Reporting group title
    Group 2: Normal Saline (NS)
    Reporting group description
    		 Group 2 (n=5) received weekly chloroquine (CQ) chemoprophylaxis for 14 weeks (98 days), and 6 ID injections of normal saline on days 8, 36 and 64. Volunteers had CHMI by the bites of five mosquitoes infected with PfSPZ of the Pf NF54 strain 33 days after the last dose of chloroquine which is day 124. Of the 5 control volunteers enrolled, all 5 were challenged of which none of the volunteers were protected.

    Reporting group title
    Group 3: PfSPZ Challenge
    Reporting group description
    		 Group 3 (n=10) received weekly chloroquine chemoprophylaxis for 14 weeks (98 days), and 6 ID injections of PfSPZ Challenge [75,000 PfSPZ (per dose) of the Pf NF54 strain] on days 8, 36 and 64. Eight of 10 volunteers restarted 6 weeks of CQ (days 225-259), and received 4th immunization on day 232. Four of these 8 volunteers received homologous CHMI (by bites of 5 NF54-infected mosquitoes) on day 369, and none were protected. Per protocol, if ≥75% of volunteers in group 1 were protected against homologous CHMI, groups 3 and 4 would have heterologous CHMI with mosquitoes infected with Pf NF135.C10 strain 75 days after the last dose of chloroquine. If <75% of volunteers in group 1 were protected against homologous CHMI, groups 3 and 4 would receive additional 6 weeks of CQ (starting day 225), a 4th immunization (75,000 PfSPZ Challenge or NS) on day 232 and homologous CHMI 110 days after last dose of CQ.

    Reporting group title
    Group 4: Normal Saline (NS)
    Reporting group description
    		 Group 4 (n=5) received weekly chloroquine chemoprophylaxis for 14 weeks (98 days), and 6 ID injections of normal saline on days 8, 36 and 64. All 4 volunteers restarted 6 weeks of CQ (days 225-259), and received 4th immunization on day 232. Three of these 4 volunteers received homologous CHMI (by bites of 5 NF54-infected mosquitoes) on day 369, and none were protected. Per protocol, if ≥75% of volunteers in group 1 were protected against homologous CHMI, groups 3 and 4 would have heterologous CHMI with mosquitoes infected with Pf NF135.C10 strain 75 days after the last dose of chloroquine. If <75% of volunteers in group 1 were protected against homologous CHMI, groups 3 and 4 would receive additional 6 weeks of CQ (starting day 225), a 4th immunization (75,000 PfSPZ Challenge or NS) on day 232 and homologous CHMI 110 days after last dose of CQ.

    Reporting group values
    		 Group 1: PfSPZ Challenge Group 2: Normal Saline (NS) Group 3: PfSPZ Challenge Group 4: Normal Saline (NS) Total
    Number of subjects
    		 10 5 10 5 30
    Age categorical
    Units: Subjects
        Adults (18-35 years)
    		 10 5 10 5 30
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 22 ( 2.67 ) 22 ( 3.24 ) 21.1 ( 1.97 ) 20.6 ( 1.52 ) -
    Gender categorical
    Units: Subjects
        Female
    		 5 2 4 3 14
        Male
    		 5 3 6 2 16
    Race
    Units: Subjects
        Caucasian
    		 10 5 10 5 30
    BMI
    Units: Subject
        arithmetic mean (standard deviation)
    		 22.3 ( 1.52 ) 21.82 ( 2.22 ) 21.63 ( 1.17 ) 22.2 ( 1.19 ) -
    Height
    Units: meter
        arithmetic mean (standard deviation)
    		 1.75 ( 0.08 ) 1.77 ( 0.11 ) 1.8 ( 0.09 ) 1.73 ( 0.09 ) -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 68.5 ( 7.74 ) 69.2 ( 15.32 ) 69.8 ( 5.79 ) 67 ( 9.35 ) -

    End points

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    End points reporting groups
    Reporting group title
    Group 1: PfSPZ Challenge
    Reporting group description
    		 Group 1 (n=10) received weekly chloroquine (CQ) chemoprophylaxis for 14 weeks (98 days), and 6 ID injections of PfSPZ Challenge [75,000 PfSPZ (per dose) of the Pf NF54 strain] on days 8, 36 and 64. Volunteers had CHMI by the bites of five mosquitoes infected with PfSPZ of the Pf NF54 strain 33 days after the last dose of chloroquine which is day 124. Of the 10 volunteers enrolled, all 10 were challenged of which 2 volunteers were protected.

    Reporting group title
    Group 2: Normal Saline (NS)
    Reporting group description
    		 Group 2 (n=5) received weekly chloroquine (CQ) chemoprophylaxis for 14 weeks (98 days), and 6 ID injections of normal saline on days 8, 36 and 64. Volunteers had CHMI by the bites of five mosquitoes infected with PfSPZ of the Pf NF54 strain 33 days after the last dose of chloroquine which is day 124. Of the 5 control volunteers enrolled, all 5 were challenged of which none of the volunteers were protected.

    Reporting group title
    Group 3: PfSPZ Challenge
    Reporting group description
    		 Group 3 (n=10) received weekly chloroquine chemoprophylaxis for 14 weeks (98 days), and 6 ID injections of PfSPZ Challenge [75,000 PfSPZ (per dose) of the Pf NF54 strain] on days 8, 36 and 64. Eight of 10 volunteers restarted 6 weeks of CQ (days 225-259), and received 4th immunization on day 232. Four of these 8 volunteers received homologous CHMI (by bites of 5 NF54-infected mosquitoes) on day 369, and none were protected. Per protocol, if ≥75% of volunteers in group 1 were protected against homologous CHMI, groups 3 and 4 would have heterologous CHMI with mosquitoes infected with Pf NF135.C10 strain 75 days after the last dose of chloroquine. If <75% of volunteers in group 1 were protected against homologous CHMI, groups 3 and 4 would receive additional 6 weeks of CQ (starting day 225), a 4th immunization (75,000 PfSPZ Challenge or NS) on day 232 and homologous CHMI 110 days after last dose of CQ.

    Reporting group title
    Group 4: Normal Saline (NS)
    Reporting group description
    		 Group 4 (n=5) received weekly chloroquine chemoprophylaxis for 14 weeks (98 days), and 6 ID injections of normal saline on days 8, 36 and 64. All 4 volunteers restarted 6 weeks of CQ (days 225-259), and received 4th immunization on day 232. Three of these 4 volunteers received homologous CHMI (by bites of 5 NF54-infected mosquitoes) on day 369, and none were protected. Per protocol, if ≥75% of volunteers in group 1 were protected against homologous CHMI, groups 3 and 4 would have heterologous CHMI with mosquitoes infected with Pf NF135.C10 strain 75 days after the last dose of chloroquine. If <75% of volunteers in group 1 were protected against homologous CHMI, groups 3 and 4 would receive additional 6 weeks of CQ (starting day 225), a 4th immunization (75,000 PfSPZ Challenge or NS) on day 232 and homologous CHMI 110 days after last dose of CQ.

    Primary: Frequency of adverse events (AEs) in study groups - Solicited

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    End point title
    		 Frequency of adverse events (AEs) in study groups - Solicited [1]
    End point description
    All events pertaining to immunization phase (before CHMI) were recorded.
    End point type
    Primary
    End point timeframe
    During immunization phase (up to day 124 for groups 1 and 2 and up to day 369 for groups 3 and 4)
    Notes
    [1] - 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: This endpoint does not require statistical analysis.
    End point values
    		 Group 1: PfSPZ Challenge Group 2: Normal Saline (NS) Group 3: PfSPZ Challenge Group 4: Normal Saline (NS)
    Number of subjects analysed
    10
    5
    10
    5
    Units: Events
        Fever
    0
    0
    0
    0
        Malaise
    0
    0
    0
    0
        Fatigue
    0
    0
    0
    0
        Dizziness
    0
    0
    0
    0
        Myalgia
    0
    0
    0
    0
        Arthralgia
    0
    0
    0
    0
        Chest pain
    0
    0
    0
    0
        Chills
    2
    0
    0
    0
        Diarrhoea
    1
    0
    0
    0
        Headache
    12
    2
    5
    6
        Nausea
    2
    2
    4
    0
        Vomiting
    2
    0
    1
    1
        Abdominal pain
    0
    1
    2
    5
        Palpitations
    0
    0
    0
    0
        Shortness of breath
    0
    0
    0
    0
        Erythema or induration/swelling at injection site
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Magnitude of AEs in study groups - Solicited AEs

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    End point title
    		 Magnitude of AEs in study groups - Solicited AEs [2]
    End point description
    All events pertaining to immunization phase (before CHMI) were recorded.
    End point type
    Primary
    End point timeframe
    During immunization phase (up to day 124 for groups 1 and 2 and up to day 369 for groups 3 and 4)
    Notes
    [2] - 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: This endpoint does not require statistical analysis.
    End point values
    		 Group 1: PfSPZ Challenge Group 2: Normal Saline (NS) Group 3: PfSPZ Challenge Group 4: Normal Saline (NS)
    Number of subjects analysed
    10
    5
    10
    5
    Units: Subjects
        Grade 1
    6
    1
    4
    2
        Grade 2
    3
    3
    3
    3
        Grade 3
    0
    0
    1
    0
        Grade 4
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Frequency of adverse events (AEs) in study groups - Unsolicited

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    End point title
    		 Frequency of adverse events (AEs) in study groups - Unsolicited [3]
    End point description
    All events pertaining to immunization phase (before CHMI) were recorded.
    End point type
    Primary
    End point timeframe
    During immunization phase (up to day 124 for groups 1 and 2 and up to day 369 for groups 3 and 4)
    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: This endpoint does not require statistical analysis.
    End point values
    		 Group 1: PfSPZ Challenge Group 2: Normal Saline (NS) Group 3: PfSPZ Challenge Group 4: Normal Saline (NS)
    Number of subjects analysed
    10
    5
    10
    5
    Units: Events
        Acute pharyngitis
    2
    0
    0
    0
        Atypical facial pain
    0
    1
    0
    0
        Common cold
    4
    0
    2
    5
        Commotio cerebri
    0
    0
    1
    0
        Contusion of ankle
    0
    0
    1
    0
        Cough
    0
    0
    0
    1
        Cystitis
    0
    0
    2
    1
        Dermatitis unspecified
    0
    0
    1
    0
        Follow-up care involving plastic surgery of left u
    0
    0
    1
    0
        Inflammation of eyelid
    0
    0
    1
    0
        Influenza with other manifestation; virus not ide
    0
    0
    2
    0
        Lumbago NOS
    0
    0
    0
    1
        Open wound of finger without damage to nail
    0
    1
    0
    0
        Open wound of thumb without damage to nail
    0
    0
    1
    0
        Pain after removal wisdom tooth
    1
    0
    0
    0
        Pain in throat
    0
    1
    0
    0
        Raised d-dimer
    0
    0
    2
    0
        Urticaria
    0
    0
    1
    0
    No statistical analyses for this end point

    Primary: Magnitude of AEs in study groups - Unsolicited AEs

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    End point title
    		 Magnitude of AEs in study groups - Unsolicited AEs [4]
    End point description
    All events pertaining to immunization phase (before CHMI) were recorded.
    End point type
    Primary
    End point timeframe
    During immunization phase (up to day 124 for groups 1 and 2 and up to day 369 for groups 3 and 4)
    Notes
    [4] - 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: This endpoint does not require statistical analysis.
    End point values
    		 Group 1: PfSPZ Challenge Group 2: Normal Saline (NS) Group 3: PfSPZ Challenge Group 4: Normal Saline (NS)
    Number of subjects analysed
    10
    5
    10
    5
    Units: Subjects
        Grade 1
    4
    1
    6
    4
        Grade 2
    3
    2
    1
    2
        Grade 3
    0
    0
    1
    0
        Grade 4
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Presence of parasitemia after CHMI as assessed by microscopy in cohort 1 (Groups 1 and 2)

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    End point title
    		 Presence of parasitemia after CHMI as assessed by microscopy in cohort 1 (Groups 1 and 2) [5]
    End point description
    Number of volunteers who became thick smear positive (TS+)
    End point type
    Secondary
    End point timeframe
    Up to Day 21 after CHMI of cohort 1
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per protocol, this endpoint was analysed only for Cohort 1 (Groups 1 and 2).
    End point values
    		 Group 1: PfSPZ Challenge Group 2: Normal Saline (NS)
    Number of subjects analysed
    10
    5
    Units: Subjects
    8
    5
    No statistical analyses for this end point

    Secondary: Time to parasitemia after CHMI as assessed by microscopy in cohort 1 (Groups 1 and 2)

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    End point title
    		 Time to parasitemia after CHMI as assessed by microscopy in cohort 1 (Groups 1 and 2) [6]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to Day 21 after CHMI of cohort 1
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per protocol, this endpoint was analysed only for Cohort 1 (Groups 1 and 2).
    End point values
    		 Group 1: PfSPZ Challenge Group 2: Normal Saline (NS)
    Number of subjects analysed
    10
    5
    Units: days
        geometric mean (full range (min-max))
    13.7 (10.5 to 15)
    12.7 (10.5 to 16)
    No statistical analyses for this end point

    Secondary: Presence of parasitemia after CHMI as assessed by qPCR in cohorts 1 and 2

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    End point title
    		 Presence of parasitemia after CHMI as assessed by qPCR in cohorts 1 and 2
    End point description
    End point type
    Secondary
    End point timeframe
    Up to Day 21 after CHMI of cohorts 1 and 2
    End point values
    		 Group 1: PfSPZ Challenge Group 2: Normal Saline (NS) Group 3: PfSPZ Challenge Group 4: Normal Saline (NS)
    Number of subjects analysed
    10
    5
    4
    4
    Units: Subjects
    10
    5
    4
    4
    No statistical analyses for this end point

    Secondary: Time to parasitemia after CHMI as assessed by qPCR in cohorts 1 and 2

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    End point title
    		 Time to parasitemia after CHMI as assessed by qPCR in cohorts 1 and 2
    End point description
    End point type
    Secondary
    End point timeframe
    Up to Day 21 after CHMI of cohort 1 and 2
    End point values
    		 Group 1: PfSPZ Challenge Group 2: Normal Saline (NS) Group 3: PfSPZ Challenge Group 4: Normal Saline (NS)
    Number of subjects analysed
    10
    5
    4
    4
    Units: day
        geometric mean (full range (min-max))
    8.1 (7 to 10.5)
    7.6 (7 to 10.5)
    9.5 (7 to 10.5)
    7.7 (7 to 10)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were recorded during immunization phase (up to day 124 for groups 1 and 2 and up to day 369 for groups 3 and 4)
    Adverse event reporting additional description
    All adverse events/reactions (solicited and unsolicited), observed by the investigators or by the subject, is documented. All non-serious AEs occured during immunization phase and SAE occured after CHMI.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 ICD
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Group 1: PfSPZ Challenge
    Reporting group description
    		 Ten volunteers in Group 1 received intradermal injection of PfSPZ Challenge

    Reporting group title
    Group 2: Normal Saline
    Reporting group description
    		 Five volunteers in group 2 received NS

    Reporting group title
    Group 3: PfSPZ Challenge
    Reporting group description
    		 Ten volunteers in Group 3 received intradermal injection of PfSPZ Challenge

    Reporting group title
    Group 4: Normal Saline
    Reporting group description
    		 Five volunteers in group 4 received NS

    Serious adverse events
    		 Group 1: PfSPZ Challenge Group 2: Normal Saline Group 3: PfSPZ Challenge Group 4: Normal Saline
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Cardiac disorders
    Acute Myocarditis
    Additional description: Acute Myocarditis diagnosed for male (age 23), with rising troponin levels on day 2 of Malarone treatment following thick smear positivity for malaria. It is considered possibly related to CHMI Outcome was 'Recovered with Sequelae.'
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Group 1: PfSPZ Challenge Group 2: Normal Saline Group 3: PfSPZ Challenge Group 4: Normal Saline
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    5 / 5 (100.00%)
    10 / 10 (100.00%)
    5 / 5 (100.00%)
    Investigations
    Raised d-dimer
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Injury, poisoning and procedural complications
    Commotio cerebri
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Contusion of ankle
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Open wound of finger without damage to nail
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Open wound of thumb without damage to nail
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pain after removal wisdom tooth
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Surgical and medical procedures
    Follow-up care involving plastic surgery of left upper extremity
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 10 (40.00%)
    2 / 5 (40.00%)
    2 / 10 (20.00%)
    2 / 5 (40.00%)
         occurrences all number
    12
    2
    5
    6
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Atypical facial pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye disorders
    Inflammation of eyelid
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    2 / 10 (20.00%)
    3 / 5 (60.00%)
         occurrences all number
    0
    1
    2
    5
    Diarrhoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 5 (20.00%)
    3 / 10 (30.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    2
    4
    0
    Vomiting
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Pain in throat
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis unspecified
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Lumbago NOS
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Acute pharyngitis
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Common cold
         subjects affected / exposed
    4 / 10 (40.00%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    4 / 5 (80.00%)
         occurrences all number
    4
    0
    2
    5
    Cystitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    2
    1
    Influenza with other manifestations; virus not identified
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jul 2012
    - Additional labs added - Updated inclusion and exclusion criteria - Added lists of concomitant medications and conditions for both chloroquine and Malarone use - Secondary and exploratory study parameters were updated - Dose preparation and administration sections were updated - Number of injections for each immunization was updated from 2 to 6 - Added statement for performing complete physical exam at baseline visit and list of focused physical exams to be performed at follow-up visits - Updated flow chart for trial procedures - Included grading scales for adverse events and lab abnormalities - Added section on safety stopping rules
    03 Sep 2012
    - Deleted statement from adverse event data collection section regarding not grading intensity of fever
    28 Sep 2012
    - Included urinalysis for presence of hemoglobinuria and proteinuria on day before CHMI and on day of treatment - Updated flow chart for trial procedures - Updated tables for grading local and systemic adverse events, and grading lab abnormalities - Included one additional category for assessment of causality and its definition - Updated safety stopping rules based on the additional category for assessment of causality
    05 Nov 2012
    - Inclusion of four extra visits (on days 8 and 9 following the 2nd and 3rd injections) during which a small blood sample will be taken on a voluntary basis. - Updated flow chart for trial procedures
    04 Dec 2012
    - Added a sub-study called “Odor profile” study - Changes related to the addition of the sub-study were made to study population, exploratory objectives, study procedures, etc. sections
    15 Jan 2013
    - Changes specific to the “Odor profile” sub-study only, were made to the study schedule
    16 May 2013
    - Study schedule and timelines were updated due to trial delay after SAE occurrence - qPCR was added as method for detection of parasitemia for cohort 2 - Safety section of the protocol was updated - Protocol was updated to include the occurrence of the SAE in the study - Additional safety recommendations were added based on the SAE – updates to exclusion criteria, increased monitoring of certain lab parameters, use of qPCR post-CHMI for diagnosis of malaria - Secondary study parameters were updated - Section on treatment with Malarone was updated - Sub-study “Odor profile” modifications were made - Updated flow chart for trial procedures
    04 Nov 2013
    - Unblinding schedule for groups 3 and 4 was updated to allow unblinding to occur one week earlier than originally stated

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    13 Mar 2013
    Due to cardiac SAE, trial was put on hold for 64 days (13-Mar-2013 – 16-May-2013) by the Safety Monitoring Committee, the Central Committee for Research Involving Human Subjects of the Netherlands, and the US FDA. New safety measures were adopted for follow-up after mosquito CHMI of Groups 3 and 4.
    16 May 2013

    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/24479524
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