<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02223871</url>
  </required_header>
  <id_info>
    <org_study_id>AC-071-102</org_study_id>
    <nct_id>NCT02223871</nct_id>
  </id_info>
  <brief_title>Effect of ACT-451840 Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Subjects</brief_title>
  <official_title>A Proof-of-concept Study to Assess the Effect of ACT-451840 Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Subjects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Idorsia Pharmaceuticals Ltd.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Idorsia Pharmaceuticals Ltd.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This was a single-center study using induced blood stage malaria infection to characterize&#xD;
      the activity of ACT-451840 against early Plasmodium falciparum blood stage infection&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The primary objective of the study was to characterize the activity of ACT-451840&#xD;
      administered orally on clearance of Plasmodium falciparum blood stage parasites from the&#xD;
      blood in healthy subjects .The inoculum used for blood stage Plasmodium falciparum challenge&#xD;
      (BSPC) contained an estimated 1,800 viable parasite-infected erythrocytes diluted into 2 mL&#xD;
      of normal saline for injection. Blood was collected for malaria parasitemia assessment by&#xD;
      polymerase chain reaction (PCR). Parasitemia ≥ 1,000 parasites/mL indicated that the subjects&#xD;
      should be treated with ACT-451840 . If PCR counts were &gt; 5,000 parasites/mL and symptomatic&#xD;
      they were dosed within 24 hours. Subsequent PCR blood sampling were performed prior to&#xD;
      ACT-451840 dosing and at 2, 4, 8, 12, 16, 20, 24, 30, 36, 48, 60, 72, 84, 96, 120, 144 hours&#xD;
      post-dosing and then approximately times per week until 2 consecutive negative samples, until&#xD;
      Riamet® rescue treatment and at the final visit.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>June 2014</start_date>
  <completion_date type="Actual">July 2014</completion_date>
  <primary_completion_date type="Actual">July 2014</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Drug-specific Parasite Reduction Ratio (PRR48) of ACT-451840 Over 48 Hours Using a Standardized Approach</measure>
    <time_frame>48 hours after study drug administration</time_frame>
    <description>After the blood stage Plasmodium falciparum challenge (BSPC), malaria parasitemia was measured by polymerase chain reaction (PCR) in regularly collected blood samples.&#xD;
The subject-specific and drug-specific parasite reduction rates over a 48 h period (PRR48) were calculated using an objective standardized approach (observed data over 48 h)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Maximum Plasma Concentration (Cmax) of ACT-451840</measure>
    <time_frame>From pre-dose to 144 hours after study drug adminsitration</time_frame>
    <description>Cmax was directly derived from the plasma concentrations-time curves of ACT-451840. Blood samples for pharmacokinetic characterization were drawn at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, and 144 hours post-dose.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Reach Maximum Plasma Concentration (Tmax) of ACT-451840</measure>
    <time_frame>From pre-dose to144 hours after study drug administration</time_frame>
    <description>tmax was directly derived from the plasma concentration-time curves of ACT-451840. Blood samples for pharmacokinetic characterization were drawn at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, and 144 hours post-dose.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Areas Under the Plasma Concentration-time Curve of ACT-451840</measure>
    <time_frame>From pre-dose to144 hours after study drug administration</time_frame>
    <description>Two AUCs were calculated using non-compartmental analysis: AUC(0-t) from pre-dose to last time-point of measure and AUC(0-inf) from pre-dose and extrapolated to infinity.&#xD;
Blood samples for pharmacokinetic characterization were drawn at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, and 144 hours post-dose</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Terminal Half-life [t(1/2)]</measure>
    <time_frame>From pre-dose to144 hours after study drug adminsitration</time_frame>
    <description>Blood samples for pharmacokinetic characterization were drawn at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, and 144 hours post-dose</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Blood Pressure to End of Study (EOS)</measure>
    <time_frame>Day 28 (EOS)</time_frame>
    <description>Vital signs, including diastolic and systolic blood pressure (DBP/SBP), were measured at each outpatient visit up to 7 days after ACT-451840 administration, every day during confinement or when malaria symptoms were presented and at the end of study visit (EOS). Other measures were performed if required.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Body Temperature up to End of Study (EOS)</measure>
    <time_frame>Day 28 (EOS)</time_frame>
    <description>Body temperature was measured orally</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Respiratory Rate to End of Study (EOS)</measure>
    <time_frame>Day 28 (EOS)</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">8</enrollment>
  <condition>Healthy Subjects</condition>
  <arm_group>
    <arm_group_label>ACT-451840 500 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All the participants were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, all the participants received 500 mg of ACT-451840 as a single oral dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required) for all participants. Primaquine was to be administered as a single dose only in participants for whom gametocytes were still identified after administration of Riamet® rescue medication</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ACT-451840:</intervention_name>
    <description>ACT-451840 500 mg was provided in 100 mL amber glass bottles formulated as a powder for oral suspension. The ACT-451840 suspension was prepared extemporaneously by addition of 25 mL of water and administered orally under fed condition.</description>
    <arm_group_label>ACT-451840 500 mg</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Plasmodium falciparum-infected human erythrocytes:</intervention_name>
    <description>Each participant was inoculated on Day 0 with approximately 1,800 viable Plasmodium falciparum-infected human erythrocytes administered intravenously.</description>
    <arm_group_label>ACT-451840 500 mg</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Artemether 20 mg and lumefantrine 120mg combination tablet:</intervention_name>
    <description>Rescue treatment to ensure clearance of Plasmodium falciparum comprising six doses of four tablets (total course of 24 tablets) given over a period of 60 hours. Each dose of tablets administered orally was immediately followed by food or drinks rich in fat (e.g., milk).</description>
    <arm_group_label>ACT-451840 500 mg</arm_group_label>
    <other_name>Riamet®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Primaquine:</intervention_name>
    <description>Rescue treatment to ensure clearance of Plasmodium falciparum, to be taken as a single oral 45 mg dose with food only if gametocytes were identified after administration of Riamet® rescue medication.</description>
    <arm_group_label>ACT-451840 500 mg</arm_group_label>
    <other_name>Primacin™</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Body weight, minimum 50 kg, body mass index 18-32 kg/m^2.&#xD;
&#xD;
          -  Certified healthy by detailed medical history and physical examination.&#xD;
&#xD;
          -  Normal vital signs.&#xD;
&#xD;
          -  Normal standard 12-lead electrocardiograph (ECG).&#xD;
&#xD;
          -  Laboratory parameters within normal range, unless the investigator considered an&#xD;
             abnormality to be clinically irrelevant.&#xD;
&#xD;
          -  Use a double barrier method of contraception (male condom plus diaphragm or plus&#xD;
             intrauterine device or plus hormonal contraceptive by female partner) for at least 14&#xD;
             days prior to the first dose of study drug until 90 days after the last dose.&#xD;
&#xD;
          -  Written informed consent prior to undertaking any study procedure.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any history of malaria.&#xD;
&#xD;
          -  Traveled to or lived (&gt;2 weeks) in a malaria-endemic country in the past 12 months or&#xD;
             planned travel to a malaria-endemic country during the course of the study.&#xD;
&#xD;
          -  Evidence of increased cardiovascular disease risk.&#xD;
&#xD;
          -  History of splenectomy.&#xD;
&#xD;
          -  Presence or history of drug hypersensitivity, or allergic disease diagnosed and&#xD;
             treated by a physician or history of a severe allergic reaction, anaphylaxis or&#xD;
             convulsions following any vaccination or infusion.&#xD;
&#xD;
          -  Presence of current or suspected serious chronic disease.&#xD;
&#xD;
          -  Receiving psychiatric drugs or hospitalized within the past 5 years prior to&#xD;
             enrollment for psychiatric illness, history of suicide attempt or confinement for&#xD;
             danger to self or others.&#xD;
&#xD;
          -  Frequent headaches and/or migraine, recurrent nausea, and/or vomiting.&#xD;
&#xD;
          -  Known inherited genetic anomaly.&#xD;
&#xD;
          -  Presence of acute infectious disease or fever within the 5 days prior to study product&#xD;
             administration.&#xD;
&#xD;
          -  Evidence of acute illness within 4 weeks prior to screening.&#xD;
&#xD;
          -  Significant intercurrent disease.&#xD;
&#xD;
          -  Clinically significant disease or condition that might affect drug absorption,&#xD;
             distribution or excretion.&#xD;
&#xD;
          -  Any investigational product study within the 12 weeks preceding the study.&#xD;
&#xD;
          -  Participation in a research study involving blood sampling greater than 450 mL/ unit&#xD;
             of blood, or blood donation to a blood bank during the 8 weeks preceding the reference&#xD;
             drug dose in the study.&#xD;
&#xD;
          -  Subject unwilling to defer blood donations for 6 months.&#xD;
&#xD;
          -  Blood donation within 1 month before inclusion.&#xD;
&#xD;
          -  Medical requirement for intravenous immunoglobulin or blood transfusions.&#xD;
&#xD;
          -  Previous blood transfusion.&#xD;
&#xD;
          -  Symptomatic postural hypotension.&#xD;
&#xD;
          -  History or presence of alcohol consumption of more than 40 g per day or drug&#xD;
             habituation, or any prior intravenous usage of an illicit substance.&#xD;
&#xD;
          -  Smoking more than 5 cigarettes or equivalent per day, unable to stop smoking during&#xD;
             the study.&#xD;
&#xD;
          -  Ingestion of poppy seeds within 24 hours of the screening blood test.&#xD;
&#xD;
          -  Excessive consumption of beverages containing xanthine bases.&#xD;
&#xD;
          -  Any medication within 14 days before inclusion or within 5 times the elimination&#xD;
             half-life of the medication, vaccination within the last 28 days.&#xD;
&#xD;
          -  Corticosteroids, anti-inflammatory drugs, immunomodulators or anticoagulants.&#xD;
&#xD;
          -  Recent or current therapy with an antibiotic or drug with potential antimalarial&#xD;
             activity.&#xD;
&#xD;
          -  Subject who, in the judgment of the investigator, was likely to be non-compliant, or&#xD;
             unable to cooperate because of a language problem or poor mental development; was in&#xD;
             the exclusion period of a previous study; lived alone; who could not be contacted in&#xD;
             case of emergency; who was directly involved in conducting the study; who had no good&#xD;
             peripheral venous access.&#xD;
&#xD;
          -  Positive result on any of the following tests: hepatitis B surface antigen,&#xD;
             anti-hepatitis B core antibodies, anti-hepatitis C virus antibodies, anti-human&#xD;
             immunodeficiency virus 1 and 2 antibodies.&#xD;
&#xD;
          -  Amphetamine, methamphetamines, barbiturates, benzodiazepines, cocaine, methadone,&#xD;
             opiates, phencyclidine, tetrahydrocannabinols, tricyclic antidepressants detected in&#xD;
             the urine drug screen unless there was an explanation acceptable to the medical&#xD;
             investigator.&#xD;
&#xD;
          -  Positive alcohol test.&#xD;
&#xD;
          -  Pre-existing prolongation of the interval from beginning of the Q wave until end of&#xD;
             the T wave corrected according to Bazett's formula (QTcB interval ) and considered&#xD;
             clinically significant.&#xD;
&#xD;
          -  Family history of sudden death, congenital prolongation of QTc interval, known&#xD;
             congenital prolongation of QTc interval, or any clinical condition known to prolong&#xD;
             the QTc interval. History of symptomatic cardiac arrhythmias or clinically relevant&#xD;
             bradycardia. Electrolyte disturbances.&#xD;
&#xD;
          -  ECG abnormalities at screening which in the opinion of the investigator is clinically&#xD;
             relevant or will interfere with the ECG analysis.&#xD;
&#xD;
          -  History of clinically significant ECG abnormalities.&#xD;
&#xD;
          -  Known hypersensitivity to ACT-451840 or any of its excipients or artemether or other&#xD;
             artemisinin derivatives, lumefantrine or other aryl aminoalcohols.&#xD;
&#xD;
          -  Unwillingness to abstain from consumption of citrus fruits or their juices, as well as&#xD;
             all fruit juices from admission to the end of the confinement period.&#xD;
&#xD;
          -  Any history or presence of lactose intolerance.&#xD;
&#xD;
          -  Ingestion of any drug since the recruitment interview (other than the doses&#xD;
             administered in this study) which, in the opinion of the investigator, could&#xD;
             compromise the study.&#xD;
&#xD;
          -  Ingestion of any drug in the week prior to dosing or during the blood sampling period&#xD;
             which, in the opinion of the investigator, could compromise the study.&#xD;
&#xD;
          -  Failure to conform to the requirements of the protocol.&#xD;
&#xD;
          -  Detection of any drug listed in the protocol in the urine drug screen unless there was&#xD;
             an explanation acceptable to the investigator.&#xD;
&#xD;
          -  Vital signs outside the reference range and clinically significant.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michelle Lee</last_name>
    <role>Study Director</role>
    <affiliation>Actelion</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Q-Pharm Clinics</name>
      <address>
        <city>Herston</city>
        <state>Queensland</state>
        <zip>4006</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
  </location_countries>
  <reference>
    <citation>Marquart L, Baker M, O'Rourke P, McCarthy JS. Evaluating the pharmacodynamic effect of antimalarial drugs in clinical trials by quantitative PCR. Antimicrob Agents Chemother. 2015 Jul;59(7):4249-59. doi: 10.1128/AAC.04942-14. Epub 2015 May 11.</citation>
    <PMID>25963983</PMID>
  </reference>
  <results_reference>
    <citation>Krause A, Dingemanse J, Mathis A, Marquart L, Mohrle JJ, McCarthy JS. Pharmacokinetic/pharmacodynamic modelling of the antimalarial effect of Actelion-451840 in an induced blood stage malaria study in healthy subjects. Br J Clin Pharmacol. 2016 Aug;82(2):412-21. doi: 10.1111/bcp.12962. Epub 2016 May 11.</citation>
    <PMID>27062080</PMID>
  </results_reference>
  <verification_date>August 2019</verification_date>
  <study_first_submitted>August 21, 2014</study_first_submitted>
  <study_first_submitted_qc>August 21, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 22, 2014</study_first_posted>
  <results_first_submitted>July 1, 2016</results_first_submitted>
  <results_first_submitted_qc>July 1, 2016</results_first_submitted_qc>
  <results_first_posted type="Estimate">August 10, 2016</results_first_posted>
  <last_update_submitted>August 8, 2019</last_update_submitted>
  <last_update_submitted_qc>August 8, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">August 22, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Malaria</keyword>
  <keyword>ACT-451840</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>Malaria</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lumefantrine</mesh_term>
    <mesh_term>Artemether</mesh_term>
    <mesh_term>Primaquine</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>This proof-of-concept study was conducted in 8 subjects at a single center in Australia. All the subjects were screened from June 6, 2014 to June 23, 2014 and all were enrolled in the study on June 25, 2014 (Study Day 0).</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>ACT-451840 500 mg</title>
          <description>The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required).</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>ACT-451840 500 mg</title>
          <description>The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes occurred 16 days after ACT-451840 administration (or earlier if required).</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="8"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Years</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="24.1" lower_limit="19" upper_limit="38"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Caucasian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Indian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Asian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Native Hawaiian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Drug-specific Parasite Reduction Ratio (PRR48) of ACT-451840 Over 48 Hours Using a Standardized Approach</title>
        <description>After the blood stage Plasmodium falciparum challenge (BSPC), malaria parasitemia was measured by polymerase chain reaction (PCR) in regularly collected blood samples.&#xD;
The subject-specific and drug-specific parasite reduction rates over a 48 h period (PRR48) were calculated using an objective standardized approach (observed data over 48 h)</description>
        <time_frame>48 hours after study drug administration</time_frame>
        <population>Only subjects with appropriate overall fit (p-value of the overall model F-test &lt;0.001) were taken into account (n = 5)</population>
        <group_list>
          <group group_id="O1">
            <title>ACT-451840 500 mg</title>
            <description>The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required).</description>
          </group>
        </group_list>
        <measure>
          <title>Drug-specific Parasite Reduction Ratio (PRR48) of ACT-451840 Over 48 Hours Using a Standardized Approach</title>
          <description>After the blood stage Plasmodium falciparum challenge (BSPC), malaria parasitemia was measured by polymerase chain reaction (PCR) in regularly collected blood samples.&#xD;
The subject-specific and drug-specific parasite reduction rates over a 48 h period (PRR48) were calculated using an objective standardized approach (observed data over 48 h)</description>
          <population>Only subjects with appropriate overall fit (p-value of the overall model F-test &lt;0.001) were taken into account (n = 5)</population>
          <units>Ratio</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="234.5" lower_limit="130.4" upper_limit="422.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Maximum Plasma Concentration (Cmax) of ACT-451840</title>
        <description>Cmax was directly derived from the plasma concentrations-time curves of ACT-451840. Blood samples for pharmacokinetic characterization were drawn at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, and 144 hours post-dose.</description>
        <time_frame>From pre-dose to 144 hours after study drug adminsitration</time_frame>
        <group_list>
          <group group_id="O1">
            <title>ACT-451840 500 mg</title>
            <description>The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required).</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Plasma Concentration (Cmax) of ACT-451840</title>
          <description>Cmax was directly derived from the plasma concentrations-time curves of ACT-451840. Blood samples for pharmacokinetic characterization were drawn at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, and 144 hours post-dose.</description>
          <units>ng/mL</units>
          <param>Geometric Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="121.7" lower_limit="90.6" upper_limit="163.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Reach Maximum Plasma Concentration (Tmax) of ACT-451840</title>
        <description>tmax was directly derived from the plasma concentration-time curves of ACT-451840. Blood samples for pharmacokinetic characterization were drawn at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, and 144 hours post-dose.</description>
        <time_frame>From pre-dose to144 hours after study drug administration</time_frame>
        <group_list>
          <group group_id="O1">
            <title>ACT-451840 500 mg</title>
            <description>The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required).</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Reach Maximum Plasma Concentration (Tmax) of ACT-451840</title>
          <description>tmax was directly derived from the plasma concentration-time curves of ACT-451840. Blood samples for pharmacokinetic characterization were drawn at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, and 144 hours post-dose.</description>
          <units>Hours</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.0" lower_limit="3.0" upper_limit="6.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Areas Under the Plasma Concentration-time Curve of ACT-451840</title>
        <description>Two AUCs were calculated using non-compartmental analysis: AUC(0-t) from pre-dose to last time-point of measure and AUC(0-inf) from pre-dose and extrapolated to infinity.&#xD;
Blood samples for pharmacokinetic characterization were drawn at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, and 144 hours post-dose</description>
        <time_frame>From pre-dose to144 hours after study drug administration</time_frame>
        <group_list>
          <group group_id="O1">
            <title>ACT-451840 500 mg</title>
            <description>The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required).</description>
          </group>
        </group_list>
        <measure>
          <title>Areas Under the Plasma Concentration-time Curve of ACT-451840</title>
          <description>Two AUCs were calculated using non-compartmental analysis: AUC(0-t) from pre-dose to last time-point of measure and AUC(0-inf) from pre-dose and extrapolated to infinity.&#xD;
Blood samples for pharmacokinetic characterization were drawn at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, and 144 hours post-dose</description>
          <units>ng*h/mL</units>
          <param>Geometric Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>AUC(0-t)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1254.8" lower_limit="906.8" upper_limit="1736.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AUC(0-inf)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1284.4" lower_limit="919.6" upper_limit="1794.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Terminal Half-life [t(1/2)]</title>
        <description>Blood samples for pharmacokinetic characterization were drawn at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, and 144 hours post-dose</description>
        <time_frame>From pre-dose to144 hours after study drug adminsitration</time_frame>
        <population>Per protocol set</population>
        <group_list>
          <group group_id="O1">
            <title>ACT-451840 500 mg</title>
            <description>The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required).</description>
          </group>
        </group_list>
        <measure>
          <title>Terminal Half-life [t(1/2)]</title>
          <description>Blood samples for pharmacokinetic characterization were drawn at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, and 144 hours post-dose</description>
          <population>Per protocol set</population>
          <units>Hours</units>
          <param>Geometric Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="36.4" lower_limit="30.2" upper_limit="43.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Blood Pressure to End of Study (EOS)</title>
        <description>Vital signs, including diastolic and systolic blood pressure (DBP/SBP), were measured at each outpatient visit up to 7 days after ACT-451840 administration, every day during confinement or when malaria symptoms were presented and at the end of study visit (EOS). Other measures were performed if required.</description>
        <time_frame>Day 28 (EOS)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>ACT-451840 500 mg</title>
            <description>The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required).</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Blood Pressure to End of Study (EOS)</title>
          <description>Vital signs, including diastolic and systolic blood pressure (DBP/SBP), were measured at each outpatient visit up to 7 days after ACT-451840 administration, every day during confinement or when malaria symptoms were presented and at the end of study visit (EOS). Other measures were performed if required.</description>
          <units>mmHg</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>SBP at baseline (Day 0)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="121.0" lower_limit="110.0" upper_limit="136.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SBP at EOS (Day 28)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="125.5" lower_limit="117.0" upper_limit="139.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change from Day 0 to Day 28 in SBP</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.5" lower_limit="-5.0" upper_limit="20.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>DBP at baseline (Day 0)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="66.0" lower_limit="51.0" upper_limit="73.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>DBP at EOS (Day 28)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="70.5" lower_limit="57.0" upper_limit="75.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change from Day 0 to Day 28 in DBP</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.5" lower_limit="-3.0" upper_limit="12.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Body Temperature up to End of Study (EOS)</title>
        <description>Body temperature was measured orally</description>
        <time_frame>Day 28 (EOS)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>ACT-451840 500 mg</title>
            <description>The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required).</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Body Temperature up to End of Study (EOS)</title>
          <description>Body temperature was measured orally</description>
          <units>Degree Celsius</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Temperature at baseline (Day 0)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="36.3" lower_limit="36.0" upper_limit="36.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Temperature at EOS (Day 28)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="35.9" lower_limit="35.8" upper_limit="36.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change from Day 0 to Day 28 in temperature</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.2" lower_limit="-0.7" upper_limit="0.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Respiratory Rate to End of Study (EOS)</title>
        <time_frame>Day 28 (EOS)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>ACT-451840 500 mg</title>
            <description>The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required).</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Respiratory Rate to End of Study (EOS)</title>
          <units>Breaths/min</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Respiratory rate at baseline (Day 0)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14" lower_limit="12" upper_limit="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Respiratory rate at EOS (Day 28)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="16" lower_limit="14" upper_limit="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change from Day 0 to Day 28 in respiratory rate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.5" lower_limit="-4" upper_limit="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Post-Hoc</type>
        <title>Drug-specific Parasite Reduction Ratio (PRR48) of ACT-451840 Over 48 Hours Using a New Approach</title>
        <description>After the blood stage Plasmodium falciparum challenge (BSPC), malaria parasitemia was measured by polymerase chain reaction (PCR) in regularly collected blood samples.&#xD;
The subject-specific and drug-specific parasite reduction rates over a 48 h period (PRR48) were calculated following the data-driven method by Marquart et al. (2015), removing potential lag and tail phases prior to log-linear regression modeling.</description>
        <time_frame>48 hours after study drug administration</time_frame>
        <population>Only subjects with appropriate overall fit (p-value of the overall model F-test &lt;0.001) were taken into account (n = 8 with the method described by Marquart et al., 2015)</population>
        <group_list>
          <group group_id="O1">
            <title>ACT-451840 500 mg</title>
            <description>The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required).</description>
          </group>
        </group_list>
        <measure>
          <title>Drug-specific Parasite Reduction Ratio (PRR48) of ACT-451840 Over 48 Hours Using a New Approach</title>
          <description>After the blood stage Plasmodium falciparum challenge (BSPC), malaria parasitemia was measured by polymerase chain reaction (PCR) in regularly collected blood samples.&#xD;
The subject-specific and drug-specific parasite reduction rates over a 48 h period (PRR48) were calculated following the data-driven method by Marquart et al. (2015), removing potential lag and tail phases prior to log-linear regression modeling.</description>
          <population>Only subjects with appropriate overall fit (p-value of the overall model F-test &lt;0.001) were taken into account (n = 8 with the method described by Marquart et al., 2015)</population>
          <units>Ratio</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="73.6" lower_limit="56.1" upper_limit="96.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From baseline to end of study</time_frame>
      <desc>None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum</desc>
      <group_list>
        <group group_id="E1">
          <title>ACT-451840 500 mg</title>
          <description>The eight subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes on Day 0 and received 500 mg of ACT-451840 on Day 7. All of them received six doses of Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, as per protocol.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 17.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Lip ulcer</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Injection site erythema</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Pain injection site</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Rigors</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Vessel puncture site pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory tract infection (not otherwise specified)</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Rhesus antibodies positive</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="10" subjects_affected="7" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Lethargy</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dermatitis contact</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Night sweats</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>Publication of the data is under the responsibility of Actelion Pharmaceuticals Ltd. The PI has the opportunity to review the analysis of the data and to discuss with the sponsor the interpretation of the study results prior to publication.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Clinical Trial Disclosure desk</name_or_title>
      <organization>Idorsia Pharmaceuticals Ltd</organization>
      <email>clinical-trials-disclosure@idorsia.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02223871
org study id: AC-071-102
nct id: NCT02223871
lead sponsor: 
has dmc: No
This was a single-center study using induced blood stage malaria infection to characterize
      the activity of ACT-451840 against early Plasmodium falciparum blood stage infection
The primary objective of the study was to characterize the activity of ACT-451840
      administered orally on clearance of Plasmodium falciparum blood stage parasites from the
      blood in healthy subjects .The inoculum used for blood stage Plasmodium falciparum challenge
      (BSPC) contained an estimated 1,800 viable parasite-infected erythrocytes diluted into 2 mL
      of normal saline for injection. Blood was collected for malaria parasitemia assessment by
      polymerase chain reaction (PCR). Parasitemia ≥ 1,000 parasites/mL indicated that the subjects
      should be treated with ACT-451840 . If PCR counts were > 5,000 parasites/mL and symptomatic
      they were dosed within 24 hours. Subsequent PCR blood sampling were performed prior to
      ACT-451840 dosing and at 2, 4, 8, 12, 16, 20, 24, 30, 36, 48, 60, 72, 84, 96, 120, 144 hours
      post-dosing and then approximately times per week until 2 consecutive negative samples, until
      Riamet® rescue treatment and at the final visit.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Other
masking: None (Open Label)
measure: Drug-specific Parasite Reduction Ratio (PRR48) of ACT-451840 Over 48 Hours Using a Standardized Approach
time frame: 48 hours after study drug administration
description: After the blood stage Plasmodium falciparum challenge (BSPC), malaria parasitemia was measured by polymerase chain reaction (PCR) in regularly collected blood samples.
The subject-specific and drug-specific parasite reduction rates over a 48 h period (PRR48) were calculated using an objective standardized approach (observed data over 48 h)
measure: Maximum Plasma Concentration (Cmax) of ACT-451840
time frame: From pre-dose to 144 hours after study drug adminsitration
description: Cmax was directly derived from the plasma concentrations-time curves of ACT-451840. Blood samples for pharmacokinetic characterization were drawn at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, and 144 hours post-dose.
measure: Time to Reach Maximum Plasma Concentration (Tmax) of ACT-451840
time frame: From pre-dose to144 hours after study drug administration
description: tmax was directly derived from the plasma concentration-time curves of ACT-451840. Blood samples for pharmacokinetic characterization were drawn at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, and 144 hours post-dose.
measure: Areas Under the Plasma Concentration-time Curve of ACT-451840
time frame: From pre-dose to144 hours after study drug administration
description: Two AUCs were calculated using non-compartmental analysis: AUC(0-t) from pre-dose to last time-point of measure and AUC(0-inf) from pre-dose and extrapolated to infinity.
Blood samples for pharmacokinetic characterization were drawn at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, and 144 hours post-dose
measure: Terminal Half-life [t(1/2)]
time frame: From pre-dose to144 hours after study drug adminsitration
description: Blood samples for pharmacokinetic characterization were drawn at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, and 144 hours post-dose
measure: Change From Baseline in Blood Pressure to End of Study (EOS)
time frame: Day 28 (EOS)
description: Vital signs, including diastolic and systolic blood pressure (DBP/SBP), were measured at each outpatient visit up to 7 days after ACT-451840 administration, every day during confinement or when malaria symptoms were presented and at the end of study visit (EOS). Other measures were performed if required.
measure: Change From Baseline in Body Temperature up to End of Study (EOS)
time frame: Day 28 (EOS)
description: Body temperature was measured orally
measure: Change From Baseline in Respiratory Rate to End of Study (EOS)
time frame: Day 28 (EOS)
arm group label: ACT-451840 500 mg
arm group type: Experimental
description: All the participants were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, all the participants received 500 mg of ACT-451840 as a single oral dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required) for all participants. Primaquine was to be administered as a single dose only in participants for whom gametocytes were still identified after administration of Riamet® rescue medication
intervention type: Drug
intervention name: ACT-451840:
description: ACT-451840 500 mg was provided in 100 mL amber glass bottles formulated as a powder for oral suspension. The ACT-451840 suspension was prepared extemporaneously by addition of 25 mL of water and administered orally under fed condition.
arm group label: ACT-451840 500 mg
intervention type: Other
intervention name: Plasmodium falciparum-infected human erythrocytes:
description: Each participant was inoculated on Day 0 with approximately 1,800 viable Plasmodium falciparum-infected human erythrocytes administered intravenously.
arm group label: ACT-451840 500 mg
intervention type: Drug
intervention name: Artemether 20 mg and lumefantrine 120mg combination tablet:
description: Rescue treatment to ensure clearance of Plasmodium falciparum comprising six doses of four tablets (total course of 24 tablets) given over a period of 60 hours. Each dose of tablets administered orally was immediately followed by food or drinks rich in fat (e.g., milk).
arm group label: ACT-451840 500 mg
other name: Riamet®
intervention type: Drug
intervention name: Primaquine:
description: Rescue treatment to ensure clearance of Plasmodium falciparum, to be taken as a single oral 45 mg dose with food only if gametocytes were identified after administration of Riamet® rescue medication.
arm group label: ACT-451840 500 mg
other name: Primacin™
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Michelle Lee
role: Study Director
affiliation: Actelion
facility: 
country: Australia
citation: Marquart L, Baker M, O'Rourke P, McCarthy JS. Evaluating the pharmacodynamic effect of antimalarial drugs in clinical trials by quantitative PCR. Antimicrob Agents Chemother. 2015 Jul;59(7):4249-59. doi: 10.1128/AAC.04942-14. Epub 2015 May 11.
PMID: 25963983
citation: Krause A, Dingemanse J, Mathis A, Marquart L, Mohrle JJ, McCarthy JS. Pharmacokinetic/pharmacodynamic modelling of the antimalarial effect of Actelion-451840 in an induced blood stage malaria study in healthy subjects. Br J Clin Pharmacol. 2016 Aug;82(2):412-21. doi: 10.1111/bcp.12962. Epub 2016 May 11.
PMID: 27062080
responsible party type: Sponsor
mesh term: Infections
mesh term: Malaria
mesh term: Lumefantrine
mesh term: Artemether
mesh term: Primaquine
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 