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Effect of ACT-451840 Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Subjects

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ClinicalTrials.gov Identifier: NCT02223871
Recruitment Status : Completed
First Posted : August 22, 2014
Results First Posted : August 10, 2016
Last Update Posted : August 22, 2019
Sponsor:
Information provided by (Responsible Party):
Idorsia Pharmaceuticals Ltd.

Tracking Information
First Submitted Date  ICMJE August 21, 2014
First Posted Date  ICMJE August 22, 2014
Results First Submitted Date  ICMJE July 1, 2016
Results First Posted Date  ICMJE August 10, 2016
Last Update Posted Date August 22, 2019
Study Start Date  ICMJE June 2014
Actual Primary Completion Date July 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 1, 2016)
Drug-specific Parasite Reduction Ratio (PRR48) of ACT-451840 Over 48 Hours Using a Standardized Approach [ Time Frame: 48 hours after study drug administration ]
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)
Original Primary Outcome Measures  ICMJE
 (submitted: August 21, 2014)
Parasite reduction ratio (PRR) of ACT-451840 on Plasmodium falciparum blood stage parasites in blood [ Time Frame: 48 hours ]
The inoculum used for blood stage Plasmodium falciparum challenge (BSPC) challenge will contain an estimated 1,800 viable parasite-infected erythrocytes diluted into 2 mL of normal saline for injection. Blood will be collected for malaria parasitemia assessment by polymerase chain reaction (PCR). Parasitemia ≥ 1,000 parasites/mL indicates that the subjects should be treated with ACT-451840 . If PCR counts are > 5,000 parasites/mL and symptomatic they will be dosed within 24 hours. PCR blood sampling will be performed prior to ACT-451840 dosing and at 2, 4, 8, 12, 16, 20, 24, 30, 36, 48 hours post-dosing. The PRR provides an estimate of the efficacy of an anti-malarial treatment and is the ratio of the parasite density between admission and 48 hours post-treatment. The PRR is estimated using the slope of the optimal fit of the log-linear relationship of the parasitemia decay.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 25, 2016)
  • Maximum Plasma Concentration (Cmax) of ACT-451840 [ Time Frame: From pre-dose to 144 hours after study drug adminsitration ]
    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.
  • Time to Reach Maximum Plasma Concentration (Tmax) of ACT-451840 [ Time Frame: From pre-dose to144 hours after study drug administration ]
    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.
  • Areas Under the Plasma Concentration-time Curve of ACT-451840 [ Time Frame: From pre-dose to144 hours after study drug administration ]
    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
  • Terminal Half-life [t(1/2)] [ Time Frame: From pre-dose to144 hours after study drug adminsitration ]
    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
  • Change From Baseline in Blood Pressure to End of Study (EOS) [ Time Frame: Day 28 (EOS) ]
    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.
  • Change From Baseline in Body Temperature up to End of Study (EOS) [ Time Frame: Day 28 (EOS) ]
    Body temperature was measured orally
  • Change From Baseline in Respiratory Rate to End of Study (EOS) [ Time Frame: Day 28 (EOS) ]
Original Secondary Outcome Measures  ICMJE
 (submitted: August 21, 2014)
  • Change in body temperature from baseline up to end of study [ Time Frame: up to 28 days ]
    Body temperature [sublingual] will be measured for up to 24 days post ACT-451840 treatment and on the final visit (Day28/End of Study)
  • Change in systolic blood pressure from baseline up to end of study [ Time Frame: up to 28 days ]
    Systolic blood pressure will be measured for up to 24 days post ACT-451840 treatment and on the final visit (Day28/End of Study)
  • Change in diastolic blood pressure from baseline up to end of study [ Time Frame: up to 28 days ]
    Diastolic blood pressure will be measured for up to 24 days post ACT-451840 treatment and on the final visit (Day28/End of Study)
  • Change in respiratory rate from baseline up to end of study [ Time Frame: up to 28 days ]
    Respiratory rate will be measured for up to 24 days post ACT-451840 treatment and on the final visit (Day28/End of Study)
  • Maximum plasma concentration (Cmax) of ACT-451840 [ Time Frame: 144 hours ]
    Blood samples will be collected to determine ACT-451840 concentrations 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. Assay of ACT-451840 will be performed using a validated bioanalytical method.
  • Time to reach maximum plasma concentration (tmax) of ACT-451840 [ Time Frame: 144 hours ]
    Blood samples will be collected to determine ACT-451840 concentrations 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. Assay of ACT-451840 will be performed using a validated bioanalytical method.
  • Area under the plasma concentration-time curve (AUC(0-t)) of ACT- 451840 [ Time Frame: 144 hours ]
    Blood samples will be collected to determine ACT-451840 concentrations 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. Assay of ACT-451840 will be performed using a validated bioanalytical method.
  • Area under the plasma concentration-time curve (AUC(0-infinity)) of ACT- 451840 [ Time Frame: 144 hours ]
    Blood samples will be collected to determine ACT-451840 concentrations 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. Assay of ACT-451840 will be performed using a validated bioanalytical method.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of ACT-451840 Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Subjects
Official Title  ICMJE A Proof-of-concept Study to Assess the Effect of ACT-451840 Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Subjects
Brief Summary 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
Detailed Description 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Healthy Subjects
Intervention  ICMJE
  • Drug: ACT-451840:
    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.
  • Other: Plasmodium falciparum-infected human erythrocytes:
    Each participant was inoculated on Day 0 with approximately 1,800 viable Plasmodium falciparum-infected human erythrocytes administered intravenously.
  • Drug: Artemether 20 mg and lumefantrine 120mg combination tablet:
    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).
    Other Name: Riamet®
  • Drug: Primaquine:
    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.
    Other Name: Primacin™
Study Arms  ICMJE Experimental: ACT-451840 500 mg
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
Interventions:
  • Drug: ACT-451840:
  • Other: Plasmodium falciparum-infected human erythrocytes:
  • Drug: Artemether 20 mg and lumefantrine 120mg combination tablet:
  • Drug: Primaquine:
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 21, 2014)
8
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE July 2014
Actual Primary Completion Date July 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Body weight, minimum 50 kg, body mass index 18-32 kg/m^2.
  • Certified healthy by detailed medical history and physical examination.
  • Normal vital signs.
  • Normal standard 12-lead electrocardiograph (ECG).
  • Laboratory parameters within normal range, unless the investigator considered an abnormality to be clinically irrelevant.
  • Use a double barrier method of contraception (male condom plus diaphragm or plus intrauterine device or plus hormonal contraceptive by female partner) for at least 14 days prior to the first dose of study drug until 90 days after the last dose.
  • Written informed consent prior to undertaking any study procedure.

Exclusion Criteria:

  • Any history of malaria.
  • Traveled to or lived (>2 weeks) in a malaria-endemic country in the past 12 months or planned travel to a malaria-endemic country during the course of the study.
  • Evidence of increased cardiovascular disease risk.
  • History of splenectomy.
  • Presence or history of drug hypersensitivity, or allergic disease diagnosed and treated by a physician or history of a severe allergic reaction, anaphylaxis or convulsions following any vaccination or infusion.
  • Presence of current or suspected serious chronic disease.
  • Receiving psychiatric drugs or hospitalized within the past 5 years prior to enrollment for psychiatric illness, history of suicide attempt or confinement for danger to self or others.
  • Frequent headaches and/or migraine, recurrent nausea, and/or vomiting.
  • Known inherited genetic anomaly.
  • Presence of acute infectious disease or fever within the 5 days prior to study product administration.
  • Evidence of acute illness within 4 weeks prior to screening.
  • Significant intercurrent disease.
  • Clinically significant disease or condition that might affect drug absorption, distribution or excretion.
  • Any investigational product study within the 12 weeks preceding the study.
  • Participation in a research study involving blood sampling greater than 450 mL/ unit of blood, or blood donation to a blood bank during the 8 weeks preceding the reference drug dose in the study.
  • Subject unwilling to defer blood donations for 6 months.
  • Blood donation within 1 month before inclusion.
  • Medical requirement for intravenous immunoglobulin or blood transfusions.
  • Previous blood transfusion.
  • Symptomatic postural hypotension.
  • History or presence of alcohol consumption of more than 40 g per day or drug habituation, or any prior intravenous usage of an illicit substance.
  • Smoking more than 5 cigarettes or equivalent per day, unable to stop smoking during the study.
  • Ingestion of poppy seeds within 24 hours of the screening blood test.
  • Excessive consumption of beverages containing xanthine bases.
  • Any medication within 14 days before inclusion or within 5 times the elimination half-life of the medication, vaccination within the last 28 days.
  • Corticosteroids, anti-inflammatory drugs, immunomodulators or anticoagulants.
  • Recent or current therapy with an antibiotic or drug with potential antimalarial activity.
  • Subject who, in the judgment of the investigator, was likely to be non-compliant, or unable to cooperate because of a language problem or poor mental development; was in the exclusion period of a previous study; lived alone; who could not be contacted in case of emergency; who was directly involved in conducting the study; who had no good peripheral venous access.
  • Positive result on any of the following tests: hepatitis B surface antigen, anti-hepatitis B core antibodies, anti-hepatitis C virus antibodies, anti-human immunodeficiency virus 1 and 2 antibodies.
  • Amphetamine, methamphetamines, barbiturates, benzodiazepines, cocaine, methadone, opiates, phencyclidine, tetrahydrocannabinols, tricyclic antidepressants detected in the urine drug screen unless there was an explanation acceptable to the medical investigator.
  • Positive alcohol test.
  • Pre-existing prolongation of the interval from beginning of the Q wave until end of the T wave corrected according to Bazett's formula (QTcB interval ) and considered clinically significant.
  • Family history of sudden death, congenital prolongation of QTc interval, known congenital prolongation of QTc interval, or any clinical condition known to prolong the QTc interval. History of symptomatic cardiac arrhythmias or clinically relevant bradycardia. Electrolyte disturbances.
  • ECG abnormalities at screening which in the opinion of the investigator is clinically relevant or will interfere with the ECG analysis.
  • History of clinically significant ECG abnormalities.
  • Known hypersensitivity to ACT-451840 or any of its excipients or artemether or other artemisinin derivatives, lumefantrine or other aryl aminoalcohols.
  • Unwillingness to abstain from consumption of citrus fruits or their juices, as well as all fruit juices from admission to the end of the confinement period.
  • Any history or presence of lactose intolerance.
  • Ingestion of any drug since the recruitment interview (other than the doses administered in this study) which, in the opinion of the investigator, could compromise the study.
  • Ingestion of any drug in the week prior to dosing or during the blood sampling period which, in the opinion of the investigator, could compromise the study.
  • Failure to conform to the requirements of the protocol.
  • Detection of any drug listed in the protocol in the urine drug screen unless there was an explanation acceptable to the investigator.
  • Vital signs outside the reference range and clinically significant.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 50 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02223871
Other Study ID Numbers  ICMJE AC-071-102
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Idorsia Pharmaceuticals Ltd.
Study Sponsor  ICMJE Idorsia Pharmaceuticals Ltd.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Michelle Lee Actelion
PRS Account Idorsia Pharmaceuticals Ltd.
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP