Healthy Subjects
Conditions
Keywords
Malaria, ACT-451840
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.
Interventions
DRUGACT-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.
OTHERPlasmodium falciparum-infected human erythrocytes:
Each participant was inoculated on Day 0 with approximately 1,800 viable Plasmodium falciparum-infected human erythrocytes administered intravenously.
DRUGArtemether 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).
DRUGPrimaquine:
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.
Sponsors
Idorsia Pharmaceuticals Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 50 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Drug-specific Parasite Reduction Ratio (PRR48) of ACT-451840 Over 48 Hours Using a Standardized Approach | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach Maximum Plasma Concentration (Tmax) of ACT-451840 | 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 | 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)] | 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 |
| Maximum Plasma Concentration (Cmax) of ACT-451840 | 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. |
| Change From Baseline in Body Temperature up to End of Study (EOS) | Day 28 (EOS) | Body temperature was measured orally |
| Change From Baseline in Respiratory Rate to End of Study (EOS) | Day 28 (EOS) | — |
| Change From Baseline in Blood Pressure to End of Study (EOS) | 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. |
Countries
Australia
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).
Participants by arm
| Arm | Count |
|---|---|
| ACT-451840 500 mg 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). | 8 |
| Total | 8 |
Baseline characteristics
| Characteristic | ACT-451840 500 mg |
|---|---|
| Age, Continuous | 24.1 Years |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 4 Participants |
| Race/Ethnicity, Customized Indian | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian | 1 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 8 / 8 |
| serious Total, serious adverse events | 0 / 8 |
Outcome results
Primary
Drug-specific Parasite Reduction Ratio (PRR48) of ACT-451840 Over 48 Hours Using a Standardized Approach
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)
Time frame: 48 hours after study drug administration
Population: Only subjects with appropriate overall fit (p-value of the overall model F-test \<0.001) were taken into account (n = 5)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ACT-451840 500 mg | Drug-specific Parasite Reduction Ratio (PRR48) of ACT-451840 Over 48 Hours Using a Standardized Approach | 234.5 Ratio |
Secondary
Areas Under the Plasma Concentration-time Curve of ACT-451840
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
Time frame: From pre-dose to144 hours after study drug administration
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| ACT-451840 500 mg | Areas Under the Plasma Concentration-time Curve of ACT-451840 | AUC(0-t) | 1254.8 ng*h/mL |
| ACT-451840 500 mg | Areas Under the Plasma Concentration-time Curve of ACT-451840 | AUC(0-inf) | 1284.4 ng*h/mL |
Secondary
Change From Baseline in Blood Pressure to End of Study (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.
Time frame: Day 28 (EOS)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| ACT-451840 500 mg | Change From Baseline in Blood Pressure to End of Study (EOS) | SBP at baseline (Day 0) | 121.0 mmHg |
| ACT-451840 500 mg | Change From Baseline in Blood Pressure to End of Study (EOS) | SBP at EOS (Day 28) | 125.5 mmHg |
| ACT-451840 500 mg | Change From Baseline in Blood Pressure to End of Study (EOS) | Change from Day 0 to Day 28 in SBP | 2.5 mmHg |
| ACT-451840 500 mg | Change From Baseline in Blood Pressure to End of Study (EOS) | DBP at baseline (Day 0) | 66.0 mmHg |
| ACT-451840 500 mg | Change From Baseline in Blood Pressure to End of Study (EOS) | DBP at EOS (Day 28) | 70.5 mmHg |
| ACT-451840 500 mg | Change From Baseline in Blood Pressure to End of Study (EOS) | Change from Day 0 to Day 28 in DBP | 0.5 mmHg |
Secondary
Change From Baseline in Body Temperature up to End of Study (EOS)
Body temperature was measured orally
Time frame: Day 28 (EOS)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| ACT-451840 500 mg | Change From Baseline in Body Temperature up to End of Study (EOS) | Temperature at baseline (Day 0) | 36.3 Degree Celsius |
| ACT-451840 500 mg | Change From Baseline in Body Temperature up to End of Study (EOS) | Temperature at EOS (Day 28) | 35.9 Degree Celsius |
| ACT-451840 500 mg | Change From Baseline in Body Temperature up to End of Study (EOS) | Change from Day 0 to Day 28 in temperature | -0.2 Degree Celsius |
Secondary
Change From Baseline in Respiratory Rate to End of Study (EOS)
Time frame: Day 28 (EOS)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| ACT-451840 500 mg | Change From Baseline in Respiratory Rate to End of Study (EOS) | Respiratory rate at baseline (Day 0) | 14 Breaths/min |
| ACT-451840 500 mg | Change From Baseline in Respiratory Rate to End of Study (EOS) | Respiratory rate at EOS (Day 28) | 16 Breaths/min |
| ACT-451840 500 mg | Change From Baseline in Respiratory Rate to End of Study (EOS) | Change from Day 0 to Day 28 in respiratory rate | 1.5 Breaths/min |
Secondary
Maximum Plasma Concentration (Cmax) of ACT-451840
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 frame: From pre-dose to 144 hours after study drug adminsitration
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| ACT-451840 500 mg | Maximum Plasma Concentration (Cmax) of ACT-451840 | 121.7 ng/mL |
Secondary
Terminal Half-life [t(1/2)]
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 frame: From pre-dose to144 hours after study drug adminsitration
Population: Per protocol set
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| ACT-451840 500 mg | Terminal Half-life [t(1/2)] | 36.4 Hours |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax) of ACT-451840
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.
Time frame: From pre-dose to144 hours after study drug administration
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ACT-451840 500 mg | Time to Reach Maximum Plasma Concentration (Tmax) of ACT-451840 | 4.0 Hours |
Post Hoc
Drug-specific Parasite Reduction Ratio (PRR48) of ACT-451840 Over 48 Hours Using a New Approach
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 following the data-driven method by Marquart et al. (2015), removing potential lag and tail phases prior to log-linear regression modeling.
Time frame: 48 hours after study drug administration
Population: Only subjects with appropriate overall fit (p-value of the overall model F-test \<0.001) were taken into account (n = 8 with the method described by Marquart et al., 2015)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ACT-451840 500 mg | Drug-specific Parasite Reduction Ratio (PRR48) of ACT-451840 Over 48 Hours Using a New Approach | 73.6 Ratio |