Malaria, Falciparum, Malaria, Vivax
Conditions
Brief summary
This Phase 2a trial recruits adult patients with uncomplicated P. vivax or P. falciparum blood-stage malaria mono-infection. The study drug SJ733 will be administered to examine its antimalarial efficacy, safety, and tolerability. This study also evaluates whether or not a fixed dose of the pharmacoenhancer cobicistat when given in combination with SJ733 significantly improves drug efficacy.
Detailed description
This is an adaptive open label Phase 2a study to examine the antimalarial efficacy, safety, and tolerability of SJ733 in adult patients with uncomplicated P. vivax or P. falciparum blood-stage malaria monoinfection. SJ733 will be administered orally once every day for three consecutive days, with or without a fixed dose of the pharmacoenhancer cobicistat. The Phase 1 clinical data (completed under a US IND) and PK/PD models suggest that SJ733 is most likely to be curative as a 3-daily-dose pharmacoenhanced therapy, due to its moderately rapid clearance. There will be 1-3 cohorts with each cohort containing two treatment arms, P. falciparum (a) and P. vivax (b). Cohort progression will be managed independently for each treatment arm. Interim analysis will determine whether the data for a given treatment arm meets the success criteria, is inconclusive, or meets the failure criteria. Antimalarial efficacy will be examined over the period of 42 days. Additional aims are to characterize the safety and pharmacokinetics of SJ733. The results of this trial will identify active, well-tolerated doses for investigation in a larger Phase 2b clinical trial.
Interventions
DRUG(+)-SJ000557733 (SJ733)
Anti-Malarial
Sponsors
Global Health Innovative Technology Fund
Eisai Inc.
Asociacion Civil Selva Amazonica
R. Kiplin Guy
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
There are 6 treatment arms (three cohorts, each with P. falciparum and P.vivax arms).Cohort progression will be managed independently for each treatment arm. Interim analysis will determine whether the data for each arm meets the success criteria
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female, aged 18 to 70 years of age (inclusive) at screening. 2. Body weight between 45 kg and 90 kg inclusive 3. Presence of mono-infection of P. falciparum or P. vivax confirmed by: 1. Fever, as defined by axillary temperature ≥ 37.5°C or oral/rectal/tympanic temperature ≥ 38°C, or history of fever in the previous 24 hours (history of fever must be documented) and, 2. Microscopically confirmed parasite infection: 1,000 to 40,000 asexual parasite count/µL blood 4. Written informed consent provided by participant, in accordance with local practice. If the participant is unable to write, witnessed consent is permitted according to local ethical considerations. 5. Ability to swallow oral medication. 6. Ability and willingness to participate and to comply with the study requirements 7. Agreement to hospitalization for at least 102 hours and/or until malarial parasites are not detected by microscopy on 2 consecutive occasions. 8. Agreement to come back to the hospital on Days 7, 10 or 11, 14, 17 or 18, 21, 24 or 25, 28, 35, and 42. 9. Women of child-bearing potential, has a negative pregnancy test at screening, and agrees to comply with one of the following during the treatment stage of the study and for a period of 90 days after stopping study drug: 1. Use of oral, implantable, or injectable hormonal contraceptive, either combined or progestogen alone used in conjunction with barrier method as defined below. 2. Use of an intrauterine device with a documented failure rate of \<1% per year. 3. Barrier method consisting of either condom or diaphragm. 4. Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female. 5. Complete abstinence from intercourse for 2 weeks prior to administration of study drug, throughout the study and for a period of 90 days after stopping study drug.
Exclusion criteria
1. Signs and symptoms of severe/complicated malaria according to the World Health Organization Criteria 2010 (Attachment 1: Definition of Severe Malaria) 2. Mixed Plasmodium infection. 3. Severe vomiting, defined as more than three times in the 24 hours prior to inclusion in the study, or severe diarrhea defined as 3 or more watery stools per day. 4. Severe malnutrition (defined as the weight-for-height being below -3 standard deviation or less than 70% of median of the NCHS/WHO normalized reference values) 5. Presence of a significant medical or psychiatric condition, or any other serious or chronic clinical condition requiring hospitalization, or any other condition that in the opinion of the investigator precludes participation in the study. 6. Female patients must not be either lactating or pregnant as demonstrated by a negative serum point-of-care pregnancy test pre-dose (the result of the pre-dose assessment must be confirmed negative prior to dosing). 7. Employment under the direct supervision of the investigators or study staff. 8. Clinically significant alterations to hematologic or clinical chemistry parameters that in the opinion of the investigator precludes participation in the study, including: 1. AST/ALT \> 3 x upper limit of normal range (ULN) and total bilirubin is normal 2. AST/ALT \> 2 x ULN and total bilirubin is \>1 and \<1.5 x ULN and conjugated bilirubin is \> 35% of the total bilirubin 3. Total bilirubin \> 1.5 x ULN 4. Serum creatinine levels \> 2 x ULN 5. Hb level \< 8 g/dL 6. Platelet level \< 50,000/mm3 9. Participation in a clinical study of another investigational small molecule within 30 days or investigational biologic within 90 days prior to study enrollment or planning to begin such participation during the study. 10. Have received any antimalarial treatment (alone or in combination) in the past containing: 1. Piperaquine, mefloquine, naphthoquine or sulphadoxine / pyrimethamine within the previous 6 weeks 2. Amodiaquine or chloroquine within the previous 4 weeks 3. Any artemisinin (artesunate, artemether, arteether or dihydroartemisinin) quinine, halofantrine, lumefantrine and any other anti-malarial treatment or antibiotics with antimalarial activity (including cotrimoxazole, tetracyclines, quinolones and fluoroquinolones, and azithromycin) within the past 14 days 11. Any medication from the list of prohibited medications.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Patients With Clinically Significant Increases in Venous Methemoglobin Levels | 42 days | Percent of patients with clinically significant increases in venous methemoglobin levels |
| Percent of Patients With Clinically Significant Abnormal Vital Signs | 42 days for each arm | Number of and seriousness of clinically significant abnormal vital signs including changes from baseline |
| Crude Adequate Clinical and Parasitological Response (ACPR) | 14 days for each arm | Crude Adequate Clinical and Parasitological Response (ACPR) defined as the absence of microscopically determined parasitemia (thick smear). |
| Percent of Patients With Treatment Related Adverse Events | 42 days for each arm | Number of and seriousness of treatment related adverse events as defined in Adult Toxicity Tables |
| Percent of Patients With Clinically Significant Abnormal Laboratory Values | 42 days for each arm | Number of and seriousness of clinically significant abnormal laboratory values including changes from baseline in (biochemistry and hematology) |
| Percent of Patients With a Decrease in Hemoglobin (HB) > 2 g/dL From Baseline to an Absolute Value of < 5 g/dL | 42 days | Percent of patients with a decrease in hemoglobin (HB) \> 2 g/dL from baseline to an absolute value of \< 5 g/dL |
| Percent of Patients With an Absolute Neutrophil Count < 1,000/μL After Baseline | 42 days | Percent of patients with an absolute Neutrophil count \< 1,000/μL after baseline |
| Percent of Patients Meeting Hy's Law Criteria | 42 days | Percent of patients meeting Hy's law criteria. Hy's law criteria: (1) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation of \>3× the upper limit of normal (ULN); (2) total bilirubin (TBL) elevation of \>2× ULN; (3) absence of initial findings of cholestasis (ie, absence of elevation of alkaline phosphatase \[ALP\] to \>2× ULN); and (4) no other reason can be found to explain the combination of increased ALT and TBL, such as viral hepatitis A through E; other preexisting or acute liver disease; or another drug capable of causing the observed injury. |
| Percent of Patients With Any ALT or AST ≥ 5 x ULN | 42 days | Percent of patients with Any ALT or AST ≥ 5 x upper limit of normal (ULN) |
| Percent of Patients With a ny AST or ALT ≥ 3 x ULN Together With the Appearance of Fatigue, Nausea, Vomiting, Right Upper Quadrant Pain or Tenderness, Fever, Rash and/or Eosinophilia | 42 days | Percent of patients with any AST or ALT ≥ 3 x ULN together with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or eosinophilia (eosinophil percent or count above the upper limit of normal (ULN)) |
| Percent of Patients With Persistent ALT ≥ 3 x ULN for a Period of More Than 4 Weeks. | 42 days | Percent of patients with persistent ALT ≥ 3 x ULN for a period of more than 4 weeks. |
| Percent of Patients With Clinical Signs of Possible Cutaneous Adverse Reactions | 42 days | Percent of patients with clinical signs of possible cutaneous adverse reactions such as dermatitis, rash, erythematous rash, macular rash, papular rash, maculo-papular rash, pruritic rash, pustular rash, vesicular rash |
| Percent of Patients With Significant Changes in ECG Findings | 42 days | Percent of patients with significant changes in ECG findings, including heart rate, ECG intervals (PR, QTcB, QTcF), conduction changes or abnormalities |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fever Clearance Time | 42 days for each arm | Time from baseline to the first of two consecutive post-dose auxiliary temperature measurements \< 37.5 C obtained within an interval of 4 to 24 hours of each other |
| Number of Participants With Signs and Symptoms of Uncomplicated Malaria | 42 days for each arm | Number of participants with symptoms (including fever) or physical examination signs related to uncomplicated P. vivax or P. falciparum malaria |
| Parasite Clearance Time | 42 days for each arm | Time to parasite clearance as measured by microscopy |
| Parasite Reduction Rate | 0->96 h, depending upon the time required to reach lower limit of detection | The parasite reduction rate is calculated as the slope of the linear portion of the regression fit of natural log of average parasitemia (per microliter) versus time (in hours). Reported slope is representative of all analyzed participants in each arm. Slope is analyzed during time frame in which there is active reduction of parasitemia by treatment (0-\>96 h). |
| Asexual Parasite Clearance Time | 42 days for each arm | Time to clearance of asexual parasites as measured by microscopy including half life of clearance. Clearance time represents the time at which the mean parasitemia has reached the given threshold for the arm/cohort. For PC100, the value represents the time at which all patients have undetectable parasitemia. |
| Percent Change in Asexual Parasites From Baseline | 42 days | Percentage change of asexual parasites as determined by microscopy, relative to baseline at the specified times. The value represents the average parasitemia in the arm/cohort at the given time (per microliter) versus time (in hours) compared to the average parasitemia at T0. Reported reduction is representative of all analyzed participants in each arm. |
| Area Under the Plasma Concentration-time Curve (AUC) | 11 days for each arm | AUC of SJ733 and its metabolite SJ506 will be reported |
| Maximum Plasma Drug Concentration (Cmax) | 11 days for each arm | Cmax of SJ733 and its metabolite SJ506 will be reported |
| Time to Reach Maximum Plasma Concentration (Tmax) | 11 days for each arm | Time to reach maximum plasma concentration (Tmax) of SJ733 will be reported |
| Drug Clearance | 11 days for each arm | Drug clearance of SJ733 and its metabolite SJ506 will be reported |
| Crude Adequate Clinical and Parasitological Response (ACPR) at Days 28, 35, and 42 | 42 days for each arm | Crude Adequate Clinical and Parasitological Response (ACPR) at Days 28, 35, and 42 as measured by microscopy. |
| Time to Recurrence of Malaria Infection | 42 days for each arm | Time to recurrence of either P. vivax or P. falciparum malaria as measured by signs and symptoms or malaria and microscopy |
Other
| Measure | Time frame | Description |
|---|---|---|
| Crude Adequate Clinical and Parasitological Response (ACPR), PCR Adjusted, at Days 7, 14, 28, 35, and 42 | 42 days for each arm | Crude Adequate Clinical and Parasitological Response (ACPR) as adjusted by quantitative PCR of parasite DNA at Days 7, 14, 28, 35, and 42 |
| Time to Recurrence of Malaria Infection, PCR Adjusted | 42 days for each arm | Time to recurrence of either P. vivax or P. falciparum malaria as measured by PCR |
Countries
Peru
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 B (Cohort 1) Combination of 600 mg SJ733 with 150 mg Cobicistat administered orally once every day for three consecutive days for patients with P.vivax
(+)-SJ000557733 (SJ733): Anti-Malarial | 10 |
| Arm 2 B (Cohort 2) 600 mg SJ733 administered orally once every day for three consecutive days for patients with P.vivax
(+)-SJ000557733 (SJ733): Anti-Malarial | 12 |
| Total | 22 |
Baseline characteristics
| Characteristic | Arm 2 B (Cohort 2) | Total | Arm 1 B (Cohort 1) |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 22 Participants | 10 Participants |
| Age, Continuous | 42.9 years STANDARD_DEVIATION 12.87 | 40.6 years STANDARD_DEVIATION 13.9 | 34.6 years STANDARD_DEVIATION 12.47 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 12 Participants | 22 Participants | 10 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Peru | 12 participants | 22 participants | 10 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Male | 11 Participants | 20 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 12 |
| other Total, other adverse events | 2 / 10 | 3 / 12 |
| serious Total, serious adverse events | 1 / 10 | 1 / 12 |
Outcome results
Primary
Crude Adequate Clinical and Parasitological Response (ACPR)
Crude Adequate Clinical and Parasitological Response (ACPR) defined as the absence of microscopically determined parasitemia (thick smear).
Time frame: 14 days for each arm
Population: Only participants eligible for efficacy analysis were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 B (Cohort 1) | Crude Adequate Clinical and Parasitological Response (ACPR) | 90 percentage of participants |
| Arm 2 B (Cohort 2) | Crude Adequate Clinical and Parasitological Response (ACPR) | 100 percentage of participants |
Primary
Percent of Patients Meeting Hy's Law Criteria
Percent of patients meeting Hy's law criteria. Hy's law criteria: (1) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation of \>3× the upper limit of normal (ULN); (2) total bilirubin (TBL) elevation of \>2× ULN; (3) absence of initial findings of cholestasis (ie, absence of elevation of alkaline phosphatase \[ALP\] to \>2× ULN); and (4) no other reason can be found to explain the combination of increased ALT and TBL, such as viral hepatitis A through E; other preexisting or acute liver disease; or another drug capable of causing the observed injury.
Time frame: 42 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 B (Cohort 1) | Percent of Patients Meeting Hy's Law Criteria | 0 Participants |
| Arm 2 B (Cohort 2) | Percent of Patients Meeting Hy's Law Criteria | 0 Participants |
Primary
Percent of Patients With a Decrease in Hemoglobin (HB) > 2 g/dL From Baseline to an Absolute Value of < 5 g/dL
Percent of patients with a decrease in hemoglobin (HB) \> 2 g/dL from baseline to an absolute value of \< 5 g/dL
Time frame: 42 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 B (Cohort 1) | Percent of Patients With a Decrease in Hemoglobin (HB) > 2 g/dL From Baseline to an Absolute Value of < 5 g/dL | 0 Participants |
| Arm 2 B (Cohort 2) | Percent of Patients With a Decrease in Hemoglobin (HB) > 2 g/dL From Baseline to an Absolute Value of < 5 g/dL | 0 Participants |
Primary
Percent of Patients With an Absolute Neutrophil Count < 1,000/μL After Baseline
Percent of patients with an absolute Neutrophil count \< 1,000/μL after baseline
Time frame: 42 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 B (Cohort 1) | Percent of Patients With an Absolute Neutrophil Count < 1,000/μL After Baseline | 1 Participants |
| Arm 2 B (Cohort 2) | Percent of Patients With an Absolute Neutrophil Count < 1,000/μL After Baseline | 0 Participants |
Primary
Percent of Patients With Any ALT or AST ≥ 5 x ULN
Percent of patients with Any ALT or AST ≥ 5 x upper limit of normal (ULN)
Time frame: 42 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 B (Cohort 1) | Percent of Patients With Any ALT or AST ≥ 5 x ULN | 0 Participants |
| Arm 2 B (Cohort 2) | Percent of Patients With Any ALT or AST ≥ 5 x ULN | 0 Participants |
Primary
Percent of Patients With a ny AST or ALT ≥ 3 x ULN Together With the Appearance of Fatigue, Nausea, Vomiting, Right Upper Quadrant Pain or Tenderness, Fever, Rash and/or Eosinophilia
Percent of patients with any AST or ALT ≥ 3 x ULN together with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or eosinophilia (eosinophil percent or count above the upper limit of normal (ULN))
Time frame: 42 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 B (Cohort 1) | Percent of Patients With a ny AST or ALT ≥ 3 x ULN Together With the Appearance of Fatigue, Nausea, Vomiting, Right Upper Quadrant Pain or Tenderness, Fever, Rash and/or Eosinophilia | 0 Participants |
| Arm 2 B (Cohort 2) | Percent of Patients With a ny AST or ALT ≥ 3 x ULN Together With the Appearance of Fatigue, Nausea, Vomiting, Right Upper Quadrant Pain or Tenderness, Fever, Rash and/or Eosinophilia | 0 Participants |
Primary
Percent of Patients With Clinically Significant Abnormal Laboratory Values
Number of and seriousness of clinically significant abnormal laboratory values including changes from baseline in (biochemistry and hematology)
Time frame: 42 days for each arm
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 B (Cohort 1) | Percent of Patients With Clinically Significant Abnormal Laboratory Values | 0 Participants |
| Arm 2 B (Cohort 2) | Percent of Patients With Clinically Significant Abnormal Laboratory Values | 2 Participants |
Primary
Percent of Patients With Clinically Significant Abnormal Vital Signs
Number of and seriousness of clinically significant abnormal vital signs including changes from baseline
Time frame: 42 days for each arm
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 B (Cohort 1) | Percent of Patients With Clinically Significant Abnormal Vital Signs | 0 Participants |
| Arm 2 B (Cohort 2) | Percent of Patients With Clinically Significant Abnormal Vital Signs | 0 Participants |
Primary
Percent of Patients With Clinically Significant Increases in Venous Methemoglobin Levels
Percent of patients with clinically significant increases in venous methemoglobin levels
Time frame: 42 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 B (Cohort 1) | Percent of Patients With Clinically Significant Increases in Venous Methemoglobin Levels | 0 Participants |
| Arm 2 B (Cohort 2) | Percent of Patients With Clinically Significant Increases in Venous Methemoglobin Levels | 0 Participants |
Primary
Percent of Patients With Clinical Signs of Possible Cutaneous Adverse Reactions
Percent of patients with clinical signs of possible cutaneous adverse reactions such as dermatitis, rash, erythematous rash, macular rash, papular rash, maculo-papular rash, pruritic rash, pustular rash, vesicular rash
Time frame: 42 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 B (Cohort 1) | Percent of Patients With Clinical Signs of Possible Cutaneous Adverse Reactions | 0 Participants |
| Arm 2 B (Cohort 2) | Percent of Patients With Clinical Signs of Possible Cutaneous Adverse Reactions | 0 Participants |
Primary
Percent of Patients With Persistent ALT ≥ 3 x ULN for a Period of More Than 4 Weeks.
Percent of patients with persistent ALT ≥ 3 x ULN for a period of more than 4 weeks.
Time frame: 42 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 B (Cohort 1) | Percent of Patients With Persistent ALT ≥ 3 x ULN for a Period of More Than 4 Weeks. | 0 Participants |
| Arm 2 B (Cohort 2) | Percent of Patients With Persistent ALT ≥ 3 x ULN for a Period of More Than 4 Weeks. | 0 Participants |
Primary
Percent of Patients With Significant Changes in ECG Findings
Percent of patients with significant changes in ECG findings, including heart rate, ECG intervals (PR, QTcB, QTcF), conduction changes or abnormalities
Time frame: 42 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 B (Cohort 1) | Percent of Patients With Significant Changes in ECG Findings | 0 Participants |
| Arm 2 B (Cohort 2) | Percent of Patients With Significant Changes in ECG Findings | 0 Participants |
Primary
Percent of Patients With Treatment Related Adverse Events
Number of and seriousness of treatment related adverse events as defined in Adult Toxicity Tables
Time frame: 42 days for each arm
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 B (Cohort 1) | Percent of Patients With Treatment Related Adverse Events | 0 Participants |
| Arm 2 B (Cohort 2) | Percent of Patients With Treatment Related Adverse Events | 0 Participants |
Secondary
Area Under the Plasma Concentration-time Curve (AUC)
AUC of SJ733 and its metabolite SJ506 will be reported
Time frame: 11 days for each arm
Population: Arm 2B participant whose condition worsened to severe malaria was not included in analysis due to no data available.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 B (Cohort 1) | Area Under the Plasma Concentration-time Curve (AUC) | AUC SJ733 at 24 hours | 110325 ug*h/L |
| Arm 1 B (Cohort 1) | Area Under the Plasma Concentration-time Curve (AUC) | AUC SJ506 at 24 hours | 14123.7 ug*h/L |
| Arm 1 B (Cohort 1) | Area Under the Plasma Concentration-time Curve (AUC) | AUC SJ733 at 48 hours | 271632.1 ug*h/L |
| Arm 1 B (Cohort 1) | Area Under the Plasma Concentration-time Curve (AUC) | AUC SJ506 at 48 hours | 29341.8 ug*h/L |
| Arm 1 B (Cohort 1) | Area Under the Plasma Concentration-time Curve (AUC) | AUC SJ733 at 72 hours | 450506.3 ug*h/L |
| Arm 1 B (Cohort 1) | Area Under the Plasma Concentration-time Curve (AUC) | AUC SJ506 at 72 hours | 46477.5 ug*h/L |
| Arm 1 B (Cohort 1) | Area Under the Plasma Concentration-time Curve (AUC) | AUC SJ733 at 96 hours | 517702.6 ug*h/L |
| Arm 1 B (Cohort 1) | Area Under the Plasma Concentration-time Curve (AUC) | AUC SJ506 at 96 hours | 73619.8 ug*h/L |
| Arm 1 B (Cohort 1) | Area Under the Plasma Concentration-time Curve (AUC) | AUC SJ733 at infinity | 538769.3 ug*h/L |
| Arm 1 B (Cohort 1) | Area Under the Plasma Concentration-time Curve (AUC) | AUC SJ506 at infinity | 93372.4 ug*h/L |
| Arm 2 B (Cohort 2) | Area Under the Plasma Concentration-time Curve (AUC) | AUC SJ506 at 96 hours | 134468 ug*h/L |
| Arm 2 B (Cohort 2) | Area Under the Plasma Concentration-time Curve (AUC) | AUC SJ733 at 24 hours | 24688.1 ug*h/L |
| Arm 2 B (Cohort 2) | Area Under the Plasma Concentration-time Curve (AUC) | AUC SJ506 at 72 hours | 118717 ug*h/L |
| Arm 2 B (Cohort 2) | Area Under the Plasma Concentration-time Curve (AUC) | AUC SJ506 at 24 hours | 31793.6 ug*h/L |
| Arm 2 B (Cohort 2) | Area Under the Plasma Concentration-time Curve (AUC) | AUC SJ506 at infinity | 141447 ug*h/L |
| Arm 2 B (Cohort 2) | Area Under the Plasma Concentration-time Curve (AUC) | AUC SJ733 at 48 hours | 56991.9 ug*h/L |
| Arm 2 B (Cohort 2) | Area Under the Plasma Concentration-time Curve (AUC) | AUC SJ733 at 96 hours | 105105.4 ug*h/L |
| Arm 2 B (Cohort 2) | Area Under the Plasma Concentration-time Curve (AUC) | AUC SJ506 at 48 hours | 74646.5 ug*h/L |
| Arm 2 B (Cohort 2) | Area Under the Plasma Concentration-time Curve (AUC) | AUC SJ733 at infinity | 111850 ug*h/L |
| Arm 2 B (Cohort 2) | Area Under the Plasma Concentration-time Curve (AUC) | AUC SJ733 at 72 hours | 92110.9 ug*h/L |
Secondary
Asexual Parasite Clearance Time
Time to clearance of asexual parasites as measured by microscopy including half life of clearance. Clearance time represents the time at which the mean parasitemia has reached the given threshold for the arm/cohort. For PC100, the value represents the time at which all patients have undetectable parasitemia.
Time frame: 42 days for each arm
Population: Only participants who were eligible for efficacy analysis were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 B (Cohort 1) | Asexual Parasite Clearance Time | 15.60 hours | Standard Deviation 8.32 |
| Arm 2 B (Cohort 2) | Asexual Parasite Clearance Time | 45.78 hours | Standard Deviation 48.33 |
Secondary
Crude Adequate Clinical and Parasitological Response (ACPR) at Days 28, 35, and 42
Crude Adequate Clinical and Parasitological Response (ACPR) at Days 28, 35, and 42 as measured by microscopy.
Time frame: 42 days for each arm
Population: One participant from Arm 2b voluntarily withdrew from the study before the 14 day primary ACPR measurement. That participant's data is not included.~One participant from Arm 2b developed severe malaria within hours after the first dose of SJ733. The participant received local treatment of standard of care for severe malaria. That participant's data is not included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 B (Cohort 1) | Crude Adequate Clinical and Parasitological Response (ACPR) at Days 28, 35, and 42 | ACPR day 28 | 20 percentage of participants |
| Arm 1 B (Cohort 1) | Crude Adequate Clinical and Parasitological Response (ACPR) at Days 28, 35, and 42 | ACPR day 35 | 20 percentage of participants |
| Arm 1 B (Cohort 1) | Crude Adequate Clinical and Parasitological Response (ACPR) at Days 28, 35, and 42 | ACPR day 42 | 20 percentage of participants |
| Arm 2 B (Cohort 2) | Crude Adequate Clinical and Parasitological Response (ACPR) at Days 28, 35, and 42 | ACPR day 28 | 30 percentage of participants |
| Arm 2 B (Cohort 2) | Crude Adequate Clinical and Parasitological Response (ACPR) at Days 28, 35, and 42 | ACPR day 35 | 20 percentage of participants |
| Arm 2 B (Cohort 2) | Crude Adequate Clinical and Parasitological Response (ACPR) at Days 28, 35, and 42 | ACPR day 42 | 10 percentage of participants |
Secondary
Drug Clearance
Drug clearance of SJ733 and its metabolite SJ506 will be reported
Time frame: 11 days for each arm
Population: Arm 2B participant whose condition progressed to severe malaria was not included in analysis as no PK data was collected.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 B (Cohort 1) | Drug Clearance | CL SJ733 | 4.51 L/h |
| Arm 1 B (Cohort 1) | Drug Clearance | CL SJ506 | 19.49 L/h |
| Arm 2 B (Cohort 2) | Drug Clearance | CL SJ733 | 16.06 L/h |
| Arm 2 B (Cohort 2) | Drug Clearance | CL SJ506 | 12.95 L/h |
Secondary
Fever Clearance Time
Time from baseline to the first of two consecutive post-dose auxiliary temperature measurements \< 37.5 C obtained within an interval of 4 to 24 hours of each other
Time frame: 42 days for each arm
Population: Analysis includes all eligible participants, including (in arm 2B) one participant who developed severe malaria.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm 1 B (Cohort 1) | Fever Clearance Time | 9.200 hours |
| Arm 2 B (Cohort 2) | Fever Clearance Time | 6.667 hours |
Secondary
Maximum Plasma Drug Concentration (Cmax)
Cmax of SJ733 and its metabolite SJ506 will be reported
Time frame: 11 days for each arm
Population: Arm 2B participant whose condition worsened to severe malaria was not included in analysis due to no data available.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 B (Cohort 1) | Maximum Plasma Drug Concentration (Cmax) | Cmax SJ733 | 9207.6 ng/mL |
| Arm 1 B (Cohort 1) | Maximum Plasma Drug Concentration (Cmax) | Cmax SJ506 | 1244 ng/mL |
| Arm 2 B (Cohort 2) | Maximum Plasma Drug Concentration (Cmax) | Cmax SJ733 | 2730.3 ng/mL |
| Arm 2 B (Cohort 2) | Maximum Plasma Drug Concentration (Cmax) | Cmax SJ506 | 2918.2 ng/mL |
Secondary
Number of Participants With Signs and Symptoms of Uncomplicated Malaria
Number of participants with symptoms (including fever) or physical examination signs related to uncomplicated P. vivax or P. falciparum malaria
Time frame: 42 days for each arm
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 B (Cohort 1) | Number of Participants With Signs and Symptoms of Uncomplicated Malaria | 10 Participants |
| Arm 2 B (Cohort 2) | Number of Participants With Signs and Symptoms of Uncomplicated Malaria | 12 Participants |
Secondary
Parasite Clearance Time
Time to parasite clearance as measured by microscopy
Time frame: 42 days for each arm
Population: Participants eligible for efficacy measurements were analyzed.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm 1 B (Cohort 1) | Parasite Clearance Time | 15.60 hours |
| Arm 2 B (Cohort 2) | Parasite Clearance Time | 45.78 hours |
Secondary
Parasite Reduction Rate
The parasite reduction rate is calculated as the slope of the linear portion of the regression fit of natural log of average parasitemia (per microliter) versus time (in hours). Reported slope is representative of all analyzed participants in each arm. Slope is analyzed during time frame in which there is active reduction of parasitemia by treatment (0-\>96 h).
Time frame: 0->96 h, depending upon the time required to reach lower limit of detection
Population: Participants eligible for efficacy analysis were analyzed
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm 1 B (Cohort 1) | Parasite Reduction Rate | -0.33 Ln(parasites/uL)/hour |
| Arm 2 B (Cohort 2) | Parasite Reduction Rate | -0.08 Ln(parasites/uL)/hour |
Secondary
Percent Change in Asexual Parasites From Baseline
Percentage change of asexual parasites as determined by microscopy, relative to baseline at the specified times. The value represents the average parasitemia in the arm/cohort at the given time (per microliter) versus time (in hours) compared to the average parasitemia at T0. Reported reduction is representative of all analyzed participants in each arm.
Time frame: 42 days
Population: Only data from participants who were eligible for efficacy analysis were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 B (Cohort 1) | Percent Change in Asexual Parasites From Baseline | Percent change in asexual parasites from baseline (24h) | -100 percentage change in parasites | Standard Deviation 0 |
| Arm 1 B (Cohort 1) | Percent Change in Asexual Parasites From Baseline | Percent change in asexual parasites from baseline (48h) | -100 percentage change in parasites | Standard Deviation 0 |
| Arm 1 B (Cohort 1) | Percent Change in Asexual Parasites From Baseline | Percent change in asexual parasites from baseline (72h) | -100 percentage change in parasites | Standard Deviation 0 |
| Arm 2 B (Cohort 2) | Percent Change in Asexual Parasites From Baseline | Percent change in asexual parasites from baseline (24h) | -97 percentage change in parasites | Standard Deviation 4.9 |
| Arm 2 B (Cohort 2) | Percent Change in Asexual Parasites From Baseline | Percent change in asexual parasites from baseline (48h) | -99.5 percentage change in parasites | Standard Deviation 1.5 |
| Arm 2 B (Cohort 2) | Percent Change in Asexual Parasites From Baseline | Percent change in asexual parasites from baseline (72h) | -99.8 percentage change in parasites | Standard Deviation 0.4 |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax)
Time to reach maximum plasma concentration (Tmax) of SJ733 will be reported
Time frame: 11 days for each arm
Population: Arm 2B participant whose condition worsened to severe malaria was not included in analysis as there was no data available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 B (Cohort 1) | Time to Reach Maximum Plasma Concentration (Tmax) | 53.97 hours |
| Arm 2 B (Cohort 2) | Time to Reach Maximum Plasma Concentration (Tmax) | 49.03 hours |
Secondary
Time to Recurrence of Malaria Infection
Time to recurrence of either P. vivax or P. falciparum malaria as measured by signs and symptoms or malaria and microscopy
Time frame: 42 days for each arm
Population: Includes participants who were eligible for efficacy analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 B (Cohort 1) | Time to Recurrence of Malaria Infection | 25.0 days | Standard Deviation 9.51 |
| Arm 2 B (Cohort 2) | Time to Recurrence of Malaria Infection | 24.1 days | Standard Deviation 8.95 |
Other Pre-specified
Crude Adequate Clinical and Parasitological Response (ACPR), PCR Adjusted, at Days 7, 14, 28, 35, and 42
Crude Adequate Clinical and Parasitological Response (ACPR) as adjusted by quantitative PCR of parasite DNA at Days 7, 14, 28, 35, and 42
Time frame: 42 days for each arm
Population: Does not include Arm 2B participant who withdrew before day 14 nor Arm 2B participant who developed severe malaria and was treated with local standard of care for severe malaria.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 B (Cohort 1) | Crude Adequate Clinical and Parasitological Response (ACPR), PCR Adjusted, at Days 7, 14, 28, 35, and 42 | ACPR 14 | 80 percentage of participants |
| Arm 1 B (Cohort 1) | Crude Adequate Clinical and Parasitological Response (ACPR), PCR Adjusted, at Days 7, 14, 28, 35, and 42 | ACPR 35 | 20 percentage of participants |
| Arm 1 B (Cohort 1) | Crude Adequate Clinical and Parasitological Response (ACPR), PCR Adjusted, at Days 7, 14, 28, 35, and 42 | ACPR 28 | 20 percentage of participants |
| Arm 1 B (Cohort 1) | Crude Adequate Clinical and Parasitological Response (ACPR), PCR Adjusted, at Days 7, 14, 28, 35, and 42 | ACPR 42 | 20 percentage of participants |
| Arm 1 B (Cohort 1) | Crude Adequate Clinical and Parasitological Response (ACPR), PCR Adjusted, at Days 7, 14, 28, 35, and 42 | ACPR 7 | 100 percentage of participants |
| Arm 2 B (Cohort 2) | Crude Adequate Clinical and Parasitological Response (ACPR), PCR Adjusted, at Days 7, 14, 28, 35, and 42 | ACPR 42 | 10 percentage of participants |
| Arm 2 B (Cohort 2) | Crude Adequate Clinical and Parasitological Response (ACPR), PCR Adjusted, at Days 7, 14, 28, 35, and 42 | ACPR 7 | 100 percentage of participants |
| Arm 2 B (Cohort 2) | Crude Adequate Clinical and Parasitological Response (ACPR), PCR Adjusted, at Days 7, 14, 28, 35, and 42 | ACPR 14 | 80 percentage of participants |
| Arm 2 B (Cohort 2) | Crude Adequate Clinical and Parasitological Response (ACPR), PCR Adjusted, at Days 7, 14, 28, 35, and 42 | ACPR 28 | 30 percentage of participants |
| Arm 2 B (Cohort 2) | Crude Adequate Clinical and Parasitological Response (ACPR), PCR Adjusted, at Days 7, 14, 28, 35, and 42 | ACPR 35 | 20 percentage of participants |
Other Pre-specified
Time to Recurrence of Malaria Infection, PCR Adjusted
Time to recurrence of either P. vivax or P. falciparum malaria as measured by PCR
Time frame: 42 days for each arm
Population: Only participants eligible for efficacy analysis were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 B (Cohort 1) | Time to Recurrence of Malaria Infection, PCR Adjusted | 24.0 days | Standard Deviation 10.1 |
| Arm 2 B (Cohort 2) | Time to Recurrence of Malaria Infection, PCR Adjusted | 22.8 days | Standard Deviation 9.94 |