Efficacy of SJ733 in Adults With Uncomplicated Plasmodium Falciparum or Vivax Malaria

Study Overview
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Brief Summary
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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
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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.

Official Title
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An Open Label Phase 2a Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of (+)-SJ000557733 (SJ733) With or Without Cobicistat in Adult Patients With Acute, Uncomplicated Malaria Over a 42 Day Period

Conditions
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Malaria, Falciparum, Malaria, Vivax

Intervention / Treatment
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* Drug: (+)-SJ000557733 (SJ733)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, aged 18 to 70 years of age (inclusive) at screening. Body weight between 45 kg and 90 kg inclusive Presence of mono-infection of P. falciparum or P. vivax confirmed by: 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, Microscopically confirmed parasite infection: 1,000 to 40,000 asexual parasite count/µL blood 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. Ability to swallow oral medication. Ability and willingness to participate and to comply with the study requirements Agreement to hospitalization for at least 102 hours and/or until malarial parasites are not detected by microscopy on 2 consecutive occasions. 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. 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: Use of oral, implantable, or injectable hormonal contraceptive, either combined or progestogen alone used in conjunction with barrier method as defined below. Use of an intrauterine device with a documented failure rate of <1% per year. Barrier method consisting of either condom or diaphragm. Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female. 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: Signs and symptoms of severe/complicated malaria according to the World Health Organization Criteria 2010 (Attachment 1: Definition of Severe Malaria) Mixed Plasmodium infection. 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. 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) 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. 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). Employment under the direct supervision of the investigators or study staff. Clinically significant alterations to hematologic or clinical chemistry parameters that in the opinion of the investigator precludes participation in the study, including: AST/ALT > 3 x upper limit of normal range (ULN) and total bilirubin is normal AST/ALT > 2 x ULN and total bilirubin is >1 and <1.5 x ULN and conjugated bilirubin is > 35% of the total bilirubin Total bilirubin > 1.5 x ULN Serum creatinine levels > 2 x ULN Hb level < 8 g/dL Platelet level < 50,000/mm3 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. Have received any antimalarial treatment (alone or in combination) in the past containing: Piperaquine, mefloquine, naphthoquine or sulphadoxine / pyrimethamine within the previous 6 weeks Amodiaquine or chloroquine within the previous 4 weeks 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 Any medication from the list of prohibited medications.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Arm 1 A (cohort 1)<br>Combination of 600 mg SJ733 with 150 mg Cobicistat administered orally once every day for three consecutive days for patients with P.vivax | Drug: (+)-SJ000557733 (SJ733)<br>* Anti-Malarial<br>* Other names: SJ733;|
| Other: Arm 1 B (cohort 1)<br>Combination of 600 mg SJ733 with 150 mg Cobicistat administered orally once every day for three consecutive days for patients with P.falciparum | Drug: (+)-SJ000557733 (SJ733)<br>* Anti-Malarial<br>* Other names: SJ733;|
| Other: Arm 2 A (cohort 2)<br>600 mg SJ733 administered orally once every day for three consecutive days for patients with P.vivax | Drug: (+)-SJ000557733 (SJ733)<br>* Anti-Malarial<br>* Other names: SJ733;|
| Other: Arm 2 B (cohort 2)<br>600 mg SJ733 administered orally once every day for three consecutive days for patients with P.falciparum | Drug: (+)-SJ000557733 (SJ733)<br>* Anti-Malarial<br>* Other names: SJ733;|
| Other: Arm 3 A (cohort 3)<br>Combination of 300 mg SJ733 with 150 mg Cobicistat administered orally once every day for three consecutive days for patients with P.vivax | Drug: (+)-SJ000557733 (SJ733)<br>* Anti-Malarial<br>* Other names: SJ733;|
| Other: Arm 3 B (cohort 3)<br>Combination of 300 mg SJ733 with 150 mg Cobicistat administered orally once every day for three consecutive days for patients with P.falciparum | Drug: (+)-SJ000557733 (SJ733)<br>* Anti-Malarial<br>* Other names: SJ733;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Crude Adequate Clinical and Parasitological Response (ACPR) | Crude Adequate Clinical and Parasitological Response (ACPR) defined as the absence of microscopically determined parasitemia (thick smear). | 14 days for each arm | 
| Percent of Patients With Treatment Related Adverse Events | Number of and seriousness of treatment related adverse events as defined in Adult Toxicity Tables | 42 days for each arm | 
| 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) | 42 days for each arm | 
| Percent of Patients With Clinically Significant Abnormal Vital Signs | Number of and seriousness of clinically significant abnormal vital signs including changes from baseline | 42 days for each arm | 
| 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 | 42 days | 
| 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 | 42 days | 
| 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. | 42 days | 
| 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) | 42 days | 
| 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)) | 42 days | 
| 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. | 42 days | 
| 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 | 42 days | 
| Percent of Patients With Clinically Significant Increases in Venous Methemoglobin Levels | Percent of patients with clinically significant increases in venous methemoglobin levels | 42 days | 
| 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 | 42 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 42 days for each arm | 
| Parasite Clearance Time | Time to parasite clearance as measured by microscopy | 42 days for each arm | 
| 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). | 0->96 h, depending upon the time required to reach lower limit of detection | 
| 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. | 42 days for each arm | 
| 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. | 42 days | 
| Area Under the Plasma Concentration-time Curve (AUC) | AUC of SJ733 and its metabolite SJ506 will be reported | 11 days for each arm | 
| Maximum Plasma Drug Concentration (Cmax) | Cmax of SJ733 and its metabolite SJ506 will be reported | 11 days for each arm | 
| Time to Reach Maximum Plasma Concentration (Tmax) | Time to reach maximum plasma concentration (Tmax) of SJ733 will be reported | 11 days for each arm | 
| Drug Clearance | Drug clearance of SJ733 and its metabolite SJ506 will be reported | 11 days for each arm | 
| 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. | 42 days for each arm | 
| 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 | 42 days for each arm | 
| 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 | 42 days for each arm |