First-in-Human Study of an Oral Plasmodium Falciparum Plasma Membrane Protein Inhibitor

Study Overview
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Brief Summary
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Malaria is an infectious disease caused by a parasite that is passed to humans when an infected mosquito bites a person. About 3.4 billion people live in areas of the world where malaria is regularly found. In many countries, malaria is one of the leading causes of illness and death. Despite this, there are a limited number of drugs, called antimalarials, that can be used to treat malaria and increasing reports of resistance to existing antimalarials. The purpose of this research study is to test a new experimental antimalarial drug called SJ733 to first assess its safety, tolerability and blood levels in healthy adult volunteers. Single-dose, multi-dose and boosted-dose cohorts (both single and multi-dose) will be studied. The pharmacoenhancer (booster), cobicistat, will be given in combination with SJ733 in the boosted dose-cohorts. PRIMARY OBJECTIVES: To assess the preliminary safety and tolerability of escalating doses of antimalarial SJ733 in healthy human volunteers. To investigate the pharmacokinetic (PK) profile of escalating doses of antimalarial SJ733 and its metabolite in healthy human volunteers. To identify a dose of SJ733 that can be tested in a separate Phase 1b human malaria challenge study. To assess the preliminary safety and tolerability of SJ733 in healthy adult volunteers after multiple oral dosing. To assess the pharmacokinetics of SJ733 and its metabolite SJ506 after multiple dosing of SJ733 in healthy adult volunteers. To assess the preliminary safety and tolerability of escalating single oral doses of SJ733 in combination with cobicistat among healthy adult volunteers. To assess the pharmacokinetics of SJ733 and its metabolite SJ506 after single oral doses of SJ733 in combination with cobicistat among healthy adult volunteers. To assess the preliminary safety and tolerability of SJ733 in combination with cobicistat in healthy adult volunteers after multiple oral dosing. To assess the pharmacokinetics of SJ733 and its metabolite SJ506 after multiple dosing of SJ733 in combination with cobicistat among healthy volunteers. SECONDARY OBJECTIVE: To assess the impact of food intake on the pharmacokinetic profile of antimalarial SJ733.

Detailed Description
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This is a single site, Phase 1a, first-in-human, oral, primarily single-dose, dose escalation study of (+)-SJ000557733 (SJ733) in healthy adult volunteers. SJ733, is an investigational oral anti-malarial agent is a novel inhibitor of Plasmodium falciparum plasma membrane protein (PfATP4). Subjects meeting eligibility criteria will be enrolled using a leap frog, fixed dose escalation design with an adaptive component where 6 subjects are enrolled per dose cohort. Following successful completion of the safety and pharmacokinetic (PK) assessment resulting from the single-dose escalation portion of the study, a three-dose cohort study will be undertaken. It includes once per day oral dosing for 3 consecutive days. Both single and multi-dose cohorts of SJ733 in combination with cobicistat (boosted cohorts) will also be completed. After the study results from the single-dose cohorts of SJ733 in combination with cobicistat (boosted cohorts) were reviewed, multi-dose cohorts of SJ733 in combination with cobicistat (boosted cohorts) were not conducted and Phase 2 study planning initiated.

Official Title
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Phase 1a, First-In-Human, Dose-Escalation Study of (+)-SJ000557733 (SJ733), an Oral, Novel Inhibitor of Plasmodium Falciparum Plasma Membrane Protein PfATP4

Conditions
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Malaria

Intervention / Treatment
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* Drug: SJ733
* Drug: Cobicistat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adult (as certified by comprehensive medical assessment including detailed history and complete physical examination), male or female, aged 18 to 55 years of age (inclusive) at screening At least 50 kg in weight and body mass index (BMI) between 18 and 34 kg/m^2 Able and willing to provide informed consent and to be available for follow-up for the planned duration of the study If female, then not of child bearing potential (i.e. permanently sterilized hysterectomy or bilateral oophorectomy at least 6 months before screening; proper documentation required] and/or post-menopausal defined as 12 months with no menses without an alternative cause and with an estradiol level of < 30 pg/mL and follicle-stimulating hormone level of > 40 IU/L at screening) Sexually active males must agree to be abstinent or use condoms for the duration of the study. Screening laboratories (hematology, chemistries, venous methemoglobin level specified in schedule of evaluations) within normal institutional range or if outside the range, not clinically significant in the opinion of the investigator. Inclusion Criteria for Participants in Single-dose Cohort Only:: Agrees not to receive any vaccination within 7 days prior to Day 0 and through Day 7. Agrees not to use nonprescription drugs, including vitamins, antacids, and herbal and dietary supplements within 7 days prior to Day 0 and through Day 7. Acetaminophen may be used at doses of ≤ 1 g/day, and ibuprofen may be used at doses of ≤ 1.2 g/day. Agrees not to use nicotine containing products from screening through Day 7. Agrees not to consume alcohol for the 24 hours prior to Day 0 and through Day 7. Agrees not to eat pomegranate, grapefruit or other citrus fruits or drink their juices within 7 days prior to Day 0 and through Day 7. Agrees to limit caffeine to no more than 200 mg on Day 0. Agrees not to eat or drink (except water) for 10 hours before the Day 0 visit and have no water for the hour prior to dosing. Exclusion Criteria: Presence of a significant medical or psychiatric condition that in the opinion of the investigator precludes participation in the study. Clinically significant abnormalities on physical examination that, in the opinion of the investigator, would preclude entry into the study. History of having a significant illness within the 2 weeks prior to screening visit. Participants can screen after illness is resolved for two weeks. History of clinically significant electrocardiogram abnormalities or clinically significant abnormalities from the screening electrocardiogram. G6PD deficiency History of hemolytic anemia or methemoglobinemia History of severe drug hypersensitivity including a severe allergic reaction, anaphylaxis or convulsions following any medication, vaccination or infusion. History of drug or alcohol abuse in the 12 months prior to screening or evidence at screening visit Use of nicotine containing products within 30 days prior to screening Positive blood test for HBsAg, HCV, or HIV-1 Participation in a clinical study of another investigational product within 30 days prior to study enrollment, or planning to begin such participation during the study. Employment under the direct supervision of the investigators or study staff. Receipt of any vaccination within 7 days of dosing. Febrile illness within 48 hours of dosing Use of any prescription medication within 14 days prior to study drug administration. Use of nonprescription drugs, including vitamins, antacids, and herbal and dietary supplements within 7 days prior to study drug administration. Acetaminophen may be used at doses of ≤ 1 g/day, and ibuprofen may be used at doses of ≤ 1.2 g/day. Consumption of pomegranate, grapefruit or other citrus fruits or their juices within 7 days prior to study drug administration. Use of nicotine containing products from screening to study drug administration. Consumption of alcohol within 24 hours prior to study drug administration. Inclusion Criteria For participants in multi-dose cohort only: Agrees not to receive any vaccination within 7 days prior to Day 1 and through Day 10. Agrees not to use nonprescription drugs, including vitamins, antacids, and herbal and dietary supplements within 7 days prior to Day 1 and through Day 10. Acetaminophen may be used at doses of ≤ 1 g/day, and ibuprofen may be used at doses of ≤ 1.2 g/day. Agrees not to use nicotine containing products from screening through Day 10. Agrees not to consume alcohol for the 24 hours prior to Day 1 and through Day 10. Agrees not to eat pomegranate, grapefruit or other citrus fruits or drink their juices within 7 days prior to Day 1 and through Day 10. Agrees to limit caffeine to no more than 200 mg on Days 1, 2, and 3. Agrees not to eat or drink (except water) for 10 hours before the Days 1, 2, and 3 visits and have no water for the hour prior to dosing on each of those days. Note: As with the single dose study, sexually active must agree to be abstinent or use condoms for the duration of the study (through the Day 14 visit).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>Participants will receive SJ733, an investigational drug developed at St. Jude Children's Research Hospital, and cobicistat. | Drug: SJ733<br>* SJ733 is an oral, novel inhibitor of Plasmodium Falciparum plasma membrane protein PFATP4. It will be administered as a single, multi, or boosted oral dose.<br>* Other names: (+)-SJ000557733;Drug: Cobicistat<br>* Commercially available cobicistat 150 mg tablets will be used. It will be administered as a single oral dose together with SJ733.<br>* Other names: Tybost®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity (DLT) | Number of DLT events will be described at each study dose level. DLT is defined as possibly, probably, or definitely related Grade 4 event, possibly, probably or definitely related Grade 3 event, or possibly, probably, or definitely related Grade 2 methemoglobinemia or anemia (attributed to hemolysis) events. | From baseline up to minimum of 7 days post-dose | 
| Maximum tolerated dose (MTD) | MTD is defined as the dose level prior to the dose cohort that 2 or more Grade 2 methemoglobinemia or anemia (attributed to hemolysis) OR any related Grade 3 OR any Grade 4, study drug adverse event (AE) occurred in. | 7 days after the last dose administration | 
| Drug absorption | Drug absorption of SJ733 and its metabolite will be reported. | From baseline through 7 days post-dose | 
| Drug clearance | Drug clearance of SJ733 and its metabolite will be reported. | From baseline through 7 days post-dose | 
| Drug volume of distribution | Drug volume of distribution of SJ733 and its metabolite will be reported. | From baseline through 7 days post-dose | 
| Area under the curve (AUC) | AUC of SJ733 and its metabolite will be reported. | From baseline through 7 days post-dose | 
| Time above threshold concentration | Time above threshold concentration of SJ733 and its metabolite will be reported. | From baseline through 7 days post-dose | 
| Maximum drug concentration (Cmax) | Cmax of SJ733 and its metabolite will be reported. | From baseline through 7 days post-dose | 
| Dose level of SJ733 | The dose chosen for the phase 1b trial will be no greater than the MTD and provide an exposure (AUC and time above threshold concentration) that equates (using applicable scaling) with those that provided maximum parasitological effect in the gold standard rodent model. | 14 days after the last dose administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Drug absorption in the fed cohort | Drug absorption of SJ733 and its metabolite in the fed cohort will be reported to assess the impact of food intake. | From baseline through 7 days post-dose | 
| Drug clearance in the fed cohort | Drug clearance of SJ733 and its metabolite in the fed cohort will be reported to assess the impact of food intake. | From baseline through 7 days post-dose | 
| Drug volume of distribution in the fed cohort | Drug volume of distribution of SJ733 and its metabolite in the fed cohort will be reported to assess the impact of food intake. | From baseline through 7 days post-dose | 
| Area under the curve (AUC) in the fed cohort | AUC of SJ733 and its metabolite in the fed cohort will be reported to assess the impact of food intake. | From baseline through 7 days post-dose | 
| Time above threshold concentration in the fed cohort | Time above threshold concentration SJ733 and its metabolite in the fed cohort will be reported to assess the impact of food intake. | From baseline through 7 days post-dose | 
| Maximum drug concentration (Cmax) in the fed cohort | Drug absorption of SJ733 and its metabolite in the fed cohort will be reported to assess the impact of food intake. | From baseline through 7 days post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antimalarial, First-in-Human, Pharmacokinetic