Clinical trial NCT04709692: Efficacy of SJ733 in Adults With Uncomplicated Plasmodium Falciparum or Vivax Malaria
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Malaria, Falciparum
Malaria, Vivax
Lead sponsor: University of Kentucky
Sponsor class: OTHER
Collaborators: name: Global Health Innovative Technology Fund
name: Eisai Inc.
name: Asociacion Civil Selva Amazonica
First posted: 2021-01-14
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
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
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Crude Adequate Clinical and Parasitological Response (ACPR)
timeFrame: 14 days for each arm
measure: Percent of Patients With Treatment Related Adverse Events
timeFrame: 42 days for each arm
measure: Percent of Patients With Clinically Significant Abnormal Laboratory Values
timeFrame: 42 days for each arm
measure: Percent of Patients With Clinically Significant Abnormal Vital Signs
timeFrame: 42 days for each arm
measure: Percent of Patients With a Decrease in Hemoglobin (HB) > 2 g/dL From Baseline to an Absolute Value of < 5 g/dL
timeFrame: 42 days
measure: Percent of Patients With an Absolute Neutrophil Count < 1,000/μL After Baseline
timeFrame: 42 days
measure: Percent of Patients Meeting Hy's Law Criteria
timeFrame: 42 days
measure: Percent of Patients With Any ALT or AST ≥ 5 x ULN
timeFrame: 42 days
measure: 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
timeFrame: 42 days
measure: Percent of Patients With Persistent ALT ≥ 3 x ULN for a Period of More Than 4 Weeks.
timeFrame: 42 days
measure: Percent of Patients With Clinical Signs of Possible Cutaneous Adverse Reactions
timeFrame: 42 days
measure: Percent of Patients With Clinically Significant Increases in Venous Methemoglobin Levels
timeFrame: 42 days
measure: Percent of Patients With Significant Changes in ECG Findings
timeFrame: 42 days
Secondary outcomes:
measure: Number of Participants With Signs and Symptoms of Uncomplicated Malaria
timeFrame: 42 days for each arm
measure: Parasite Clearance Time
timeFrame: 42 days for each arm
measure: Parasite Reduction Rate
timeFrame: 0->96 h, depending upon the time required to reach lower limit of detection
measure: Asexual Parasite Clearance Time
timeFrame: 42 days for each arm
measure: Percent Change in Asexual Parasites From Baseline
timeFrame: 42 days
measure: Area Under the Plasma Concentration-time Curve (AUC)
timeFrame: 11 days for each arm
measure: Maximum Plasma Drug Concentration (Cmax)
timeFrame: 11 days for each arm
measure: Time to Reach Maximum Plasma Concentration (Tmax)
timeFrame: 11 days for each arm
measure: Drug Clearance
timeFrame: 11 days for each arm
measure: Crude Adequate Clinical and Parasitological Response (ACPR) at Days 28, 35, and 42
timeFrame: 42 days for each arm
measure: Time to Recurrence of Malaria Infection
timeFrame: 42 days for each arm
measure: Fever Clearance Time
timeFrame: 42 days for each arm
Other outcomes:
measure: Crude Adequate Clinical and Parasitological Response (ACPR), PCR Adjusted, at Days 7, 14, 28, 35, and 42
timeFrame: 42 days for each arm
measure: Time to Recurrence of Malaria Infection, PCR Adjusted
timeFrame: 42 days for each arm
Locations:
city: Iquitos
country: Peru
facility: Asociación Civil Selva Amazónica (ACSA)
state: Loreto
Study officials:
affiliation: Asociación Civil Selva Amazónica (ACSA)
name: Alejandro L Cuentas, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jimenez-Diaz MB, Ebert D, Salinas Y, Pradhan A, Lehane AM, Myrand-Lapierre ME, O'Loughlin KG, Shackleford DM, Justino de Almeida M, Carrillo AK, Clark JA, Dennis AS, Diep J, Deng X, Duffy S, Endsley AN, Fedewa G, Guiguemde WA, Gomez MG, Holbrook G, Horst J, Kim CC, Liu J, Lee MC, Matheny A, Martinez MS, Miller G, Rodriguez-Alejandre A, Sanz L, Sigal M, Spillman NJ, Stein PD, Wang Z, Zhu F, Waterson D, Knapp S, Shelat A, Avery VM, Fidock DA, Gamo FJ, Charman SA, Mirsalis JC, Ma H, Ferrer S, Kirk K, Angulo-Barturen I, Kyle DE, DeRisi JL, Floyd DM, Guy RK. (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium. Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):E5455-62. doi: 10.1073/pnas.1414221111. Epub 2014 Dec 1.
citation: Gaur AH, McCarthy JS, Panetta JC, Dallas RH, Woodford J, Tang L, Smith AM, Stewart TB, Branum KC, Freeman BB 3rd, Patel ND, John E, Chalon S, Ost S, Heine RN, Richardson JL, Christensen R, Flynn PM, Van Gessel Y, Mitasev B, Mohrle JJ, Gusovsky F, Bebrevska L, Guy RK. Safety, tolerability, pharmacokinetics, and antimalarial efficacy of a novel Plasmodium falciparum ATP4 inhibitor SJ733: a first-in-human and induced blood-stage malaria phase 1a/b trial. Lancet Infect Dis. 2020 Aug;20(8):964-975. doi: 10.1016/S1473-3099(19)30611-5. Epub 2020 Apr 8.