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

• ClinicalTrials.gov Identifier: NCT04709692
• Recruitment Status: Completed
• First Posted: January 14, 2021
• Last Update Posted: November 8, 2022
• Sponsor: R. Kiplin Guy
• Collaborators: Global Health Innovative Technology Fund; Eisai Inc.; Asociacion Civil Selva Amazonica
• Information provided by (Responsible Party): R. Kiplin Guy, University of Kentucky

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Malaria, Falciparum; Malaria, Vivax	Drug: (+)-SJ000557733 (SJ733)	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 22 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• 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
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: April 14, 2021
• Actual Primary Completion Date: April 15, 2022
• Actual Study Completion Date: April 15, 2022

Arms and Interventions

Arm	Intervention/treatment
Arm 1 A (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	Drug: (+)-SJ000557733 (SJ733); Anti-Malarial; Other Name: SJ733
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.falciparum	Drug: (+)-SJ000557733 (SJ733); Anti-Malarial; Other Name: SJ733
Arm 2 A (cohort 2); 600 mg SJ733 administered orally once every day for three consecutive days for patients with P.vivax	Drug: (+)-SJ000557733 (SJ733); Anti-Malarial; Other Name: SJ733
Arm 2 B (cohort 2); 600 mg SJ733 administered orally once every day for three consecutive days for patients with P.falciparum	Drug: (+)-SJ000557733 (SJ733); Anti-Malarial; Other Name: SJ733
Arm 3 A (cohort 3); 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); Anti-Malarial; Other Name: SJ733
Arm 3 B (cohort 3); 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); Anti-Malarial; Other Name: SJ733

Outcome Measures

Primary Outcome Measures :

1. Crude Adequate Clinical and Parasitological Response (ACPR) [ Time Frame: 14 days for each arm ]
   Crude Adequate Clinical and Parasitological Response (ACPR) defined as the absence of microscopically determined parasitemia (thick smear)
2. Treatment emergent adverse events [ Time Frame: 42 days for each arm ]
   Incidence and seriousness of treatment emergent adverse events as defined in Adult Toxicity Tables
3. Clinically significant abnormal laboratory values [ Time Frame: 42 days for each arm ]
   Incidence and seriousness of clinically significant abnormal laboratory values including changes from baseline in (biochemistry and hematology)
4. Clinically significant abnormal vital signs [ Time Frame: 42 days for each arm ]
   Incidence and seriousness of clinically significant abnormal vital signs including changes from baseline

Secondary Outcome Measures :

1. Number of participants with signs and symptoms of uncomplicated malaria [ Time Frame: 42 days for each arm ]
   symptoms (fever clearance time) or physical examination signs related to uncomplicated P. vivax or P. falciparum malaria
2. Parasite clearance time [ Time Frame: 42 days for each arm ]
   Parasite clearance kinetics as measured by microscopy
3. Parasite reduction rate [ Time Frame: 42 days for each arm ]
   Parasite clearance kinetics as measured by microscopy - PRR (parasite reduction rate) and parasitemia half life
4. Asexual parasite clearance time [ Time Frame: 42 days for each arm ]
   Parasite clearance kinetics of asexual parasites as measured by microscopy including half life of clearance
5. Percentage reduction in asexual parasites from baseline [ Time Frame: 42 days for each arm ]
   Percentage reduction of asexual parasites as determined by microscopy
6. Area under the plasma concentration-time curve (AUC) [ Time Frame: 11 days for each arm ]
   AUC of SJ733 and its metabolite SJ506 will be reported
7. Maximum plasma drug concentration (Cmax) [ Time Frame: 11 days for each arm ]
   Cmax of SJ733 and its metabolite SJ506 will be reported
8. Time to reach maximum plasma concentration (Tmax) [ Time Frame: 11 days for each arm ]
   Tmax of SJ733 and its metabolite SJ506 will be reported
9. Drug Clearance [ Time Frame: 11 days for each arm ]
   Drug clearance of SJ733 and its metabolite SJ506 will be reported
10. Crude Adequate Clinical and Parasitological Response (ACPR) [ Time Frame: 42 days for each arm ]
    Crude ACPR at Days 28, 35, and 42 as measured by microscopy
11. Recurrence of malaria infection [ Time Frame: 42 days for each arm ]
    Recurrence of either P. vivax or P. falciparum malaria as measured by signs and symptoms or malaria and microscopy

Other Outcome Measures:

1. Crude Adequate Clinical and Parasitological Response (ACPR), PCR adjusted [ Time Frame: 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
2. Recurrence of malaria infection, PCR adjusted [ Time Frame: 42 days for each arm ]
   Recurrence of either P. vivax or P. falciparum malaria as measured by PCR

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

Peru

Asociación Civil Selva Amazónica (ACSA)

Iquitos, Loreto, Peru

Sponsors and Collaborators

R. Kiplin Guy

Global Health Innovative Technology Fund

Eisai Inc.

Asociacion Civil Selva Amazonica

Investigators

• Principal Investigator: Alejandro L Cuentas, MD, PhD; Asociación Civil Selva Amazónica (ACSA)

More Information

Publications:

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. Erratum In: Proc Natl Acad Sci U S A. 2015 Oct 20;112(42):E5764.

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.

• Responsible Party: R. Kiplin Guy, Professor and Dean, University of Kentucky
• ClinicalTrials.gov Identifier: NCT04709692
• Other Study ID Numbers: 53333
• First Posted: January 14, 2021
• Last Update Posted: November 8, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:

Malaria; Malaria, Falciparum; Malaria, Vivax; Protozoan Infections; Parasitic Diseases; Infections; Vector Borne Diseases