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

NCT04709692 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 53333
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

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.

Conditions

Malaria, Falciparum; Malaria, Vivax

Outcome Measures

Primary Outcomes (13)

• 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 Outcomes (12)

• Number of Participants With Signs and Symptoms of Uncomplicated Malaria

  42 days for each arm

• Parasite Clearance Time

  42 days for each arm

• Parasite Reduction Rate

  0->96 h, depending upon the time required to reach lower limit of detection

• Asexual Parasite Clearance Time

  42 days for each arm

• Percent Change in Asexual Parasites From Baseline

  42 days

Other Outcomes (2)

• Crude Adequate Clinical and Parasitological Response (ACPR), PCR Adjusted, at Days 7, 14, 28, 35, and 42

  42 days for each arm

• Time to Recurrence of Malaria Infection, PCR Adjusted

  42 days for each arm

Study Arms (6)

Arm 1 A (cohort 1)

OTHER

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)

Arm 1 B (cohort 1)

OTHER

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)

Arm 2 A (cohort 2)

OTHER

600 mg SJ733 administered orally once every day for three consecutive days for patients with P.vivax

Drug: (+)-SJ000557733 (SJ733)

Arm 2 B (cohort 2)

OTHER

600 mg SJ733 administered orally once every day for three consecutive days for patients with P.falciparum

Drug: (+)-SJ000557733 (SJ733)

Arm 3 A (cohort 3)

OTHER

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)

Arm 3 B (cohort 3)

OTHER

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)

Interventions

(+)-SJ000557733 (SJ733) DRUG

Anti-Malarial

Also known as: SJ733

Arm 1 A (cohort 1); Arm 1 B (cohort 1); Arm 2 A (cohort 2); Arm 2 B (cohort 2); Arm 3 A (cohort 3); Arm 3 B (cohort 3)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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 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:

Sponsors & Collaborators

• R. Kiplin Guy: lead
• Global Health Innovative Technology Fund: collaborator
• Eisai Inc.: collaborator
• Asociacion Civil Selva Amazonica: collaborator

Study Sites (1)

Asociación Civil Selva Amazónica (ACSA)

Iquitos, Loreto, Peru

Location

Related Publications (2)

• 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.

  PMID: 25453091 BACKGROUND

• 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.

  PMID: 32275867 BACKGROUND

MeSH Terms

Conditions

Malaria, Falciparum; Malaria, Vivax

Interventions

SJ733

Condition Hierarchy (Ancestors)

Malaria; Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Limitations and Caveats

No participants were recruited into the P. falciparum arm as no participants who tested positive for P. falciparum met monoinfection inclusion criteria due to a decrease in P. falciparum monoinfection in the region.

Results Point of Contact

• Title: R. Kiplin Guy
• Organization: University of Kentucky

kip.guy@uky.edu

859-257-5290

Study Officials

• Alejandro L Cuentas, MD, PhD

  Asociación Civil Selva Amazónica (ACSA)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor and Dean

Model Details: 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

Study Record Dates

• First Submitted: December 15, 2020
• First Posted: January 14, 2021
• Study Start: April 14, 2021
• Primary Completion: April 15, 2022
• Study Completion: April 15, 2022
• Last Updated: December 4, 2023
• Results First Posted: December 4, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

PE (1)