SJ733 Induced Blood Stage Malaria Challenge Study

NCT02867059 | Completed Phase 1 Results

• 1 other identifier: QP15C20
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 2

Brief Summary

This is a single-centre, open-label, study using induced blood stage malaria (IBSM) infection to characterize the activity of (+)-SJ000557733 or SJ733 for short, against early Plasmodium falciparum blood stage infection. The study will be conducted in two cohorts (n=8 per cohort). The anticipated efficacious dose range is expected to be within a range of 125 to 600 mg. The dose used in the first cohort was determined on the basis of the safety and PK data generated in the FIM study (NCT02661373) currently ongoing in United States (US) and will be 150 mg. Depending on the pharmacodynamics data (effect of SJ733 on parasitaemia) obtained from this first cohort, the dose in Cohort 2 may be adjusted but will not exceed 600 mg. Based on the PK from all three cohort from the FIM study, the median estimated dose to obtain the target SJ733 AUC of 13,000 (ug hr/L) is 370 mg. The dose of cohort 2 (≤600mg) is intended to provide further concentration-response information in the human challenge model. For Cohort 2 only, a second dose of SJ733 may be administered at peak gametocytaemia to assess if SJ733 can reduce gametocytes and subsequent infectivity to mosquitoes (a washout of \~15 days post initial SJ733 treatment will be observed). Depending on the data obtained from the first two cohorts, there may be a subsequent cohort, with the investigated dose of SJ733 to be determined by the Sponsor and Principal Investigator (PI) and endorsed by the Safety Review Team. Should this third dose be investigated, a substantial amendment including preliminary data from the first two cohorts will be submitted to the HREC for approval.

Conditions

Plasmodium Falciparum Malaria

Outcome Measures

Primary Outcomes (2)

• Activity of SJ733 Administered Orally on Clearance of P. Falciparum Blood Stage Parasites From the Blood in Healthy Subjects (Men and WNCBP)

  The parasite reduction ratio (PRR) provides an estimate of the efficacy of an antimalarial treatment and is the ratio of the parasite density between admission and 48 h post antimalarial treatment. The primary efficacy variable is parasite reduction ratio (PRR) of parasites based on qPCR after administration of SJ733. The PRR was estimated using the slope of the optimal fit of the log-linear relationship of the parasitaemia decay. PRR was calculated for each subject using the retrospective 18S rRNA qPCR data. If the model fit was adequate for the subject (defined as overall model p-value \<0.001), the slope and corresponding standard error from the log-linear regression was used to calculate the overall cohort specific PRR.

  Until End of Study (Day 28±3)

• Number of Participants With Adverse Events

  The safety and tolerability of SJ733 in healthy subjects (men and WNCBP) following infection with blood stage P. falciparum during the IBSM challenge study will be evaluated by observation of occurrence of adverse events.

  for up to 25th day post SJ733 treatment or longer as determind by the principal investigator

Study Arms (2)

first dose

EXPERIMENTAL

The dose used in the first cohort was determined on the basis of the safety and PK data generated in the FIM study (NCT02661373) currently ongoing in United States (US) and will be 150 mg.

Drug: (+)-SJ000557733

second dose

EXPERIMENTAL

Depending on the pharmacodynamics data (effect of SJ733 on parasitaemia) obtained from this first cohort, the dose in Cohort 2 may be adjusted but will not exceed 600 mg.

Drug: (+)-SJ000557733

Interventions

(+)-SJ000557733 DRUG

(+)-SJ000557733 (SJ733), in short SJ733, will be the second PfATP4 inhibitor to enter clinical development after KAE609 (Novartis) which is currently in Phase 2 stage. KAE609 (cipargamin; previously known as NITD609) is a spirotetrahydro-β-carbolines (spiroindolone). KAE609 inhibits QP15C20\_SJ733\_Challenge Protocol\_v2.0\_26July2016 Page 28 of 110 PfATP4, which results in a disruption of parasite sodium homeostasis. Compared to KAE609, SJ733 has the potential to be a very fast acting, antimalarial drug for human therapeutic application and may have a different safety profile in human participants. Finally, SJ733 blocks parasite transmission in vivo at potencies close to those where it is efficacious in blood stages, indicating its potential for transmission blockade in humans.

Also known as: SJ733

first dose; second dose

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Adult, male and women of non-child bearing potential (WNCBP as defined in Section 6.17), participants between 18 and 55 years of age inclusive, who do not live alone (from Day 0 until at least the end of the antimalarial drug treatment) and will be contactable and available for the duration of the trial (maximum of 6 weeks).
• Body weight minimum 50.0 kg, body mass index between 18.0 and 32.0 kg/m2, inclusive.
• Certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination).
• Normal vital signs after 5 minutes resting in supine position:
• mmHg ≤ systolic blood pressure (SBP) ≤ 140 mmHg, 50 mmHg ≤ diastolic blood pressure (DBP) ≤ 90 mmHg, 40 bpm ≤ heart rate (HR) ≤ 100 bpm.
• Normal standard 12-lead electrocardiogram (ECG) after 5 minutes resting in supine position; QTcF≤450 ms with absence of second or third degree atrioventricular block or abnormal T wave morphology.
• Laboratory parameters within the normal range, unless the Investigator considers an abnormality to be clinically irrelevant for healthy participants enrolled in this clinical investigation in accordance with Sponsor-approved clinically acceptable laboratory ranges documented prior to study start. More specifically for serum creatinine, hepatic transaminase enzymes (aspartate aminotransferase, alanine aminotransferase), and total bilirubin (unless the Participant has documented Gilbert syndrome) should not exceed the acceptable ranges approved by the Sponsor and haemoglobin must be equal or higher than the lower limit of the normal range.
• Male participants must agree to use a double barrier method of contraception including condom plus diaphragm or condom plus IUD or condom plus stable oral/transdermal/injectable hormonal contraceptive by female partner for at least 7 days prior to the time of the first dose of study drug through 90 days after the 5th half-life of the last dose of study drug (half-life of \~20 hours). Abstinent participants have to agree starting a double barrier method if they start sexual relationships during the study and up to 95 days after the last dose of study drug.
• Having given written informed consent prior to undertaking any study-related procedure.

You may not qualify if:

• Any history of malaria or participation to a previous malaria challenge study.
• Must not have travelled to or lived (\>2 weeks) in a malaria-endemic region during the past 12 months or planned travel to a malaria-endemic region during the course of the study (for endemic regions see http://www.map.ox.ac.uk/browse-resources/).
• Has evidence of increased cardiovascular disease risk (defined as \>10%, 5 year risk for those greater than 35 years of age), as determined by the Australian Absolute Cardiovascular Disease Risk Calculator (http://www.cvdcheck.org.au/). Risk factors include sex, age, systolic blood pressure (mm/Hg), smoking status, total and HDL cholesterol (mmol/L) and reported diabetes status.
• History of splenectomy.
• Presence or history of drug hypersensitivity, or allergic disease diagnosed and treated by a physician or history of a severe allergic reaction, anaphylaxis or convulsions following any vaccination or infusion.
• Presence of current or suspected serious chronic diseases such as cardiac or autoimmune disease (HIV or other immunodeficiencies), insulin-dependent and non-insulin dependent diabetes (excluding glucose intolerance if E03 is met), progressive neurological disease, severe malnutrition, acute or progressive hepatic disease, acute or progressive renal disease, psoriasis, rheumatoid arthritis, asthma, epilepsy or obsessive compulsive disorder, skin carcinoma excluding non-spreadable skin cancers such as basal cell and squamous cell carcinoma.
• History of photosensitivity.
• History of G6PD deficiency.
• Participants with history of schizophrenia, bi-polar disease, or other severe (disabling) chronic psychiatric diagnosis, including depression or receiving psychiatric drugs or who has been hospitalized within the past 5 years prior to enrollment for psychiatric illness, history of suicide attempt or confinement for danger to self or others.
• Migraine, recurrent nausea, and/or vomiting (more than twice a month).
• Presence of acute infectious disease or fever (e.g., sub-lingual temperature ≥ 38.5°C) within the five days prior to inoculation with malaria parasites.
• Evidence of acute illness within the four weeks before trial prior to screening that the Investigator deems may compromise participant safety.
• Significant inter-current disease of any type, in particular liver, renal, cardiac, pulmonary, neurologic, rheumatologic, or autoimmune disease by history, physical examination, and/or laboratory studies including urinalysis.
• Participant has a clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion, e.g. gastrectomy, diarrhea.
• Participation in any investigational product study within the 12 weeks preceding the study.

Sponsors & Collaborators

• Medicines for Malaria Venture: lead
• QIMR Berghofer Medical Research Institute: collaborator
• Q-Pharm Pty Limited: collaborator
• Clinical Network Services (CNS) Pty Ltd: collaborator

Study Sites (2)

Q-Pharm Clinics, Royal Brisbane and Women's Hospital

Brisbane, Queensland, 4006, Australia

Location

Q-Pharm Clinics

Herston, Queensland, 4006, Australia

Location

Related Publications (2)

• Woodford J, Gillman A, Jenvey P, Roberts J, Woolley S, Barber BE, Fernandez M, Rose S, Thomas P, Anstey NM, McCarthy JS. Positron emission tomography and magnetic resonance imaging in experimental human malaria to identify organ-specific changes in morphology and glucose metabolism: A prospective cohort study. PLoS Med. 2021 May 26;18(5):e1003567. doi: 10.1371/journal.pmed.1003567. eCollection 2021 May.

  PMID: 34038421 DERIVED

• 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 DERIVED

MeSH Terms

Conditions

Malaria, Falciparum

Interventions

SJ733

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Andrew Slade
• Organization: Medicines for Malaria Venture

sladea@mmv.org

+41 22 555 0415

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 5, 2016
• First Posted: August 15, 2016
• Study Start: September 13, 2016
• Primary Completion: December 22, 2016
• Study Completion: December 22, 2016
• Last Updated: May 5, 2020
• Results First Posted: April 15, 2020

Record last verified: 2020-04

Data Sharing

• IPD Sharing: Will not share

Locations

AU (2)