Clinical trial NCT02867059
Conditions: Plasmodium Falciparum Malaria
Sponsor: Medicines for Malaria Venture
Start date: 2016-09-13; Completion date: 2016-12-22
Enrollment: 17 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

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.

Detailed description:
Each participant in the cohort will be inoculated on Day 0 with \~2,800 viable Plasmodium falciparum-infected human erythrocytes (BSPC) administered intravenously. On an outpatient basis, participants will be monitored daily via phone call and then will attend the clinic daily (AM) from day 4 (until PCR positive for presence of malaria parasites). Once PCR positive they will be monitored twice-daily, morning (AM) and evening (PM) until treatment, for adverse events and the unexpected early onset of symptoms, signs or parasitological evidence of malaria. Microscopic examination for evidence of parasitaemia may be conducted at the discretion of the Investigator. On the day designated for commencement of treatment, as determined by qPCR results, participants will be admitted to the study unit and monitored. The threshold for commencement of treatment will be when PCR quantification of all participants is ≥ 5,000 parasites/mL. If the PCR quantification of any participant is ≥ 5,000 parasites/mL, and is accompanied by a clinical symptom score \>6, before all participants have reached the treatment threshold (PCR quantification of ≥ 5,000), then treatment of that participant will begin within a 24 h period.

Following treatment with SJ733, participants will be followed up as inpatients for at least 72 hours to ensure tolerance of the treatment and clinical response, then on an outpatient basis if clinically well, for monitoring of safety and clearance of malaria parasites via PCR. The plasma concentration-time profiles of SJ733 will be assessed from blood samples collected pre-dose and then following administration of the treatment drug. Wherever possible, PK sampling will coincide with post-dose blood collection for PCR monitoring of parasitaemia.

Participants may also be evaluated for the presence of gametocytes in the blood, as determined by qPCR (amplification of pfs25 gametocyte-specific transcript). Transmission blocking activity of SJ733 in P. falciparum IBSM infection may be assessed if there are \>500 parasites/ml (determined by 18S qPCR) verified as gametocytes by PCR for pfs25 and/or ring stage marker as appropriate. Transmission studies may be undertaken by direct skin feeding and/or indirect membrane feeding of mosquitoes. For indirect Membrane Feeding Assays (MFA), blood will be collected from each participant for membrane feeds using Anopheles vector mosquitoes. For direct skin feeding assays (DFA), participants will be escorted to the PC3 quarantine insectary facility at QIMR Berghofer Medical Research Institute and asked to allow Anopheles vector mosquitoes to feed on the volar surface of their forearms, calves or thighs for a period of 15±5 minutes. Microscopic examination for confirmation of gametocytaemia may be conducted at the discretion of the Investigator.

If gametocytaemia is detected, in Cohort 2 only, a second same strength dose of SJ733 may be administered on Day 23, to assess if SJ733 can reduce gametocytes and subsequent infectivity to mosquitoes. To receive the second SJ733 dose, participants will have \>500 parasites/ml (determined by 18S qPCR) verified as gametocytes by PCR for pfs25 and/or ring stage marker as appropriate. Membrane feeding and direct skin feeding may occur before and/or after this second SJ733 dose. Participants receiving the second SJ733 dose will visit the study unit on the morning of Day 23 for dosing and will be allowed to leave after \~10 hours. Participants will have blood samples taken during this visit at time-points indicated in the protocol.

Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) will occur 16 days (±3 days) post initial SJ733 treatment unless required earlier (Cohort 1 and Cohort 2 if not given second SJ733 dose). If a second dose of SJ733 is given in Cohort 2, Riamet® treatment will occur 11 days (± 3 days) post the second SJ733 treatment unless required earlier. Early intervention can occur if either poor responses or fast responses are seen following SJ733 treatment. This is to ensure participant safety and to avoid participant inconvenience if useful data cannot be obtained. A poor response is defined as a decrease in parasitaemia of less than 20% from baseline by 3 days post SJ733 treatment. A fast response occurs when, within the seven day period, two consecutive PCR assessments in 48 hours are negative. However, pre-emptive treatment with Riamet® can commence whenever deemed necessary by the Investigator. Participants can be administered the curative Riamet® on site for initial dosing followed by monitoring, either in clinic, or by telephone for three days to ensure adherence to Riamet® therapy.

Participants will be treated with a single dose (45 mg) of primaquine (Primacin™) as described in Section 4.3 in this protocol at the time of their Riamet® treatment if gametocytes are identified, to ensure complete clearance of any gametocytes present.

Adverse events will be monitored via telephone monitoring, during confinement within the clinical research unit, and on outpatient review following malaria challenge inoculation and administration of the antimalarial treatment. Blood samples for safety evaluation, including for LFT assessment, malaria monitoring, pharmacokinetic determination of drug levels in plasma and/or blood, and red blood cell antibodies will be drawn at screening and/or baseline and at nominated times after malaria challenge.

This study includes evaluation of optional, exploratory markers, which require separate informed consent for participants agreeing to participate in any of these.

Arms: arm 1: 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. arm 2: 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.
Interventions: intervention 1: (+)-SJ000557733
Intervention descriptions: intervention 1: (+)-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.

Protocol documents: