Evaluating the safety, tolerability and anti-parasitic immunity boosting activity of ruxolitinib when co-administered with artemether-lumefantrine in adults with Plasmodium falciparum Induced Blood Stage Malaria

Malaria challenge agent Each P. falciparum 3D7 challenge agent dose will contain parasitised and non-parasitised red blood cells (RBCs), resuspended in 0.9 percent Sodium Chloride Intravenous Infusion, in a total volume of 2 mL in syringes. The syringes will be double contained following preparation and labelled in accordance with Good Clinical Practice (GCP) guidelines and the Australian clinical trial handbook: guidance on conducting clinical trials in Australia using ‘unapproved’ therapeutic goods. Each volunteer administered 3D7 will be inoculated intravenously with a dose of approximately 2,800 viable P. falciparum 3D7-infected erythrocytes in 2 mL of saline for injection. Each volunteer will receive two inoculations as part of this study, the second inoculation being 90 plus/minus 7 days after the first inoculation. Investigational Medicinal Products Riamet (artemether-lumefantrine [AL]) Two courses of Riamet will be administered to all 26 volunteers during the study (one course after the first malaria inoculation and another course after the second inoculation). Each tablet contains 20 mg artemether and 120 mg lumefantrine. The standard adult dosing regimen will be used in this trial: 6 doses of 4 tablets administered orally twice daily over 3 consecutive days (total course of 24 tablets). Each dose should be taken with food or drinks rich in fat (e.g., milk). No food permitted within 30 minutes prior to AL dosing, or between AL and Rux dosing. Meals are not required to be standardized. Times of meals and completion times will be documented. The volunteers’ first treatment course (after the first malaria inoculation) will commence on Day 9 when parasitaemia for the majority of volunteers is expected to be above 5,000 parasites/mL. Earlier treatment for individual volunteers will be initiated if: •they experience a serious adverse event (SAE) related to the malaria challenge agent, or •they have a grade 3 AE graded in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) deemed related to malaria and not self-resolved or relieved with concomitant medications, or •the Investigator considers it necessary for volunteer safety The second treatment course (after the second malaria inoculation) will commence on an individualised basis, when: • qPCR parasitaemia reaches greater than or equal to 50,000 parasites/mL, or • they have a malaria clinical score greater than 6, and presence of parasitaemia, or • they experience an SAE related to the malaria challenge agent, or • they have a CTCAE grade 3 AE deemed related to malaria and not self-resolved or relieved with concomitant medications, or • the Investigator considers it necessary for volunteer safety. • If none of the above criteria for AL administration are reached by Day 118 plus or minus 7 days (28 days after second inoculation) then compulsory AL administration must occur. Volunteers may be assessed for the above criteria, by clinical evaluation and blood sampling up to twice-daily, separated by approximately 12 h. In the event that parasitaemia remains low and stable, clinic visits for blood sampling may be reduced to a minimum of 3 times per week, at the discretion of the Principal Investigator. Jakavi (ruxolitinib [Rux]) Commencing on Day 9, a single course of Jakavi will be administered only to the 13 volunteers randomised to the active group (after the first malaria inoculation). The equivalent of the standard adult dosing regimen according to the Product Information (PI) and Consumer Medicines Information (CMI) will be used: 1 tablet (1× 20 mg) administered orally with 250 mL water twice daily over 3 consecutive days (6 doses, total course of 6 tablets) and will be taken 2 hours after administration of AL. Participants will be instructed to swallow the tablet whole without biting or chewing. Doses will be administered by an unblinded staff member (not an investigator). Volunteers will be blindfolded for dosing; other participants will be prevented from witnessing dosing. No food permitted between AL and Rux, and for at least 1 hour post-Rux. Meals are not required to be standardized. Times of meals and completion times will be documented. Antimalarial rescue treatments Primacin (if required): Volunteers may be treated with Primacin after each course of AL if gametocytaemia is suspected from parasite lifecycle stage qRT-PCR to ensure complete clearance of gametocytes. If needed, volunteers will take six Primacin tablets (the total dose of 45 mg primaquine) as a single dose with food. Volunteers that are mildly G6PD deficient will take two Primacin tablets (the total dose of 15 mg primaquine) as a single dose with food. Volunteers who are severely G6PD deficient will not be administered Primacin. Volunteers will be reminded of the potential side effects of Primacin and will be given the CMI for Primacin. Malarone (if required): If an allergy or contraindication to Riamet develops, Malarone may be administered at Investigator’s discretion. The dose administered will be as recommended by the manufacturer for treatment of malaria. A treatment course of Malarone consists of four tablets of Malarone (atovaquone 250 mg, proguanil hydrochloride 100 mg) once daily orally for three days. Volunteers will be reminded of the potential side effects of Malarone and will be given the CMI for Malarone. Artesunate (if required): Intravenous artesunate may be used as a rescue medication if the volunteer cannot tolerate oral drugs. Artesunate dosage will be managed in hospital. Overall study duration is up to 130 days post-first malaria inoculation, participants may choose to attend optional study visits at 3, 6 and 13 months after the final study visit (Day 130) if they wish.