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Trial registered on ANZCTR


Registration number
ACTRN12621000866808
Ethics application status
Approved
Date submitted
6/05/2021
Date registered
6/07/2021
Date last updated
23/08/2022
Date data sharing statement initially provided
6/07/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
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
Scientific title
A randomised, double blind, placebo controlled trial to evaluate the safety, tolerability and anti-parasitic immunity boosting activity of ruxolitinib when co-administered with artemether-lumefantrine in healthy volunteers with Plasmodium falciparum Induced Blood Stage Malaria
Secondary ID [1] 304084 0
CTM2003
Universal Trial Number (UTN)
N/A
Trial acronym
N/A
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Malaria 321750 0
Condition category
Condition code
Infection 319490 319490 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 320416 0
Treatment: Drugs
Comparator / control treatment
A placebo of microcrystalline cellulose in tablet form will be administered only to the 13 volunteers randomised to the placebo group (after the first malaria inoculation). The same dosing procedures and food restrictions to those described for Rux above will apply.
Control group
Placebo

Outcomes
Primary outcome [1] 327361 0
Incidence, severity, and relationship as a composite outcome of observed and self-reported adverse events by treatment regimen. These may include headaches, diarrhoea, blood sampling catheter haemorrhage and neutropenia.
Safety assessments including physical examination, clinical laboratory analysis (biochemistry, haematology, and urinalysis), malaria clinical score recording, and electrocardiographs will be used for assessment.
Timepoint [1] 327361 0
Adverse event recording at all clinic visits and by phone contact from parasite inoculation (Day 0) to End of Study (EOS) at the following time-points: Days 0, 1, 2, 3 (phone contact), 9, 10, 11, 12 (clinical confinement), 14, 16, 19, 23 and 29 (out-patient visits), 30-85 plus/minus 7 (phone contact every 2 weeks), 85 plus/minus 7, 90 plus/minus 7, 91-93 plus/minus 7 (phone contact), 94-AL administration or 118 plus/minus 7 whichever comes first (out-patient visits), AL plus 3, AL plus 7 AL plus 20 and AL plus 28 (EOS).
Secondary outcome [1] 394738 0
Anti-parasitic immune response using parasite-specific IFNy from plasma and peripheral blood mononuclear cells (PBMCs) samples.
Timepoint [1] 394738 0
Days 0 (parasite inoculation), 9, 10, 11, 12 (clinical confinement) 14, 16, 29, 90 plus/minus 7, 94 plus/minus 7, 97 plus/minus 7, every 3 days until AL administration and AL plus 3, AL plus 7 AL plus 20 and AL plus 28 (EOS). Optional – 3, 6 and 12 month’s post-EOS.
Secondary outcome [2] 394739 0
Anti-parasitic immune response investigating IL-10 levels from plasma and peripheral blood mononuclear cells (PBMCs) samples.
Timepoint [2] 394739 0
Days 0 (parasite inoculation), 9, 10, 11, 12 (clinical confinement) 14, 16, 29, 90 plus/minus 7, 94 plus/minus 7, 97 plus/minus 7, every 3 days until AL administration and AL plus 3, AL plus 7 AL plus 20 and AL plus 28 (EOS). Optional – 3, 6 and 12 month’s post-EOS.
Secondary outcome [3] 394740 0
pSTAT3 inhibition will be assessed ex-vivo on whole blood cells
Timepoint [3] 394740 0
Day 0 (parasite inoculation), Day 9 (pre IMP administration), Day 10 (28 hours post-first IMP administration) and Day 14
Secondary outcome [4] 394741 0
PK parameters of lumefantrine using non-compartmental methods: AUClast, AUC0-8, Cmax (first and last dose), tmax (first and last dose), elimination t1/2, tlag, C168h (for lumefantrine only), CL/F, Vz/F and terminal rate constant in plasma of all volunteers.
Timepoint [4] 394741 0
0, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, 62, 66, 72 and 84 h on Days 9, 10, 11 and 12 and Days 16 (168 h post dosing), 19 (240 h post dosing), 23 (336 h post dosing) and 29 (480 h post dosing).
Secondary outcome [5] 394742 0
Antimalarial activity assessed by the following parameters - Parasite clearance half-life, Parasite reduction ratio and Percentage of volunteers with recrudescence of parasitaemia using 18S qPCR assays as a composite outcome
Timepoint [5] 394742 0
Day 0 (parasite inoculation),Day 4, twice daily on Days 5, 6 and 7 and at 0, 2, 4, 8, 12, 14, 16, 20, 24, 28, 36, 42, 48, 54, 60, 66 and 72 h on Days 9, 10, 11 and 12 and on Days 16, 23 and 29.
Secondary outcome [6] 394802 0
Parasite growth will be characterised by ‘time to parasitaemia’ (the first time-point that parasites are detected) using 18S qPCR assays from whole blood.
Timepoint [6] 394802 0
Day 90 (pre parasite inoculation), Days 94, 95, 96, 97 and daily until parasite positive, then on Riamet Dosing Day and at 3, 7, 20 and 28 Days post-Riamet Dosing.
Secondary outcome [7] 394803 0
Parasite growth will be characterised by parasite multiplication rate (PMR) using 18S qPCR assays from whole blood.
Timepoint [7] 394803 0
Day 90 (pre parasite inoculation), Days 94, 95, 96, 97 and daily until parasite positive, then on Riamet Dosing Day and at 3, 7, 20 and 28 Days post-Riamet Dosing.
Secondary outcome [8] 396959 0
PK parameters of artemether using non-compartmental methods: AUClast, AUC0-8, Cmax (first and last dose), tmax (first and last dose), elimination t1/2, tlag, CL/F, Vz/F and terminal rate constant in plasma of all volunteers.
Timepoint [8] 396959 0
0, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, 62, 66, 72 and 84 h on Days 9, 10, 11 and 12 and Days 16 (168 h post dosing), 19 (240 h post dosing), 23 (336 h post dosing) and 29 (480 h post dosing).
Secondary outcome [9] 396960 0
PK parameters of DHA using non-compartmental methods: AUClast, AUC0-8, Cmax (first and last dose), tmax (first and last dose), elimination t1/2, tlag, CL/F, Vz/F and terminal rate constant in plasma of all volunteers.
Timepoint [9] 396960 0
0, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, 62, 66, 72 and 84 h on Days 9, 10, 11 and 12 and Days 16 (168 h post dosing), 19 (240 h post dosing), 23 (336 h post dosing) and 29 (480 h post dosing).
Secondary outcome [10] 396961 0
PK parameters of Rux using non-compartmental methods: AUClast, AUC0-8, Cmax (first and last dose), tmax (first and last dose), elimination t1/2, tlag, CL/F, Vz/F and terminal rate constant in plasma of all volunteers.
Timepoint [10] 396961 0
0, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, 62, 66, 72 and 84 h on Days 9, 10, 11 and 12 and Days 16 (168 h post dosing), 19 (240 h post dosing), 23 (336 h post dosing) and 29 (480 h post dosing).

Eligibility
Key inclusion criteria
1. Male or female (non-pregnant, non-lactating) aged 18 to 55 years inclusive who will be contactable and available for the duration of the trial and up to two weeks following the EOS visit.
2. Total body weight greater than or equal to 50 kg, and a body mass index (BMI) within the range of 18 to 32 kg/m2 (inclusive).
3. Certified as healthy by a comprehensive clinical assessment (detailed medical history and full physical examination).
4. Vital signs at screening (measured after 5 min in the supine position):
• Systolic blood pressure (SBP) - 90–140 mmHg,
• Diastolic blood pressure (DBP) - 40–90 mmHg,
• Heart rate (HR) 40–100 bpm.
5. At screening, continued eligibility (Day 85 plus or minus 7), pre-inoculation (first and second) and pre IMP dosing: QTcF less than or equal to 450 msec (male volunteers); QTcF less than or equal to 470 msec (female volunteers); PR interval less than or equal to 210 msec for both males and females.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Known hypersensitivity to ruxolitinib, artesunate or any of its derivatives, artemether, lumefantrine or other artemisinin derivatives, proguanil/atovaquone, primaquine, or 4-aminoquinolines.
2. Haematology, biochemistry or urinalysis results at screening or at the eligibility visit, or at the Day 85 plus or minus 7 continued eligibility visit that are outside of Sponsor-approved clinically acceptable laboratory ranges, or are considered clinically significant by the Investigator or their delegate.
3. Participation in any investigational product trial within the 12 weeks preceding IMP administration.
4. Symptomatic postural hypotension at screening (confirmed on two consecutive readings).
5. History or presence of diagnosed (by an allergist/immunologist) or treated (by a physician) food or known drug allergies (including but not limited to allergy to any of the antimalarial rescue medications), or any history of anaphylaxis or other severe allergic reactions including face, mouth, or throat swelling or any difficulty breathing.
6. History of convulsion (including drug or vaccine-induced episodes).
7. Presence of current or suspected serious chronic diseases
8. Individuals with history of schizophrenia, bipolar disorder psychoses, disorders requiring lithium, attempted or planned suicide, or any other severe (disabling) chronic psychiatric diagnosis including generalised anxiety disorder.
9. Presence of clinically significant infectious disease or fever (e.g., sublingual temperature greater than or equal to 38.5°C) within the five days prior to first and second inoculation.
10. Individual has a clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion (e.g. gastrectomy, diarrhoea).
11. Blood donation of any volume within one month before inclusion, or participation in any research trial involving blood sampling (more than 300 mL/unit of blood) within one month prior to IMP administration, or blood donation to Life Blood (Blood Service) or other blood bank during the 8 weeks prior to IMP administration.
12. Medical requirement for intravenous immunoglobulin or blood transfusions.
13. Any vaccination within the last 28 days.
14. Any history of malaria or participation in a previous malaria challenge trial or malaria vaccine trial.
15. Must not have had malaria exposure that is considered by the Investigator or delegate to be significant.
16. Cardiac/QT risk
17. Recent herpes zoster infection (within the previous 6-months) as determined by clinical history.
18. Positive result for M. tuberculosis infection by QuantiFERON-TB Gold assay.
19. Any recent (less than 6 weeks) or current systemic therapy with an antibiotic or drug with potential antimalarial activity
20. Has evidence of increased cardiovascular disease risk

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation
The randomisation schedule will be provided via e-mail from the unblinded statistician to the unblinded pharmacist and unblinded nurse who will be administering the active or placebo.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The planned sample size in this study is 26 volunteers, with 13 volunteers randomised to AL+RUX and 13 volunteers randomised to AL+placebo. Sample size calculations were based on one of the secondary endpoints of the study, namely the anti-parasitic immune response (IFN gamma and IL-10 levels) by treatment regimen. It was considered appropriate to base the sample size on this endpoint because it represents the basis of the rationale of this study, that RUX adjunctive treatment can enhance Th1 CD4+ T cells (characterised by IFN gamma production) but not Tr1 regulatory CD4+ T cells (characterised by IL-10 production). Nevertheless, the planned sample size is also considered appropriate to assess the primary endpoint of this study associated with safety and tolerability, namely the incidence, severity, and relationship of observed and self-reported AEs by treatment regimen. Thus the planned sample size of 26 volunteers is within this range and will allow assessment of the safety and tolerability of RUX adjunctive treatment in the context of induced blood-stage malaria.

Sample size calculations were based on data obtained from a study which measured cytokine production following P. falciparum parasite stimulation of peripheral blood mononuclear cells (PBMCs) collected from volunteers participating in previous P. falciparum induced blood stage malaria trials. The natural log transformed IL-10 and IFN gamma response at day 14 post-inoculation was found to be normally distributed with a mean (SD) of 6.70 pg/mL (0.472) and 6.01 pg/mL (1.20) respectively. With 13 volunteers per group in the current study, a two-sided two-sample t-test will have 80 percent power to detect a true difference at Day 15 (168 hr after treatment) in the mean IL-10, 0.541 pg/mL, which is equivalent to a 8 percent change from the mean of 6.70 pg/mL and IFN gamma response of 1.374 pg/mL which is equivalent to 22.9 percent change from the mean of 6.01 pg/mL with a type I error rate of 5 percent.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
3/06/2021
Date of last participant enrolment
Anticipated
18/11/2022
Actual
Date of last data collection
Anticipated
19/05/2023
Actual
Sample size
Target
26
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment postcode(s) [1] 33817 0
4506 - Morayfield

Funding & Sponsors
Funding source category [1] 308467 0
Government body
Name [1] 308467 0
NHMRC Ideas Grant
Country [1] 308467 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
QIMR Berghofer Medical Research Institute
Address
QIMR Berghofer Medical Research Institute,
300 Herston Rd,
Herston QLD 4006
Country
Australia
Secondary sponsor category [1] 309317 0
None
Name [1] 309317 0
Address [1] 309317 0
Country [1] 309317 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308423 0
QIMR Berghofer Medical Research Institute Human Research Ethics Committee (QIMR Berghofer HREC; EC00278)
Ethics committee address [1] 308423 0
Locked Bag 2000
Royal Brisbane and Women’s Hospital
Brisbane Qld 4029, Australia
Ethics committee country [1] 308423 0
Australia
Date submitted for ethics approval [1] 308423 0
16/02/2021
Approval date [1] 308423 0
16/04/2021
Ethics approval number [1] 308423 0
P3696

Summary
Brief summary
This is a, randomised, double-blind, placebo-controlled, phase 1b trial to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic (malaria parasitaemia 18S qPCR, pSTAT3, and immune responses) of artemether-lumefantrine (AL)+ Ruxolitinib (Rux) in healthy adults with P. falciparum IBSM.

Twenty-six malaria-naïve, healthy males or females, aged between 18-55 years old, who meet all of the inclusion criteria and none of the exclusion criteria, are planned to be enrolled. Volunteers will be randomised in a 1:1 ratio to receive oral twice daily doses of AL+Rux or AL+placebo on Days 9, 10 and 11.. A sentinel dosing strategy will be used whereby two volunteers (one randomised to AL+Rux and one randomised to AL+placebo) will be dosed initially. The Safety Data Review Team will review safety and tolerability data up to and including Day 15 before dosing of the remaining 24 volunteers.

As part of the informed consent process, volunteers will be asked if they agree to be contacted at approximately 3, 6 and 12 months after their end of study visit for blood sampling to investigate anti-parasitic immune response longevity.
Trial website
N/A
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 110662 0
A/Prof Bridget Barber
Address 110662 0
USC Clinical Trials Centre and
QIMR Berghofer Medical Research Institute
Level 5, 300C Herston Road
Herston QLD 4006, Australia
Country 110662 0
Australia
Phone 110662 0
+61 7 3362 0498
Fax 110662 0
Email 110662 0
[email protected]
Contact person for public queries
Name 110663 0
Bridget Barber
Address 110663 0
USC Clinical Trials Centre and QIMR Berghofer Medical Research Insitute
Level 5, 300C Herston Road
Herston QLD 4006, Australia
Country 110663 0
Australia
Phone 110663 0
+61 7 3362 0498
Fax 110663 0
Email 110663 0
[email protected]
Contact person for scientific queries
Name 110664 0
Bridget Barber
Address 110664 0
USC Clinical Trials Centre and QIMR Berghofer Medical Research Insitute
Level 5, 300C Herston Road
Herston QLD 4006, Australia
Country 110664 0
Australia
Phone 110664 0
+61 7 3362 0498
Fax 110664 0
Email 110664 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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