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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT04456634




Registration number
NCT04456634
Ethics application status
Date submitted
18/06/2020
Date registered
2/07/2020
Date last updated
24/11/2020

Titles & IDs
Public title
Assess Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Profile of Ruxolitinib With Artemether-lumefantrine
Scientific title
A Randomised, Single Blind, Placebo Controlled, Phase 1 Trial to Evaluate the Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Activity of Ruxolitinib When Co-administered With Artemether-lumefantrine in Healthy Participants
Secondary ID [1] 0 0
MMV_Ruxolitinib_19_01
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 0 0
Condition category
Condition code
Infection 0 0 0 0
Other infectious diseases
Infection 0 0 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - 20 mg/120 mg artemether-lumefantrine (AL) + 20 mg ruxolitinib phosphate (Rux)
Other interventions - 20 mg/120 mg artemether-lumefantrine (AL) + Placebo

Experimental: AL&RUX - Oral administration of:
• 20 mg/120 mg artemether-lumefantrine (AL) + 20 mg ruxolitinib phosphate (Rux)

Placebo Comparator: AL& Placebo - 20 mg/120 mg artemether-lumefantrine (AL) + Placebo


Treatment: Drugs: 20 mg/120 mg artemether-lumefantrine (AL) + 20 mg ruxolitinib phosphate (Rux)
Rux administered 2 hours after AL administration, twice daily (b.i.d) for 3 consecutive days (6 doses in total).

Other interventions: 20 mg/120 mg artemether-lumefantrine (AL) + Placebo
Placebo administered 2 hours after AL administration, twice daily (b.i.d) for 3 consecutive days (6 doses in total).

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Participant with Treatment-Related Adverse Events as Assessed by CTCAE V4.03, all of observed and self-reported AEs affected, by treatment regimen.
Timepoint [1] 0 0
up to 28 days after AL+Rux and AL+placebo administration
Primary outcome [2] 0 0
Number of Participants with changes of systolic and diastolic blood pressure - Number of Participants with changes in systolic and diastolic blood pressure in mmHg
Timepoint [2] 0 0
up to 28 days after AL+Rux and AL+placebo administration
Primary outcome [3] 0 0
Number of Participants with changes in heart rate - Number of Participants with changes of heart rate beats/ min
Timepoint [3] 0 0
up to 28 days after AL+Rux and AL+placebo administration
Primary outcome [4] 0 0
Number of Participants with ECG changes - Number of Participants with changes of QT, QTcB and QTcF, QRS
Timepoint [4] 0 0
up to 28 days after AL+Rux and AL+placebo administration
Secondary outcome [1] 0 0
Changes of pSTAT3 levels pre- and post- AL+Rux administration intra participant - pSTAT3 level versus time
Timepoint [1] 0 0
up to 28 days after AL+Rux and AL+placebo administration
Secondary outcome [2] 0 0
Changes of pSTAT3 levels pre- and post- AL+Rux administration per treatment - pSTAT3 level versus time
Timepoint [2] 0 0
up to 28 days after AL+Rux and AL+placebo administration

Eligibility
Key inclusion criteria
1. Male or female (non-pregnant, non-lactating) aged 18 to 55 years inclusive.

2. Contactable and available for the duration of the trial and for up to two weeks
following the EOS visit.

3. 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) at Screening and Day -1. BMI is an estimate of
body weight adjusted for height. It is calculated by dividing the weight in kilograms
by the square of the height in metres.

Health status

4. Certified as healthy by a comprehensive clinical assessment (detailed medical history,
full physical examination and special investigations).

5. Vital signs 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.

6. ECG parameters for both males and females: QT = 500 msec, QTcF =450 msec, QTcB =450
msec; PR interval =210 msec.

7. Heterosexual female participants of childbearing potential who have, or may have, male
sexual partners during the course of the study should be using an insertable (implant
or IUD), injectable, transdermal or combination oral contraceptive approved by the TGA
combined with a barrier contraceptive from the time of informed consent until EOS.
Abstinent female participants must agree to start a double method if they start a
sexual relationship with a male during the trial. Female participants must not be
planning in vitro fertilisation within the required contraception period.

Women of non-childbearing potential who will not require contraception during the
trial are defined as: surgically sterile (tubal ligation is not considered surgically
sterile), post-menopausal (spontaneous amenorrhoea for =12 months, or spontaneous
amenorrhoea for 6-12 months and follicle-stimulating hormone (FSH) =40 IU/mL; either
should be together with the absence of oral contraceptive use for >12 months).

Male participants who have, or may have female sexual partners during the course of
the study must agree to use a double method of contraception including condom plus
diaphragm, or condom plus stable insertable (implant or IUD), injectable, transdermal
or combination oral contraceptive by the female partner, from the time of informed
consent through to EOS. Abstinent male participants must agree to start a double
method if they begin a sexual relationship with a female during the trial, and through
to EOS. Male participants with female partners that are surgically sterile or
post-menopausal, or male participants who have undergone sterilisation and have had
testing to confirm the success of the sterilisation, may also be included and will not
be required to use above described methods of contraception.

Regulations

8. Completion of the written informed consent process prior to undertaking any
trial-related procedure.

9. Must be willing and able to communicate and participate in the whole trial.

10. Agree to adhere to Lifestyle Considerations (see Section 4.3.3) throughout trial
duration and be willing to consume 250 mL full-fat milk with each dose of AL.
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Medical history and clinical status

1. Known hypersensitivity to ruxolitinib, artesunate or any of its excipients,
artemether, lumefantrine or other artemisinin derivatives, proguanil/atovaquone,
primaquine, or 4-aminoquinolines.

2. Haematology, biochemistry or urinalysis results that are abnormal/outside of the
laboratory normal reference ranges AND are either:

- Considered clinically signficant by the Principal Investigator or delegate; OR

- Considered not clinically significant by the Principal Investigator or delegate
BUT ARE ALSO outside of Sponsor-approved clinically acceptable laboratory ranges
in Appendix 1.

NOTE: Participants are not excluded if abnormal/out of laboratory normal reference
range results are considered not clinically significant by the Principal Investigator
or delegate AND are within the ranges specified in Appendix 1.

3. Platelets < 200x109/L at Screening or prior to IMP administration is exclusionary. One
re-test is permitted if original test result does not reflect the assumed medical
status of the individual.

4. Participation in any other investigational product trial within 5 half-lives or 12
weeks preceding IMP administration, whichever is longer, or in the exclusion period of
a previous trial according to applicable regulations.

5. Symptomatic postural hypotension at screening and pre-first dose of IMP on Day 1
(confirmed on two consecutive readings), irrespective of the decrease in blood
pressure, or asymptomatic postural hypotension defined as a decrease in systolic blood
pressure =20 mmHg within 2-3 min when changing from supine to standing position.

6. History or presence of diagnosed (by an allergist/immunologist) or treated (by a
physician) food or known drug allergies, or any history of anaphylaxis or other severe
allergic reactions including face, mouth, or throat swelling or any difficulty
breathing. Participants with seasonal allergies/hay fever or allergy to animals or
house dust mite that are untreated and asymptomatic at the time of dosing can be
enrolled in the trial.

7. History of convulsion (including drug or vaccine-induced episodes). A medical history
of a single febrile convulsion during childhood is not an exclusion criterion.

8. Presence of current or suspected serious chronic diseases such as cardiac or
autoimmune disease (HIV or other immuno-deficiencies), insulin-dependent and
non-insulin-dependent diabetes, progressive neurological disease, severe malnutrition,
acute or progressive hepatic disease, acute or progressive renal disease, porphyria,
psoriasis, rheumatoid arthritis, asthma (excluding childhood asthma), epilepsy, or
obsessive-compulsive disorder.

9. History of malignancy of any organ system (other than localised and considered cured
basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated,
within five years of screening, regardless of whether there is no evidence of local
recurrence or metastases.

10. 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.

11. Individuals who have been hospitalised within five years prior to enrolment for either
a psychiatric illness or due to danger to self or others.

12. History of an episode of mild/moderate depression lasting more than 6 months that
required pharmacological therapy and/or psychotherapy within the last 5 years; or any
episode of major depression. The Beck Depression Inventory (BDI-II) will be used as a
validated tool for the assessment of depression at screening. In addition to the
conditions listed above, individuals with a score of 20 or more on the BDI-II and/or a
response of 1, 2 or 3 for item 9 of this inventory (related to suicidal ideation) will
not be eligible for participation. These individuals will be referred to a general
practitioner or medical specialist as appropriate. Individuals with a BDI-II score of
17 to 19 may be enrolled at the discretion of an Investigator if they do not have a
history of the psychiatric conditions mentioned in this criterion and their mental
state is not considered to pose additional risk to the health of the individual or to
the execution of the trial and interpretation of the data gathered.

13. History of recurrent headache (e.g. tension-type, cluster, or migraine) with a
frequency of =2 episodes per month on average and severe enough to require medical
therapy, during the 2 years preceding screening.

14. Acute illness within the 4 weeks prior to screening and prior to IMP administration.

15. 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.

16. Individual has a clinically significant disease or any condition or disease that might
affect drug absorption, distribution or excretion (e.g. gastrectomy, cholecystectomy,
diarrhoea) or known lactose/dairy intolerance.

17. 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 Australian
Red Cross Blood Service (Blood Service) or other blood bank during the 8 weeks prior
to IMP administration.

18. Medical requirement for intravenous immunoglobulin or blood transfusions.

19. History or presence of alcohol abuse (alcohol consumption more than 40 g/4 units/4
standard drinks per day), or drug habituation, or any prior intravenous usage of an
illicit substance.

20. Any individual who has ever smoked >1 pack of cigarettes per day for >10 years, or who
currently (within 14 days prior to Screening or prior to IMP administration smokes >5
cigarettes/day.

21. Female who is breastfeeding.

22. Any vaccination within the last 28 days prior to screening or prior to IMP
administration.

23. Prior to screening or IMP administration: any systemic or inhaled corticosteroids,
anti-inflammatory drugs (excluding commonly used over-the-counter anti-inflammatory
drugs such as ibuprofen, acetylsalicylic acid, diclofenac), immunomodulators or
anticoagulants within the past three months. Any topical, nasal or ophthalmic
corticosteroids within the past 2 weeks. Any individual currently receiving or having
previously received immunosuppressive therapy (including systemic steroids,
adrenocorticotrophic hormone or inhaled steroids) at a dose or duration potentially
associated with hypothalamic-pituitary-adrenal axis suppression within the past year.

24. Use of antidepressant medication in the past 12 months prior to screening or prior to
IMP administration.

25. Use of any other medication except contraceptives (including herbal, vitamin
supplement, OTC or prescription) within 14 days or five half-lives (whichever is
longest) prior to IMP administration. Participants areCONFIDENTIAL Page 7 of 78
requested to refrain from taking non-approved concomitant medications from recruitment
until the conclusion of the trial.

26. Cardiac/QT risk:

- Family history of sudden death or of congenital prolongation of the QTc interval
or known congenital prolongation of the QTc interval or any clinical condition
known to prolong the QTc interval.

- History of symptomatic cardiac arrhythmias or with clinically relevant
bradycardia.

- Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia, or
hypomagnesaemia.

- ECG abnormalities in the standard 12-lead ECG (at screening or prior to IMP
administration) which in the opinion of an Investigator is clinically relevant or
will interfere with the ECG analyses.

General conditions

27. Any individual who, in the judgement of an Investigator, is likely to be non-compliant
during the trial, or is unable to cooperate because of a language problem or poor
mental development.

28. Any individual for whom study participation would pose an additional safety risk as
assessed by the Principal Investigator.

29. Any individual who is an Investigator, research assistant, pharmacist, trial
coordinator, or other staff thereof, directly involved in conducting the trial.

30. Any individual without good peripheral venous access. Biological status

31. Positive result on any of the following tests: hepatitis B surface antigen (HBs Ag),
anti-hepatitis B core antibodies (anti-HBc Ab), anti-hepatitis C virus (anti-HCV)
antibodies, anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and
anti-HIV2 Ab).

32. Recent herpes zoster infection (within the previous 6 months) as determined by
clinical history.

33. Positive result for M. tuberculosis infection by QuantiFERON-TB Gold assay.

34. Positive urine drug test for any drug listed in Section 7.4.5. Any individual testing
positive for acetaminophen (paracetamol) at screening and/or pre-dose may still be
eligible for trial participation at the discretion of the Principal Investigator or
delegate.

35. Positive alcohol breath test.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 0 0
Nucleus Network Brisbane - Brisbane
Recruitment postcode(s) [1] 0 0
- Brisbane

Funding & Sponsors
Primary sponsor type
Other
Name
Medicines for Malaria Venture
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Southern Star Research Pty Ltd.
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
Nucleus Network Ltd
Address [2] 0 0
Country [2] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Phase 1, single -center study in 2 parts. The study designs for each part are well
established for first-in-human studies and are appropriate to assess safety, tolerability and
preliminary pharmacokinetics& pharmacodynamics.
Trial website
https://clinicaltrials.gov/show/NCT04456634
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Paul Griffin, MD
Address 0 0
Nucleus Network Corporate
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications