Assess Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Profile of Ruxolitinib With Artemether-lumefantrine
Condition: Malaria
MeSH terms: Malaria
Intervention: 20 mg/120 mg artemether-lumefantrine (AL) + 20 mg ruxolitinib phosphate (Rux); 20 mg/120 mg artemether-lumefantrine (AL) + Placebo
Intervention description: Rux administered 2 hours after AL administration, twice daily (b.i.d) for 3 consecutive days (6 doses in total).; Placebo administered 2 hours after AL administration, twice daily (b.i.d) for 3 consecutive days (6 doses in total).
Intervention MeSH terms: Lumefantrine; Artemether; Artemether, Lumefantrine Drug Combination
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: 2 groups each to be enrolled sequentially. Group 1a will be a sentinel group of 2 participants, and Group 1b will be composed of 6 participants; to be administered either AL + Ruxolitinib or AL + placebo.
Masking: Single (Participant)
Masking description: Randomised (single blinded; treatment allocation concealed to participants but not Investigator)
Enrollment: 8.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Saftey; Tolerability

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.
    

Eligibility criteria:

        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.

        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.