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Trial details imported from ClinicalTrials.gov

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




Registration number
NCT04456634
Ethics application status
Date submitted
18/06/2020
Date registered
2/07/2020
Date last updated
9/07/2021

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
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
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
Timepoint [4] 0 0
up to 28 days after AL+Rux and AL+placebo administration
Secondary outcome [1] 0 0
AUECt of pSTAT3 Inhibition
Timepoint [1] 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
Sex
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
10/09/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
17/11/2020
Sample size
Target
Accrual to date
Final
8
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
Commercial sector/industry
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/study/NCT04456634
Trial related presentations / publications
Chughlay MF, Barnes KI, El Gaaloul M, Abla N, Mohrle JJ, Griffin P, van Giersbergen P, Reuter SE, Schultz HB, Kress A, Tapley P, Webster RA, Wells T, McCarthy JS, Barber BE, Marquart L, Boyle MJ, Engwerda CR, Chalon S. Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Coadministered Ruxolitinib and Artemether-Lumefantrine in Healthy Adults. Antimicrob Agents Chemother. 2022 Jan 18;66(1):e0158421. doi: 10.1128/AAC.01584-21. Epub 2021 Oct 25.
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

For IPD and results data, please see https://clinicaltrials.gov/study/NCT04456634