Assess Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Profile of Ruxolitinib With Artemether-lumefantrine

NCT04456634 | Completed Phase 1 Results DMC

• 1 other identifier: MMV_Ruxolitinib_19_01
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

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.

Conditions

Malaria

Keywords

Saftey; Tolerability

Outcome Measures

Primary Outcomes (4)

• 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.

  Incidence, severity and relationship of observed and self-reported adverse events (AEs) were reported during the study up to 28 days after AL+Rux and AL+Placebo administration in all participants by treatment regimens.

  up to 28 days after AL+Rux and AL+placebo administration

• Number of Participants With Changes of Systolic and Diastolic Blood Pressure

  Safety signals, trends or significant differences in blood pressure between treatment groups were were reported during the study up to 28 days after AL+Rux and AL+Placebo administration in all participants by treatment regimens.

  up to 28 days after AL+Rux and AL+placebo administration

• Number of Participants With Changes in Heart Rate

  Safety signals, trends or significant differences in heart rate ( beats / min)between treatment groups were were reported during the study up to 28 days after AL+Rux and AL+Placebo administration in all participants by treatment regimens.

  up to 28 days after AL+Rux and AL+placebo administration

• Number of Participants With ECG Changes

  Safety signals, trends or significant differences in QT, QTcB and QTcF, QRS between treatment groups were were reported during the study up to 28 days after AL+Rux and AL+Placebo administration in all participants by treatment regimens.

  up to 28 days after AL+Rux and AL+placebo administration

Secondary Outcomes (1)

• AUECt of pSTAT3 Inhibition

  up to 28 days after AL+Rux and AL+placebo administration

Study Arms (2)

AL&RUX

EXPERIMENTAL

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

Drug: 20 mg/120 mg artemether-lumefantrine (AL) + 20 mg ruxolitinib phosphate (Rux)

AL& Placebo

PLACEBO COMPARATOR

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

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

Interventions

20 mg/120 mg artemether-lumefantrine (AL) + 20 mg ruxolitinib phosphate (Rux) DRUG

Rux administered 2 hours after AL administration, twice daily (b.i.d) for 3 consecutive days (6 doses in total).

Also known as: Sentinel Group 1 a and 1 b

AL&RUX

20 mg/120 mg artemether-lumefantrine (AL) + Placebo OTHER

Placebo administered 2 hours after AL administration, twice daily (b.i.d) for 3 consecutive days (6 doses in total).

Also known as: Sentinel Group 1 a and 1 b

AL& Placebo

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Male or female (non-pregnant, non-lactating) aged 18 to 55 years inclusive.
• Contactable and available for the duration of the trial and for up to two weeks following the EOS visit.
• 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
• Certified as healthy by a comprehensive clinical assessment (detailed medical history, full physical examination and special investigations).
• 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.
• ECG parameters for both males and females: QT ≤ 500 msec, QTcF ≤450 msec, QTcB ≤450 msec; PR interval ≤210 msec.
• 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
• Completion of the written informed consent process prior to undertaking any trial-related procedure.

You may not qualify if:

• Medical history and clinical status
• Known hypersensitivity to ruxolitinib, artesunate or any of its excipients, artemether, lumefantrine or other artemisinin derivatives, proguanil/atovaquone, primaquine, or 4-aminoquinolines.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Individuals who have been hospitalised within five years prior to enrolment for either a psychiatric illness or due to danger to self or others.
• 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.
• 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.
• Acute illness within the 4 weeks prior to screening and prior to IMP administration.

Sponsors & Collaborators

• Medicines for Malaria Venture: lead
• Southern Star Research: collaborator
• Nucleus Network Ltd: collaborator

Study Sites (1)

Nucleus Network Brisbane

Brisbane, Queensland, Australia

Location

Related Publications (1)

• 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.

  PMID: 34694880 DERIVED

MeSH Terms

Conditions

Malaria

Interventions

Artemether, Lumefantrine Drug Combination; ruxolitinib

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Artemether; Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Lumefantrine; Fluorenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sesquiterpenes; Terpenes; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Limitations and Caveats

A PK drug-drug interaction between artemether and Rux cannot be excluded, and more data is needed to properly characterize such a potential interaction. Investigation of possible PK drug-drug interactions were not within the scope of this study, due to small participant numbers, differing PK blood sampling schemes on Days 1 and 3, variability of artemether and lumefantrine PK parameters in the AL+Rux treatment group, and absence of a Rux-only treatment group.

Results Point of Contact

• Title: Jacques Herve
• Organization: Medicines for Malaria Venture (MMV)

hervej@mmv.org

+41 79 370 40 63

Study Officials

• Paul Griffin, MD

  Nucleus Network Corporate

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Randomised (single blinded; treatment allocation concealed to participants but not Investigator)
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: June 18, 2020
• First Posted: July 2, 2020
• Study Start: September 10, 2020
• Primary Completion: November 17, 2020
• Study Completion: November 17, 2020
• Last Updated: July 9, 2021
• Results First Posted: July 9, 2021

Record last verified: 2021-06

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)