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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT05287893




Registration number
NCT05287893
Ethics application status
Date submitted
10/03/2022
Date registered
18/03/2022
Date last updated
4/11/2022

Titles & IDs
Public title
Pyronaridine in Healthy Adult Participants Infected With Blood Stage Malaria
Scientific title
A Phase 1b Study to Characterise the Pharmacokinetic/Pharmacodynamic Relationship of Pyronaridine in Healthy Adult Participants Experimentally Infected With Blood Stage Plasmodium Falciparum.
Secondary ID [1] 0 0
MMV_Pyronaridine_21_01
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria,Falciparum 0 0
Malaria 0 0
Malaria Recrudescence 0 0
Parasitemia 0 0
Protozoan Infections 0 0
Parasitic Disease 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
Inflammatory and Immune System 0 0 0 0
Other inflammatory or immune system disorders
Blood 0 0 0 0
Other blood disorders
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Pyronaridine
Treatment: Other - P. falciparum IBSM infection

Experimental: IBSM challenge and pyronaridine PK/PD population profile - Up to 18 healthy, malaria naïve adult participants are planned to be enrolled into this study, in cohorts of up to six participants each. on Day 0 participants will be inoculated intravenously with approximately 2,800 viable P. falciparum-infected erythrocytes.

Day 8 participants will be dosed with pyronaridine when parasitaemia for the majority of participants is expected to be above 5,000 parasites/mL.

Different doses of pyronaridine will be administered across and within cohorts in order to effectively characterise the PK/PD relationship.

The highest dose of pyronaridine administered will be no more than 720 mg; the lowest dose administered will be no less than 180 mg.

Regular safety assessments will be performed and blood will be collected to monitor parasite clearance and pyronaridine concentration.

Participants will receive compulsory antimalarial rescue treatment with Riamet® (artemether/lumefantrine) on Day 47±2, or earlier.


Treatment: Drugs: Pyronaridine
Single dose

Treatment: Other: P. falciparum IBSM infection
Induced Blood Stage Malaria
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Other
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Emax
Timepoint [1] 0 0
Day 8 to Day 50+/-2
Primary outcome [2] 0 0
EC50
Timepoint [2] 0 0
Day 8 to Day 50+/-2
Primary outcome [3] 0 0
Hill coefficient
Timepoint [3] 0 0
Day 8 to Day 50+/-2
Primary outcome [4] 0 0
Minimum Inhibitory Concentration (MIC)
Timepoint [4] 0 0
Day 8 to Day 50+/-2
Primary outcome [5] 0 0
Minimal Parasiticidal Concentration (MPC90)
Timepoint [5] 0 0
Day 8 to Day 50+/-2
Primary outcome [6] 0 0
Parasite Reduction Rate in 48 h (log10PRR48)
Timepoint [6] 0 0
Day 8 to Day 50+/-2

Eligibility
Key inclusion criteria
Demography

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). 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
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 and pre-inoculation with the malaria challenge agent: normal standard mean of triplicate 12-lead electrocardiogram (ECG) parameters after 5 minutes resting in supine position in the following ranges:

1. QTcF =450 msec (male participants); QTcF =470 msec (female participants);
2. QRS 50-120 msec
3. PR interval = 210 msec for both males and females, and
4. Normal ECG tracing unless the PI or delegate considers an ECG tracing abnormality to be not clinically relevant.
6. Women of childbearing potential (WOCBP) who anticipate being sexually active with a male during the trial must agree to the use of a highly effective method of birth control (see below) combined with a barrier contraceptive from the screening visit until 100 days after the last dose of pyronaridine (covering a full menstrual cycle of 30 days starting after 5 half-lives of last dose pyronaridine) and have a negative result on urine pregnancy test performed before inoculation with the malaria challenge agent.

Note:

a. Highly effective birth control methods include: combined (oestrogen and progestogen containing) oral/intravaginal/transdermal/implantable hormonal contraception associated with inhibition of ovulation, progestogen-only oral/injectable/implantable hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner, or sexual abstinence or same sex relationship.

b. Female participants who are abstinent (from penile-vaginal intercourse) must agree to start a double method if they start a sexual relationship with a male during the study. Female participants must not be planning in vitro fertilisation within the required contraception period.

7. Women of non-childbearing potential (WONCBP) are defined as:

1. Natural (spontaneous) post-menopausal defined as being amenorrhoeic for at least 12 months without an alternative medical cause with a screening follicle stimulating hormone level (FSH) >25 IU/L (or at the local laboratory levels for post-menopause)
2. Premenopausal with irreversible surgical sterilization by hysterectomy and/or bilateral oophorectomy or salpingectomy at least 6 months before screening (as determined by participant medical history) 8. Males who have, or may have, female sexual partners of child bearing potential during the course of the study must agree to use a double method of contraception including condom plus diaphragm, or condom plus intrauterine device, or condom plus stable oral/transdermal/injectable/implantable hormonal contraceptive by the female partner, from the time of informed consent through to 70 days (covering a spermatogenesis cycle) after pyronaridine administration. Abstinent males must agree to start a double method if they begin sexual relationship with a female during the study and up to 70 days after the last dose of pyronaridine. Males with female partners of child-bearing potential that are surgically sterile, or males 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 9. Completion of the written informed consent process prior to undertaking any trial-related procedure.

10. Must be willing and able to communicate and participate in the whole trial. 11. Agreement to adhere to Lifestyle Considerations (see Section 5.3) throughout trial duration 12. Agreement to provide current contact details (two telephone numbers including a mobile number and a responsible adult as an emergency contact) and a relevant email address.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
* Individual who lives alone, OR, does not satisfy the following criteria: Participants who live alone may be included on a case-by-case basis, following discussion with the Principal Investigator. Participants who live alone must identify and provide contact details of a support person who is aware of the participant's participation in the study and is available to provide assistance if required (for example with contacting the participant in the event that study staff are unable to, or with transporting the participant to and from the study site if required).

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

3. Haematology, biochemistry or urinalysis results at screening or at the eligibility visit that are outside of Sponsor-approved clinically acceptable laboratory ranges (appendix) or are considered clinically significant by the PI or their delegate.

4. Participation in any investigational product trial within the 12 weeks preceding pyronaridine administration.

5. Symptomatic postural hypotension at screening (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. Any history of anaphylaxis or other severe allergic reactions including face, mouth, or throat swelling or any difficulty breathing, or other food or drug allergy that the Investigator considers may impact on participant safety. 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 (< 5 years) is not an exclusion criterion.

8. Presence of current or suspected serious chronic diseases such as cardiac or autoimmune disease, diabetes, progressive neurological disease, severe malnutrition, hepatic or renal disease. Acute or progressive hepatic or renal disease, porphyria, psoriasis, rheumatoid arthritis, asthma (excluding childhood asthma, or mild asthma with preventative asthma medication required less than monthly), or epilepsy.

9. History of malignancy of any organ system (other than localised basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within five years of screening, regardless of whether there is 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.

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-II (BDI-II) will be used as a validated tool for the assessment of depression at screening. In addition to the conditions listed above, participants 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 participants will be referred to a general practitioner or medical specialist as appropriate. Participants 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 participant 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. Presence of clinically significant infectious disease or fever (e.g., sublingual temperature =38.5°C) within the five days prior to inoculation.

15. Blood product donation to any blood bank during the 8 weeks (whole blood) or 4 weeks (plasma and platelets) prior to admission in the clinical unit on Day 8.

16. 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.

17. Any individual who currently (within 14 days prior to inoculation) smokes >5 cigarettes/day.

18. Breastfeeding or lactating; positive serum pregnancy test at screening, positive urine pregnancy test upon admission or at other time points as specified by schedule of activities tables.

19. Any COVID-19 vaccine within 14 days of inoculation, any other vaccination within 28 days of IMP intake, and any vaccination (including COVID-19 initial or second dose) planned up to the final follow-up visit.

20. Any 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 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.

21. Use of prescription drugs (excluding contraceptives) or non-prescription drugs or herbal supplements (such as St John's Wort), within 14 days or five half-lives (whichever is longer) prior to inoculation. Limited use of other non-prescription medications or dietary supplements, not believed to affect participant safety or the overall results of the trial, may be permitted on a case-by-case basis following approval by the Sponsor in consultation with the PI. Participants are requested to refrain from taking non-approved concomitant medications from recruitment until the conclusion of the trial.

22. 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.

23. Any history of malaria or participation in a previous malaria challenge trial or malaria vaccine trial.

24. Must not have had malaria exposure that is considered by the PI or their delegate to be significant. This includes but is not limited to: history of having travelled to or lived (>2 weeks) in a malaria-endemic region during the past 12 months or planned travel to a malaria-endemic region during the course of the trial; history of having lived for >1 year in a malaria-endemic region in the past 10 years; history of having ever lived in a malaria-endemic region for more than 10 years inclusive. For endemic regions see https://malariaatlas.org/explorer/#/, Bali is not considered a malaria-endemic region.

25. Has evidence of increased cardiovascular disease risk (defined as >10%, 5-year risk for those greater than 35 years of age, as determined by the Australian Absolute Cardiovascular Disease Risk Calculator [http://www.cvdcheck.org.au/]). Risk factors include sex, age, systolic blood pressure (mm/Hg), smoking status, total and HDL cholesterol (mmol/L), and reported diabetes status.

26. History of splenectomy. 27. Individual unwilling to defer blood donations to the Blood Service for at least twelve months after the EOS visit.

28. Individual who has ever received a blood transfusion. 29. Any recent (<6 weeks) therapy with an antibiotic or drug with potential antimalarial activity (e.g. chloroquine, piperaquine phosphate, benzodiazepine, flunarizine, fluoxetine, tetracycline, azithromycin, clindamycin, doxycycline etc.).

General conditions 30. 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.

31. Any individual in the exclusion period of a previous trial according to applicable regulations.

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

33. Any individual without good peripheral venous access. Biological status 34. 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).

35. Positive urine drug test. Any drug listed in the urine drug screen unless there is an explanation acceptable to an Investigator (e.g., the participant has stated in advance that they consumed a prescription or over-the-counter product that contained the detected drug) and the participant has a negative urine drug screen on retest by the pathology laboratory.

36. Severe G6PD deficiency. 37. Positive alcohol breath test. 38. Positive for SARS-CoV-2 by PCR. NPA testing is to occur between Day -3 to Day -1 but only in the event that there is community transmission in South East Queensland (see section 8.3.7) 39. Positive for red cell antibodies

Study design
Purpose of the study
Other
Allocation to intervention
Non-randomised 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
Open (masking not used)
Who is / are masked / blinded?



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
4/04/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
26/09/2022
Sample size
Target
Accrual to date
Final
10
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 0 0
South Bank - Brisbane
Recruitment hospital [2] 0 0
USC Clinical Trials, Morayfield - Brisbane
Recruitment postcode(s) [1] 0 0
4101 - Brisbane
Recruitment postcode(s) [2] 0 0
4506 - 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
QIMR Berghofer Medical Research Institute
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/industry
Name [2] 0 0
Southern Star Research Pty Ltd.
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
Swiss BioQuant A.G., Switzerland
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Other
Name [4] 0 0
Children's Health Queensland Hospital and Health Service
Address [4] 0 0
Country [4] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
This is an open-label, adaptive study that will utilise the P. falciparum induced blood stage malaria (IBSM) model to characterise the pharmacokinetic/pharmacodynamic (PK/PD) profile of pyronaridine. Up to 18 healthy, malaria naïve adult participants are planned to be enrolled into this study, in cohorts of up to six participants each. Following a screening period of up to 28 days, cohorts of up to 6 healthy participants will be enrolled. Each participant will be inoculated intravenously on Day 0 with P. falciparum infected erythrocytes. Participants will be followed up daily on Days 1 to 3, and will attend the clinical unit once on Days 4, 5, 6 and 7 for clinical evaluation and blood sampling. Participants will be admitted to the clinical trial unit on Day 8 for a single oral dose of pyronaridine.

Different doses of pyronaridine will be administered across and within cohorts. Participants will be randomised to a dose group on the day of dosing. The highest dose of pyronaridine administered will be no more than 720 mg; the lowest dose administered will be no less than 180 mg.

Each subsequent cohort will be composed of up to 3 dose groups. The Safety Data Review Team (SDRT) will review all available safety and tolerability data from the previous cohort/s prior to inoculation of the next cohort.

Participants will be confined in the clinical unit for at least 96 h (Days 8 - 12) to monitor the safety and tolerability of pyronaridine dosing. Upon discharge from the clinical unit participants will be monitored on an outpatient basis up to Day 50±2. Participants will receive compulsory antimalarial rescue treatment with Riamet® (artemether/lumefantrine) on Day 47±2 or earlier.
Trial website
https://clinicaltrials.gov/study/NCT05287893
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Jörg Möhrle, PhD
Address 0 0
Medicines for Malaria Venture
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/NCT05287893