Pyronaridine in Healthy Adult Participants Infected With Blood Stage Malaria

NCT05287893 | Completed Phase 1 Results DMC

• 1 other identifier: MMV_Pyronaridine_21_01
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 2

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.

Conditions

Malaria,Falciparum; Malaria; Malaria Recrudescence; Parasitemia; Protozoan Infections; Parasitic Disease

Keywords

Malaria; Malaria,Falciparum; Malaria Recrudescence; Parasitaemia; Pyronaridine

Outcome Measures

Primary Outcomes (6)

• Emax

  Maximum drug killing rate, calculated using the combined data from all doses/arms/groups in both period 1 and 2, as prespecified in section 10 of the Statistical Analysis Plan. The PKPD relationship was identified using SysFit as an Emax model with the parameters estimated from the parasitaemia data.

  Day 8 to Day 50+/-2

• EC50

  Half Maximal Effective Concentration Calculated using the combined data from all doses/arms/groups in both period 1 and 2, as prespecified in section 10 of the Statistical Analysis Plan. The PKPD relationship was identified using SysFit as an Emax model with the parameters estimated from the parasitaemia data.

  Day 8 to Day 50+/-2

• Hill Coefficient

  Hill coefficient is the slope of the drug concentration-response curve (i.e. response in this study is the parasite killing). Calculated using the combined data from all doses/arms/groups in both period 1 and 2, as prespecified in section 10 of the Statistical Analysis Plan. The PKPD relationship was identified using SysFit as an Emax model with the parameters estimated from the parasitaemia data. The "Emax-model" assumes a direct effect of concentrations on parasite killing/clearance, such as: Kill = Emax x (Cc\^Hill /(Cc\^Hill + EC50\^Hill)) where Cc is the concentration in the central compartment, Emax is the maximum effect of the drug, EC50 is the concentration that results in 50% of the maximum effect, and Hill is the Hill coefficient.

  Day 8 to Day 50+/-2

• Minimum Inhibitory Concentration (MIC)

  MIC is defined as the concentration when drug killing equals the parasite growth, i.e., the time at which the minimum parasite concentration is observed. Calculated using the combined data from all doses/arms/groups in both period 1 and 2, as prespecified in section 10 of the Statistical Analysis Plan.

  Day 8 to Day 50+/-2

• Minimal Parasiticidal Concentration (MPC90)

  MPC90 is defined as the concentration at which the clearance effect is at 90% of the maximum. Calculated using the combined data from all doses/arms/groups in both period 1 and 2, as prespecified in section 10 of the Statistical Analysis Plan.

  Day 8 to Day 50+/-2

• Parasite Reduction Ratio in 48 h (log10PRR48)

  PRR48 is defined as the parasite reduction ratio achieved within 48 hours, usually given as the reduction of values on log10 transformed scale. PRR48 provides an efficacy estimate of anti-malarial treatment and is the ratio of the parasite density over a 48 hour time-period. PRR48 is estimated using the slope of the optimal fit of the log-linear relationship of the parasitemia decay. Optimal fit is derived using the geometric mean parasitemia data (i.e. 18S qPCR measuring all blood stage malaria parasites). Optimal fit of log-linear parasitemia by time relationship is determined using left and right censoring to systematically remove potential lag phase and tail phase of parasitemia decay. The PRR48 was calculated per subject in MMV\_PYR using daily PCR data; and if the model fit was adequate for the subject (defined as overall model p-value\<0.001), the slope and corresponding standard error (SE) from the log-linear regression was used to calculate the overall dose-specific PRR48

  Day 8 to Day 50+/-2

Study Arms (4)

Pyronaridine 360 mg

EXPERIMENTAL

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. 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.

Drug: Pyronaridine; Biological: P. falciparum IBSM infection

Pyronaridine 540 mg

EXPERIMENTAL

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. 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.

Drug: Pyronaridine; Biological: P. falciparum IBSM infection

Pyronaridine 720 mg

EXPERIMENTAL

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. 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.

Drug: Pyronaridine; Biological: P. falciparum IBSM infection

Not treated

OTHER

This inoculated participant was treated with rescue medication instead of pyronaridine due to testing positive for SARS-CoV-2 (COVID-19). Ten (10) participants were inoculated with P. falciparum and were included in the Full Analysis Set (FAS). Nine (9) inoculated participants were subsequently administered pyronaridine, and were included in the IMP Set, PK Analysis Set, PD Analysis Set, and the PK/PD Analysis Set. Some of the 18S qPCR data for the inoculated participant who was not administered pyronaridine was used in the PD model for PK/PD analyses.

Biological: P. falciparum IBSM infection

Interventions

Pyronaridine DRUG

Single dose

Pyronaridine 360 mg; Pyronaridine 540 mg; Pyronaridine 720 mg

P. falciparum IBSM infection BIOLOGICAL

Induced Blood Stage Malaria

Not treated; Pyronaridine 360 mg; Pyronaridine 540 mg; Pyronaridine 720 mg

Eligibility Criteria

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

You may qualify if:

• Demography
• 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.
• 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
• Certified as healthy by a comprehensive clinical assessment (detailed medical history and full physical examination).
• 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.
• 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:
• QTcF ≤450 msec (male participants); QTcF ≤470 msec (female participants);
• QRS 50-120 msec
• PR interval ≤ 210 msec for both males and females, and
• Normal ECG tracing unless the PI or delegate considers an ECG tracing abnormality to be not clinically relevant.
• 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.

You may not qualify if:

• 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).
• \. Known hypersensitivity to pyronaridine, artesunate or any of its derivatives, artemether, lumefantrine or other artemisinin derivatives, proguanil/atovaquone, primaquine, or 4-aminoquinolines.
• \. 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.
• \. Participation in any investigational product trial within the 12 weeks preceding pyronaridine administration.
• \. 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.
• \. 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.
• \. 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.
• \. 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.
• \. 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-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.
• \. 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.
• \. Presence of clinically significant infectious disease or fever (e.g., sublingual temperature ≥38.5°C) within the five days prior to inoculation.
• \. 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.

Sponsors & Collaborators

• Medicines for Malaria Venture: lead
• QIMR Berghofer Medical Research Institute: collaborator
• Southern Star Research: collaborator
• Swiss BioQuant: collaborator
• Children's Health Queensland Hospital and Health Service: collaborator

Study Sites (2)

South Bank

Brisbane, Queensland, 4101, Australia

Location

USC Clinical Trials, Morayfield

Brisbane, Queensland, 4506, Australia

Location

MeSH Terms

Conditions

Malaria, Falciparum; Malaria; Parasitemia; Protozoan Infections; Parasitic Diseases

Interventions

pyronaridine

Condition Hierarchy (Ancestors)

Infections; Mosquito-Borne Diseases; Vector Borne Diseases; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Joerg Moehrle
• Organization: Medicines for Malaria Venture

info@mmv.org

+41 22 555 03 00

Study Officials

• Jörg Möhrle, PhD

  Medicines for Malaria Venture

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Different doses of pyronaridine will be administered across and within cohorts in order to effectively characterise the PK/PD relationship. Each cohort will comprise up to three dose groups, with participants 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. The proposed dosing regimen for the Cohort 1, assuming six participants are enrolled, is as below. If less than six participants are enrolled the Safety Data Review Team (SDRT) will meet between Day 0 and Day 8, to decide on the dose/s to be administered.

Study Record Dates

• First Submitted: March 10, 2022
• First Posted: March 18, 2022
• Study Start: April 4, 2022
• Primary Completion: September 26, 2022
• Study Completion: September 26, 2022
• Last Updated: April 16, 2025
• Results First Posted: April 16, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

AU (2)