Blood stage antimalarial activity of tafenoquine in healthy subjects infected with Plasmodium falciparum
A phase 1b study to evaluate the blood stage antimalarial activity of a single oral dose of tafenoquine in healthy subjects experimentally infected with Plasmodium falciparum
QIMR Berghofer Medical Research Institute
60 participants
Oct 27, 2020
Interventional
Conditions
Summary
This is a single-centre, open-label phase 1b study using the P. falciparum induced blood stage malaria (IBSM) model to evaluate the antimalarial activity of a single oral dose of tafenoquine in healthy subjects. The study will be conducted in three parts. Part 1 will be composed of an initial cohort of four subjects followed by up to three cohorts of up to eight subjects per cohort, and will evaluate the potential of different single oral doses of tafenoquine to clear asexual blood stage P. falciparum parasites and inhibit the development of the sexual stage of the parasite (gametocyte) responsible for transmission to mosquitoes. Part 2 will be composed of up to two cohorts of up to eight subjects per cohort, and will evaluate the potential of a single oral dose of tafenoquine administered prior to intravenous inoculation with blood stage P. falciparum to protect against infection. Part 3 will be composed of up to two cohorts of up to eight subjects per cohort and will determine if a single oral dose of tafenoquine is active against mature gametocytes, and is able to block transmission to mosquitoes. Parts 2 and 3 of the study are optional and are dependent on the results obtained in Part 1.
Eligibility
Inclusion Criteria15
- Male or female (non-pregnant, non-lactating) aged 18 to 55 years inclusive who will be contactable and available for the duration of the study and up to two weeks following the End of Study 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).
- Certified as healthy by a comprehensive clinical assessment (detailed medical history, complete physical examination and special investigations).
- At least normal G6PD enzyme activity levels as defined by the parameters of the specific quantitative G6PD test employed.
- Vital signs at screening and pre-inoculation (measured after five minutes in the supine position):
- Systolic blood pressure (SBP) - 90-140 mmHg,
- Diastolic blood pressure (DBP) - 40-90 mmHg,
- Heart rate (HR) 40-100 bpm.
- Electrocardiograph (ECG) ranges at screening and pre-inoculation: QTcB/QTcF less than or equal to 450 ms for male subjects, QTcB/QTcF less than or equal to 470 ms for female subjects, and PR interval less than or equal to 210 ms.
- Female subjects of childbearing potential who have, or may have, male sexual partner(s) during the course of the study should be using an insertable (implant and IUD, injectable, transdermal or combination oral contraceptive approved by the TGA combined with a barrier contraceptive from the time of informed consent through to 11 days after inoculation with the malaria challenge agent. Abstinent female subjects must agree to start a double method if they start a sexual relationship with a male during the study. Adequate contraception does not apply to subjects of childbearing potential with same sex partners (abstinence from penile-vaginal intercourse), when this is their preferred and usual lifestyle. Female subjects must not be planning in vitro fertilisation within the required contraception period.
- Women of non-childbearing potential who will not require contraception during the study are defined as: surgically sterile (tubal ligation is not considered surgically sterile), post-menopausal (spontaneous amenorrhoea for greater than or equal to 12 months, or spontaneous amenorrhoea for 6-12 months and follicle-stimulating hormone (FSH) greater than or equal to 40 IU/mL; either should be together with the absence of oral contraceptive use for greater than 12 months).
- Male subjects who have, or may have, female sexual partner(s) during the course of the study must agree to use a double method of contraception including condom plus diaphragm, or condom plus insertable device, or condom plus stable oral/transdermal/injectable hormonal contraceptive by the female partner, from the time of informed consent through to 90 days after the last dose of tafenoquine. Abstinent male subjects must agree to start a double method if they begin sexual relationships with a female during the study, and through to 90 days after the last dose of tafenoquine. Male subjects with female partners that are surgically sterile, or male subjects who have undergone sterilisation and have had testing to confirm the success of the sterilisation may also be included.
- Completion of the written informed consent process prior to undertaking any study-related procedure.
- Must be willing and able to communicate and participate in the whole study.
- Agreement to adhere to Lifestyle Considerations throughout study duration.
Exclusion Criteria24
- Subject lives alone (at any stage from inoculation day until the end of the artemether/lumefantrine treatment).
- Any history of malaria or participation in a previous malaria challenge study or malaria vaccine study.
- Must not have travelled to or lived (GREATER THAN 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 study. Must not have lived for greater than 1 year in a malaria-endemic region in the past 10 years. Must not have ever lived in a malaria-endemic region for more than 10 years inclusive. For endemic regions see https://map.ox.ac.uk/country-profiles/#!/. Bali is not considered a malaria-endemic region.
- Has evidence of increased cardiovascular disease risk (defined as greater than 10 percent, 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.
- History of splenectomy.
- Subject unwilling to defer blood donations to the Blood Service for at least six months after the EOS visit.
- Subject who has ever received a blood transfusion.
- Any recent (less than 6 weeks) or current systemic therapy with an antibiotic or drug with potential antimalarial activity (e.g. chloroquine, piperaquine phosphate, benzodiazepine, flunarizine, fluoxetine, tetracycline, azithromycin, clindamycin, doxycycline etc.).
- Known hypersensitivity to artesunate or any of its excipients, artemether or other artemisinin derivatives, proguanil/atovaquone, primaquine, or 4-aminoquinolines.
- Haematology, clinical chemistry or urinalysis results at screening or at the Day -1 to Day -3 eligibility visit that are outside of Sponsor-approved clinically acceptable laboratory ranges, and/or are considered clinically significant by the Investigator.
- Participation in any investigational product study within the 12 weeks preceding inoculation in Part 1, or IMP administration in Part 2.
- 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 greater than or equal to 20 mmHg within 2-3 minutes 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 (including but not limited to allergy to any of the antimalarial rescue treatments), or any history of anaphylaxis or other severe allergic reactions including face, mouth, or throat swelling or any difficulty breathing. Subjects 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 study.
- History of convulsion (including intravenous drug or vaccine-induced episodes). A medical history of a single febrile convulsion during childhood is not an exclusion criterion.
- 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, or mild asthma with preventative asthma medication required less than monthly), epilepsy, or obsessive-compulsive disorder.
- 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.
- Subjects with history of schizophrenia, bi-polar disease, psychoses, disorders requiring lithium, attempted or planned suicide, or any other severe (disabling) chronic psychiatric diagnosis.
- Subjects who have received psychiatric medications within one year prior to enrolment, or 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 minor depression that required at least six months of pharmacological therapy and/or psychotherapy within the last five years; or any episode of major depression.
- The Beck Depression Inventory will be used as an objective tool for the assessment of depression at screening. In addition to the conditions listed above, subjects with a score of 20 or more on the Beck Depression Inventory 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 subjects will be referred to a general practitioner or medical specialist as appropriate. Subjects with a Beck score of 17 to 19 may be enrolled at the discretion of the 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 subject or to the execution of the study and interpretation of the data gathered.
- History of recurrent headache (e.g. tension-type, cluster or migraine) with a frequency of greater than or equal to 2 episodes per month on average and severe enough to require medical therapy, during the 5 years preceding screening.
- Presence of clinically significant infectious disease or fever (e.g. sublingual temperature greater than or equal to 38.5°C) within the five days prior to Inoculation in Part 1, or IMP administration in Part 2.
- Evidence of acute illness within the four weeks prior to screening that the Investigator deems may compromise subject safety.
- 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.
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Interventions
This is a single-centre, open-label phase 1b study using the P. falciparum induced blood stage malaria (IBSM) model to evaluate the antimalarial activity of a single oral dose of tafenoquine in healthy subjects. The study will be conducted in up to three parts. Part 1: Part 1 will evaluate the activity of different single oral doses of tafenoquine administered after intravenous inoculation with blood stage P. falciparum in clearing parasites. Subjects will be intravenously inoculated with approx. 2,800 viable P. falciparum parasite-infected human erythrocytes on Day 0. Subjects will be admitted to the clinical trial site for single-dose administration of tafenoquine on Day 8. Subjects in Cohort 1 will be administered a single oral dose of 300 mg tafenoquine. Participants are observed during tafenoquine administration and mouth checks performed. The Safety and Data Review Team (SDRT) will review safety, tolerability and parasitaemia data up to and including Day 10 to determine if parasitaemia is safely and effectively cleared at this dose level and decide on the dose to be administered to Cohort 2. A similar procedure will be followed to select the dose to be administered to Cohorts 3 and 4. Screening for these subsequent cohorts can commence once the SDRT have made a decision regarding the previous cohort. The SDRT will review data up to and including Day 10. Thus it is likely that screening for subsequent cohorts will begin at a minimum of 14 days after the previous cohort commences. The maximum single dose of tafenoquine administered in the study will not exceed 600 mg, and the minimum dose will be no less than 25 mg. All subjects will receive compulsory antimalarial rescue treatment with artemether/lumefantrine (six doses of four tablets administered orally over three consecutive days) on Day 48±2, or earlier in the event that tafenoquine treatment fails to clear asexual parasitaemia. If gametocytes are present at or after the time of treatment with artemether/lumefantrine, 45 mg primaquine may be administered as a single oral dose at the Investigator’s discretion. If an allergy or contraindication to artemether/lumefantrine develops, then atovaquone/proguanil will be administered. If subjects are unable to complete oral antimalarial rescue treatment, they will receive intravenous artesunate The SDRT will review safety, tolerability and parasitaemia data up to and including Day 10 of Cohort 2 to determine if parasitaemia is safely and effectively cleared at the dose level chosen for Cohort 2 and decide on the dose to be administered to Cohort 3. The SDRT will review safety, tolerability and parasitaemia data up to and including Day 10 of Cohort 3 to determine if parasitaemia is safely and effectively cleared at the dose level chosen for Cohort 3 and decide on the dose to be administered to Cohort 4. If parasitaemia is safely and effectively cleared at the dose level chosen for the previous cohort, then it is likely that the SDRT may choose a lower dose for the subsequent cohort. The minimum single dose of tafenoquine administered in this study will be no less than 25 mg. If parasitaemia is not safely and effectively cleared at the dose level chosen for the previous cohort, then the SDRT may choose a higher dose for the subsequent cohort. The maximum single dose of tafenoquine administered in the study will not exceed 600 mg. Part 2: The decision to commence part 2 occur after safety review and submission to the funding sponsor the Bill and Melinda Gates Foundation, as additional funding will be required to proceed with Parts 2 and 3. Part 2 of the study is optional, and is dependent on the results obtained in Part 1. Part 2 will be composed of up to two cohorts of up to eight subjects per cohort, and will evaluate the potential of a single oral dose of tafenoquine administered prior to intravenous inoculation with blood stage P. falciparum to protect against infection. Subjects will be randomised on Day 0 to receive either a single oral dose of tafenoquine (active group) or no tafenoquine (control group) in a 7:1 ratio (active: control). No blinding will be performed. All subjects will be intravenously inoculated with ~ 2,800 viable P. falciparum parasite-infected human erythrocytes on Day 3. Subjects will then be followed up as outpatients at least three times per week for safety assessments and blood sampling to monitor parasitaemia and blood and plasma concentrations of tafenoquine up to Day 35±2. In the event that parasitaemia reaches =10,000 parasites/mL, antimalarial rescue treatment with artemether/lumefantrine will be initiated. Artemether/lumefantrine treatment may also be initiated before parasitaemia reaches this threshold at Investigator’s discretion in the interest of subject safety. All subjects will receive compulsory antimalarial rescue treatment with artemether/lumefantrine on Day 32±2 if not given earlier. If gametocytes are present at or after the time of treatment with artemether/lumefantrine, 45 mg primaquine may be administered as a single oral dose at Investigator’s discretion. If an allergy or contraindication to artemether/lumefantrine develops, then atovaquone/proguanil will be administered. If subjects are unable to complete oral antimalarial rescue treatment, they will receive intravenous artesunate. The dose of tafenoquine administered to the active group in Part 2 will be the lowest dose that was found to safely and effectively clear parasites in Part 1 of the study. The SDRT will meet between the two proposed cohorts in Part 2 to review safety, tolerability and parasitaemia data from the first cohort. If the dose chosen in cohort 1 part 2, safely protects against infection, then a second cohort may occur with the same dose as used in cohort 1 (to achieve statistical power). If the dose chosen in cohort 1 part 2, does not safely protect against infection, then a second cohort may not occur. Part 3: Part 3 of the study is optional, and is dependent on the results obtained in Part 1. Subjects will be inoculated with P. falciparum and monitored up to approximately Day 8 as described above for part 1. On approximately Day 8 (or earlier if one of the criteria listed above for part 1 occur), subjects will be administered a low dose of piperaquine (480 mg). Subjects will return to the clinic on Day 9 and Day 10 to ensure adequate clinical and parasitological response to treatment. It is expected that a single 480 mg dose of piperaquine will be insufficient to prevent recrudescence, thus an additional dose of piperaquine (960 mg) will be administered on Day 10. The purpose of this piperaquine treatment regimen is to clear asexual parasites (responsible for clinical symptoms) and prevent recrudescence, while allowing transmissible gametocytes to develop. Between Day 11 and Day 23, regular outpatient visits will occur to monitor parasitaemia and gametocytaemia, and perform safety assessments and blood sampling to determine piperaquine exposure by measuring blood and plasma piperaquine concentrations. On Day 24, the transmission of gametocytes to Anopheles mosquitoes will be assessed using an enriched membrane feeding assay (eMFA). Subjects will then be randomised to receive either a single oral dose of tafenoquine (active group) or no tafenoquine (control group) in a 7:1 ratio (active: control). No blinding will be performed. Additional eMFAs will be performed on Days 25, 28 and 31 to determine the effect of tafenoquine on transmission. Blood and plasma concentrations of tafenoquine and its 5, 6-orthoquinoine metabolite will be measured to monitor tafenoquine exposure. All subjects will begin compulsory antimalarial rescue treatment with artemether/lumefantrine following the eMFA on Day 31, or earlier in the event that piperaquine treatment fails to clear asexual parasitaemia or prevent recrudescence. Artemether/lumefantrine treatment may also be initiated at any time at the Investigator’s discretion in the interest of subject safety. If gametocytes are present at or after the time of treatment with artemether/lumefantrine, 45 mg primaquine may be administered as a single oral dose at Investigator’s discretion. If an allergy or contraindication to artemether/lumefantrine develops, then atovaquone/proguanil will be administered. If subjects are unable to complete oral antimalarial rescue treatment, they will receive intravenous artesunate. The end of study visit will occur on Day 34±2. The dose of tafenoquine administered to the active group in Part 3 will be the lowest dose that was found to safely and effectively clear parasites in Part 1 of the study. The SDRT will meet between the two proposed cohorts in Part 3 to review safety, tolerability, parasitaemia, gametocytaemia, and transmission data from the first cohort.
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ACTRN12620000995976