Blood stage challenge study to assess Tafenoquine prophlyaxis against Plasmodium falciparum in healthy volunteers.
A randomized, double-blinded, placebo-controlled study in healthy, non-immune adults to determine the schizonticidal activity of tafenoquine after challenge with Plasmodium falciparum blood stage parasites.
60 Degrees Pharmaceuticals Australia (60P) Pty Ltd
16 participants
Feb 1, 2017
Interventional
Conditions
Summary
Previous studies suggest that tafenoquine is an effective antimalarial, acting against both Plasmodium liver stages and subsequent asexual blood stages, although it is difficult to determine the contribution of each activity to the overall prophylatic effect of tafenoquine. Both activites would be important as any parasites that escape killing in the liver would need to be killed at the subsequent asexual blood stage. Furthermore, there was a paucity of observed P. falciparumin fections in non-immune participants during Study 033 (Nasveld 2010). Therefore, confirmation of blood parasite activity separate to any liver activity is warranted in a non-immune population to confirm the findings of the activity tafenoquine demonstrated in semi-immune participants in Africa (Dow 2015). This Phase Ib study will evaluate the prophylatic activity of a multiple dose regime of tafenoquine against challenge with P. falciparum asexual blood stage parasites in nonimmune participants. The Induced Blood Stage Malaria (IBSM) challenge model in which healthy non-immune participants are administered ~2,800 viable P. falciparum parasites within red blood cells is well suited to test this hypothesis. This study will help identify if a single dose of tafenoquine following three loading doses can prevent symptomatic blood stage infection following P. falciparum exposure. This study will also enable characterisation of the exposure-response relationship for tafenoquine and will also provide data regarding the safety and tolerability of tafenoquine in a controlled disease-like setting.
Eligibility
Inclusion Criteria32
- Completion of the written informed consent process;
- Men or women age 18 to 55 years, in good health as determined by past medical history,
- physical examination, vital signs, ECG, and laboratory tests at screening;
- Male participants agree to use acceptable methods of contraception if the male participant’s partner could become pregnant from the time of the first administration of the IMP until 90 days following administration of the IMP.
- Women of childbearing potential (WOCBP) agree to use the above acceptable methods of
- contraception from the time of the first administration of the IMP until 90 days following
- administration of the IMP;
- Females of non-childbearing potential as determined by having undergone one of the
- following sterilization procedures:
- a. Essure (Registered Trademark) sterilization (with a copy of the confirmation test);
- b. Bilateral tubal ligation;
- c. Hysterectomy;
- d. Bilateral oophorectomy;
- e. or be postmenopausal with amenorrhea for at least 1 year prior to screening and
- confirmed by a serum FSH test at screening.
- Hematology, biochemistry and urinalysis results at screening that are within the local
- laboratory reference range or, if outside the range, not clinically significant as judged by
- the Investigator in accordance with approved clinically acceptable laboratory ranges,
- documented prior to study start.More specifically, serum creatinine, hepatic
- transaminase enzymes (aspartate aminotransferase [AST], alanine aminotransferase
- [ALT]), and total bilirubin (unless the participant has documented Gilbert syndrome)
- should not exceed the approved acceptable ranges, and hemoglobin must be equal to or
- higher than the lower limit of the normal range;
- Total body weight greater than 50 kg and a body mass index (BMI) within the range of 18 to 32 kg/m2 (inclusive);
- Non-smoker or ex-smoker for more than 90 days prior to screening, or smoke no more than 5 cigarettes per day as determined by history.
- Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and
- other study procedures;
- Agree to stay in contact with the study site for the duration of the study and up to
- weeks following the EOS visit, provide updated contact information as necessary, and
- have no current plans to move away from the study area for the duration of the study;
- and
- At least normal G6PD enzyme activity levels as defined by the parameters of the specific G6PD test employed.
Exclusion Criteria86
- Male participants with a female partner(s) who is (are) pregnant or lactating from the
- time of the administration of study medication;
- Female participants who are pregnant or nursing (lactating);
- Evidence or history of clinically significant hematological, renal, endocrine, pulmonary,
- gastrointestinal (including gallbladder), cardiovascular (including a family history of
- long QT syndrome or sudden death), hepatic, psychiatric, neurologic, or allergic disease
- (including drug or food allergies, anaphylaxis or other severe allergic reactions but
- excluding untreated, asymptomatic, seasonal allergies at the time of dosing);
- History of retinal abnormalities, disease of the retina or macula of the eye, visual field
- defects, hearing disorders (e.g. reduced hearing, tinnitus);
- History of malignancy of any organ system (other than localized basal cell carcinoma of
- the skin), treated or untreated, within the past five years, regardless of whether there is
- evidence of local recurrence or metastases;
- Other severe acute or chronic medical or psychiatric condition or laboratory abnormality
- that may increase the risk associated with study participation or IMP administration or
- may interfere with the interpretation of study results and, in the judgment of the
- Investigator, would make the participant inappropriate for entry into this study;
- Any surgical or medical condition possibly affecting drug absorption (e.g. cholecystectomy, gastrectomy, bowel disease, etc.), distribution, metabolism or
- excretion;
- Previous splenectomy;
- Participant positive for any of the following:
- a. Anti-human immunodeficiency virus 1 or 2 antibodies (anti-HIV1 or anti-HIV2
- Ab) (Enzyme Linked Immunosorbent Assay [ELISA]);
- b. Hepatitis B surface antigen (HBsAg);
- c. Anti-Hepatitis B core antibodies (anti-HBcAb); and
- d. Anti-Hepatitis C antibodies (anti-HCV).
- Resting vital signs (measured after 5 minutes) at screening or pre-IMP dose outside of
- the following study-specific ranges:
- a. body temperature greater than 38.0 degrees C;
- b. systolic blood pressure less than or equal to 90 mmHg or greater than or equal to 140 mmHg;
- c. diastolic blood pressure less than or equal to 50 mmHg or greater than or equal to 90 mmHg; and
- d. pulse rate less than or equal to 40 bpm or greater than or equal to 100 bpm.
- A history of clinically significant ECG abnormalities,
- Presence of acute infectious disease or fever (i.e. body temperature greater than 38.5 degrees C) within
- days prior to the first dose of study medication;
- Use of prescription or non-prescription drugs, herbal and dietary supplements within
- days or 5 half-lives (whichever is the longer) prior to the first dose of study medication. As an exception, ibuprofen (preferred) may be used at doses of up to 1.2 g/day, or paracetamol at doses of up to 4 g/day. Limited use of other non-prescription medications or dietary supplements not believed to affect participant safety or the overall results of the study, may be permitted on a case-by-case basis following approval by the Sponsor in consultation with the Investigator];
- Recipient of any vaccination within 28 days prior to the first dose of study medication;
- Urine drug screen at screening, pre-IMP dose or pre-inoculation positive for any drug as
- listed in protocol unless there is an explanation acceptable to the medical
- Investigator (e.g. the participant has stated in advance that they consumed a prescription
- or over the counter product which contained the detected drug) and/or the participant has
- a negative urine drug screen on retest by the pathology laboratory;
- Ingestion of any poppy seeds within the 24 hours prior to the screening blood test;
- An alcohol breathalyzer test at screening indicating a greater than 0.0 blood alcohol, pre-IMP dose or pre-inoculation;
- History of regular alcohol consumption exceeding a weekly intake of more than 21 units
- for males and more than 14 units for females (one unit is equivalent to 8-10 g of ethanol,
- mL of beer or lager, one glass [125 mL] of wine, or 25 mL of spirits) within 6
- months of screening;
- History of drug habituation, or any prior intravenous usage of an illicit substance;
- Participation in any IMP study within 12 weeks or five half-lives (whichever is longer)
- prior to the first dose of the study medication;
- Participation in any research study involving blood sampling (more than 450 mL /unit of
- blood), or blood donation to the Australian Red Cross Blood Service (ARCBS) or other
- blood bank during the 8 weeks prior to IMP administration;
- Medical requirement for intravenous immunoglobulin or blood transfusions;
- Participant with poor peripheral venous access;
- Participant unwilling or unable to comply with the restrictions described in this protocol;
- Any participant who, in the judgment of the Investigator, is likely to be noncompliant
- during the study, or unable to cooperate because of a language problem or poor mental
- development;
- Any subject who is, directly involved in conducting the study;
- Recent (within the last three years) and/or recurrent history of autonomic dysfunction
- (e.g. recurrent episodes of fainting, palpitations, etc.);
- Any history of malaria;
- Participation in a previous malaria challenge study;
- Participation in a malaria vaccine trial;
- Has travelled to or lived (for more than 2 weeks) in a malaria-endemic region during the
- past 12 months (for endemic regions see http://www.map.ox.ac.uk/browse-resources/);
- Any plan to travel to a malaria-endemic region during the course of the study;
- Evidence of increased cardiovascular disease risk
- Frequent headaches and/or migraine, recurrent nausea, and/or vomiting (more than twice a month);
- Participant unwilling to defer blood donations to the ARCBS for 6 months;
- Participant who has ever received a blood transfusion;
- Participant currently receiving, or having previously received, immunosuppressive
- therapy (including systemic steroids, adrenocorticotrophic hormone or inhaled steroids)
- at a dose or duration associated with hypothalamic-pituitary-adrenal axis suppression
- (e.g. 1 mg/kg/day of prednisone or its equivalent, or chronic use of inhaled high potency
- corticosteroids such as budesonide 800 microg per day or fluticasone 750 microg);
- Any recent (<6 weeks) or current systemic therapy with drugs known to have potential
- antimalarial activity;
- Known allergy to one of the antimalarial rescue medications proposed for the challenge study;
- Participant is unwilling to abstain from consumption of quinine containing
- foods/beverages such as tonic water, lemon bitter, throughout the study period;
- Participant lives alone (at any stage from Day 1 until at least the end of the antimalarial
- drug treatment) period.
Interested in this trial?
Get notified about updates and connect with the research team.
Interventions
This single-centre study enrolling up to 16 healthy, non-immune men and women aged 18 to 55 years, This is a randomized, double-blinded, placebo-controlled study comprising two cohorts of eight participants each. Participants will visit the clinical research unit (CRU) where they will be randomized within each cohort to receive tafenoquine or placebo in a 6:2 ratio. The participant, Investigator, clinic staff and laboratory conducting the qPCR and PK endpoint assessment will be blinded to this randomization. Tafenoquine will be administered as one 200 mg dose per day (oral tablet) for three consecutive days (loading doses; Days 1-3) given after the participant’s normal breakfast. This will be followed by another 200 mg base dose (oral tablet) 7 days later given after the participant’s normal breakfast (Day 10). Participants will then be inoculated with erthrocytes containing viable ~2,800 viable P. falciparum parasites on Day 13 to assess the schizonticidal activity of tafenoquine against early blood stage infection. After inoculation, participants will be followed up regularly for safety assessments, clinical evaluation, PK sampling, and sampling for qPCR monitoring of malaria infection. All participants will receive a standard course of therapy with Riamet (Registered Trademark) (artemether 20mg/lumefantrine 120mg) tablets for oral use (4 tablets 12 hourly for 3 days) on Day 32 or earlier in the event of failure of TQ to inhibit uncontrolled parasite growth, or at the discretion of the Investigator. If required for clearance of gametocytes, Primacin (Trademark) (primaquine) 45 mg will also be administered as a single oral dose at the time of Riamet (Registered Trademark) treatment. An End of Study (EOS) visit will occur on Day 34. Each participant will participate in only one cohort. Participants will begin the Riamet (Registered Trademark) while at the clinic and will be then be contacted by telephone every day to ensure they continue the treatment course for 3 days.
Locations(1)
View Full Details on ANZCTR
For the most up-to-date information, visit the official listing.
ACTRN12617000102370