Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617000102370
Ethics application status
Approved
Date submitted
12/01/2017
Date registered
18/01/2017
Date last updated
10/07/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Blood stage challenge study to assess Tafenoquine prophlyaxis against Plasmodium falciparum in healthy volunteers.
Scientific title
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.
Secondary ID [1] 290726 0
TQ-2016-02 (QP16C11)
Universal Trial Number (UTN)
Nil
Trial acronym
NA
Linked study record
NA

Health condition
Health condition(s) or problem(s) studied:
Malaria infection 301303 0
Condition category
Condition code
Infection 301056 301056 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 296626 0
Prevention
Intervention code [2] 296869 0
Treatment: Drugs
Comparator / control treatment
Participants randomised to the control group will receive matching placebo tablets (oral microcellulose tablets 200mg) and all other treatments are identical to the intervention group is inoculation, malaria rescue treatment etc.
Control group
Placebo

Outcomes
Primary outcome [1] 300479 0
The number of participants requiring rescue treatment due to a Malaria Failure in each pooled treatment group before the mandated Riamet (Registered Trademark) treatment phase (Day 32). Malaria failure is defined as a participant with a qPCR parasitemia of > 5,000 asexual blood stage parasites accompanied by a clinical symptom score of > 6 OR parasitemia of > 5,000 asexual blood stage parasites and increasing 2 fold within 48 hours) in each pooled treatment group before the mandated Riamet (Registered Trademark) treatment phase
Timepoint [1] 300479 0
At Day 32 of each cohort.
Secondary outcome [1] 330060 0
The incidence, severity and relationship to the Investigational Medicinal Product (IMP) of AEs (unexpected toxicities, AEs encountered during or after IMP administration), safety laboratory parameters, and vital signs up to and including the EOS visit on Day 34.
Timepoint [1] 330060 0
Vitals and safety labs will be taken throughout 34 day cohort on days 1 10, 13, 17, 24, 32 and 34. Vitals will additionally be taken on days 2, 3, 20, 29 and 33.
Secondary outcome [2] 330061 0
Estimation of Tafenoquine drug concentration associated with first detection of Malaria Failure measured by a serum assay for pharmacokinetic (PK) parameters..
Timepoint [2] 330061 0
PK sampling throughout cohort at the following time-points include: pre-IMP dose on Day 1, Day 2, Day 3, and Day 10; pre inoculum on Day 13; and then on Day 20, Day 29 and Day 34/EOS.
Secondary outcome [3] 330062 0
Appearance of gametocytemia (pfs25 mRNA) in each pooled treatment group from Day 29 to EOS will be assessed by PCR from serum samples.
Timepoint [3] 330062 0
Blood samples will be taken at the investigators discretion from Day 29 to Day 34 only if pfs25 mRNA qRT-PCR establishes that significant gametocytemia (> 2,000/mL) has developed.

Eligibility
Key inclusion criteria
1. Completion of the written informed consent process;
2. 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;
3. 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;
5. 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.
6. 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;
7. Total body weight greater than 50 kg and a body mass index (BMI) within the range of 18 to 32 kg/m2 (inclusive);
8. 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.
9. Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and
other study procedures;
10. Agree to stay in contact with the study site for the duration of the study and up to
2 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
11. At least normal G6PD enzyme activity levels as defined by the parameters of the specific G6PD test employed.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Male participants with a female partner(s) who is (are) pregnant or lactating from the
time of the administration of study medication;
2. Female participants who are pregnant or nursing (lactating);
3. 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);
4. History of retinal abnormalities, disease of the retina or macula of the eye, visual field
defects, hearing disorders (e.g. reduced hearing, tinnitus);
5. 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;
6. 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;
7. Any surgical or medical condition possibly affecting drug absorption (e.g. cholecystectomy, gastrectomy, bowel disease, etc.), distribution, metabolism or
excretion;
8. Previous splenectomy;
9. 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).
10. 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.
11. A history of clinically significant ECG abnormalities,
12. Presence of acute infectious disease or fever (i.e. body temperature greater than 38.5 degrees C) within
5 days prior to the first dose of study medication;
13. Use of prescription or non-prescription drugs, herbal and dietary supplements within
14 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];
14. Recipient of any vaccination within 28 days prior to the first dose of study medication;
15. 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;
16. Ingestion of any poppy seeds within the 24 hours prior to the screening blood test;
17. An alcohol breathalyzer test at screening indicating a greater than 0.0 blood alcohol, pre-IMP dose or pre-inoculation;
18. 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,
285 mL of beer or lager, one glass [125 mL] of wine, or 25 mL of spirits) within 6
months of screening;
19. History of drug habituation, or any prior intravenous usage of an illicit substance;
20. Participation in any IMP study within 12 weeks or five half-lives (whichever is longer)
prior to the first dose of the study medication;
21. 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;
22. Medical requirement for intravenous immunoglobulin or blood transfusions;
23. Participant with poor peripheral venous access;
24. Participant unwilling or unable to comply with the restrictions described in this protocol;
25. 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;
26. Any subject who is, directly involved in conducting the study;
27. Recent (within the last three years) and/or recurrent history of autonomic dysfunction
(e.g. recurrent episodes of fainting, palpitations, etc.);
28. Any history of malaria;
29. Participation in a previous malaria challenge study;
30. Participation in a malaria vaccine trial;
31. 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/);
32. Any plan to travel to a malaria-endemic region during the course of the study;
33. Evidence of increased cardiovascular disease risk
34. Frequent headaches and/or migraine, recurrent nausea, and/or vomiting (more than twice a month);
35. Participant unwilling to defer blood donations to the ARCBS for 6 months;
36. Participant who has ever received a blood transfusion;
37. 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);
38. Any recent (<6 weeks) or current systemic therapy with drugs known to have potential
antimalarial activity;
39. Known allergy to one of the antimalarial rescue medications proposed for the challenge study;
40. Participant is unwilling to abstain from consumption of quinine containing
foods/beverages such as tonic water, lemon bitter, throughout the study period;
41. Participant lives alone (at any stage from Day 1 until at least the end of the antimalarial
drug treatment) period.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/02/2017
Actual
1/02/2017
Date of last participant enrolment
Anticipated
22/02/2017
Actual
22/02/2017
Date of last data collection
Anticipated
27/03/2017
Actual
31/03/2017
Sample size
Target
16
Accrual to date
Final
16
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 7103 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 14861 0
4006 - Herston

Funding & Sponsors
Funding source category [1] 295158 0
Government body
Name [1] 295158 0
United States Army Department of Defense, Medical Research and Materiel Command
Country [1] 295158 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
60 Degrees Pharmaceuticals Australia (60P) Pty Ltd
Address
105 North Steyne
Manly, NSW, 2095
Australia
Country
Australia
Secondary sponsor category [1] 293981 0
Commercial sector/Industry
Name [1] 293981 0
Clinical Network Services Pty Ltd
Address [1] 293981 0
Level 4
88 Jephson Street
Toowong
QLD, 4066
Country [1] 293981 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296510 0
QIMR Berghofer Human Research Ethics Committee
Ethics committee address [1] 296510 0
300 Herston Road, Herston, QLD 4006
Ethics committee country [1] 296510 0
Australia
Date submitted for ethics approval [1] 296510 0
01/11/2016
Approval date [1] 296510 0
02/12/2016
Ethics approval number [1] 296510 0
Ethics committee name [2] 296659 0
USAMRMC HRPO
Ethics committee address [2] 296659 0
U.S. Army Medical Research and Materiel Command
810 Schreider Street
Fort Detrick, MD 21702-5000
Ethics committee country [2] 296659 0
United States of America
Date submitted for ethics approval [2] 296659 0
31/10/2016
Approval date [2] 296659 0
10/01/2017
Ethics approval number [2] 296659 0
W81XWH-16-C-0002

Summary
Brief 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.
Trial website
NA
Trial related presentations / publications
NA
Public notes
NA

Contacts
Principal investigator
Name 71094 0
Prof James McCarthy
Address 71094 0
Q-Pharm Pty Limited
Level 5, Clive Berghofer Cancer Research Centre (CBCRC)
300C Herston Rd
Herston QLD 4006
Country 71094 0
Australia
Phone 71094 0
+61 7 3845 3636
Fax 71094 0
+61 7 3845 3637
Email 71094 0
[email protected]
Contact person for public queries
Name 71095 0
Dr Claire Williams
Address 71095 0
Q-Pharm Pty Limited
Level 5, Clive Berghofer Cancer Research Centre (CBCRC)
300C Herston Rd
Herston QLD 4006
Country 71095 0
Australia
Phone 71095 0
+61738453661
Fax 71095 0
Email 71095 0
[email protected]
Contact person for scientific queries
Name 71096 0
Prof James McCarthy
Address 71096 0
Q-Pharm Pty Limited
Level 5, Clive Berghofer Cancer Research Centre (CBCRC)
300C Herston Rd
Herston QLD 4006
Country 71096 0
Australia
Phone 71096 0
+61 7 3845 3636
Fax 71096 0
Email 71096 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseBlood Schizonticidal Activity and Safety of Tafenoquine When Administered as Chemoprophylaxis to Healthy, Nonimmune Participants Followed by Blood Stage Plasmodium falciparum Challenge: A Randomized, Double-blind, Placebo-controlled Phase 1b Study.2019https://dx.doi.org/10.1093/cid/ciy939
N.B. These documents automatically identified may not have been verified by the study sponsor.