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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02389348




Registration number
NCT02389348
Ethics application status
Date submitted
20/02/2015
Date registered
17/03/2015
Date last updated
7/10/2015

Titles & IDs
Public title
A Phase Ib Induced Malaria Infection Study With the Combination of OZ439 and DSM265
Scientific title
A Proof-of-concept Study to Assess the Effect of a Range of Doses of Combined Therapy With OZ439 and DSM265 Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Participants
Secondary ID [1] 0 0
QP14C12
Universal Trial Number (UTN)
Trial acronym
OZ/DSMCombo
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 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

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - DSM265
Treatment: Drugs - OZ439

Experimental: combination OZ439 and DSM265 - Subjects will receive 1800 P falciparum infected red blood cells. Development of parasitemia will be monitored by quantitative PCR. When the parasitemia reached the threshold of 1000 p/ml subjects will receive a single oral dose of OZ439 and DSM265.
Subsequent doses in subsequent cohort(s) will be determined following a review of observed OZ439 and DSM265 safety, and pharmacokinetic and pharmacodynamic interaction outcomes as well as the activity of the drugs as defined by parasite clearance kinetics.


Treatment: Drugs: DSM265
Single oral doses of DSM265

Treatment: Drugs: OZ439
Single oral doses of OZ439

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
PK/PD relationship on clearance of P falciparum parasites from the blood - The Parasite Reduction Ratio (PRR) is estimated using the slope of the optimal fit of the log-linear relationship of the parasitemia decay.
Timepoint [1] 0 0
From treatment administration to clearance of parasites or administration of Standard of Care therapy, whichever comes first, and up to 42 days following inoculum
Secondary outcome [1] 0 0
Incidence, relation to study drug and severity of AE - Assessment of tolerability and safety of OZ439 and DSM265 in the challenge model
Timepoint [1] 0 0
From challenge inoculum and up to 42 days following inoculum
Secondary outcome [2] 0 0
Cmax, Tmax, AUC of DSM265 and OZ439 - Appropriate PK parameters will be determined including non-compartmental and modeling characterisation
Timepoint [2] 0 0
From Drug administration up to 42 days following inoculum

Eligibility
Key inclusion criteria
Demography

- Adults (male and non-pregnant and non-lactating females) participants between 18 and
55 years of age, inclusive who do not live alone (from Day 0 until at least the end of
the antimalarial drug treatment) and be contactable and available for the duration of
the trial (maximum of 4 months).

- Female participants of childbearing potential must have adequate contraception in
place (see section 6.7) for the duration of the study and extended duration, and have
negative results on a serum or urine pregnancy test done before administration of
study product. Males prepared to use adequate contraception for the duration of study
and extended duration (See section 6.7)

- Body weight, minimum 50.0 kg, body mass index between 18.0 and 32.0 kg/m2, inclusive.

Health status

- Certified as healthy by a comprehensive clinical assessment (detailed medical history
and complete physical examination).

- Normal vital signs after 5 minutes resting in supine position:

- 95 mmHg < systolic blood pressure (SBP) <140 mmHg,

- 50 mmHg < diastolic blood pressure (DBP) <90 mmHg,

- 40 bpm< heart rate (HR) <100 bpm.

- Oral body temperature between 35.0 - 37.5?C

- Normal standard 12-lead electrocardiogram (ECG) after 5 minutes resting in supine
position, QTcF=450 ms with absence of second or third degree atrioventricular block or
abnormal T wave morphology.

- Laboratory parameters within the normal range, unless the Investigator considers an
abnormality to be clinically irrelevant for healthy participants enrolled in this
clinical investigation. More specifically for serum creatinine, hepatic transaminase
enzymes (aspartate aminotransferase, alanine aminotransferase), and total bilirubin
(unless the Participant has documented Gilbert syndrome) should not exceed the upper
laboratory normal and haemoglobin must be equal or higher than the lower limit of the
normal range, Regulations

- Having given written informed consent prior to undertaking any study-related
procedure.
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Medical history and clinical status

- Any history of malaria or participation to a previous malaria challenge study

- Must not have travelled to or lived (>2 weeks) in a malaria-endemic country during the
past 12 months or planned travel to a malaria-endemic country during the course of the
study.

- Has evidence of increased cardiovascular disease risk (defined as >10%, 5 year risk)
as determined by the method of Gaziano et al. (1). Risk factors include sex, age,
systolic blood pressure (mm/Hg), smoking status, body mass index (BMI, kg/m2) and
reported diabetes status.

- History of splenectomy.

- Presence or history of drug hypersensitivity, or allergic disease diagnosed and
treated by a physician or history of a severe allergic reaction, anaphylaxis or
convulsions following any vaccination or infusion. Lactose Intolerant.

- Presence of current or suspected serious chronic diseases such as cardiac or
autoimmune disease (HIV or other immunodeficiencies), insulin-dependent Type 1 and
Type 2 and NIDDM diabetes (excluding glucose intolerance if Exclusion criteria 3 is
met), progressive neurological disease, severe malnutrition, acute or progressive
hepatic disease, acute or progressive renal disease, psoriasis, rheumatoid arthritis,
uncontrolled asthma, epilepsy or obsessive compulsive disorder, skin carcinoma
excluding non-spreadable skin cancers such as basal cell and squamous cell carcinoma.

- Any surgical or medical condition which might significantly alter the absorption,
distribution, metabolism, or excretion of drugs, or which may jeopardize the subject
in case of participation in the study. The Investigator should make this determination
in consideration of the subject's medical history and/or clinical or laboratory
evidence of any of the following:

- Inflammatory bowel disease, ulcers, gastrointestinal or rectal bleeding in the
last 6 months;

- Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or
bowel resection;

- Pancreatic injury or pancreatitis in the last 6 months;

- Participants with history of schizophrenia, bi-polar disease, or other severe
(disabling) chronic psychiatric diagnosis. including depression or receiving
psychiatric drugs or who has been hospitalized within the past 5 years prior to
enrollment for psychiatric illness, history of suicide attempt or confinement for
danger to self or others.

- Frequent headaches and/or migraine, recurrent nausea, and/or vomiting (more than twice
a month).

- Presence of acute infectious disease or fever (e.g., sub-lingual temperature = 38.5°C)
within the five QP14C12_OZ439-DSM265 MMV Challenge Protocol_v1.1_26Nov 2014 Page 9 of
71 days prior to inoculation with malaria parasites.

- Evidence of acute illness within the four weeks before trial 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 urin analysis.

- Participant has a clinically significant disease or any condition or disease that
might affect drug absorption, distribution or excretion, e.g. gastrectomy, diarrhoea.

- Participation in any investigational product study within the 12 weeks preceding the
study.

- Participation in any research study involving to be desired blood sampling (more than
450 mL/ unit of blood), or blood donation to Australian Red Cross (or other) blood
bank during the 8 weeks preceding the reference drug dose in the study.

- Participant unwilling to defer blood donations to the ARCBS for 6 months.

- Blood donation, any volume, within 1 month before inclusion.

- Medical requirement for intravenous immunoglobulin or blood transfusions.

- Participant who has ever received a blood transfusion.

- Symptomatic postural hypotension at screening, irrespective of the decrease in blood
pressure, or asymptomatic postural hypotension defined as a decrease in systolic blood
pressure =20 mmHg within 2-3 minutes when changing from supine to standing position.

- History or presence of alcohol abuse (alcohol consumption more than 40 g per day, ( 3
standard drinks per day) or drug habituation, or any prior intravenous usage of an
illicit substance.

- Smoking more than 5 cigarettes or equivalent per day and unable to stop smoking during
the study.

- Ingestion of any poppy seeds within the 24 hours prior to the screening blood test
(participants will be advised by phone not to consume any poppy seeds in this time
period).

- Excessive consumption of beverages containing xanthine bases, including red bull,
chocolate, etc, (eg, more than 400 mg of caffeine per day (more than 4 cups or glasses
per day).

Interfering substance

- Any medication (including St John's Wort) within 14 days malaria inoculum (day 0) or
within 5 times the elimination half-life (whichever is longer) of the medication.

- Any vaccination within the last 28 days.

- Any corticosteroids, anti-inflammatory drugs, immunomodulators or anticoagulants. Any
participant currently receiving or having previously received immunosuppressive
therapy, including systemic steroids including adrenocorticotrophic hormone (ACTH) or
inhaled steroids in dosages which are associated with hypothalamic-pituitary-adrenal
axis suppression such as 1 mg/kg/day of prednisone or its equivalent or chronic use of
inhaled high potency corticosteroids (budesonide 800 µg per day or fluticasone 750
µg).

- Any recent or current systemic therapy with an antibiotic or drug with potential
antimalarial activity (chloroquine, piperaquine, benzodiazepine, flunarizine,
fluoxetine, tetracycline, azithromycin, clindamycin, hydroxychloroquine, etc.).

General conditions

- Any participant who, in the judgment of the Investigator, is likely to be noncompliant
during the study, QP14C12_OZ439-DSM265 MMV Challenge Protocol_v1.1_26Nov 2014 Page 10
of 71 or unable to cooperate because of a language problem or poor mental development.

- Any participant in the exclusion period of a previous study according to applicable
regulations.

- Any participant who lives alone (from Day 0 until at least the end of the antimalarial
drug treatment).

- Any participant who cannot be contacted in case of emergency for the duration of the
trial and up to 2 weeks following end of study visit.

- Any participant who is the Investigator or any sub-investigator, research assistant,
pharmacist, study coordinator, or other staff thereof, directly involved in conducting
the study.

- Any participant without a good peripheral venous access. Biological status

- Positive result on any of the following tests: hepatitis B surface (HBs Ag) antigen,
antihepatitis 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),

- Participant is found to be G6PD deficient

- Any drug listed in Table 2 in the urine drug screen unless there is an explanation
acceptable to the medical investigator (e.g., the participant has stated in advance
that they consumed a prescription or OTC product which contained the detected drug)
and/or the Participant has a negative urine drug screen on retest by the pathology
laboratory.

- Positive alcohol urine or breath test. Specific to the study

- Cardiac/QT risk:

- Known pre-existing prolongation of the QTcB interval considered clinically
significant,

- 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. Electrolyte disturbances,particularly
hypokalaemia, hypocalcaemia or hypomagnesaemia,

- Electrocardiogram (ECG) abnormalities in the standard 12-lead ECG (at screening)
which in the opinion of the Investigator is clinically relevant or will interfere
with the ECG analysis,

- A history of clinically significant ECG abnormalities.

- Known hypersensitivity to OZ439 or DSM265 or any of its excipients or excipients or
artemether or other artemisinin derivatives, lumefantrine, or other arylamino
alcohols.

- Unwillingness to abstain from consumption of citrus (grapefruit, Seville orange, etc.)
as well as quinine containing foods/beverages such as tonic water, lemon bitter, from
inoculation (Day 0) to the end of the malaria treatment or as advised by the clinical
personnel.

- Use of any prescription drugs, herbal supplements, within four (4) weeks prior to
initial dosing, and/or over-the-counter (OTC) medication, dietary supplements
(vitamins included) within two (2) weeks prior to initial dosing (note that diazepam
interferes with the analysis of DSM265 and should not have been used for 8 weeks prior
to initial dosing). If needed, (i.e. an incidental and limited need) paracetamol is
acceptable up 4 g/day.

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
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
Single group
Other design features
Phase
Phase 1/Phase 2
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
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 0 0
Q-Pharm Clinics - Herston
Recruitment postcode(s) [1] 0 0
4006 - Herston

Funding & Sponsors
Primary sponsor type
Other
Name
Medicines for Malaria Venture
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Q-Pharm Pty Limited
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
QIMR Berghofer Medical Research Institute
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Commercial sector/Industry
Name [3] 0 0
Clinical Network Services (CNS) Pty Ltd
Address [3] 0 0
Country [3] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
This is a single-centre, open-label, dose finding study using induced blood stage malaria
(IBSM) infection to characterize the pharmacodynamic interaction between OZ439 and DSM265,
administered around 120 minutes apart for treatment of early Plasmodium falciparum blood
stage infection. The study will be conducted in up to three cohorts (n=8 per cohort) using
different doses of OZ439 and DSM265. The doses of OZ439 and DSM265 that will be investigated
in the first cohort will be 200 mg of OZ439 and 100mg of DSM265, both administered as single
doses around 120 minutes apart. Subsequent doses in subsequent cohort(s) will be determined
following a review of observed OZ439 and DSM265 safety, and pharmacokinetic and
pharmacodynamic interaction outcomes, particularly the antimalarial activity of the drugs
given in combination as defined by parasite clearance kinetics. The doses used in Cohort 2
and 3 may be adjusted but will not exceed the maximum acceptable doses predefined for this
study (which are 400 mg for DSM265 and 500mg for OZ439) as determined in previous safety and
pilot efficacy studies. The dose will be determined by the funding sponsor and the principal
investigator (PI) following Safety Review team (SRT) and scientific evaluation. If no safe
alternative dose can be determined the option exists to curtail the study to less than three
cohorts.

Each participant in the cohort will be inoculated on Day 0 with ~1,800 viable parasites of
Plasmodium falciparum-infected human erythrocytes (BSPC) administered intravenously. On an
outpatient basis, participants will be monitored daily via phone call and then daily (AM)
from day 4 (until PCR positive for presence of malaria parasites). Once PCR positive they
will be monitored twice-daily morning (AM) and evening (PM) until treatment, for adverse
events and the unexpected early onset of symptoms, signs or parasitological evidence of
malaria. On the day designated for commencement of treatment, as determined by qPCR results,
participants will be admitted to the study unit and monitored. The threshold for commencement
of treatment will be when PCR quantification of all participants is = 1,000 parasites/mL. If
the PCR quantification of any participant is = 5,000 parasites/mL and is accompanied by a
clinical symptom score >5, or if clinical or parasitological evidence of malaria occurs in
any participant before all participants have reached the treatment threshold (PCR
quantification of = 1,000), then treatment of that participant will begin within a 24 h
period.

Following treatment with OZ439 and DSM265, participants will be followed up as inpatients for
at least 48 hours to ensure tolerance of the treatment and clinical response, then if
clinically well on an outpatient basis for safety and clearance of malaria parasites via PCR.

Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) will occur on
study day 16 ±3 days post OZ439 and DSM265 treatment unless required earlier. Early standard
anti-malarial drug intervention can occur if either poor responses or fast responses are seen
following OZ439 and DSM265 treatment. This is to ensure participant safety and to avoid
participant inconvenience if useful data cannot be obtained. A poor response is defined as a
decrease in parasitaemia of less than 20% from baseline by 3 days post OZ439 and DSM265
treatment. A fast response occurs when, within the seven day period following the treatment,
two consecutive PCR assessments in 48 hours are negative. However, pre-emptive treatment with
Riamet® can commence whenever deemed necessary by the investigator. Participants will be
monitored, either in clinic, or by telephone for three days to ensure adherence to Riamet®
therapy.

Participants will be treated with a single dose (45 mg) of primaquine as described in section
4.3 in this protocol at the end of their Riamet® treatment if gametocytes are identified, to
ensure complete clearance of any gametocytes present.

Adverse events will be monitored via telephone monitoring, within the clinical research unit,
and on outpatient review after malaria challenge inoculation and antimalarial study drugs
administration. Blood samples for safety evaluation, malaria monitoring, and red blood cell
antibodies will be drawn at screening and/ or baseline and at nominated times after malaria
challenge.
Trial website
https://clinicaltrials.gov/show/NCT02389348
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
James McCarthy, Prof
Address 0 0
Q-Pharm Pty Limited
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
Other publications