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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT02573857




Registration number
NCT02573857
Ethics application status
Date submitted
6/10/2015
Date registered
12/10/2015
Date last updated
5/06/2020

Titles & IDs
Public title
A Study to Characterise the Antimalarial and Transmission Blocking Activity of a Single Dose of DSM265 or OZ439 in Healthy Subjects With Induced Blood Stage Plasmodium Falciparum or Plasmodium Vivax Infection
Scientific title
A Phase Ib Study to Characterise the Antimalarial and Transmission Blocking Activity of a Single Dose of DSM265 or OZ439 in Healthy Subjects With Induced Blood Stage Plasmodium Falciparum or Plasmodium Vivax Infection
Secondary ID [1] 0 0
QP15C11
Universal Trial Number (UTN)
Trial acronym
DSMOZ-2
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: DSM265 P. falciparum - Cohort 1: the efficacy of a single administration of 400 mg DSM265 for the clearance of asexual blood stages of P. falciparum will be determined. Activity of a second single dose of 400 mg DSM265 against gametocytes will be assessed in this cohort only if sexual stages are identified by PCR following the initial drug treatment.

Experimental: OZ439 P. vivax - Cohort 2: subjects will be infected with P. vivax by IBSM, then treated with a single 200 mg dose OZ439. If recrudescence occurs following initial drug treatment with 200 mg OZ439, then affected participants who reach the treatment threshold will receive a single 400 mg dose of OZ439.

Experimental: DSM265 P. vivax - Cohort 3: subjects will be infected with P. vivax by IBSM, then treated with a single 400 mg dose of DSM265


Treatment: Drugs: DSM265
Oral suspension from bulk powder

Treatment: Drugs: OZ439
Oral suspension from powder in a bottle
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Efficacy (PRR) of DSM265 or OZ439
Timepoint [1] 0 0
From baseline to 48 hours post antimalarial treatment
Primary outcome [2] 0 0
Efficacy of OZ439 on P. Vivax
Timepoint [2] 0 0
From baseline to 48 hours post antimalarial treatment
Primary outcome [3] 0 0
Safety of DSM265 or OZ439 - Number of Adverse Events
Timepoint [3] 0 0
From challenge inoculum (day 0) up to day 28 (+/-3 days)
Secondary outcome [1] 0 0
Gametocytemia Clearance With DSM265
Timepoint [1] 0 0
From Drug administration up to day 28 (+/-3 days) following inoculum
Secondary outcome [2] 0 0
P. Vivax Transmission
Timepoint [2] 0 0
From challenge inoculum (day 0) and up to day 28 (+/-3 days)
Secondary outcome [3] 0 0
Parasite Density (Parasite/ml) Assessed by qPCR
Timepoint [3] 0 0
From From drug administration until Standard of Care administration, or up to day 28 (+/-3 days)
Secondary outcome [4] 0 0
Drug Concentration (PK) (ng/ml)
Timepoint [4] 0 0
From From drug administration until Standard of Care administration, or up to day 28 (+/-3 days)

Eligibility
Key inclusion criteria
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:

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

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

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

- Normal standard 12-lead electrocardiogram (ECG) after 5 minutes resting in supine
position, QTcF=450 ms (males and females) 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 norm and haemoglobin must be equal or higher than the lower limit of the
normal range

- As there is the risk of adverse effects of the investigational drugs (DSM265 and
OZ439), and standard curative treatment (Riamet and primaquine - cohort 1 only) in
pregnancy, it is important that any participants involved in this study do not get
pregnant or get their female partners pregnant (refer to Section 6.7).

For cohort 1 and 3 (treatment with DSM265):

Female participants of childbearing potential (WOCBP) may be enrolled in the DSM265 cohorts
but must have adequate contraception in place for the duration of the study and up to 60
days (9 weeks) after the last dose of DSM265, with adequate contraception defined as:

- Stable hormonal contraception (with an approved oral, transdermal or depot regimen)
for at least 3 months prior to screening i.e. oral contraceptives, either combined or
progestogen alone, hormonal implantable contraception, vaginal ring, contraceptive
patches

- Intrauterine (IUD) device or system in place for at least 3 months prior to screening

- Male partner sterilization prior to the female participant's entry into the study, and
this male is the sole partner for that participant Abstinent female participants must
agree to start a double method if they start a sexual relationship during the study
and for up to 60 days (9 weeks) following the last dose of DSM265.

Male participants to be dosed with DSM265 in cohort 1 or 3 must agree to use a double
method of contraception including condom plus diaphragm or condom plus stable
oral/transdermal/injectable hormonal contraceptive by female partner from at least 14 days
prior to the time of the dose of the study drug through 120 days (17 weeks) after the last
dose of DSM265.

Abstinent male participants must agree to start a double method if they start a sexual
relationship during the study and for up to 120 days (17 weeks) weeks following the last
dose of DSM265.

For cohort 2 (treatment with OZ439):

Female subjects must be considered as women of not childbearing potential (WONCBP) to be
eligible. WONCBP is defined as:

- Spontaneous amenorrhoea for at least 1 year or spontaneous amenorrhea for at least 6
months confirmed by an FSH result above the laboratory defined range for
post-menopausal

- or permanently sterilised (eg tubal occlusion, hysterectomy, bilateral salpingectomy)
Female subjects with same sex partners (abstinence from penile-vaginal intercourse),
are eligible when this is their preferred and usual lifestyle.

Male participants to be dosed with OZ439 in cohort 2 must agree to use a double method of
contraception including condom plus diaphragm or condom plus stable
oral/transdermal/injectable hormonal contraceptive by female partner from at least 14 days
prior to the time of the dose of the study drug through 96 days (14 weeks) after the last
dose of OZ439.

Abstinent male participants must agree to start a double method if they start a sexual
relationship during the study and for up to 96 days (14 weeks) following the last dose of
OZ439.

For Part B only (cohort 2 and 3):

- All subjects must be Duffy Blood group positive. Female subjects of childbearing
potential (Cohort 3 only) should be blood group Rh positive.

Regulations:

- Having given written informed consent prior to undertaking any study-related procedure.
Minimum age
18 Years
Maximum age
55 Years
Sex
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 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 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.

- 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.

- Presence of current or suspected serious chronic diseases such as cardiac or
autoimmune disease (HIV or other immunodeficiencies), insulin-dependent and
non-insulin dependent diabetes, progressive neurological disease, severe malnutrition,
acute or progressive hepatic disease, acute or progressive renal disease, psoriasis,
rheumatoid arthritis, asthma, epilepsy or obsessive compulsive disorder

- History of malignancy of any organ system (other than localized basal cell carcinoma
of the skin or in situ cervical cancer), treated or untreated, within 5 years of
screening, regardless of whether there is evidence of local recurrence or metastases

- 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 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 urinalysis.

- 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.

- Blood donation, any volume, within 1 month before inclusion or participation in any
research study involving blood sampling (more than 450 mL/ unit of blood), or blood
donation to 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 Australian Red Cross Blood
Service (ARCBS) for 6 months.

- 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) 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 for
the duration of 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. more than 400 mg caffeine per day (equivalent to more than 4 cups per
day)

Interfering substance:

- Any medication (including St John's Wort) within 14 days before inclusion 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 (< 6 weeks) or current systemic therapy with an antibiotic or drug with
potential anti-malarial activity (i.e. 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, or is unable to cooperate because of a language or mental deficit.

- 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
anti-malarial 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,
anti-hepatitis B core antibodies (anti-HBc Ab), anti-hepatitis C virus (anti-HCV)
antibodies, anti-hepatitis A or E virus (IgM) antibodies, anti-human immunodeficiency
virus 1 and 2 antibodies (anti-HIV1 and anti HIV2 Ab)

- Any drug listed in Table 2 (Drug Screening) 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.

Specific to the study_

- Cardiac/QT risk

- 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 analyses on study

- Known hypersensitivity to DSM265 or OZ439, or any of its excipients or
4-aminoquinolines, artemether or other artemisinin derivatives, lumefantrine, or other
arylaminoalcohols.

- Known severe reaction to mosquito bites other than local itching and redness.

- Unwillingness to abstain from consumption of citrus (grapefruit, Seville orange, etc.)
for =21 days prior to initiation of the study (inoculation; Day 0) and for the study
duration.

- Unwillingness to abstain from consumption of quinine containing foods/beverages such
as tonic water, lemon bitter, from inoculation (Day 0) to the end of the malaria
treatment.

- Any history or presence of lactose intolerance.

- Use of prescription drugs, herbal supplements, within four weeks prior to
administration of the study drug, and/or over-the-counter (OTC) medication, dietary
supplements (including vitamins) within two weeks prior to initial dosing (Note:
diazepam interferes with the analysis of blood levels of DSM265 and thus should not
have been used for at least 8 weeks prior to administration of the study drug). If
needed (i.e. an incidental and limited need) paracetamol is acceptable up to 4 g/day.

Participants are requested to refrain from taking non-approved concomitant medication from
recruitment until the conclusion of the study.

Participants who are excluded from participation on study days for any of the above reasons
may be eligible to participate on a postponed schedule if the Investigator considers this
appropriate.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
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
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/10/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/05/2016
Sample size
Target
Accrual to date
Final
16
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
Clinical Network Services (CNS) Pty Ltd
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/Industry
Name [2] 0 0
Q-Pharm Pty Limited
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
Queensland Institute of Medical Research
Address [3] 0 0
Country [3] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Part A

-Cohort 1 DSM265 will be administered as a single dose (400 mg). For cohort 1 only, an
additional single dose (400 mg) of DSM265 may be given if gametocytemia develops. Treatment
with DSM265 will be given after an overnight fasting period of = 8 hours. If dosing is to
occur in the evening, subjects will be required to fast for =4 hours prior to receiving
treatment. Subjects will be required to fast for a further four hours anytime after dosing
with DSM265.

Part B

- Cohort 2 OZ439 will be administered as a single 200 mg dose. If recrudescence is
observed, a single 400 mg dose of OZ439 will be given. Treatment with OZ439 will be
administered after an overnight fasting period of = 6 hours. If dosing is to occur in
the evening, subjects will be required to fast for =4 hours prior to receiving
treatment. Participants will drink 200 mL of milk prior to drug administration, and then
swallow the appropriate volume of OZ439 suspension. Subjects will be required to fast
for a further six hours anytime after dosing with OZ439.

- Cohort 3 DSM265 will be administered as a single dose (400 mg) as described for cohort
1. No additional dose will be administered.
Trial website
https://clinicaltrials.gov/ct2/show/NCT02573857
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

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT02573857