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Trial registered on ANZCTR


Registration number
ACTRN12618000968279
Ethics application status
Approved
Date submitted
1/06/2018
Date registered
8/06/2018
Date last updated
21/10/2019
Date data sharing statement initially provided
21/10/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A comparative assessment of two lumefantrine formulations compared to the standard reference formulation in healthy male and female volunteers of non-childbearing potential.
Scientific title
A two-period, open-label, randomized, parallel-group, partial cross-over study to evaluate the relative bioavailability and pharmacokinetics of two lumefantrine formulations in comparison to a reference formulation in healthy volunteers
Secondary ID [1] 295032 0
CLUM566X2102
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 308060 0
Condition category
Condition code
Infection 307113 307113 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A two-period, open-label, parallel-group and partial cross-over study to evaluate the
safety, tolerability and PK of two lumefantrine (LUM) formulations in comparison to a reference formulation. In Period 1, the PK of the LUM formulations will be compared to the SDF.
After an internal review of the results in Period 1, Period 2 will evaluate the effect of a standard African meal and 250mls of whole milk on the bioavailability of the SDF at a single dose (480 mg).

Period 1:
Following a 28-day screening period, and Day -1 baseline assessments, eligible subjects will be randomized to receive one of three treatments administered as an oral sachet: lumefantrine (LUM) Standard Reference Formulation (480mg), LUM Formulation 1 (480 mg), LUM Formulation 2 (480mg). Day 1 predose assessments will be collected in the morning and once eligibility is confirmed the subjects will receive a single oral dose of the assigned study medication. Subjects will be domiciled up to 24 hours postdose with safety and sequential PK samples collected during the 24 hours. Subjects will return to the study center on Days 3, 5, 8, 10, 12 for PK sample collections. End
of treatment assessments will take place on Day 14 when the subjects return to the clinic.

Period 2:
Subjects who complete Period 1 will be asked to return for Period 2. New replacement subjects will be allowed to enter Period 2 in the event there are insufficient subjects returning from Period 1.
After a minimum 4 week washout period, subjects from Period 1 who agree and meet eligibility will continue in Period 2. 6 subjects, have received a single dose of the SDF with standard African meal and up to 12 subjects will receive a single dose of SDF and 250mls of whole milk.
Day 1 predose assessments will be collected in the morning and once eligibility is confirmed the subjects will receive a single oral dose of the assigned study medication. Subjects will be domiciled up to 24 hours postdose with safety and sequential PK samples collected during the 24 hours. Subjects will return to the study site on Days 3, 5, 8, 10, 12 for PK collections. End of study assessments will take place on Day 14 or when the subjects return to the clinic.
At the time of this update, six subjects returned from the recruited 30 in Period 1 into Period 2. All six subjects entered Treatment Group 6. As a result, replacement subjects will be enrolled into Period 2, Treatment Group 7 following a 28 day screening period, and Day 1 baseline assessments.
Intervention code [1] 301364 0
Treatment: Drugs
Comparator / control treatment
Two-period, parallel-group, partial cross over study whereby one cohort will receive the reference solid dispersion formulation (SDF) and two cohorts will receive an alternate formulation (Lumefantrine Formulation 1 and Lumefantrine Formulation 2). After a 4 week washout, subjects who received the selected lumefantrine formulation will receive a dose of the same formulation with standard African meal, and up to 12 replacement subjects will receive a single dose of SDF and 250 mL of whole milk.
Control group
Active

Outcomes
Primary outcome [1] 306061 0
To assess the relative bioavailability of LUM from two formulations in comparison with the
reference solid dispersion formulation at a single dose in healthy volunteers under fasted conditions by evaluating the geometric mean ratio and 90% confidence interval of AUC0-24h for test to reference formulation measured by plasma assay.
Timepoint [1] 306061 0
Period 1 only:
0, 1, 2, 3, 6, 8, 12, 24, 48, 96, 168, 216, 264 hours post dosing.
Primary outcome [2] 306062 0
To assess the effect of a standard African meal on LUM PK of the SDF at a single dose of 480 mg by evaluating the geometric mean ratio and 90% confidence interval of AUC0-24h, Cmax, AUC0-last, and AUC0-inf of LUM for Period 2 to Period 1 for selected formulation measured by plasma assay.
Timepoint [2] 306062 0
Period 2 only:
0, 1, 2, 3, 6, 8, 12, 24, 48, 96, 168, 216, 264 hours post dosing.
Primary outcome [3] 306063 0
To assess the effect of 250 mL of whole milk on LUM PK of the SDF at a single dose of 480 mg by evaluating the geometric mean ratio and 90% confidence interval of AUC0-24h, Cmax, AUC0-last, and AUC0-inf of LUM for Period 2 to Period 1 for selected formulation measured by plasma assay.
Timepoint [3] 306063 0
Period 2 only:
0, 1, 2, 3, 6, 8, 12, 24, 48, 96, 168, 216, 264 hours post dosing.
Secondary outcome [1] 347462 0
To evaluate the safety and tolerability of LUM treatment in all cohorts by evaluating adverse events, vital signs (blood pressure, pulse rate and oral body temperature), body weight, ECG intervals and safety laboratory assessments.
Timepoint [1] 347462 0
Period 1 and Period 2:
0, 1, 2, 3, 6, 8, 12, 24, 48, 96, 168, 216, 264 hours post dosing.

Eligibility
Key inclusion criteria
Written informed consent must be obtained prior to participation in the study.

Healthy male and female subjects of non-childbearing potential aged 18 to 55 years included, and in good health as determined by past medical history, physical examination, vital signs, ECG, and laboratory tests at Screening.

At Screening, vital signs (systolic and diastolic blood pressure and
pulse rate) will be assessed in the sitting position after the subject has rested for at least 5 minutes, and again after 3 minutes in the standing position at Screening only. Sitting vital signs will be captured for the duration of the study and should be within the normal range:
-oral body temperature between 35.0°C to 37.5°C
-systolic blood pressure, 90 to 139 mmHg
-diastolic blood pressure, 40 to 89 mmHg
-pulse rate, 40 to 90 bpm

Subjects must weigh at least 50 kg to participate in the study, and must have a body mass index (BMI) within the range of 18 to 30 kg/m2. BMI = body weight (kg)/(height [m])2.

Able to communicate well with the Investigator, to understand and
comply with the requirements of the study.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Women of childbearing potential, defined as all women physiologically capable of becoming pregnant. Women are considered postmenopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks ago. In the case of oophorectomy alone, a woman will only be considered not of childbearing potential if her reproductive status has been confirmed by follow-up hormone level assessment.

Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin laboratory test.

Sexually active males unwilling to use a condom during intercourse or unwilling to refrain from sperm donation for greater than or equal to 4 weeks (28 days) after last dosing. A condom is required for all sexually active male participants to prevent them from either fathering a child OR donating sperms.

Use of any prescription drugs or over-the-counter medication (vitamins, herbal supplements, and dietary supplements) within 4 weeks or 5 times the terminal half-life of each drug prior to dosing.

Use of other investigational drugs at the time of enrollment, or within
30 days, whichever is longer; or longer if required by local regulations.

History of hypersensitivity to the study drug or any of its excipients or to drugs of similar chemical classes.

A past medical history of clinically significant cardiac or ECG
abnormalities (including arrhythmias) or a family history (grandparents, parents and siblings) of a prolonged QT interval syndrome, defined as a corrected QT interval, by Fridericia formula of > 450 msec of males and > 460 msec for females at Screening or first Baseline.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled 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
Other
Other design features
Two period, open-label, randomized, parallel-group, partial cross-over
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
21/08/2018
Actual
1/10/2018
Date of last participant enrolment
Anticipated
25/09/2018
Actual
21/09/2019
Date of last data collection
Anticipated
7/11/2018
Actual
5/10/2019
Sample size
Target
60
Accrual to date
Final
42
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 299611 0
Commercial sector/Industry
Name [1] 299611 0
Novartis Pharmaceuticals Corporation
Country [1] 299611 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Novartis Pharmaceuticals Corporation
Address
Novartis Pharmaceuticals Corporation
One Health Plaza
East Hanover, NJ 07936-1080
Country
United States of America
Secondary sponsor category [1] 298932 0
Commercial sector/Industry
Name [1] 298932 0
Novaritis Pharmaceuticals Australia Pty Limited
Address [1] 298932 0
Novartis Pharmaceuticals Australia Pty Limited (ABN 18 004 244 160) of 54 Waterloo Road, Macquarie Park NSW 2113
Country [1] 298932 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300514 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 300514 0
Ethics committee country [1] 300514 0
Australia
Date submitted for ethics approval [1] 300514 0
30/05/2018
Approval date [1] 300514 0
13/07/2018
Ethics approval number [1] 300514 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 83906 0
Dr Jason Lickliter
Address 83906 0
Nucleus Network Limited
Senior Medical Officer
Level 5, Burnet Tower
89 Commercial Road
Melbourne VIC 3004
Country 83906 0
Australia
Phone 83906 0
+61 3 9076 8960
Fax 83906 0
Email 83906 0
J.Lickliter@nucleusnetwork.com.au
Contact person for public queries
Name 83907 0
Melissa Hackling
Address 83907 0
Novartis Institutes for BioMedical Research Clinical Sciences and Innovation Building 435 / 3158C One Health Plaza East Hanover, NJ 07936-1080 USA
Country 83907 0
United States of America
Phone 83907 0
+001 862 7782590
Fax 83907 0
Email 83907 0
melissa.hackling@novartis.com
Contact person for scientific queries
Name 83908 0
Melissa Hackling
Address 83908 0
Novartis Institutes for BioMedical Research Clinical Sciences and Innovation Building 435 / 3158C One Health Plaza East Hanover, NJ 07936-1080 USA
Country 83908 0
United States of America
Phone 83908 0
+001 862 7782590
Fax 83908 0
Email 83908 0
melissa.hackling@novartis.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not required for healthy volunteer studies.


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
No additional documents have been identified.