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Trial registered on ANZCTR


Registration number
ACTRN12618001441202
Ethics application status
Approved
Date submitted
21/08/2018
Date registered
28/08/2018
Date last updated
28/08/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase I Study to Determine the Safety of Multiple Oral Doses of Niclosamide in Healthy Volunteers
Scientific title
An Open-Label, Cross-Over Phase I Study to Determine the Safety, Tolerability and Pharmacokinetics of Multiple Oral Doses of Niclosamide under Fed and Fasted Conditions in Healthy Volunteers
Secondary ID [1] 295870 0
None
Universal Trial Number (UTN)
U1111-1219-2542
Trial acronym
AWP MDFF
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Therapeutic for Zika virus treatment 309335 0
Condition category
Condition code
Infection 308200 308200 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The purpose of the study is to ascertain whether steady state PK of niclosamide at levels therapeutic for Zika virus treatment can be achieved by once daily dosing of niclosamide 2 g.
Investigational product, dosage and mode of administration:
Niclosamide oral tablet (Yomesan 500 mg chewable tablet, 2 g/day)
Duration of treatment:
Six days dosing in total, over 20 days (assuming the minimum 2-week washout period):
Dosing period 1: 2 g/day for 3 days (Fed/Fasted)
Dosing period 2: 2 g/day for 3 days (Fasted/Fed)
Dosing periods 1 and 2 will be separated by at least a 14 day washout period.
In addition; All dosing is completed in clinic and study unit staff will perform a compliance check of the mouth and hand (if applicable) of each participant following dose administration.
Intervention code [1] 312203 0
Treatment: Drugs
Comparator / control treatment
Single-centre, open label, randomized, cross over, food effect, multiple oral dose study to determine the safety, tolerability and PK of niclosamide in 12 healthy participants. Fed and fasted conditions. Participants will be randomized to either the Period 1 Fed/ Period 2 Fasting or Period 1 Fasting/Period 2 Fed group following confirmation of eligibility (n = at least 6 per group).
No treatment is the comparator.
Control group
Active

Outcomes
Primary outcome [1] 307168 0
To assess the pharmacokinetics (PK) of daily oral doses of niclosamide over 3 days when administered to healthy volunteers in the presence and absence of food.
Individual niclosamide concentration data will be listed and summarised by treatment with descriptive statistics (sample size [N], arithmetic mean, standard deviation [SD], median, minimum, maximum and geometric mean). Individual and mean niclosamide concentration-time profiles for each treatment (Fed/Fasted) will also be presented graphically.
Plasma PK parameters will be computed from individual plasma niclosamide concentrations using a non-compartmental analysis (NCA) approach. Parameters to be evaluated are: area under the drug concentration-time curve, from time zero to the last measurable concentration (AUClast), AUC from time 0 to infinity (AUC0-inf), maximum observed drug concentration (Cmax), time of the maximum drug concentration (Tmax), apparent terminal elimination rate constant (kel), apparent elimination half-life (t½), apparent oral clearance (Dose 1:CL/F; Dose 3: CL/Fss) and apparent terminal volume of distribution (Dose 1:Vz/F; Dose 3: Vz/Fss).
PK parameters will be summarized by cohort using descriptive statistics (arithmetic means, standard deviations [SD], coefficients of variation [CV], sample size [N] minimum, maximum and median). In addition, geometric means will be calculated for Ae0-24, AUC and Cmax.
No value for kel, t½ AUC0-inf, CL/F or Vz/F will be reported for cases that do not exhibit a terminal log-linear phase in the concentration versus time profile. Additional analyses will be performed as deemed necessary upon review of the data.
Timepoint [1] 307168 0
3 days
PK samples are collected at the following timepoints: 0.25, 0.5, 0.75, 1, 1.5, 2, 3 and 4, 6, 8, 12 on Days 1, 3, 18 and 20 and 24 hours on Days 2 and 9.
Secondary outcome [1] 350951 0
To assess the safety and tolerability of daily oral doses of niclosamide over 3 days when administered to healthy volunteers in the presence and absence of food.

Safety and tolerability, based on monitoring of AEs and serious AEs (SAEs), physical examination findings including vital signs (body temperature, heart rate, respiratory rate, systolic and diastolic blood pressure), 12-lead ECGs, and laboratory parameters (haematology, coagulation, serum chemistry and urinalysis).

The secondary outcomes are based on monitoring of AEs and serious AEs (SAEs), physical examination findings including vital signs (body temperature, heart rate, respiratory rate, systolic and diastolic blood pressure), 12-lead ECGs, and laboratory parameters (haematology, coagulation, serum chemistry and urinalysis).
Timepoint [1] 350951 0
3 days
Safety assesments are collected as follows: Physical exam before dosing and at 3 Days post dosing for each dosing period; vital signs collected every half hour till 2hour post dosing then 3, 4, 6, 8 and 12 hours post dosing for each dosing day; triplicate ECG collected on first day of dosing for each dosing period and single ECGs collected at 1, 2, 4, 6 and 12 hours post dosing on each dosing day; clinical safety lab samples are collected prior dosing and Day 3 post dosing for both dosing periods. Adverse events are reviewed and collected throughout the entire study.

Eligibility
Key inclusion criteria
Inclusion criteria:
1. Adult male and/or female healthy volunteers, age 18–65 years inclusive. Participants are to have evidence of clinically insignificant screening results (e.g. laboratory profiles, medical history, ECGs, physical examinations) as judged by the Investigator.
2. Negative urine drug screen /alcohol breath test prior to Day -1.
3. Available for the entire study period and willing to adhere to protocol requirements.
4. Male participants, and female participants of childbearing potential, must either be sexually inactive (abstinent) for 14 days prior to the first administration of IP and remain so 30 days following the final dosing of the IP, or have been using one of the following acceptable methods of birth control for the times specified:
- Intra-uterine device (IUD) in place for at least 3 months prior to the first administration of IP.
- Double barrier method (e.g., condom and diaphragm).
- Male partner who is surgical sterile (vasectomy) at least 6 months prior to the first administration of IP and is the sole sexual partner for that female participant.
- Adequate hormonal contraception.
Partners of participants, including same sex couples, should also use effective forms of contraception (e.g. hormonal contraception or IUD).
Participants who claim to be sexually inactive, but become sexually active during the course of the study must agree to use a double barrier method (e.g., condom and diaphragm) from the time of the start of sexual activity to 30 days following final dose.
Protocol Number: AWP 2017-01 Ala Wai Pharma Pty Ltd - Confidential
Version 2.0 Dated 11 July 2018 Page 16 of 66
In addition, female participants of childbearing potential will be advised to remain sexually inactive or to keep the same birth control method for at least 30 days following the final dosing of the IP.
Female participants of childbearing potential must not be lactating during the study.
Females of non-childbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to the first administration of IP:
- Sterilization (with a copy of the confirmation test) and be using a barrier method (condom or diaphragm) throughout the study;
- bilateral tubal ligation with a barrier method (condom or diaphragm) throughout the study;
- hysterectomy;
- bilateral oophorectomy,
or be postmenopausal with amenorrhea for at least 1 year prior to the first administration of IP and FSH serum levels = 20 IU/L.
Males must not donate sperm during the study or for 30 days after the final dose of the IP.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion criteria:
1. History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric disease, presence or known history of a viral infection (e.g. influenza) within 6 weeks prior to Screening.
2. Pregnant women or sexually active women of childbearing age not on contraception as described above.
3. Any of the following at Baseline:
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than or equal to 3x upper limit of normal (ULN) and bilirubin greater than or equal to 2x ULN, or
b. ALT greater than or equal to 5x ULN.
4. Participation in a clinical trial with an investigational drug within 30 days preceding the trial.
5. Donated blood within 45 days preceding the trial
6. Participant has known serum hepatitis, is a carrier of the hepatitis B surface antigen (HBsAg) or hepatitis C antibody, or positive for HIV
7. In receipt of medications with potential drug-drug interactions with niclosamide, including tizanidine (an absolute contraindication for niclosamide), losetron, levobupivacaine, duloxetine (Cymbalta), duloxetine (Irenka), bendamustine, sodium iodide and ropinirole.

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)
Allocation is not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants who have given their informed consent, completed all pre-study evaluations, and meet all eligibility criteria will be randomised in a 1:1 ratio to receive niclosamide in the Fed or Fasted state during the first study period, and the opposite state in the second period.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint(s)
Pharmacokinetics
Statistical methods / analysis
A detailed Statistical Analysis Plan (SAP) will be prepared for approval by the Sponsor. The SAP will include the procedure for accounting for missing, unused or spurious data, and procedures for reporting deviation(s) from the original statistical plan (any deviations from the original statistical plan should be described and justified in the protocol and/or in the final report, as appropriate).
The sample size chosen for this study was selected without statistical considerations. It has been determined adequate to meet the study objectives.

Recruitment
Recruitment status
Not yet recruiting
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)
VIC
Recruitment postcode(s) [1] 23781 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 300466 0
Commercial sector/Industry
Name [1] 300466 0
Ala Wai Pharma Pty Ltd
Address [1] 300466 0
17 Praeger Street
Chapel Hill 4069
Queensland
Country [1] 300466 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Ala Wai Pharma Pty Ltd
Address
17 Praeger Street
Chapel Hill
QLD 4069
Country
Australia
Secondary sponsor category [1] 299936 0
None
Name [1] 299936 0
Address [1] 299936 0
Country [1] 299936 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301269 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 301269 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 301269 0
Australia
Date submitted for ethics approval [1] 301269 0
24/07/2018
Approval date [1] 301269 0
02/08/2018
Ethics approval number [1] 301269 0

Summary
Brief summary
A safety study to assess various doses of reformulated niclosamide, under fed and fasted conditions. This study is intended to answer how the reformulation of the drug affects bioavailability and uptake. Niclosamide is an anticestodal drug that has been used to treat tapeworm infection since initial approval in the 1960s. Ala Wai Pharma Pty Ltd is investigating use of niclosamide for treatment of Zika virus infection. This study is a safety and PK study to determine whether daily dosing of approved doses of niclosamide can maintain a plasma concentration of active substance within therapeutic levels.
Trial website
None
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 69770 0
Dr Niquita Tugiono
Address 69770 0
Nucleus Network Limited
Level 5, Burnet Tower AMREP Precinct 89 Commercial Road Melbourne Victoria 3004
Country 69770 0
Australia
Phone 69770 0
+ 613 9076 8900
Fax 69770 0
Email 69770 0
N.Tugiono@nucleusnetwork.com.au
Contact person for public queries
Name 69771 0
Dr Niquita Tugiono
Address 69771 0
Nucleus Network Limited
Level 5, Burnet Tower AMREP Precinct 89 Commercial Road Melbourne Victoria 3004
Country 69771 0
Australia
Phone 69771 0
+ 613 9076 8900
Fax 69771 0
Email 69771 0
N.Tugiono@nucleusnetwork.com.au
Contact person for scientific queries
Name 69772 0
Dr Niquita Tugiono
Address 69772 0
Nucleus Network Limited
Level 5, Burnet Tower AMREP Precinct 89 Commercial Road Melbourne Victoria 3004
Country 69772 0
Australia
Phone 69772 0
+ 613 9076 8900
Fax 69772 0
Email 69772 0
N.Tugiono@nucleusnetwork.com.au

No information has been provided regarding IPD availability
Summary results
No Results