Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000002987
Ethics application status
Approved
Date submitted
13/11/2019
Date registered
8/01/2020
Date last updated
1/12/2020
Date data sharing statement initially provided
8/01/2020
Date results information initially provided
1/12/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
The Absorption and Elimination profile and Safety of NOX66 in Healthy Volunteers.
Scientific title
A Single Centre Study of Pharmacokinetics and Safety of NOX66 in
Healthy Subjects
Secondary ID [1] 299810 0
NOX66-006
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Healthy Volunteers 315183 0
Condition category
Condition code
Cancer 313500 313500 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study drug (NOX66) is formulated in a single use suppository with a proprietary lipophilic base containing 400 or 600 mg of idronoxil. This open-label, replicate, Phase 1 study will evaluate the safety/tolerability of single doses of NOX66 administered rectally at a single centre.
Approximately 24 subjects will be enrolled in 2 dose cohorts. Cohort 1 will receive NOX66 400 mg and cohort 2 will be dose escalated to receive 600 mg. Each dose will be given twice, separated by at least 7 days.
Intervention code [1] 316065 0
Treatment: Drugs
Comparator / control treatment
No control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 321958 0
To characterise the pharmacokinetics of rectally administered Idronoxil in a
suppository base (NOX66) at 400 and 600 mg doses.
The main PK parameters will include area under the curve to the last quantifiable concentration and area under the curve from dosing to infinity 0 to infinity (AUCinf), maximum observed plasma concentration (Cmax), time to reach maximum observed concentration (Tmax), terminal half-life (t1/2), total clearance (CL/F) and apparent volume of distribution ( Vz/F) Timepoint: Analysis of plasma for idronoxil and metabolites will be performed using a validate liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for each administration (single andrepeat) and each dose group.
Plasma samples will be collected pre-dose and post dose at following timepoints: 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, and 144 hours.
Timepoint [1] 321958 0
Analysis of idronoxil and metabolites eliminated in urine will be performed using a
validate liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for each
administration (single and repeat) and each dose group.
Urine samples will be collected in each treatment period at the following time point intervals: Day 1 within 2 hours of dosing and pooled from 00:00–12:00 and 12:00–24:00 hours intervals. After each void urine volume will be measured.
Secondary outcome [1] 376798 0
To evaluate safety and tolerability after single and repeat administration of
400 and 600 mg doses of NOX66.
Timepoint [1] 376798 0
Safety as assessed through the following: Adverse event information recorded from the time of admission to the study unit until 30 days after the last dose of study drug. Severity of adverse events will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse events, version 5.0 scoring system.
Physical examination to be performed at Screening, Day-2 and at on Day 7 hours post-dose in each treatment period or Early Termination.
Vital signs (blood pressure, respiratory rate, body temperature) to be measured on at Screening and on Check-in (Day-2) and on Day 1 pre-dose and at 1, 2, 4, 6, 12, 24 and 144-hours post-dose in each treatment period or Early Termination.
Safety laboratory testing for serum chemistry and haematology and urinalysis to be measured at Screening and on Day -2, 24- and 144 hours post-dose in each treatment period or Early Termination.
Cardiac monitoring for each treatment period will be assessed by continuous ECGs via Holter device will be conducted from 24 h prior to dosing and up to 24 hours post dose and by triplicate 12-Lead ECGs will be performed at Screening and Day -1 (time-matched to Day 1 pre and post dose) and Day 1 at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24hours post-dose and at 48, 72, and 144 hours post-dose (Day 7) or Early Termination.
Secondary outcome [2] 377597 0
Explorative objective – to explore the relationship of drug exposure with changes in corrected QT interval using Fridericia’s formula (QTcF).
Timepoint [2] 377597 0
12-lead ECG including measurements of heart rate, PR,RR,QRS, QT and QTCF intervals
will be performed at Screening and Day -1 (time-matched to Day 1 pre and post dose) and Day 1 at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24hours post-dose. QTcF from Day 1 will be compared to Day -1 measurements.
Secondary outcome [3] 377598 0
Explorative objective – to explore the changes of the gut microbiome through
metagenomics and metabolomics analyses.
Timepoint [3] 377598 0
Stool samples for metagenomic and metabolomic testing will be collected pre-dose and
from first bowel movement post dosing in each treatment period. Blood samples for metabolomic testing will be collected pre-dose on Day-1 and post dose at 3 and 8 hours.

Eligibility
Key inclusion criteria
1. Provision of informed consent.
2. Healthy male and female subjects, 18 - 50 years of age inclusive.
3. BMI of 17.5 to 30.0 kg/m2 and a total body weight >50 kg.
4. Good health as determined at Screening and Check-in by examining medical history
(Screening only) and performing physical examinations, vital signs, ECGs, serum
chemistry including liver function test, haematology, coagulation tests, and urinalysis.
Laboratory test maybe repeated once at the discretion of the investigator.
5. Negative test result for human immunodeficiency virus (HIV) antibody, hepatitis B
surface antigen (HBsAg), and hepatitis C virus (HCV) antibody at Screening.
6. Negative urine test for drugs of abuse (opiates, benzodiazepines, amphetamines,
cannabinoids, cocaine, barbiturates, and phencyclidine), and breath alcohol at
Screening and Check-in for both treatment periods. Tests at Screening maybe
repeated once at the discretion of the investigator.
7. Negative urine pregnancy test at Screening and during Check-in (both treatment
periods for all female subjects).
8. Females must be of nonchildbearing potential, non-lactating and be:
• Surgically sterile (i.e., bilateral tubal ligation or removal of both ovaries and/or
uterus at least 6 months prior to dosing OR
• Naturally postmenopausal (spontaneous cessation of menses) for at least 12
consecutive months prior to dosing, confirmed with a Screening serum
follicle-stimulating hormone level > 40 mIU/mL.
9. Males with partners who are females of childbearing potential must agree to use
condoms and their female partner must also use contraception (e.g., hormonal or
intrauterine device). The double contraception must be used from the first dose of
study drug until at least 90 days following the last dose of study drug. Male subjects
are required to refrain from sperm donation during the study and for at least 90 days
following the last dose of study drug.
• Male subjects who identify as abstinent must agree to adhere to contraception
restrictions as outlined above should they become sexually active with female
partners during the specified time frame. Male subjects who are exclusively in
same sex relationships (as part of their preferred and usual lifestyle) are not
required to use contraception.
Willingness to refrain from consuming food or beverages containing caffeine/xanthine
or alcohol for 48 hours prior to Check-in on Day -2 at each treatment period.
10. Willingness to refrain from consuming grapefruit/grapefruit juice and Seville oranges
7 days before the first dose of study drug on Day 1 until the end of the study.
11. Have regular bowel movements (e.g. once daily)
12. Must be able to eat a soya free diet for approximately 2 weeks.
Minimum age
18 Years
Maximum age
50 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1.Evidence or history of clinically significant haematological, renal, endocrine,
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or
allergic disease (including drug allergies, but excluding untreated asymptomatic,
penicillin, seasonal allergies at the time of dosing) in the last 5 years or any disorder
that prevent the successful completion of the study.
2. History of or presence of anorectal abnormalities that would potentially alter
absorption of rectally administered drugs (except for hemorrhoids).
3. History or presence of an abnormal ECG, which, in the investigator’s opinion, is
clinically significant and/or a corrected QT interval using Fridericia’s formula (QTcF) greater or equal to 450 msec for males and greater or equal to 470 msec for females or QRS interval greater or equal to 110 msec at Screening.
4. Echocardiogram findings not within normal limits and/or ejection fraction <50% at
Screening.
5. Renal Function (using the Cockcroft-Gault equation) < 90 mL/min at Screening.
6. Diagnosis of Gilbert’s syndrome
7. Other severe acute or chronic medical conditions or a clinical laboratory test
abnormality that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation of
study results and, in the judgement of the Principal Investigator (PI), would make the
subject inappropriate for entry into this study.
8. Use of any prescription medications including those medication/products known to
induce or inhibit Cytochrome p450 (CYP) and Uridine 5'-diphospho-
glucuronosyltransferase (UGT) within 28 days from the first dose and during the study.
9. Use of over the counter (OTC), non-prescription medication (including vitamin D
preparations and calcium) within 7 days from the first dose and during the study
(excluding paracetamol (= 2 g/d). unless approved by the PI and Sponsor
10. Use of supplements (including phytotherapeutic/herbal/plant-derived preparations,
vitamins and minerals) within 7 days from the first dose and during the study.
11. Treatment with an investigational drug /device within 30 days or 5 half-lives preceding
12. Use of nicotine-containing substances within past 2 months or a positive cotinine test
at screening and Check-in (both periods).
13. Blood donation of 500 mL or more or a significant loss of blood within 56 days prior to
the first dose of study drug and during the study.
14. Receipt of a transfusion or any blood products within 30 days prior to the first dose of
study drug.
15. Consumption of more than 21 units of alcohol per week (males) or 14 units of alcohol
per week (females), where 1 unit of alcohol equals 1/2 pint of beer, 150 mL of wine,
or 30 mL of spirits, or significant history of alcoholism or drug/chemical abuse within
the last 2 years.
16. Consumption of alcohol within 48 hours prior to Check-in and during the entire study.

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)
Allocation is not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not Applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Single study drug dose will be administered on two occasions, separated by 7 days.
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Approximately 24 subjects between 18 and 50 years will be enrolled. The sample size is not based on formal statistical considerations, but deemed sufficient to estimate the PK parameters of idronoxil form rectal administration. Results from this study will inform on sample size calculations of subsequent studies.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
5/11/2019
Date of last participant enrolment
Anticipated
5/02/2020
Actual
5/02/2020
Date of last data collection
Anticipated
20/02/2020
Actual
20/05/2020
Sample size
Target
24
Accrual to date
Final
24
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 15144 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 28440 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 304270 0
Commercial sector/Industry
Name [1] 304270 0
Noxopharm Limited
Country [1] 304270 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Noxopharm Limited
Address
Suite 3, Level 4, 828 Pacific Highway
GORDON NSW 2072
Country
Australia
Secondary sponsor category [1] 304516 0
None
Name [1] 304516 0
Address [1] 304516 0
Country [1] 304516 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304727 0
Bellberry Limited
Ethics committee address [1] 304727 0
123 Glen Osmond Road
Eastwood SA 5063
Ethics committee country [1] 304727 0
Australia
Date submitted for ethics approval [1] 304727 0
25/09/2019
Approval date [1] 304727 0
23/10/2019
Ethics approval number [1] 304727 0
2019-09-824

Summary
Brief summary
The purpose of this study is to test the safety and absorption of a new formulation of a drug called NOX66.

Who is it for?
You may be eligible for this study if you are aged 18 to 50, and in generally good health.

Study details
All participants will be administered two doses of the study drug with a week between doses. The study drug is administered as a suppository (inserted into the rectum). As part of the study, participants will provide blood, urine and stool samples; and wear a heart monitor on their chest.

It is hoped this research will provide some baseline information about how this new formulation of NOX66 is metabolised by the body, and show the medication is safe in this form.
Trial website
Trial related presentations / publications
Public notes
Please note: this study is not the same as NCT03780465. NCT03780465 (NOX66-003) did not proceed and was withdrawn from clinicaltrials.gov. This study (NOX66-006) replaces the previous study.

Contacts
Principal investigator
Name 98014 0
A/Prof Andrew Redfern
Address 98014 0
Linear Clinical Research, Level 1 B Block, QEII Medical Centre, Hospital Avenue
Nedlands, WA 6009
Country 98014 0
Australia
Phone 98014 0
+61 863825100
Fax 98014 0
Email 98014 0
[email protected]
Contact person for public queries
Name 98015 0
Dr Marinella Messina
Address 98015 0
Noxopharm Limited
Suite 3, Level 4, 828 Pacific Highway
GORDON NSW 2072 Australia
Country 98015 0
Australia
Phone 98015 0
+61 291442223
Fax 98015 0
Email 98015 0
[email protected]
Contact person for scientific queries
Name 98016 0
Dr Marinella Messina
Address 98016 0
Noxopharm Limited
Suite 3, Level 4, 828 Pacific Highway
GORDON NSW 2072 Australia
Country 98016 0
Australia
Phone 98016 0
+61 291442223
Fax 98016 0
Email 98016 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
IPD will not be available.


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.