Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619000908134
Ethics application status
Approved
Date submitted
10/06/2019
Date registered
27/06/2019
Date last updated
28/11/2019
Date data sharing statement initially provided
27/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study of AR882 in Healthy Adult Male Volunteers
Scientific title
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study of AR882, a Potent Uricosuric Agent, in Healthy Adult Male Volunteers
Secondary ID [1] 298166 0
AR882-102
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic gout 312724 0
Hyperuricemia 312725 0
Condition category
Condition code
Musculoskeletal 311223 311223 0 0
Other muscular and skeletal disorders
Metabolic and Endocrine 311224 311224 0 0
Other metabolic disorders
Inflammatory and Immune System 311860 311860 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will be conducted at a single center. There will be up to 4 cohorts with 10 subjects per cohort.
Subjects in each cohort will be randomized to receive treatment with AR882 (8 subjects) or placebo (2 subjects). Cohorts 1 to 4 will enroll sequentially following review of safety and PK data of prior cohorts by the Investigator and Sponsor Medical Monitor.
Dosing: Subjects will ingest Investigational Product(IP) after an overnight fast of at least 10 hours and will remain fasted until at least 4 hours post-dose. Subjects may ingest water ad libitum during the period of fasting before and after IP administration. Starting dose of IP will be 50mg.
Planned cohorts;
Cohort 1: (50mg) AR882 or placebo once daily for 10 days
Cohort 2: (75mg) AR882 or placebo once daily for 10 days
Cohort 3: (100mg) AR882 or placebo once daily for 10 days
Cohort 4 (less than or equal to 100mg): Subjects will be dosed with a lower or intermediate dose of AR882 or placebo once daily for 10 days. Decision to proceed with Cohort 4 will be based on preliminary review of previous cohorts’ PK/PD and Safety/tolerability data.

Strategies used to monitor adherence to the intervention: Laboratory tests and pharmacokinetic analyses.
Strategies used to ensure compliance with the fasts: Inpatient stay and observation
Intervention code [1] 314393 0
Treatment: Drugs
Comparator / control treatment
Study is placebo-controlled, as described in the 'description of the intervention/exposure' section
Composition: HPMC (Hydroxy propyl methyl cellulose) capsule shell matched to IP, which contains the same excipients as the IP. Reference: ACTRN12619000127101. It is matched to AR882 containing the same excipients as AR882.
Control group
Placebo

Outcomes
Primary outcome [1] 319984 0
To evaluate the safety of AR882 when administered as rising multiple oral doses.
Outcome is assessed: Serum assay, Urine Assay, Physical examination
Timepoint [1] 319984 0
Cohort 1 to 4: Monitored from pre-dose through Day 22 (Follow up).
frequency of assessments: Day -2, Day -1, Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14, Day 15, Day 22 (Follow Up) after the last dose of the study treatment.
Primary outcome [2] 319985 0
To evaluate the tolerability of AR882 when administered as rising multiple oral doses.
Outcome is assessed: Serum assay, Urine Assay, Physical examination
Timepoint [2] 319985 0
Cohort 1 to 4: Monitored from pre-dose through Day 22 (Follow up).
frequency of assessments: Day -2, Day -1, Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14, Day 15, Day 22 (Follow Up) after the last dose
of the study treatment.
Primary outcome [3] 319986 0
To evaluate the plasma pharmacokinetics (PK) of AR882 following multiple oral doses of AR882.
Outcome is assessed: Plasma parameters Cmax, Tmax, AUClast, and AUC0-24 and urinary parameters Ae and CLr will be summarized for AR882 by descriptive statistics.
Timepoint [3] 319986 0
PK parameters, will be assessed at the below time points
Day 1: Pre-dose (within 30 minutes before dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8,
10, and 12 hours post-dose.
Days 2 to 9: 24, 48, 72, 96, 120, 168, and 192 hours post Day 1 dose.
Days 10 to 15: Pre-dose of last dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10 and 12, 24,
30, 36, 48, 54, 60, 72, 96, and 120 hours post Day 10 dose.
Secondary outcome [1] 370111 0
To evaluate the pharmacodynamic (PD) effects (sUA lowering) following multiple oral doses of AR882.
Outcome is assessed: Serum assay, Urine assay
Timepoint [1] 370111 0
PD parameters will be assessed from pre-dose till 196 hours to 15 days
Frequency will include 6-hour, 12-hour, and 24-hour intervals from Day -1 to Day 15.
Secondary outcome [2] 370112 0
To evaluate the urinary pharmacokinetics (PK) of AR882 following multiple oral doses of AR882.
Urinary PK parameters to be assessed: Ae and CLr
Timepoint [2] 370112 0
PK parameters, will be assessed at following time points
Urine (total catch) will be collected over the following intervals in relation to dosing on
Day 1: -24 to -18, -18 to -12, -12 to 0, 0 to 6, 6 to 12, 12 to 24, 24 to 30, 30 to 36, 36 to
48, 48 to 54, 54 to 60, and 60 to 72 hours post-Day 1 dose.
Days 10 to 13: 0 to 6, 6 to 12, 12 to 24, 24 to 30, 30 to 36, 36 to 48, 48 to 54, 54 to 60,
and 60 to 72 hours in relation to Day 10 dose.

Eligibility
Key inclusion criteria
1. Healthy male adult subjects greater than or equal to 18 and lesser than or equal to 55 years of age.
2. Males must be surgically sterile, abstinent* or, if engaged in sexual relations with a female of child-bearing potential, the subject must agree to use 2 forms of a highly effective contraceptive methods from the time of signing the informed consent form until at least 90 days after receiving IP (AR882 or placebo).
* Abstinence is only acceptable as true abstinence as part of a preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar ovulation, symptom-thermal, post-ovulation methods), declaration of abstinences for the duration of the trial and withdrawal are not acceptable methods of contraception.
3. Males must agree to refrain from sperm donation from the time of signing the informed consent form until at least 90 days after receiving IP (AR882 or placebo).
4. Able to understand the study procedures, the risks involved and willing to provide written Informed Consent before the first trial related activity.
5. Body weight no less than 50 kg and body mass index (BMI) within the range of
greater than or equal to 18 and lesser than or equal to 33 kg/m2.
6. All laboratory parameters (chemistry, hematology, and urinalysis) should be within normal limits or considered not clinically significant by the Investigator, in consultation with the Sponsor.
7. Screening serum uric acid level greater than or equal to 4.5 mg/dL (268 micromol/L) and less than 9 mg/dL (535 micromol/L) and estimated Glomerular Filtration Rate (eGFR) greater than or equal to 90 mL/min/1.73 m².
8. Subjects must be free of any clinically significant disease that requires a physician’s care and/or would interfere with study evaluations or procedures.
9. Normal or clinically acceptable physical examination.
10. No clinically relevant abnormalities in twelve-lead electrocardiogram as per Investigator judgment.
11. No clinically relevant abnormalities in blood pressure (BP), heart rate (HR), body temperature and respiratory rate as per the Investigator’s judgment, see normal values for information:
a. 90 mm Hg lesser than or equal to systolic BP lesser than or equal to 140 mmHg in supine position.
b. 40 mm Hg lesser than or equal to diastolic BP lesser than or equal to 90 mm Hg in supine position.
c. 40 bpm lesser than or equal to heart rate lesser than or equal to 100 bpm in supine position.
d. 35.5 °C lesser than or equal to body temperature lesser than or equal to 37.5 °C.
e. 10 bpm lesser than or equal to respiratory rate lesser than or equal to 22 bpm.
Minimum age
18 Years
Maximum age
55 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Inadequate venous access or unsuitable veins for repeated venipuncture.
2. Any concomitant chronic or acute illness or an acute febrile illness within 1 week
of dose administration.
3. Positive serology to HIV (HIV1 and HIV2) and/or Hepatitis C antibodies (HCV),
and/or Hepatitis B surface antigen (HBsAg).
4. History or clinical manifestations of significant metabolic, hematological,
pulmonary, cardiovascular, gastrointestinal, neurologic, hepatic, renal, urological,
or psychiatric disorders.
5. Malignancy within 5 years, except for basal or squamous cell carcinoma of the
skin that has been successfully treated. Healthy volunteers with a history of other
malignancies that have been treated with curative intent and which have no
recurrence within 5 years may also be eligible if approved by the Sponsor
Medical Monitor (or designee).
6. History of cardiac abnormalities including abnormal and clinically relevant ECG
changes such as bradycardia (sinus rate < 40 bpm), complete LBBB, RBBB,
incomplete LBBB, second or third degree heart block, intraventricular conduction
delay with QRS duration > 120 msec, symptomatic or asymptomatic arrhythmias
with the exception of sinus arrhythmia, evidence of ventricular pre-excitation,
frequent palpitations or syncopal episodes, heart failure, hypokalemia, family
history of Long QT Syndrome, family history of sudden death in otherwise
healthy individual between the ages of 1 and 30 years.
7. Conditions predisposing to QT prolongation including pathological Q-wave
(defined as Q-wave >40 msec or depth > 0.4-0.5 mV).
8. Any use of concomitant medications that prolong the QT/QTc interval within
14 days prior to Day 1.
9. Subjects with a QTcF interval (QT interval corrected for heart rate according to
Fridericia) > 450 milliseconds (ms) at Screening or on Day –1 or at pre-dose on
Day 1.
10. Subjects who have undergone major surgery within 3 months of Day 1.
11. Subjects who previously received AR882 or an investigational product, biological
agent, or device within 3 months or 5 half-lives of the investigational agent,
whichever is longer.
12. Subjects who donated blood within 12 weeks prior to Day 1 or who have given a
plasma donation within 4 weeks prior to the screening visit.
13. Any drug treatment, including prescribed or OTC medicines or herbal
preparations, taken in the 14 days (2 months for enzyme-inducing drugs or
products e.g., glucocorticoids, phenobarbital, isoniazid, St. John’s Wort)
preceding the dosing of IP.
14. Use of tobacco products within 30 days prior to dosing.
15. Heavy caffeine drinker (> 5 cups or glasses of caffeinated beverages e.g., coffee,
tea, cola per day).
16. Subjects who refuse to abstain from alcohol, or caffeine containing foods or
beverages, or grapefruit containing foods or beverages, or Seville orange
containing foods or beverages, or fruit juice, or sweetened soft drinks from 48
hours prior to dosing and for the entire duration of the study.
17. History and/or presence of drug addiction or excessive use of alcohol within 6
months prior to Screening defined as > 14 drinks/week (1 drink = 5 ounces
(150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard
liquor).
18. Subjects who have a positive alcohol test (breath or urine test) at Screening or at
Day -2 (Admission).
19. Subjects who have a positive test for drugs of abuse (cocaine,
tetrahydrocannabinol, methamphetamine, amphetamine, benzodiazepines,
methadone, barbiturates, amphetamine, opiates, methylenedioxy
methamphetamine, phencyclidine) or cotinine (metabolite of nicotine) at
Screening or at Day -2 (Admission).
20. Subjects who refuse to refrain from strenuous exercise within 48 hours of dose
administration through study completion.
21. Subjects who have a clinically relevant intolerance or allergy to foods or drugs or
are known or suspected to have hypersensitivity to benzbromarone and/or any
ingredient in the investigational products.
22. Subjects in a situation or with a condition that, in the opinion of the Investigator,
may interfere with optimal participation in the study.
23. Subjects unable to comply with study restrictions.

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)
It is a randomized placebo controlled trial
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Other
Other design features
Subjects will be randomized on AR882-Placebo arm in 8:2 ratio in a blinded manner
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
28/06/2019
Actual
28/06/2019
Date of last participant enrolment
Anticipated
18/09/2019
Actual
23/08/2019
Date of last data collection
Anticipated
12/10/2019
Actual
18/09/2019
Sample size
Target
50
Accrual to date
Final
30
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 13692 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 26383 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 302700 0
Commercial sector/Industry
Name [1] 302700 0
Arthrosi Therapeutics Australia Pty, Ltd a subsidiary of Arthrosi Therapeutics, Inc.
Country [1] 302700 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Arthrosi Therapeutics Australia Pty, Ltd a subsidiary of Arthrosi Therapeutics, Inc.
Address
58 Gipps Street
Collingwood, VIC 3066, Australia
Country
Australia
Secondary sponsor category [1] 302628 0
None
Name [1] 302628 0
Address [1] 302628 0
Country [1] 302628 0
Other collaborator category [1] 280683 0
Commercial sector/Industry
Name [1] 280683 0
Novotech (Australia) Pty Limited
Address [1] 280683 0
Level 3, 235 Pyrmont Street, Pyrmont NSW 2009
Country [1] 280683 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303311 0
Alfred Hospital Human Research Ethics Committee
Ethics committee address [1] 303311 0
Ethics committee country [1] 303311 0
Australia
Date submitted for ethics approval [1] 303311 0
08/05/2019
Approval date [1] 303311 0
06/06/2019
Ethics approval number [1] 303311 0

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

Contacts
Principal investigator
Name 93226 0
Dr Ben Snyder
Address 93226 0
Nucleus Network Pty Ltd.
Address: Level 5, Burnet Tower, AMREP Precinct, 89 Commercial Road
Melbourne, VIC 3004
Country 93226 0
Australia
Phone 93226 0
+61 3 8593 9838
Fax 93226 0
Email 93226 0
[email protected]
Contact person for public queries
Name 93227 0
Arti Patel
Address 93227 0
Novotech Australia Pty Ltd
PO Box 244 PYRMONT NSW 2009, Australia
Country 93227 0
Australia
Phone 93227 0
+61 3 9341 1910
Fax 93227 0
Email 93227 0
[email protected]
Contact person for scientific queries
Name 93228 0
Arti Patel
Address 93228 0
Novotech Australia Pty Ltd
PO Box 244 PYRMONT NSW 2009, Australia
Country 93228 0
Australia
Phone 93228 0
+61 3 9341 1910
Fax 93228 0
Email 93228 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
Not Applicable


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.