Please be advised that due to the high volume of submissions, the ANZCTR is currently experiencing delays in processing submissions from those outside of Australia and New Zealand. As the ANZCTR is funded by Australia and New Zealand, we must prioritise submissions from these countries first. International submissions should allow additional time for registration. Apologies for any inconvenience caused.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12618000430235
Ethics application status
Approved
Date submitted
16/03/2018
Date registered
26/03/2018
Date last updated
21/02/2019
Date data sharing statement initially provided
21/02/2019
Date results information initially provided
21/02/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Safety, tolerability, pharmacokinetics and food effect of ATN-249 in healthy volunteers
Scientific title
A randomized, double-blind, placebo-controlled, single-ascending–dose and two-way crossover food effect study to determine the safety, tolerability, pharmacokinetics and food effect of ATN-249 in healthy male participants
Secondary ID [1] 293916 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hereditary Angioedema 306462 0
Condition category
Condition code
Inflammatory and Immune System 305552 305552 0 0
Normal development and function of the immune system
Human Genetics and Inherited Disorders 306242 306242 0 0
Other human genetics and inherited disorders
Cardiovascular 306247 306247 0 0
Other cardiovascular diseases
Skin 306248 306248 0 0
Other skin conditions

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Up to 48 participants will be enrolled into up to 6 cohorts:

Participants in Cohort 1 will be randomized to receive an oral dose of either 50 mg (1x50 mg capsule) of ATN-249 (6 participants) or placebo (2 participants). Two sentinel participants (one allocated to placebo and one allocated to ATN-249) will be dosed initially. If dosing of these sentinel participant proceeds without clinically-significant adverse events (AEs) over 24 hours (as adjudicated by the SMC), the remaining 6 participants will be dosed. Participants will be dosed following an overnight fasting of at least 10 hours.

Cohort 2 will be subject to a crossover design with two treatment periods. Participants will be randomized to receive either 100 mg (2x50 mg capsules) of ATN-249 (6 participants) or placebo (2 participants). Dosing will follow at least 10 hours overnight fasting in the first treatment period; and high fat meal in the second treatment period. The wash-out period between treatments will be of at least 7 days. As with Cohort 1, two sentinel participants (one allocated to placebo and one allocated to ATN-249) will be dosed initially during the first treatment period. The planned study procedures for Cohort 2 will proceed if dosing of these sentinel participants proceeds without clinically significant AEs.

Up to four additional cohorts, of 8 participants each, analogous to Cohort 1 in terms of study procedures may be enrolled. The dose level of these cohorts will be established following review of PK and safety information from the preceding cohorts. The anticipated dose levels for Cohorts 3 to 6 are 150 mg, 200 mg, 400 mg and 800 mg ATN-249.

Two sentinel participants in each of these cohorts (one allocated to placebo and one allocated to ATN-249) will be dosed initially. If dosing of these sentinel participant proceeds without clinically-significant adverse events (AEs) over 24 hours (as adjudicated by the SMC), the remaining 6 participants will be dosed. Participants will be dosed following an overnight fasting of at least 10 hours.
Intervention code [1] 300224 0
Treatment: Drugs
Comparator / control treatment
Size 4 hard gelatin capsules identical to those containing active. The composition is lactose hydrate (75mg), microcrystalline cellulose (48.75mg) and magnesium stearate (1.25mg); OR
Size 0 hard gelatin capsules identical to those containing active. The composition is lactose hydrate (300mg), microcrystalline cellulose (195mg) and magnesium stearate (5mg).
Control group
Placebo

Outcomes
Primary outcome [1] 304681 0
Safety and tolerability of ATN-249, assessed by monitoring adverse event throughout the study.
Timepoint [1] 304681 0
Up to 7 days following last administration.
AEs will be patient reported and observed by researchers. Since this is a first in human studies all the recorded adverse events are unexpected.
Primary outcome [2] 304682 0
Plasma concentration and pharmacokinetic parameters of ATN-249 in fasted state.
Pharmacokinetic parameters will be calculated using non-compartmental approach and will include Tmax, Cmax, AUC and apparent Kel.
Timepoint [2] 304682 0
Up to 48 hours following last administration. Sampling time points are predose, and 15min, 30min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 7h, 9h, 12h, 16h, 24h and 48h post-dose.
Primary outcome [3] 304683 0
Plasma concentration and pharmacokinetic parameters of ATN-249 following ingestion of high fat meal
Pharmacokinetic parameters will be calculated using non-compartmental approach and will include Tmax, Cmax, AUC and apparent Kel.
Timepoint [3] 304683 0
Cohort 2: Up to 48 hours following last administration. Sampling time points are predose, and 15min, 30min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 7h, 9h, 12h, 16h, 24h and 48h post-dose.
Secondary outcome [1] 342771 0
Pharmacodynamics of ATN-249 on contact pathway activation.
Contact pathway activation will be assessed by means of blood assay.
Timepoint [1] 342771 0
Up to 24 hours following last administration. Sampling time points are predose, and 2h, 4h, 9h, 12h, and 24h post-dose.

Eligibility
Key inclusion criteria
1. Male healthy volunteers, age 18 to 55 years, inclusive;
2. Participants must be in good general health, with no significant medical history, have no clinically significant abnormalities on physical examination at screening, and/or before administration of the initial dose of study drug;
3. Participants must have a Body Mass Index (BMI) between 18.0 and 30.0 kg/m2 inclusive;
4. Participants must have clinical laboratory values within normal range as specified by the testing laboratory, unless deemed not clinically significant by the Investigator or delegate;
5. Participants must be a non-smoker, and must not have used any tobacco products within two months prior to screening;
6. Participant must have no relevant dietary restrictions, and be willing to consume standard meals provided;
7. Participants who have not been sterilized must make a commitment to ensure that their partners (if of child bearing potential) use highly effective contraception during the period from dosing to 7 days post-dose (acceptable forms of contraception are oral, injected or implanted hormonal methods, or placement of an intrauterine device or intrauterine system, or abstinence); in addition to these measures, male participants should use a condom for sexual intercourse during this period. This requirement does not apply to participants in same sex relationships;
8. Participants must have the ability and willingness to attend the necessary visits to the study center;
9. Written informed consent signed prior to entry into the study.
Minimum age
18 Years
Maximum age
55 Years
Gender
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Prior or ongoing medical condition, medical history, physical findings, or laboratory abnormality that, in the Investigator’s (or delegate’s) opinion, could adversely affect the safety of the participant.
2. Mentally or legally incapacitated, has significant emotional problems at the time of screening visit or expected during the conduct of the study, or has a history of a clinically significant psychiatric disorder within the last 5 years. Note: Participants who have had situational depression may be enrolled in the study at the discretion of the Investigator or delegate.
3. Fever (body temperature greater than 38°C) or symptomatic viral or bacterial infection within 2 weeks prior to screening.
4. History of severe allergic or anaphylactic reactions.
5. Resting blood pressure greater than 140/90 mm Hg, resting heart rate greater than 90 beats per minute or resting heart rate lower than 50 beats per minute at screening or at Day -1 (repeat measurements are allowed at the discretion of the Investigator. The resting heart rate measurement may be repeated only once if below 50 beats per minute).
6. Alkaline phosphatase (ALP), aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) greater than1.5 x upper limit of normal at screening. Repeat testing at screening is acceptable for out of range values following approval by the Investigator or delegate.
7. Serum potassium lower than 3.7 mmol/L or greater than 5.5 mmol/L at Screening or Day -1. Repeat testing at screening is acceptable for out of range values following approval by the Investigator or delegate.
8. Positive test for hepatitis C antibody, hepatitis B surface antigen, or human immunodeficiency virus (HIV) antibody at screening.
9. Participants with a positive toxicology screening panel (urine test including qualitative identification of barbiturates, Tetrahydrocannabinol (THC), amphetamines, benzodiazepines, opiates and cocaine), cotinine test or alcohol breath test.
10. Participants with a history of substance abuse or dependency or history of recreational intravenous (IV) drug use over the last 5 years (by self-declaration).
11. Regular alcohol consumption defined as greater than 21 alcohol units per week (where 1 unit equal to 284 mL of beer, 25 ml of 40% spirit or a 125 ml glass of wine). Participant is unwilling to abstain from alcohol beginning 48 hours prior to admission to the CRU until completion of the final follow-up visit.
12. Participant has left ventricular hypertrophy defined as the combination of the following ECG criteria (both #a and #b must be met):
12.a. Voltage criteria (both criteria must be met):
12.a.1. S in V1 and R in V5 or V6 (whichever is larger) equal to 35 mm; and
12.a.2. R in aVL equal to 11 mm
12.b. Repolarization abnormalities (at least one criteria needs to be met):
12.b.1. At least 1mm ST depression (horizontal or down-sloping); or
12.b.2. Abnormal T wave inversions
13. Participant has other significant ECG abnormalities that might interfere with ECG analysis including evidence of a previous myocardial infarction (MI), flat T waves (particularly in the inferior leads) or more than minor non- specific ST-T wave changes or:
13.a. QRS greater than 110 milliseconds (msec),
13.b. QT interval corrected using Fridericia’s formula (QTcF) greater than 440 msec (men and women),
13.c. PR interval greater than 220 msec
13.d. Heart rate lower than 50 BPM or greater than 90 BPM
13.e. Complete right bundle branch block or left bundle branch block.
14. History of cardiac disease or cerebrovascular disease, including coronary artery disease (including MI, angina), cardiac arrhythmias, long QT syndrome (in self or family), valvular disease, heart failure, hypertension or hypotension.
15. Family history of hereditary angioedema.
16. Use of any prescription medication, over-the-counter medication, herbal products, vitamins or minerals, within 7 days or 5 half-lives (whichever is longer) prior to study drug administration, unless in the opinion of the Principal Investigator and/or Medical Monitor the medication will not compromise participant safety or interfere with study procedures or data validity.
17. Use of any potential inducer or inhibitor of cytochrome P450 [CYP] 3A4 or P-glycoprotein [P gp] [eg, St. John’s Wort, rifampin, cyclosporine, or ritonavir]) within 14 days or 5 half lives (whichever is longer) prior to study drug administration, unless in the opinion of the Principal Investigator and/or Medical Monitor the medication will not compromise participant safety or interfere with study procedures or data validity.
18. Anticipated use of prescription medication or over-the-counter medication during study participation, with the exception of 1-2 therapeutic doses per week of paracetamol/acetaminophen or non-steroidal anti-inflammatory drugs (e.g: ibuprofen, naproxen).
19. Participant is unwilling to refrain from strenuous exercise from 7 days prior to admission to the CRU until completion of the final follow-up visit.
20. Participant is unwilling to abstain from ingestion of caffeine or xanthine-containing products (eg, tea, coffee, chocolate, cola, etc.) beginning 96 hours prior to admission to the CRU for each study period until the final pharmacokinetic (PK) sample of each study period has been collected.
21. Participant has consumed grapefruit and/or grapefruit juice within 14 days prior to admission to the CRU and is unwilling to abstain from consuming grapefruit and/or grapefruit juice until completion of the final follow-up visit.
22. Participant has consumed citrus fruit or citrus fruit juices within 48 hours prior to admission to the CRU for each study period and is unwilling to abstain from these items for 48 hours prior to admission for each study period until the final PK sample of each study period has been collected.
23. Participants who are unlikely to comply with the study protocol or, in the opinion of the investigator, would not be a suitable candidate for participation in the study.

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 to treatment in accordance with randomization list issued prior to start of recruitment and provided to the site pharmacy. The site pharmacy is unblinded and will dispense investigational drug in accordance with the allocation sequence disclosed in the randomization list.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created using SAS EG 7.12 software package
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Other
Other design features
Cohort 1, 3, 4, 5 and 6 follow parallel design
Cohort 2 follows crossover design
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
A detailed Statistical Analysis Plan will be prepared for approval by the Sponsor prior to clinical database lock.
There is currently no clinical information about ATN 249. The sample size for safety evaluation was determined based on experience from other initial clinical safety studies.
Safety Analysis Set: All participants who received any amount of study drug.
PK Analysis Set: All participants who received study drug (ATN 249) and have sufficient PK data for analysis.

Recruitment
Recruitment status
Completed
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)
WA
Recruitment hospital [1] 9951 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 18763 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 298542 0
Commercial sector/Industry
Name [1] 298542 0
LifeSci Pharmaceuticals, inc.
Address [1] 298542 0
Whitepark House, White Park Road,
Bridgetown, St. Michael
BB11135, Barbados
Country [1] 298542 0
Barbados
Funding source category [2] 298590 0
Commercial sector/Industry
Name [2] 298590 0
Attune Pharmaceuticals
Address [2] 298590 0
250 West 55th Street Suite 16B
New York, NY 10019, US
Country [2] 298590 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
LifeSci Pharmaceuticals, inc.
Address
Whitepark House, White Park Road,
Bridgetown, St. Michael
BB11135, Barbados
Country
Barbados
Secondary sponsor category [1] 297688 0
Commercial sector/Industry
Name [1] 297688 0
Attune Pharmaceuticals
Address [1] 297688 0
250 West 55th Street Suite 16B
New York, NY 10019, US
Country [1] 297688 0
United States of America
Secondary sponsor category [2] 297743 0
Commercial sector/Industry
Name [2] 297743 0
Clinical Network Services (CNS) Pty Ltd
Address [2] 297743 0
Level 4, 88 Jephson Street
Toowong, QLD 4066
Australia
Country [2] 297743 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299514 0
Bellberry Limited
Ethics committee address [1] 299514 0
129 Glen Osmond Road, Eastwood
SA 5065, Australia
Ethics committee country [1] 299514 0
Australia
Date submitted for ethics approval [1] 299514 0
24/01/2018
Approval date [1] 299514 0
21/02/2018
Ethics approval number [1] 299514 0
2018-01-061

Summary
Brief summary
Hereditary Angiodema (HAE) is a rare disease caused by low levels of C1 serine protease inhibitor in the body. Deficiencies in this protein leads to increased activation of inflammatory pathways which can cause swelling, severe abdominal pain and airway obstruction that can be life threatening. ATN-249 is a potential once a day oral treatment for HAE.
The purpose of this research study is to test the safety and tolerability of ATN-249 as well as the pharmacokinetics and pharmacodynamics of the study drug. The study is open to healthy male volunteers and the research goals are:
- Does the drug have any side-effects and is it well tolerated when given as a single dose?
- How much of the drug gets into the blood stream, and how long does the body take to get rid of it?
- What effect does food have on the PK profile of the study drug?
This study will look at how the human body uses ATN-249 at different dose levels with and without food. The effects of the drug will be studied.
This is a double-blind, randomised and placebo-controlled and consists of two parts. Part A will look at the effects of a single dose of the study drug given as 1 dose and Part B will look at the effects of a single dose of the study drug given as 2 doses 12 hours apart.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 80678 0
Dr Peter Schrader
Address 80678 0
Linear Clinical Research
Level 1, B Block, QEII Medical
Centre,
Hospital Avenue
NEDLANDS WA 6009
Country 80678 0
Australia
Phone 80678 0
+61 (0) 8 6382 5100
Fax 80678 0
Email 80678 0
pschrader@linear.org.au
Contact person for public queries
Name 80679 0
Mr Alex Castellarnau
Address 80679 0
Clinical Network Services (CNS) Pty Ltd
Level 4, 88 Jephson St,
TOOWONG, QLD 4066

Country 80679 0
Australia
Phone 80679 0
+61(0)7 3719 6000
Fax 80679 0
Email 80679 0
alex.castellarnau@clinical.net.au
Contact person for scientific queries
Name 80680 0
Mr Jason Bablak
Address 80680 0
Attune Pharmaceuticals
250 West 55th Street Suite 16B
New York, NY 10019
Country 80680 0
United States of America
Phone 80680 0
+1 412 445-1705
Fax 80680 0
Email 80680 0
jason@attunepharma.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary