Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001417279
Ethics application status
Approved
Date submitted
23/08/2018
Date registered
24/08/2018
Date last updated
3/07/2019
Date data sharing statement initially provided
3/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Safety, tolerability and pharmacokinetics of extended release formulations of ATN-249 in healthy volunteers when dosed once a day or over several days
Scientific title
An Open-Label, Single- and Multiple-Ascending-Dose Study to Determine the Safety, Tolerability and Pharmacokinetics of Extended Release Formulations of ATN 249 in Healthy Male Participants
Secondary ID [1] 295889 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hereditary Angioedema 309357 0
Condition category
Condition code
Inflammatory and Immune System 308222 308222 0 0
Normal development and function of the immune system
Human Genetics and Inherited Disorders 308223 308223 0 0
Other human genetics and inherited disorders
Cardiovascular 308224 308224 0 0
Other cardiovascular diseases
Skin 308225 308225 0 0
Other skin conditions

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Up to 28 days before enrolment into the study, participants will be required to sign a consent form, after which screening assessments will be carried out.

This study consists of two parts.

PART A: SINGLE ASCENDING DOSE

Up to 12 participants will be enrolled into up to 2 cohorts:

Cohort A1 (6 participants) will receive a single dose of an extended release formulation of ATN-249 200 mg (4 x 50 mg tablet) following overnight fasting for at least 10 hours.

Cohort A2 (6 participants) will receive a single dose of an extended release formulation of ATN-249 following overnight fasting for at least 10 hours. The dose will be determined based on Cohort A1 PK and safety data.

Dosing in Cohort A2 will not commence until SMC review of PK and safety information from Cohort A1. Dose escalation between cohorts will be reviewed by SMC at least 7 days after participants have been dosed. Participants will remain onsite from the day before dosing until review of the 48 hour post-dose assessments.

The duration of this study part is of approximately 5 weeks (this includes a 28-day screening period, one 3-day study period with 3 overnight stays and a follow-up visit 7 days after your dose of study medication).

PART B: MULTIPLE ASCENDING DOSE

Study part B aims to investigate the selected formulation candidate (from Part A) in a multiple dosing design.

Up to 12 participants will be enrolled into up to 2 cohorts:

Cohort B1 (6 participants) will receive a single daily dose of an extended release formulation of ATN-249 200 mg (4 x 50 mg tablet) for 14 days following overnight fasting for at least 10 hours.

Cohort B2 (6 participants) will receive a single dose of an extended release formulation of ATN-249 for 14 days following overnight fasting for at least 10 hours. The dose will be determined based on Cohort B1 PK and safety data.

Dosing in Cohort B1 can commence following completion of Cohort A1. Dosing in Cohort B2 will not commence until review of PK and safety information from Cohort B1. Dose escalation between cohorts will be reviewed at least 7 days after participants have been dosed. Participants will remain onsite from the day before dosing until review of the 48 hour post-last dose assessments.
The duration of this study part is of approximately 7 weeks (this includes a 28-day screening period, one 16-day study period with 16 overnight stays and a follow up visit 7 days after your last dose of study medication).

ADDITIONAL COHORTS

Additional single and/or multiple ascending dose cohorts up to a daily dose of 800 mg/day may be tested provided the anticipated exposure based on interim PK data from earlier cohorts in this trial would not exceed that of the female rat at the NOAEL (100 mg/kg) and adequate safety and tolerability from lower dose cohorts is available. Each cohort (6 participants) will receive a single or daily dose of an extended release formulation of ATN-249 following overnight fasting for at least 10 hours.

POTENTIAL FOR ADDITIONAL EXTENDED RELEASE FORMULATIONS

This study has an adaptive design to allow for the potential addition of up to three additional extended release formulations.
Part A of the study will start by assessing the first potential extended release formulation of ATN-249. Following analysis of the PK data, the study will either progress to Part B with the selected formulation or Part A will be repeated to analyze a second formulation (formulation 2). The PK data will be analyzed throughout the study to determine whether a formulation should continue through the single and multiple-ascending cohorts, or should be replaced by a different formulation.
Intervention code [1] 312219 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 307191 0
Safety and tolerability of single and multiple ascending oral dosing regimens of ATN 249 in healthy participants.
Assessments include vital signs, physical examinations, clinical laboratory testing (hematology, coagulation, serum chemistry and urinalysis/urine microscopy), ECGs and Adverse Events.
Timepoint [1] 307191 0
#A Single Ascending Dose (Cohorts A1 and A2):
Adverse Events: Throughout the study
Vital signs: Day -1, Day 1 (pre-dose and 1h, 2h, 3h, 4h, 5h, 7h, 9h, 12h and 16h post-dose), Days 2, 3 and 8.
ECG: Day -1, Day 1 (pre-dose and 1h, 2h, 3h, 4h, 5h, 7h, 9h and 12h post-dose), Days 2, 3 and 8.
Physical Examination: Day -1, Day 1 (pre-dose and 7h post-dose), Day 2 and Day 8.
Clinical Laboratory Testing: Day -1, Day 2, Day 3 and Day 8.


#B Multiple Ascending Dose (Cohorts B1 and B2):
Adverse Events: Throughout the study
Vital signs: Day -1, Day 1 (pre-dose and 1h, 2h, 3h, 4h, 5h, 7h, 9h, 12h and 16h post-dose), Days 2 to 13, Day 14 (same schedule as Day 1), Day 15, Day 16 and Day 21.
ECG: Day -1, Day 1 (pre-dose and 1h, 2h, 3h, 4h, 5h, 7h, 9h and 12h post-dose), Days 2 to 13, Day 14 (same schedule as Day 1), Day 15, Day 16 and Day 21.
Physical Examination: Day -1, Day 1 (pre-dose and 7h post-dose), Day 2, Day 7, Day 14 (pre-dose and 7h post-dose), Day 15 and Day 21.
Clinical Laboratory Testing: Day -1, Day 2, Day 4, Day 7, Day 14, Day 15 and Day 21.
Primary outcome [2] 307192 0
Plasma concentration of single and multiple ascending oral dosing regimens of ATN-249 in healthy participants.
Pharmacokinetic parameters will be calculated using non-compartmental approach and will include Tmax, Cmax, AUC and apparent Kel.
Timepoint [2] 307192 0
#A Single Ascending Dose (Cohorts A1 and A2):
Up to 48 hours following administration. Sampling points are pre-dose; and 15min, 30min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 7h, 9h, 12h, 24h and 48h post-dose.

#B Multiple Ascending Dose (Cohorts B1 and B2):
Up to 48 hours following last administration on Day 14. Sampling points are on Day 1 (pre-dose; and 15min, 30min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 7h, 9h, 12h and 16h post-dose); on Days 2 to 13 (once a day at the same time; on Day 14 (same schedule as Day 1); on Day 15 and Day 16 (once a day at the same time).
Secondary outcome [1] 351066 0
Pharmacodynamics of ATN-249 on contact pathway activation.
Contact pathway activation will be assessed by means of blood assay.
Timepoint [1] 351066 0
#A Single Ascending Dose (Cohorts A1 and A2):
Up to 24 hours following administration. Sampling points are pre-dose; and 2h, 4h, 9h, 12h and 24h post-dose.

#B Multiple Ascending Dose (Cohorts B1 and B2):
Up to 24 hours following last administration on Day 14. Sampling points are on Day 1 (pre-dose; and 2h, 4h, 9h and 12h post-dose); on Day 2 and Day 7; on Day 14 (same schedule as Day 1); and on Day 15.

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 contraindications 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
Sex
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. Previous exposure to ATN-249.
3. 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.
4. Fever (body temperature greater than 38°C) or symptomatic viral or bacterial infection within 2 weeks prior to screening.
5. History of severe allergic or anaphylactic reactions.
6. 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).
7. Alkaline phosphatase (ALP), aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) greater than 1.5 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.
8. 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.
9. Positive test for hepatitis C antibody, hepatitis B surface antigen, or human immunodeficiency virus (HIV) antibody at screening.
10. 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.
11. 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).
12. 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.
13. Participant has left ventricular hypertrophy defined as the combination of the following ECG criteria (both #a and #b must be met):
13.a. Voltage criteria (both criteria must be met):
13.a.1 S in V1 plus R in V5 or V6 (whichever is larger) greater or equal than 35 mm; and
13.a.2 R in aVL greater or equal than 11 mm
13.b. Repolarization abnormalities (at least one criteria needs to be met):
13.b.1 At least 1mm ST depression (horizontal or down-sloping); or
13.b.2 Abnormal T wave inversions
14. 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:
14.a. QRS greater than 110 milliseconds (msec),
14.b. QT interval corrected using Fridericia’s formula (QTcF) greater than 440 msec,
14.c. PR interval greater than 220 msec
14.d. Heart rate lower than 50 beats per minute (BPM) or greater than 90 BPM (the resting heart rate measurement may be repeated only once if below 50 beats per minute)
14.e. Complete right bundle branch block or left bundle branch block.
15. History of cardiac disease or cerebrovascular disease, including coronary artery disease (including myocardial infarction [MI], angina), cardiac arrhythmias, long QT syndrome (in self or family), valvular disease, heart failure, hypertension or hypotension.
16. Family history of hereditary angioedema.
17. 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.
18. 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.
19. 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).
20. Participant is lactose intolerant.
21. 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.
22. Participant is unwilling to abstain from ingestion of caffeine or xanthine-containing products (e.g., tea, coffee, chocolate, cola,) beginning 96 hours prior to admission to the CRU until the final pharmacokinetic (PK) sample has been collected.
23. 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 follow-up visit.
24. Participant has consumed citrus fruit or citrus fruit juices within 48 hours prior to admission to the CRU and is unwilling to abstain from these items until the final PK sample has been collected.
25. 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
Non-randomised 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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
No data analysis planned
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
The study was stopped after completing Cohort 1 because of futility. There were no safety concerns associated with the administration of ATN 249.
Date of first participant enrolment
Anticipated
10/10/2018
Actual
10/10/2018
Date of last participant enrolment
Anticipated
Actual
10/10/2018
Date of last data collection
Anticipated
5/02/2019
Actual
18/10/2018
Sample size
Target
24
Accrual to date
Final
6
Recruitment in Australia
Recruitment state(s)
WA

Funding & Sponsors
Funding source category [1] 300483 0
Commercial sector/Industry
Name [1] 300483 0
LifeSci Pharmaceuticals, inc.
Country [1] 300483 0
Barbados
Funding source category [2] 300485 0
Commercial sector/Industry
Name [2] 300485 0
Attune Pharmaceuticals
Country [2] 300485 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] 299955 0
Commercial sector/Industry
Name [1] 299955 0
Attune Pharmaceuticals
Address [1] 299955 0
250 West 55th Street Suite 16B
New York, NY 10019, US
Country [1] 299955 0
United States of America
Secondary sponsor category [2] 299958 0
Commercial sector/Industry
Name [2] 299958 0
Clinical Network Services (CNS) Pty Ltd
Address [2] 299958 0
Level 4, 88 Jephson Street
Toowong, QLD 4066
Australia
Country [2] 299958 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301284 0
Bellberry Limited
Ethics committee address [1] 301284 0
129 Glen Osmond Road, Eastwood SA 5065, Australia
Ethics committee country [1] 301284 0
Australia
Date submitted for ethics approval [1] 301284 0
08/08/2018
Approval date [1] 301284 0
07/09/2018
Ethics approval number [1] 301284 0
2018-08-625

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 extended release formulations 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 multiple dose over several days?
- How much of the drug gets into the blood stream, and how long does the body take to get rid of it?

This study will also look at how the human body uses ATN-249 at different dose levels and under different dosing regimens (single day dosing or 14-day dosing).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 86486 0
Dr Peter Schrader
Address 86486 0
Linear Clinical Research
Level 1, B Block, QEII Medical
Centre,
Hospital Avenue
NEDLANDS WA 6009
Country 86486 0
Australia
Phone 86486 0
+61 (0) 8 6382 5100
Fax 86486 0
Email 86486 0
pschrader@linear.org.au
Contact person for public queries
Name 86487 0
Mr Alex Castellarnau
Address 86487 0
Clinical Network Services (CNS) Pty Ltd
Level 4, 88 Jephson St,
TOOWONG, QLD 4066
Country 86487 0
Australia
Phone 86487 0
+61(0)7 3719 6000
Fax 86487 0
Email 86487 0
alex.castellarnau@clinical.net.au
Contact person for scientific queries
Name 86488 0
Mr Jason Bablak
Address 86488 0
Attune Pharmaceuticals
250 West 55th Street Suite 16B
New York, NY 10019
Country 86488 0
United States of America
Phone 86488 0
+1 412 445-1705
Fax 86488 0
Email 86488 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 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.