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Trial registered on ANZCTR


Registration number
ACTRN12617001308381
Ethics application status
Approved
Date submitted
5/09/2017
Date registered
12/09/2017
Date last updated
30/01/2019
Date data sharing statement initially provided
30/01/2019
Date results information initially provided
30/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase I, Double-blind, Randomized, Placebo-controlled, Single Ascending Dose Study of Intravenous APL-9 in Healthy Volunteers
Scientific title
Phase I, Double-blind, Randomized, Placebo-controlled, Single Ascending Dose Study of Intravenous APL-9 in Healthy Volunteers
Secondary ID [1] 292800 0
None
Universal Trial Number (UTN)
None
Trial acronym
None
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Ischaemic stroke 304613 0
Condition category
Condition code
Stroke 303933 303933 0 0
Ischaemic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Subjects will be randomly assigned to treatment with either a single intravenous (IV) infusion of APL-9 or a single IV infusion of placebo. Doses will be administered by healthcare professionals at the study site and are expected to take approximately 30 min for subjects in the first 4 cohorts; 12 hours for subjects in the 5th cohort, and 24 hours for subjects in the 6th cohort.
This study will be conducted in 5 sequential cohorts.
The first cohort received 30 mg of APL-9 (4 subjects) or placebo (2 subjects).
The second cohort received 90 mg of APL-9 (4 subjects) or placebo (2 subjects).
The third cohort received 270 mg of APL-9 (4 subjects) or placebo (2 subjects).
The fourth cohort received 540 mg of APL-9 (4 subjects) or placebo (2 subjects).
The fifth cohort received 540 mg of APL-9 (4 subjects) or placebo (2 subjects).
The sixth cohort received 536 mg of APL-9 (4 subjects) or placebo (1 subject).
Intervention code [1] 299057 0
Treatment: Drugs
Comparator / control treatment
Placebo (intravenous infusion of acetate-buffered saline solution)
Control group
Placebo

Outcomes
Primary outcome [1] 303294 0
The safety and tolerability of single intraveneous doses of APL-9 when administered to healthy adults.
Timepoint [1] 303294 0
Throughout the study, routine clinical tests will be conducted, including vital signs, ECGs, and blood and urine tests.
Vital signs will be recorded at screening, upon check-in to the clinic on the day before dosing; during dosing on Day 1; at 1, 2, 4, 8 and 12 hours after dosing on Day 1, and then once per day on Day 2, 3, 4, 5, 6, 7, 8, 11, 15, 29, and 43. ECGs will be recorded at screening, upon check-in to the clinic on the day before dosing on Day 1; before dosing; at 1, 2, 4, 8 and 12 hours after dosing on Day 1, and then once per day on Day 2, 3, 4, 5, 6, 7, 8, 11, 15, 29, and 43.
Blood and urine samples will be collected for testing at screening, upon check-in to the clinic on the day before dosing. then on Day 2, 4, 8, 15, 29, and 43.
Secondary outcome [1] 338546 0
Serum pharmacokinetics of single subcutaneous doses of APL-9 when administered to healthy adults. AUC, Cmax, tmax, CL/F, VZ/F and t1/2 will be determined.
Timepoint [1] 338546 0
Blood will be collected for serum APL-9 measurements before dosing; at 15 and 30 minutes and 1, 1.5, 2, 3, 4, 8 and 12 hours post-dosing on Day 1, and then once per day on Day 2, 3, 4, 5, 6, 7, 8, 11 and 15.
Secondary outcome [2] 338547 0
Serum pharmacodynamics of single subcutaneous doses of APL-9 when administered to healthy adults, AH50, CH50, C3 and C3a will be measured.
Timepoint [2] 338547 0
Blood will be collected for serum complement activation marker measurements at screening; before dosing; at 1, 2, 4, 8 and 12 hours after dosing on Day 1, and then once per day on Day 2, 3, 4, 5, 6, 7, 8, 11, 15, 18, 22,25, 29, and 43.

Eligibility
Key inclusion criteria
Medically healthy adults
Weigh more than 55 kg and less than 90 kg and have a BMI higher than 18.5 kg/m2 and lower than 32.0 kg/m2.
Have been vaccinated against Neisseria meningitidis within two years or willing to receive vaccinations.
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Mentally or legally incapacitated or has significant emotional problems or has a history of a significant medical or psychiatric condition or a history of hypersensitivity to compounds related to APL-9 or a history of chronic infections or a recent active infection or recent surgery.
Use of any prescription or non-prescription medications, herbal remedies, or vitamin supplements within the last 14 days
Blood donation or significant blood loss within previous 56 days or plasma donation within previous 7 days
Participation in another clinical trial within the previous 28 days or participation in any previous clinical trial with APL-9.

Female subjects who are pregnant or lactating.

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)
A statistician will prepare a Randomization Schedule and send a copy to the study pharmacist. The pharmacist will fill dosing syringes with either APL-9 or placebo, and will label the syringes in a blinded fashion in accordance with the Randomization Schedule (i.e. the label for each syringe will include the Randomization Number but will not include the identity of the treatment). The Randomization Schedule will not be made available to clinic personnel.
Subjects who complete the screening assessments and meet all of the eligibility criteria will be enrolled into the study and will be assigned a unique Randomisation Number.
Randomisation Numbers will be comprised of the letter R followed by a four-digit number of the format ‘Rcrnn’, where c denotes the cohort number (i.e. for Cohort 1, c=1), r is a replacement indicator and nn is a sequential randomisation number, i.e. R1001, R1002, etc. If a subject is replaced, the digit represented by r will be sequentially increased by one, e.g. R2003 would be replaced by R2103. The replacement subject will be administered the same treatment allocated to the original participant, as indicated by the last two digits of the randomisation number (i.e. 03 for participant R2003 and R2103).
Dosing syringes will be dispensed for the subject with the corresponding Randomisation Number and the injections will be administered by blinded clinic personnel or by personnel who will not be involved in the study assessments.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computerised randomisation schedule will be created by a statistician who is not otherwise involved in the study.
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
The people analysing the results/data
Intervention assignment
Other
Other design features
Single ascending dose study in 5 sequential cohorts
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
Given the exploratory nature of the study no formal statistical hypothesis testing will be performed. As no formal hypothesis testing will be conducted, the study sample sizes were not based on statistical power calculations.
Data will be presented by cohort/dose (including placebo where applicable), study day and nominal time post-dose (if appropriate). Subjects receiving placebo will be pooled across dosing cohorts for summaries. All data will be listed by cohort and dose (including placebo where applicable).
For continuous variables, the number of available observations (n), mean, standard deviation (SD), median, minimum, and maximum will be provided. For categorical variables, the frequency and percentage in each category will be displayed. Unless otherwise specified percentages of subjects will be based on the number of subjects randomized (Safety Analysis Set).

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)
VIC
Recruitment hospital [1] 8962 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 17334 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 297431 0
Commercial sector/Industry
Name [1] 297431 0
Apellis Pharmaceuticals Inc
Address [1] 297431 0
6400 Westwind Way, Suite A
Crestwood KY 40014
Country [1] 297431 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Clinical Network Services Pty Ltd
Address
Level 4, 88 Jephson Street
Toowong QLD 4066
Country
Australia
Secondary sponsor category [1] 296427 0
None
Name [1] 296427 0
Address [1] 296427 0
Country [1] 296427 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298540 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 298540 0
129 Glen Osmond Road Eastwood South Australia 5063
Ethics committee country [1] 298540 0
Australia
Date submitted for ethics approval [1] 298540 0
30/08/2017
Approval date [1] 298540 0
27/10/2017
Ethics approval number [1] 298540 0

Summary
Brief summary
APL-9 is formed by a pentadecapeptide (combining a cyclic tridecapeptide active C3-inhibiting moiety and a 2-amino acid linker) covalently coupled to each end of a linear 10 kDa PEG chain, such that there are two peptide moieties per molecule of APL-9.
APL-9 is a broad inhibitor of the complement cascade, a biological process that is part of innate immunity and is involved in multiple inflammatory processes. The PEGylation of the molecule imparts slower elimination following administration. APL-9 for intravenous route of administration is currently being considered as a potential treatment for acute conditions that would benefit from rapid and short-term inhibition of the complement system. One of the acute conditions is ischemic stroke. This single ascending dose study is the second in a planned series of studies for the clinical development of APL-9. The primary objective of the study is to assess the pharmacokinetics (PK) of single intravenous doses of APL 9 in healthy volunteers. The secondary objective of the study is to assess the pharmacokinetics of single intravenous doses of APL 9 in healthy volunteers. An exploratory objective of the study is to assess the pharmacodynamics (PD) of single intravenous doses of APL 9 when administered to healthy volunteers.
The study will recruit 35 subjects in six dose cohorts. Subjects will participate in only one cohort and will receive a single dose of APL 9 or placebo administered intravenously.
Safety will be assessed throughout the study; serial blood samples and urine samples will be collected for these assessments. Blood samples will also be collected for the PK, PD, and immunogenicity assessment of APL 9.
Dose escalation to the next dose level (i.e. next cohort) will not take place until a Safety Monitoring Committee comprised of the Principal Investigator and the Sponsor have determined that adequate safety and tolerability from the previous cohort has been demonstrated to permit proceeding to the next cohort.
Subjects will be resident in the clinical facility (Nucleus Network Ltd) from the day before dosing until 168 hours (Day 8) after dosing. Subjects will return to the clinical facility for follow-up visits and the exit visit for subsequent study procedures.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 77394 0
Dr Jason Lickliter
Address 77394 0
Nucleus Network Limited
Level 5, Burnet Institute, AMREP Precinct
89 Commercial Road
Melbourne VIC 3004
Country 77394 0
Australia
Phone 77394 0
+61 3 9076 8906
Fax 77394 0
+61 3 9076 8911
Email 77394 0
j.lickliter@nucleusnetwork.com.au
Contact person for public queries
Name 77395 0
Dr Lil Edis
Address 77395 0
Apellis Australia Pty Ltd
Level 12, 10 Eagle Street
Brisbane QLD 4000
Country 77395 0
Australia
Phone 77395 0
+61 2 6236 9091
Fax 77395 0
Email 77395 0
lil@apellis.com
Contact person for scientific queries
Name 77396 0
Dr Lil Edis
Address 77396 0
Apellis Australia Pty Ltd
Level 12, 10 Eagle Street
Brisbane QLD 4000
Country 77396 0
Australia
Phone 77396 0
+61 2 6236 9091
Fax 77396 0
Email 77396 0
lil@apellis.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
There are no plans to share line by line data due to the confidential nature of the data.
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?
No
Results – basic reporting
Results – plain English summary