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Trial registered on ANZCTR


Registration number
ACTRN12617000982314
Ethics application status
Approved
Date submitted
4/07/2017
Date registered
7/07/2017
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 Study of Daily, Twice-Weekly and Once-Weekly APL 2 in Healthy Volunteers
Scientific title
Phase I, Double-Blind, Randomized Study of Daily, Twice-Weekly and Once-Weekly APL 2 in Healthy Volunteers
Secondary ID [1] 292360 0
None
Universal Trial Number (UTN)
Trial acronym
None
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Paroxysmal Nocturnal Hemoglobinuria (PNH) 303907 0
Condition category
Condition code
Blood 303271 303271 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Subjects in Cohort 1 were randomly assigned to treatment with APL-2 360 mg (4 subjects) or matching placebo (1 subject) by subcutaneous injection (SC) once daily for 28 days. Subjects in Cohort 2 were randomly assigned to treatment with APL-2 1,300 mg (4 subjects) or matching placebo (1 subject) SC twice weekly for 28 days. Subjects in Cohort 3 were randomly assigned to treatment with APL-2 2,600 mg (4 subjects) or matching placebo (2 subjects) SC once per week for 28 days. All subjects in Cohort 4 were assigned treatment with APL-2 1080 mg (16 subjects) SC twice weekly for 28 days. All subjects in Cohort 5 were assigned treatment with APL-2 1080 mg (8 subjects) SC twice weekly for 28 days. The Subjects will participate in one cohort only. Cohort1 and Cohort 2 were conducted in parallel. Cohort 3 was enrolled after completion of Cohort 1 and Cohort 2; Cohort 4 was enrolled after completion of Cohort 3, and Cohort 5 was enrolled after completion of Cohort 4.
Doses were administered by healthcare professionals at the study site.
Subjects attended a Screening visit (Day -28 to Day -14), resided in the clinic for 35 days from Day -1 (the day before the first dose) until Day 35, and returned to the clinic for 3 follow-up visits on Day 42, 56, and 70, and for a final exit visit on Day 84.
Intervention code [1] 298536 0
Treatment: Drugs
Comparator / control treatment
Placebo (subcutaneous injection of acetate buffered sorbitol solution)
Control group
Placebo

Outcomes
Primary outcome [1] 302651 0
The pharmacokinetics of daily, twice a week and once a week regimens of SC APL-2 in healthy volunteers. Noncompartmental PK parameters of AUC0-24, Cmax, Cmin, and Cav will be calculated from serum concentrations of APL-2 for Day 1 and/or for Day 22 to 29.
Timepoint [1] 302651 0
Throughout the study, blood samples will be collected for pharmacokinetic (PK) testing, including a blood sample before dosing and at 1, 2, 4, 8, and 12 hours post-dosing on Day 1, and then once per day on Day 2, 3, 4, 5, 6, 8, 15, 22, 23, 24, 25, 26, 27, 28, 29, 35, 42, 56, 79, and 84.
Primary outcome [2] 302669 0
The safety and tolerability of daily, twice a week and once a week regimens of SC APL-2 in healthy volunteers.
Timepoint [2] 302669 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, and on Day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 42, 56, 79, and 84. ECGs will be recorded at screening, and on Day 1, 8, 15, 22, 25, 29, 35, 42, 56, 79, and 84. Blood samples will be collected for safety testing at screening, at check-in on the day before dosing, and on Day 7, 14, 21, 28, 35, 56, and 84. Urine samples will be collected for safety testing at screening, at check-in on the day before dosing, and on Day 7, 14, 21, 28, 35, and 84.
Secondary outcome [1] 336663 0
The pharmacodynamics (PD) of daily, twice a week and once a week regimens of SC APL-2 in healthy volunteers. PD assessments include the serum complement activation markers CH50, AP50, C3, and C3a.
Timepoint [1] 336663 0
Throughout the study, blood samples will be collected to measure serum complement activation markers (CH50, AP50, C3, and C3a), including blood samples at screening and on Day1, 8, 15, 22, 25, 29, 35, 42, 56, 79, and 84.

Eligibility
Key inclusion criteria
Medically healthy adults

Weigh more than 49 kg and less than 91 kg and have a BMI higher than 18.4 kg/m2 and lower than 32.1 kg/m2.

Have been vaccinated against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenza 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-2 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
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 Clinical Trial Pharmacist. The Pharmacist will fill dosing syringes with either APL-2 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 the clinical trial team except for the Pharmacists.
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 ‘Rprnn’, where p denotes the cohort number (i.e. for Cohort 1, p=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 to the subject with the corresponding Randomisation Number and the injections will be administered by blinded study 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
There will be up to 5 cohorts with a total of 40 subjects. Cohort 1 and Cohort 2 were enrolled in parallel and each included 4 subjects randomised to receive APL-2 and 1 subject randomised to receive placebo. Cohort 3 was enrolled after completion of Cohort 1 and Cohort 2 and included 2 Sentinel subjects with 1 randomised to receive APL-2 and 1 randomised to receive placebo, followed by 4 more subjects one week later, with 3 randomised to received APL-2 and 1 randomised to receive placebo. Cohort 4 was enrolled after completion of treatment by Cohort 3 and was comprised of 16 subjects receiving APL-2. Cohort 5 was enrolled after completion of treatment by Cohort 4 and was comprised of 8 subjects who received APL-2.
Subjects will participate in one cohort only.
Phase
Phase 1
Type of endpoint(s)
Pharmacokinetics / pharmacodynamics
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).
PK parameters for APL-2 will be computed from the individual serum concentrations-time data, using actual sample times and a non-compartmental approach.

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] 8483 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 16566 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 296913 0
Commercial sector/Industry
Name [1] 296913 0
Apellis Pharmaceuticals Inc
Address [1] 296913 0
6400 Westwind Way, Suite A
Crestwood KY 40014
Country [1] 296913 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] 295916 0
None
Name [1] 295916 0
Address [1] 295916 0
Country [1] 295916 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298123 0
Alfred Health Ethics Committee
Ethics committee address [1] 298123 0
89 Commercial Road
Melbourne VIC 3004
Ethics committee country [1] 298123 0
Australia
Date submitted for ethics approval [1] 298123 0
26/06/2017
Approval date [1] 298123 0
20/09/2017
Ethics approval number [1] 298123 0
307/17

Summary
Brief summary
APL-2 is a small peptide coupled to each end of a linear polyethylene glycol (PEG) chain. The peptide portion of the drug binds to complement C3 and is a broad inhibitor of the complement cascade, a biological process that is part of innate immunity. The PEG chain imparts longer residence time in the body after administration of the drug.
APL-2 is being developed for the management of paroxysmal nocturnal hemoglobinuria (PNH) and daily SC administration of APL-2 is being investigated in two ongoing studies in patients with PNH. However, daily SC infusions are burdensome. The aim of this study is to evaluate and confirm whether less frequent dosing such as twice or once a week is safe and associated with a pharmacokinetic and pharmacodynamic profile likely to provide clinical benefits comparable to the daily SC infusions.
An exploratory objective of the study is to compare the pharmacodynamics (PD) of daily, twice a week, and once a week dose regimens of APL 2 in healthy volunteers.
For each subject, the study will consist of:
* Screening Visit(s) between Day -28 and Day -14
* Admission into clinic on Day -1
* First APL-2 dose on Day 1
* Discharge from clinic on Day 35
* Follow-up visits on Day 42, 56, and 70
* Exit visit on Day 84
The total duration of each subject’s participation is expected to be approximately 112 days.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 76074 0
Dr Jason Lickliter
Address 76074 0
Nucleus Network Limited
Level 5, Burnet Institute, AMREP Precinct
89 Commercial Road
Melbourne VIC 3004
Country 76074 0
Australia
Phone 76074 0
+61 3 9076 8906
Fax 76074 0
+61 3 9076 8911
Email 76074 0
j.lickliter@nucleusnetwork.com.au
Contact person for public queries
Name 76075 0
Dr Lil Edis
Address 76075 0
Apellis Australia Pty Ltd
Level 16, 120 Edward Street
Brisbane Queensland 4000
Country 76075 0
Australia
Phone 76075 0
+61 2 6236 9091
Fax 76075 0
Email 76075 0
lil@apellis.com
Contact person for scientific queries
Name 76076 0
Dr Lil Edis
Address 76076 0
Apellis Australia Pty Ltd
Level 16, 120 Edward Street
Brisbane Queensland 4000
Country 76076 0
Australia
Phone 76076 0
+ 61 2 6236 9091
Fax 76076 0
Email 76076 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 the raw line-by-line participant 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