Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000862448
Ethics application status
Approved
Date submitted
29/06/2016
Date registered
1/07/2016
Date last updated
13/10/2020
Date data sharing statement initially provided
13/10/2020
Date results information initially provided
13/10/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase 1, Double-blind, Randomized, Placebo-controlled, Single Ascending Dose Study of Subcutaneous APL-9 in Healthy Volunteers
Scientific title
Phase 1, Double-blind, Randomized, Placebo-controlled, Single Ascending Dose Study of Subcutaneous APL-9 in Healthy Volunteers
Secondary ID [1] 289568 0
Nil
Universal Trial Number (UTN)
Trial acronym
APL9-CP-HV-205
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Paroxysmal nocturnal hemoglobinuria (PNH) 299298 0
Condition category
Condition code
Blood 299293 299293 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Subjects will be randomly assigned to treatment with either a single dose of APL-9 or a single dose of placebo by subcutaneous injection. Doses will be administered by healthcare professionals at the study site. This study will be conducted in 4 sequential cohorts.
The first cohort will receive 90 mg of APL-9 (4 subjects) or placebo (2 subjects).
The second cohort will receive 225 mg of APL-9 (4 subjects) or placebo (1 subject).
The exact doses for the third and fourth cohort will be determined after the second cohort has been dosed.
The third cohort will receive up to 450 mg of APL-9 (4 subjects) or placebo (1 subject).
The fourth cohort will receive up to 450 mg of APL-9 (4 subjects) or placebo (1 subject).
Intervention code [1] 295165 0
Treatment: Drugs
Comparator / control treatment
Placebo (subcutaneous injection of 5% glucose solution)
Control group
Placebo

Outcomes
Primary outcome [1] 298786 0
The safety and tolerability of single subcutaneous doses of APL-9 when administered to healthy adults.
Timepoint [1] 298786 0
Throughout the study, routine clinical tests will be conducted, including vital signs, ECGs, and blood and urine tests.
Vital signs and ECGs will be recorded at screening, upon check-in to the clinic on the day before dosing, before dosing; at 1 and 4 hours post-dosing on Day 1, and then once per day on Day 2, 3, 4, 5, 6, 7, 8, 15, 22, 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] 325192 0
Serum pharmacokinetics of single subcutaneous doses of APL-9 when administered to healthy adults. AUC, Cmax, tmax, Kel and t1/2 will be determined.
Timepoint [1] 325192 0
Blood will be collected for serum APL-9 measurements before dosing; at 15 and 30 minutes and 1, 4, 8 and 12 hours post-dosing on Day 1, and then once per day on Day 2, 3, 4, 5, 6, 7, 8, 15, 22, 29, and 43.
Secondary outcome [2] 325193 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] 325193 0
Blood will be collected for serum complement activation marker measurements before dosing; at 1, 4 and 12 hours post-dosing on Day 1, and then once per day on Day 2, 3, 4, 5, 6, 7, 8, 15, 22, 29, and 43.

Eligibility
Key inclusion criteria
Medically healthy adults

Weigh more than 50 kg and less than 95 kg and have a BMI higher than 18.0 kg/m2 and lower than 32.0 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
Sex
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 60 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 manufacturer of the dosing syringes. The manufacturer 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 the clinical trial team.
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
Single ascending dose study in 4 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
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Safety concerns
Date of first participant enrolment
Anticipated
11/07/2016
Actual
11/07/2016
Date of last participant enrolment
Anticipated
9/11/2017
Actual
4/08/2016
Date of last data collection
Anticipated
31/12/2017
Actual
7/10/2016
Sample size
Target
21
Accrual to date
Final
6
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 6044 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 13492 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 293948 0
Commercial sector/Industry
Name [1] 293948 0
Apellis Pharmaceuticals Inc
Country [1] 293948 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] 292770 0
None
Name [1] 292770 0
Address [1] 292770 0
Country [1] 292770 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295372 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 295372 0
89 Commercial Road
Melbourne VIC 3004
Ethics committee country [1] 295372 0
Australia
Date submitted for ethics approval [1] 295372 0
23/05/2016
Approval date [1] 295372 0
30/06/2016
Ethics approval number [1] 295372 0

Summary
Brief summary
APL-9 is a PEGylated peptide wherein a small pharmacologically moiety binds to primate complement C3 and exerts a broad inhibition of the complement cascade. The PEG portion of the drug molecule imparts longer residence time in the body after administration of the drug.
APL-9 for SC injection is currently in development as a potential treatment for paroxysmal nocturnal hematuria (PNH), which is an acquired hematological disease characterized by complement-mediated red blood cell (RBC) hemolysis, with or without hemoglobinuria, and increased susceptibility to thrombotic episodes, and/or some degree of bone marrow dysfunction.
This single ascending dose study is the first study in a planned series of studies for the clinical development of APL-9. The primary objective of the study is to assess the safety and tolerability of single subcutaneous (SC) doses of APL 9 in healthy volunteers. The secondary objective of the study is to assess the pharmacokinetics (PK) of single SC doses of APL 9 in healthy volunteers. An exploratory objective of the study is to assess the pharmacodynamics (PD) of single SC doses of APL 9 when administered to healthy volunteers.
The study will recruit 21 subjects in four dose cohorts. Subjects will participate in only one cohort and will receive a single dose of APL 9 or placebo administered subcutaneously.
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 (SMC) comprised of the Principal Investigator (PI), the Medical Monitor, 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 for follow-up visits and the exit visit for subsequent study procedures.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 67010 0
Dr Jason Lickliter
Address 67010 0
Nucleus Network Limited
Level 5, Burnet Institute, AMREP Precinct
89 Commercial Road
Melbourne VIC 3004
Country 67010 0
Australia
Phone 67010 0
+61 3 9076 8906
Fax 67010 0
+61 3 9076 8911
Email 67010 0
j.lickliter@nucleusnetwork.com.au
Contact person for public queries
Name 67011 0
Dr Lil Edis
Address 67011 0
Apellis Australia Pty Ltd
Level 12, 10 Eagle Street
Brisbane QLD 4000
Country 67011 0
Australia
Phone 67011 0
+61 447447403
Fax 67011 0
Email 67011 0
lil@apellis.com
Contact person for scientific queries
Name 67012 0
Dr Lil Edis
Address 67012 0
Apellis Australia Pty Ltd
Level 12, 10 Eagle Street
Brisbane QLD 4000
Country 67012 0
Australia
Phone 67012 0
+61 447447403
Fax 67012 0
Email 67012 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


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
SourceTitleYear of PublicationDOI
Dimensions AIThe renaissance of complement therapeutics2017https://doi.org/10.1038/nrneph.2017.156
N.B. These documents automatically identified may not have been verified by the study sponsor.