Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000700437
Ethics application status
Approved
Date submitted
24/05/2016
Date registered
27/05/2016
Date last updated
10/01/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase 1, Double-blind, Randomized, Placebo-controlled, Single Ascending Dose Study of Intravenous APL-2 in Healthy Volunteers
Scientific title
Phase 1, Double-blind, Randomized, Placebo-controlled, Single Ascending Dose Study to Evaluate the Safety of Intravenous APL-2 in Healthy Volunteers
Secondary ID [1] 289275 0
None
Universal Trial Number (UTN)
U1111-1183-1160
Trial acronym
APL2 CP-HV-401
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ischaemic stroke 298860 0
Condition category
Condition code
Stroke 298964 298964 0 0
Ischaemic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a phase I, double-blind, randomized, placebo controlled, single ascending dose study of APL-2 administered intravenously to healthy volunteers. It will be conducted at a single site in Australia. The study will recruit four dose cohorts each comprising four subjects receiving APL-2 and one subject receiving placebo. A fifth cohort may be recruited if required.
Subjects will receive a single intravenous bolus injection of APL-2 administered over 30 minutes. Meals will be restricted from 1 hour prior to dosing to 4 hours after dosing.
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 pharmacokinetic (PK), pharmacodynamic (PD), and immunogenicity assessments of APL- 2. The safety, PK, PD and immunogenicity profiles of APL-2 will be compared to placebo. On Day 1 of each cohort, 4 subjects will receive APL-2 and 1 will receive placebo.
APL- 2 will be supplied as a sterile solution in acetate-buffered saline at a concentration of 24 mg/mL.
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. The planned dose for cohorts 1 and 2 is 200 mg and 600 mg respectively, the dose for cohorts 3 and 4 will be determined by the SMC following their review of safety, PK and PD data from the previous cohort(s).
Subjects will be resident in the Unit (Nucleus Network Ltd) from the day before dosing until 168 hours (Day 8) after dosing. Subjects will return for follow-up visits on Days 15, 22 and 29 and the exit visit on Day 43 for subsequent study procedures. The study duration per subject is approximately 70 days with a screening interval of up to 28 days.
Interim PK analyses will be performed to guide the dose-escalation decision and to reconsider the sampling time points as the study progresses.
Intervention code [1] 294825 0
Treatment: Drugs
Comparator / control treatment
Placebo will be supplied as acetate-buffered saline.
Control group
Placebo

Outcomes
Primary outcome [1] 298402 0
Number of treatment emergent adverse events (TEAEs) of APL-2 following administration of single intravenous doses.
Number of TEAEs will be assessed through evaluation of physical examinations, vital signs, electrocardiograms (ECGs), clinical laboratory parameters, and monitoring of AEs.
TEAEs will be summarised by dose, System Organ Class and Preferred Term, according to the Medical Dictionary for Regulatory Activities (MedDRA).
Timepoint [1] 298402 0
This will be assessed continuously from dosing to Day 8 whilst subjects are in-house, at the follow-up visits on Days 15, 22 ,29,and at the end of study visits on Day 43.
Primary outcome [2] 298431 0
Severity of treatment emergent adverse events (TEAEs) of APL-2 following administration of single intravenous doses.
Severity of TEAEs will be graded according to the FDA toxicity grading scale for healthy volunteers 4-point severity scale (Grade 1, 2, 3 and 4 where Mild - Grade 1; Moderate - Grade 2; Severe - Grade 3 and Life threatening - Grade 4).
Timepoint [2] 298431 0
This will be assessed continuously from dosing to Day 8 whilst subjects are in-house, at the follow-up visits on Days 15, 22 ,29,and at the end of study visits on Day 43.
Secondary outcome [1] 324040 0
The pharmacokinetics of single intravenous doses of APL-2 in healthy volunteers. PK of APL-2 will be assessed on serum samples collected at various time-points.
Parameters to be assessed:
AUC0-t, area under the serum concentration versus time curve, from time 0 to the last measurable concentration;
AUC0-inf, area under the serum concentration versus time curve from time 0 to infinity,
Cmax, maximum observed serum concentration,
tmax, time of the maximum measured serum concentration,
kel, apparent first-order terminal elimination rate constant,
t1/2, apparent first-order terminal elimination half-life,
CL, total body clearance after IV administration,
Vz, total volume of distribution after IV administration.
Timepoint [1] 324040 0
Day 1 (pre-dose, 15 min, 30 min and 1, 4, 8,and 12 hr post-dose), Days 2-8 inclusive, Days 15, 22, 29 and 43.
Secondary outcome [2] 324041 0
The pharmacodynamics of single intravenous doses of APL-2 in healthy volunteers.
PD markers will be assessed on serum and plasma samples collected at various time-points.
Haemolytic complement activation through the classical (e.g., CH50) and alternative (e.g., AP50) pathway will be assessed as well as levels of C3 and C3a.
Timepoint [2] 324041 0
Day 1 (pre-dose and at 1, 4,and 12 hr post-dose), Days 2-8 inclusive and Days 15, 29 and 43.

Eligibility
Key inclusion criteria
1. Healthy male or female,
2. Continuous non-smoker for at least 3 months prior to dosing.
3. Weigh more than or equal to 55 kg and less than or equal to 90 kg and have a Body Mass Index (BMI) of greater than or equal to 18.5 and less than or equal to 32.0 kg/m2.
4. Medically healthy with no clinically significant screening results as deemed by the principal investigator (PI).
5. Able to provide documentary evidence of vaccination with Neisseria menigitides types A, C, W, Y and B, Streptococcus pneumoniae (PCV13 or PPSV23) and Haemophilus influenza (Hib) within 2 years of dosing, or willing to receive vaccinations against Neisseria menigitides, PCV13 and Hib vaccines at least two weeks prior to dosing.
6. Women of child bearing potential (WOCBP) must have a negative pregnancy test at screening and during the study and must agree to use protocol defined methods of contraception for the duration of the study.
7. Women of non-childbearing potential (WONCBP) must have undergone one of the protocol defined sterilization procedures at least 6 months prior to dosing or be postmenopausal for at least 1 year prior to dosing and have FSH serum levels consistent with postmenopausal status upon Screening.
8. Males must agree to use protocol defined methods of contraception and agree to refrain from donating sperm for 3 months after the final dose of APL-2.
10. Willing and able to give informed consent.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Mental or legal incapacitation or significant emotional problems at screening or expected during the study in the opinion of the PI.
2. History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the principal investigator (PI).
3. History of any illness that, in the opinion of the PI, might confound the study results or poses an additional risk to the subject by their participation in the study.
4. History or presence of alcoholism or drug abuse within the past 2 years prior to screening.
5. History or presence of hypersensitivity or idiosyncratic reaction to compounds related to the investigational product.
6. History of chronic infections or active infection at check-in (as determined by the PI)
7. Pregnant or lactating women.
8. Positive results for the urine drug or alcohol breath test at screening or check-in.
9. Positive urine cotinine at screening or check in.
10. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B or hepatitis C.
11. Clinically relevant clinical laboratory results at screening or check in, as deemed by the PI.
12. Seated systolic blood pressure less than 90/40 mmHg or greater than 140/90 at screening or greater than 155/90 mmHg at any other assessment prior to dosing.
13. Heart rate lower than 40 bpm or higher than 99 bpm at screening or at any other assessment prior to dosing.
14. QTcF interval greater than 450 msec for males or greater than 470 msec for females, or history of prolonged QT syndrome at screening or prior to dosing.
15. Estimated creatinine clearance (CrCl) less than 90 mL/min (Cockcroft Gault formula)or serum creatinine greater than 1.5 mg/mL (133 µmol/L) at screening.
16. Unable to refrain from or anticipates the use of:
-Any drug, including prescription and non prescription medications, herbal remedies, or vitamin supplements from 14 days prior to dosing and throughout the study, with the exception of paracetamol.
-Any drugs known to be significant inducers of CYP enzymes and/or P gp, including St. John’s Wort, for 28 days prior to dosing and throughout the study.
17. Blood donation or significant blood loss within 56 days prior to dosing.
18. Plasma donation within 7 days prior to dosing.
19. Participation in another clinical trial within 28 days prior to dosing.
20. Clinically relevant surgery within 90 days prior to dosing..
21. Any condition or circumstance, in the opinion of the PI, which may make the subject unlikely to complete the study or comply with study procedures and requirements, or may pose a risk to the subject’s safety.
22. Subjects who have participated in the any study with APL-2.

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)
This study is a randomized, double-blind study. Study subjects, site staff including the principal investigator and sub-investigators, monitoring staff and sponsor staff will all be blinded to treatment allocation. Unblinded personnel will include the site pharmacists, one biostatistician and the local depot staff. Subjects will be centrally randomized to either APL-2 or placebo in a 4:1 ratio.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Central randomization will be undertaken with randomization numbers assigned sequentially to each subject as they are confirmed eligible for dosing and enrolled in the study.
The study plans to enrol up to 20 subjects in 4 cohorts, with a possible 5th cohort. All subjects within a cohort will be dosed on the same day; thus no blocking or stratification will be performed.
Upon enrolment, a randomisation number will be assigned to each subject by the unblinded site pharmacist in accordance with a computerized randomization list generated by the unblinded statistician.
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
Parallel
Other design features
Not applicable
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
Safety Data Analyses
Treatment-emergent adverse events will be summarised by dose, System Organ Class and Preferred Term, according to the Medical Dictionary for Regulatory Activities (MedDRA). The number of subjects reporting each AE preferred term will be tabulated for all TEAEs and separately for those considered as possibly related to study treatment by the Investigator. Number of subjects reporting SAEs will also be tabulated.
Changes from baseline in laboratory, vital sign and ECG parameters will be summarised by dose, study day and nominal time post-dose (if appropriate). The number of patients reporting QTcF values greater than or equal to 450 ms for males and greater than or equal to 470 ms for females, or an increase from baseline of greater than or equal to 30 ms will also be tabulated. Baseline will be taken as the last measurement prior to the start of dosing.
For the laboratory safety data, out of range values will be flagged in the data listings and listed separately.
Pharmacokinetic Analyses
Pharmacokinetic Parameters
PK parameters for APL-2 will be computed from the individual serum concentrations-time data, using actual sample times using a non-compartmental approach. Appropriate validated PK software (e.g., Phoenix WinNonlin 'Registered Trademark' Version 6.3 or higher) will be used.
AUC0-t The area under the serum concentration versus time curve, from time 0 to the last measurable concentration, as calculated by the linear-log trapezoidal method.
AUC0-inf The area under the serum concentration versus time curve from time 0 to infinity. AUC0-inf is calculated as the sum of AUC0-t plus the ratio of the last measurable serum concentration to the elimination rate constant.
Cmax Maximum observed serum concentration.
tmax Time of the maximum measured serum concentration. If the maximum value occurs at more than one time point, tmax is defined as the first time point with this value.
kel Apparent first-order terminal elimination rate constant calculated from a semi-log plot of the serum concentration versus time curve. The parameter will be calculated by linear least-squares regression analysis using the maximum number of points in the terminal log-linear phase (e.g., three or more non-zero serum concentrations).
t1/2 Apparent first-order terminal elimination half-life will be calculated as 0.693/kel.
CL: Total body clearance after IV administration, calculated as Dose/AUC0-inf (parent only).
Vz: Total volume of distribution after IV administration, calculated as Dose/(AUC0-inf x kel) (parent only).
Statistical Methods for Pharmacokinetic Analyses
Descriptive Statistics
PK parameters will be summarized by cohort using descriptive statistics (arithmetic means, SD, coefficients of variation [CV], N, minimum, maximum and median). In addition, geometric means will be calculated for AUC parameters, and Cmax. Figures will be created to display median and individual APL-2 concentration-time curves. Additional PK analyses may be performed if deemed appropriate.
No value for kel, t1/2, AUC0-inf, CL, or Vz, as appropriate, will be reported for cases that do not exhibit a terminal log-linear phase in the concentration versus time profile.
Additional analyses will be performed as deemed necessary upon review of the data.
Dose Proportionality Analysis
Dose proportionality will be evaluated for APL-2 AUC parameters and Cmax. Due to the complex nature of the association between the systemic exposure and the dose, the assessment of the dose proportionality will not be based solely on a strict statistical rule given the small sample size for each dose level.
The relationship between dose and PK parameters of APL-2 will be examined graphically and a power law model will fitted to the data. For the power law analysis a linear regression model will be fitted to the ln transformed PK parameters using ln transformed dose as the linear explanatory variable. Quadratic and cubic terms for ln-transformed dose will be added to test for departures from linearity; if these are not significant (p-value greater than 0.05) the linear slope and associated 95 per cent confidence interval will be estimated. Dose proportionality would be implied by a slope of 1, but to be able to conclude proportionality the confidence interval will need to exclude clinically relevant deviations from proportionality.
Pharmacodynamic Analyses
Absolute values and changes from baseline in complement level and immunoglobulin parameters will be summarised by dose and study day. Individual subject and median profiles of the absolute and change from baseline data will be plotted by dose and study day. Baseline will be taken as the last measurement prior to the start of dosing.
Handling of Dropouts and/or Missing Data
No imputation of missing data for early terminations will be performed.
Missing dates/times will be reviewed on a case by case basis for potential imputations, but the original data will always be presented in data listings.
PK concentration values below the limit of quantification will take the value of 0 in individual linear-linear profile plots and the limit of quantification in linear-log profile plots.
Other Data Analyses
Demographics will be summarised by dose and overall.
Physical examination, concomitant medication and medical history data will be listed for each dose. WHO and MedDRA coding dictionaries will be used for the concomitant medications and medical histories respectively.
Interim Analyses
There will be a planned review of safety/tolerability, PK and PD data between cohorts.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
31/05/2016
Actual
31/05/2016
Date of last participant enrolment
Anticipated
28/11/2016
Actual
18/10/2016
Date of last data collection
Anticipated
Actual
30/11/2016
Sample size
Target
25
Accrual to date
Final
20
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 5838 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 13283 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 293658 0
Commercial sector/Industry
Name [1] 293658 0
Apellis Pharmaceuticals Inc.
Country [1] 293658 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Clinical Network Services Pty Ltd
Address
Level 4, 88 Jephson St
Toowong
Queensland 4066
Australia
Country
Australia
Secondary sponsor category [1] 292493 0
None
Name [1] 292493 0
Address [1] 292493 0
Country [1] 292493 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295095 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 295095 0
Ethics committee country [1] 295095 0
Australia
Date submitted for ethics approval [1] 295095 0
06/04/2016
Approval date [1] 295095 0
03/05/2016
Ethics approval number [1] 295095 0
170/16

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 66094 0
Dr Jason Lickliter
Address 66094 0
Nucleus Network Limited
Level 5 Burnet Institute, AMREP Precinct,
89 Commercial Road, Melbourne
VIC 3004
Country 66094 0
Australia
Phone 66094 0
+61 3 9076 8906
Fax 66094 0
+61 3 9076 8911
Email 66094 0
[email protected]
Contact person for public queries
Name 66095 0
Lil Edis
Address 66095 0
Apellis Australia Pty Ltd
A wholly-owned subsidiary of Apellis Pharmaceuticals, Inc
6400 Westwind Way,
Suite A, Crestwood,
Kentucky 40014
USA
Country 66095 0
Australia
Phone 66095 0
+61 2 6236 9091
Fax 66095 0
NA
Email 66095 0
[email protected]
Contact person for scientific queries
Name 66096 0
Pascal Deschatelets
Address 66096 0
Apellis Pharmaceuticals, Inc
6400 Westwind Way,
Suite A, Crestwood,
Kentucky 40014
USA
Country 66096 0
United States of America
Phone 66096 0
+1 502 241 4114
Fax 66096 0
+1 502 241 4116
Email 66096 0
[email protected]

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