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Trial registered on ANZCTR


Registration number
ACTRN12616000145404
Ethics application status
Approved
Date submitted
2/02/2016
Date registered
8/02/2016
Date last updated
10/01/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase I randomized blinded single dose comparison of the safety pharmacokinetics and pharmacodynamics of SYN008 and omalizumab (Xolair) in healthy adult subjects
Scientific title
A Phase I randomized blinded single dose comparison of the safety pharmacokinetics and pharmacodynamics of SYN008 and omalizumab (Xolair) in healthy adult subjects
Secondary ID [1] 288235 0
none
Universal Trial Number (UTN)
U1111-1178-0639
Trial acronym
S08-01
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Moderate to severe persistent asthma 297161 0
Chronic idiopathic urticaria 297162 0
Condition category
Condition code
Inflammatory and Immune System 297380 297380 0 0
Allergies
Respiratory 297381 297381 0 0
Asthma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is a Phase I, randomized, double blind, parallel group comparison of the safety, pharmacokinetics, pharmacodynamics and immunogenicity of a single dose of SYN008 (150mg) with a single dose of omalizumab (Xolair) control (150mg) in adult healthy volunteers.
Eighty subjects will be centrally randomized in a 1:1 ratio to receive either the bio-similar SYN008 or the comparator omalizumab resulting in 40 subjects per group.
The study duration is 84 days consisting of an in-house stay of 3 nights (Day -1 to Day 2)followed by 6 out-patient visits (Days 3, 5, 7, 14, 28 and 56) and a follow-up visit at Day 84; the screening interval is 14 days for a total study duration of 98 days per subject.
On Day 0, subjects will be administered 150mg of either SYN008 or omalizumab (Xolair) by subcutaneous injection in the thigh or abdomen.
Intervention code [1] 293524 0
Treatment: Drugs
Comparator / control treatment
The safety, pharmacokinetics, pharmacodynamics and immunogenicity profiles of the bio-similar SYN008 will be compared with the corresponding profiles for the comparator omalizumab (Xolair).
On Day 0, subjects will be administered 150mg of either SYN008 or omalizumab (Xolair) by subcutaneous injection in the thigh or abdomen.
Control group
Active

Outcomes
Primary outcome [1] 297198 0
Safety: comparison of the adverse event profile of SYN008 with omalizumab (Xolair Registered Trademark)
Expected adverse events are as for listed in the Xolair product information and include: nausea, nasopharyngitis, sinusitis, upper respiratory infection, arthralgia, headache and cough.
These will be assessed by close medical monitoring and questioning of subjects at the Phase I unit for 48 hours post-dose and at outpatient visits on days 3, 5, 7, 14, 28 ,56, and 84
Timepoint [1] 297198 0
Screening, Day -1, Day 0 (pre- and post-IP administration), and at Days 1, 2, 3, 5, 7, 14, 28 ,56 ,and 84 following the single dose administration of IP on Day 0.
Secondary outcome [1] 320320 0
Pharmacokinetic: Comparison of the pharmacokinetic profile of SYN008 to omalizumab (Xolair Registered Trademark) in serum.
The following parameters will be determined for each individual: Cmax, Tmax, t1/2, AUC0-t, lambda, Volume of distribution for each study drug administration.
Timepoint [1] 320320 0
Day 0 (pre-IP administration and 12 hrs post IP administration), and at Days 1, 3, 5, 7, 14, 28, 56 and 84 following the single dose administration of IP on Day 0.
Secondary outcome [2] 320321 0
Pharmacodynamic: Comparison of the free IgE lowering effects of SYN008 to omalizumab (Xolair Registered Trademark) in serum samples.
Timepoint [2] 320321 0
At screening, Day 0 (pre-dose), and at Days 1,3, 5, 7, 14, 28, and 56 following the single dose administration of IP on Day 0.
Secondary outcome [3] 320322 0
Comparison of the immunogenicity of SYN008 to omalizumab (Xolair Registered Trademark) in serum samples.
Timepoint [3] 320322 0
Day 0,pre-dose and at Days 7, 14, 28, 56 and 84 following the single dose administration of IP on Day 0.

Eligibility
Key inclusion criteria
To be eligible, subjects must
1. Have completed the written informed consent process
2. be male or female
3. be aged between age 18 years and 56 years on Study Day 0
4. be in general good health confirmed by medical history and physical examination
5. Agree to stay in contact with the study site for the duration of the study, provide updated contact information as necessary, and have no current plans to move from the study area for the duration of the study
6. Agree to avoid elective surgery for the full duration of the study
7. For female subjects: agree to be within 14 days from the start of her last menses or have avoided pregnancy from 28 days prior to Study Day 0. Agree to avoid pregnancy until 112 days after Study Day 0. Women physically capable of pregnancy (not sterilized and still menstruating or within 1 year of the last menses if menopausal) in sexual relationships with men must use an acceptable method of avoiding pregnancy during this period. Acceptable methods of avoiding pregnancy include a sterile male sexual partner, sexual abstinence (not engaging in sexual intercourse), female hormonal contraceptives (oral, injection, transdermal patch, or implant), progesterone intrauterine device, copper intrauterine device (IUD), or condoms.
8. Have body mass index (BMI) between 19 and 33 (weight/height2) by calculation: body weight (kg) divided by [height(meters)]2
9. Have body weight less than or equal to 150 kg
Minimum age
18 Years
Maximum age
56 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Subjects must have none of the following :
1. Acute illness on Study Day 0
2. Oral temperature more than or equal to 37.5 degrees on Study Day 0
3. Abnormal laboratory values per local laboratory parameters from blood collected within 14 days prior to Study Day 0 randomization as follows:
-hemoglobin, hematocrit, absolute neutrophil count, or absolute lymphocyte count below lower limit of normal (LLN)
-white blood cell count above upper limit of normal (ULN) or below LLN (i.e., must be within normal limits)
-ALT, AST, total bilirubin, alkaline phosphatase (ALP), creatinine, blood urea nitrogen (BUN), prothrombin time (PT or INR), or partial thromboplastin time (PTT) above ULN
4. Urinalysis must reflect no evidence of systemic or clinically important local disease process
5. Severe anemia, defined as less than 10 g/dL or hematocrit less than 30 per cent
6. Evidence of significant active infection
7. Previous receipt of omalizumab
8. History of autoimmune disease or immunosuppression
9. Used immunosuppressive medication within 42 days before Study Day 0 (inhaled and topical corticosteroids are permitted)
10. Received immunoglobulin or blood products within 42 days before Study Day 0
11. Received any investigational drug therapy or investigational drug within 60 days before Study Day 0, or planned participation in any other investigational study during the study period
12. Current chronic drug therapy such as insulin, or hormone replacement (thyroid replacement, estrogen and progesterone replacement and contraceptives are acceptable)
13. History or laboratory evidence of any past, present, or future possible immunodeficiency state including but not limited to any laboratory indication of HIV 1 infection
14. Previous medical history that may compromise the safety of the subject in the study, including but not limited to: severe impairment of pulmonary function from tuberculosis infection or other pulmonary disease; chronic illness with signs of cardiac or renal failure; suspected progressive neurological disease; or uncontrolled epilepsy or infantile spasms
15. Evidence of a new acute illness that may compromise the safety of the subject in the study
16. Evidence of chronic hepatitis (e.g., hepatitis B antigen or hepatitis C antibody or PCR)
17. Inability to discontinue daily medications, except contraceptives, and thyroid hormone during the study period
18. History of alcohol or drug abuse within the past 2 years
19. Positive urine test for illicit drugs (opiates, cocaine, amphetamines)
20. History or evidence on physical examination of any systemic disease or any acute or chronic illness that, in the opinion of the investigator, may interfere with the evaluation of the safety or immunogenicity of the study drug, including axillary lymphadenopathy
21. Any current medical, psychiatric, occupational, or substance abuse problems that, in the opinion of the investigator, will make it unlikely that the subject will comply with the protocol

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 blinded study; study participants, site staff including principal investigators, monitoring staff and sponsor staff are blinded to treatment allocated. Unblinded personnel will include site pharmacists, unblinded monitor, 1 unblinded sponsor personnel and biostatistician. Subjects will be randomized in a parallel 1:1 ratio to either SYNE008 or Omalizumab
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Central randomisation will be undertaken, with randomisation numbers assigned sequentially for each participant as they are confirmed eligible for dosing and enrolled in the study.
A total of 80 participants will be randomized in parallel in an overall 1:1 ratio to either SYN008 or omalizumab. As this is a single site study with a homogenous healthy adult population, no stratification will be applied.
This study includes the first clinical administration of SYN008, therefore no more than 2 of the first 4 subjects to be dosed may receive study drug within the same 24-hour period. In addition, the first 4 participants dosed will be evaluated at their first post-study drug administration follow-up visit (Study Day 3) before any additional participants are dosed. As such, the first 2 participants to be enrolled will be randomised in a 1:1 ratio to either SYN008 or omalizumab. Following this the third and fourth subjects will be randomised in a 1:1 ratio to either SYN008 or omalizumab. If the Principal Investigator determines that there is no reason to pause the study, based on the study pausing rules as outlined in Section 6.1 of the protocol, then the site may proceed to enrol the remainder of the participants. The remainder participants will be enrolled and dosed in sequential cohorts over a total period of approximately 2 months. Each cohort will consist of approximately 20 participants. Blocking will be employed to prevent bias related to any cohort/dosing date effect and to also reduce unbalanced treatment assignment if the study is ceased prematurely. As such there will be 19 blocks of size 4, with participants randomised in a 1:1 ratio to either SYN008 or omalizumab within each block.
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
Subject Populations
The safety population will consist of all randomized subjects who received at least one dose of study drug.
Demographics and Protocol Compliance
Demographic parameters (age, gender, and race/ethnicity) and other baseline characteristics will be summarized by treatment group for all subjects in the safety population.
Efficacy Analyses
There will be no efficacy analyses performed in this study.
Pharmacokinetics, Immunogenicity and Other Immunology Analyses
All immunogenicity analyses will be based on subjects who received one dose of study drug. Immunogenicity will be summarized for all time points as collected and as available. No imputation for missing data will be performed. Data will be transformed as appropriate prior to analysis.
Free Serum IgE
Free serum IgE is usually available from a clinical laboratory and is used to determine the initial dose of study drug but since the study drug mediates its effects by binding to free IgE this is also a pharmacodynamic effect of the study drug that might correlate with future efficacy.
Summaries will include immune response at all available pre- and post-study drug administration immunology time points, and change from pre-study drug administration to post-study drug administration time points.
Serum SYN008 Concentrations and Pharmacokinetics
SYN008 and omalizumab concentrations will be determined by an ELISA analysis A non-compartmental pharmacokinetic analysis of SYN008 and omalizumab concentrations will be performed. The availability of SYN008 will be determined by calculating the AUC0-t/mg/kg dose for the one dose group and comparing the associated 95 per cent CI between the SYN008 and omalizumab through the last post-study drug administration time point. A single dose regimen will be compared to the corresponding regimen with omalizumab.
Serum Omalizumab Concentrations and Pharmacokinetics
The availability of omalizumab will be determined by the AUC0-t/mg/kg dose for the one dose group.
Anti-SYN008 Antibodies
The population for analysis of anti-SYN008 antibodies will be all subjects who receive a dose of SYN008. Immunogenicity will be summarized for pre-administration and Day 84. If the Study Day 84 time point is not available, then the time point farthest from SYN008 administration will be evaluated. Data will be transformed as appropriate prior to analysis. The presence and amount of anti-SYN008 antibodies will be tabulated by group and analyzed to determine if they have any effect on AUCs.
Safety Analyses
Safety analyses will be performed using the safety population as defined above. Count (percentage) summaries will be presented by treatment group for all subjects in the safety population.
Adverse Events
The safety profile of the study drugs will be described by treatment group. The primary variable for evaluation of the safety profile will be the number and percentage of unsolicited and solicited adverse events recorded at all available post-study drug administration time points. For all presentations of adverse events, additional summaries based on reporting period of adverse events following each study drug administration may also be presented.
The number (percentage) of subjects with adverse events for each study drug will be summarized by MedDRA system organ class (SOC) and preferred term (PT). Additional summaries will present the number (percentage) of subjects with adverse events by severity and by relationship to study drug; each subject will be counted once per preferred term at the greatest severity or most related state recorded for that term.
Separate summaries of the number (percentage) of subjects with solicited adverse events will also be presented. Solicited adverse events will also be summarized by severity and relationship to study drug; each subject will be counted once per preferred term at the greatest severity or most related state recorded for that term.
Serious adverse events will be recorded through the final study visit for all subjects. Listings will be provided for subjects with serious adverse events.
Listings will be provided for subjects who have discontinued prematurely due to an adverse event.
The number (percentage) of subjects with post-study drug administration clinical laboratory values or vital sign values recorded as newly abnormal following study drug administration and meeting toxicity mild criteria (Grade 1) defined in the protocol will be tabulated at each post-study drug administration time point and overall. Clinical laboratory and vital sign abnormalities will also be reported as adverse events and will be included in the summary of adverse events.
Clinical Laboratory and Vital Sign Parameters
For each clinical laboratory parameter and vital sign parameter pre-specified in the protocol, summary statistics for continuous parameters will be presented by treatment regimen for all pre- and post-study drug administration assessments and for change from pre-vaccination to post-study drug administration assessments.
Sample Size Considerations
The sample size for this Phase I study was selected as adequate for an initial review of the safety profile, rather than for statistical reasons. If no SAE are observed among 40 subjects receiving active study drug, the exact upper 95 per cent confidence bound on the rate of SAE occurrence would be 8.81 per cent.



Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
9/02/2016
Actual
9/02/2016
Date of last participant enrolment
Anticipated
15/04/2016
Actual
22/04/2016
Date of last data collection
Anticipated
Actual
20/07/2016
Sample size
Target
80
Accrual to date
Final
80
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 5210 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 12679 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 292794 0
Commercial sector/Industry
Name [1] 292794 0
Synermore Biologics Co., Ltd
Country [1] 292794 0
Taiwan, Province Of China
Primary sponsor type
Commercial sector/Industry
Name
Clinical Network Services (CNS) Pty Ltd
Address
Level 4, 88 Jephson Street
Toowong, QLD 4066
Australia
Country
Australia
Secondary sponsor category [1] 291532 0
None
Name [1] 291532 0
Address [1] 291532 0
Country [1] 291532 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294298 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 294298 0
89 Commercial Road
Melbourne
VIC 3004
Ethics committee country [1] 294298 0
Australia
Date submitted for ethics approval [1] 294298 0
16/11/2015
Approval date [1] 294298 0
23/12/2015
Ethics approval number [1] 294298 0
593/15

Summary
Brief summary
This study is a Phase I single site randomized, and double blinded comparison of the safety pharmacokinetics, pharmacodynamics and immunogenicity of one dose of SYN008 to one dose of omalizumab (Xolair) control.
The primary objective is to compare the safety of SYN008 to Omalizumab.
Omalizumab is an effective therapy for both moderate to severe asthma as well as chronic idiopathic urticaria. SYN008 is intended to be a biosimilar agent (generic) to omalizumab. The availability of a highly similar alternative will help to provide a more robust marketplace and provide this treatment to more patients who might need it. The current study is performed in normal adults to reduce the background of adverse events. The dosage (single dose of 150mg) and administration (by injection under the skin) of the study drugs SYN008 and omalizumab are identical providing a comparison of the adverse reactions to the agents.
The bioavailability and immunogenicity of the study drugs will be evaluated with pharmacokinetics and anti-drug antibody determinations. The effect of SYN008 and omalizumab on free IgE concentrations will be measured as a pharmacodynamic effect. A single dose will be used to reduce any long term adverse effects from the agents and to mimic the way that the antibodies will be used clinically.
This initial study will enroll healthy volunteers. This latter selection is made to facilitate the safety evaluation. This study is a double blinded comparison of SYN008 and omalizumab. A total of 80 subjects will be randomized in a parallel 1:1 ratio to either SYN008 or omalizumab resulting in 40 subjects in each group. The study will be conducted at a dedicated Phase I Unit in Melbourne, Australia. The dose will be 150 mg for both study drugs. This dose is the minimum dose in the omalizumab product information.
The study duration is 84 days and the screening interval is 14 days for a total duration of 98 days for an individual. The major outcomes measured in the trial will be solicited adverse events, adverse events and serious adverse events that will be collected according during the trial. The follow-up for comparison of safety (adverse events) will continue through the day 84 Study Visit. Standard assessments of serum chemistry including liver function tests, renal function tests, complete blood count, and blood clotting studies, urinalysis findings, vital signs and ECG evaluations will be performed. Baseline values for pulse oximetry and blood tryptase will be recorded to assist in adverse event evaluation. The pharmacodynamic parameter being measured is the change in free IgE serum concentrations. The development of anti-SYN008 antibodies will also be evaluated. There are 11 scheduled clinical visits after the screening visit(s).
Trial website
NA
Trial related presentations / publications
NA
Public notes
NA

Contacts
Principal investigator
Name 62458 0
Dr Jason Lickliter
Address 62458 0
Nucleus Network Limited
Level 5 Burnet Institute,
AMREP Precinct,
89 Commercial Road,
Melbourne
VIC 3004
Country 62458 0
Australia
Phone 62458 0
+61 3 9076 8906
Fax 62458 0
+61 3 9076 8911
Email 62458 0
[email protected]
Contact person for public queries
Name 62459 0
Ariel Chuang
Address 62459 0
Synermore Biologics Co., Ltd
6F, No 5-6, Aly 22, Ln 513 Ruiguang Rd
Neihu Dist., Taipei City 11492
Country 62459 0
Taiwan, Province Of China
Phone 62459 0
+886 2 659 0988
Fax 62459 0
+866 2 659 0950
Email 62459 0
[email protected]
Contact person for scientific queries
Name 62460 0
Ariel Chuang
Address 62460 0
Synermore Biologics Co., Ltd
6F, No 5-6, Aly 22, Ln 513 Ruiguang Rd
Neihu Dist., Taipei City 11492
Country 62460 0
Taiwan, Province Of China
Phone 62460 0
+886 2 659 0988
Fax 62460 0
+866 2 659 0950
Email 62460 0
[email protected]

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