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Trial registered on ANZCTR


Registration number
ACTRN12621000041853
Ethics application status
Approved
Date submitted
26/10/2020
Date registered
18/01/2021
Date last updated
18/01/2021
Date data sharing statement initially provided
18/01/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1 first-in-human study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of KP104.
Scientific title
SYNERGY-1: A Phase 1 first-in-human, randomized, double-blind, placebo-controlled, study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of escalating single and multiple doses of KP104.
Secondary ID [1] 302542 0
KP104-101
Universal Trial Number (UTN)
None
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Paroxysmal Nocturnal Hemoglobinuria (PNH) 319412 0
Condition category
Condition code
Blood 317385 317385 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will be conducted in 2 parts: Part 1 Single Ascending dose (SAD) and Part 2 Multiple Ascending dose (MAD).
Subjects in SAD will be enrolled in 1 of 5 cohorts (8 subjects per cohort).
Subjects in Cohorts 1 to 4 will be randomized in a 3:1 ratio (3 KP104: 1 placebo) to receive a single intravenously dose. Starting dose of 60 mg, increasing to 180mg, 360mg, 600mg
Subjects enrolled in Cohort 5 will be randomized in a 3:1 ratio (3 KP104: 1 placebo) to receive a single 180mg dose via subcutaneous injection. Dose escalation to the next cohort may occur after review by the Safety Monitoring Committee (SMC) of blinded safety, and available Pharmacokinetics and Pharmacodynamics data from all subjects in all cohorts through Day 15. Up to 5 SAD cohorts are planned, comprising a total of approximately 40 subjects .
Part 2 ( MAD) of the study can only be initiated once SAD Cohort 2 has been completed and the Safety Monitoring Committee has approved dose escalation to SAD Cohort 3.
Subjects in MAD will be enrolled to receive an initial intravenous loading dose of KP104 followed by one or more subsequent sub cutaneous maintenance doses of KP104. Subjects will be randomized in a 3:1 ratio (3 KP104: 1 placebo) to receive a single 180mg dose via sub-cutaneous injection.
One initial intravenous loading dose of KP104 followed 1-2 weeks later by one or more SC maintenance doses spaced 1-2 weeks apart; the final number of doses and time between doses to be decided from data obtained in the preceding single dose study.
The initial intravenous loading dose will be between 180 and 600mg. The subsequent subcutaneous maintenance doses will be between 180 and 360mg.
Dose escalation to the next cohort may occur after review by the SMC of cumulative blinded safety, Pharmacokinetics and Pharmacodynamics data from all subjects in all cohorts through Day 15. Up to 3 MAD cohorts are planned, comprising a total of approximately 24 subjects to be administered IP.
In each Cohort for both SAD and MAD, 2 sentinels will be enrolled and dosed in a 1:2 ratio ) ( 1KP104: 1 placebo), and the rest of cohort ( ROC) (6 subjects) can be enrolled following a 7 day- observation period of the sentinels


Intervention code [1] 318830 0
Treatment: Drugs
Comparator / control treatment
Placebo is KP104 vehicle containing sodium phosphate, sodium chloride, and L-Lys-HCL at pH of 6.0.
Control group
Placebo

Outcomes
Primary outcome [1] 325423 0
To assess the safety and tolerability of single and multiple doses of KP104 when administered by the intravenous (IV) and subcutaneous (SC) routes at escalating dose levels in healthy volunteers
Timepoint [1] 325423 0
Safety and tolerability of KP104 as assessed by:
• Type and frequency of treatment-emergent adverse events (TEAEs) - This will be collected from the date of Informed Consent Form (ICF) signed to the end of the trial.
• Type and frequency of treatment-emergent serious adverse events (TESAEs) - This will be collected from the date of Informed Consent Form (ICF) signed to the end of the trial. Adverse events will be assessed by study personnel during study visits and/or as reported by the subjects to the study site between official study visits in the case of TESAEs and potentially AESIs.
• Type and frequency of dose-limiting toxicities (DLTs) and adverse events of special interest (AESIs) including infections and local or systemic administration reactions- This will be collected from the date of Informed Consent Form (ICF) signed to the end of the trial.
• Type and frequency of changes in clinical laboratory values, ECGs, physical examinations, and vital signs
. Clinical laboratory assessment (Hematology, Biochemistry, and Urinanalysis) will be performed on screening, Day -1, Day 8, Day 15, Day 29, End of study (Day 57), End of Treatment.
. 12-lead ECG - For IV subjects, it would be performed at the end of infusion on Day 1 only; for SC subjects, ECG will be performed on Day 4 only.
Vital signs would be performed on screening, Day-1, Day 1, Day2, Day 3, Day 4, Day 6, Day 8, Day 15, Day 29, End of Study (Day 57), End of Treatment.
Secondary outcome [1] 387902 0
To determine the maximum tolerated dose (MTD)- The MTD determination will be made based on the safety, PK, and PD data of MAD cohorts.
Outcome for Safety is assessed by Patient report ; PK and PD by Serum Assay.
Timepoint [1] 387902 0
Timepoints for PK and PD: Day 1 predose, at end of infusion (EOI), and at 30 minutes, 1 hour, 6 hours on Day 1 and on Days 2, 8, 11, 15, 22, 29, 32, 36, 43, 57, and 85 post dose.
Outcome is assessed at 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, and 48 hours post dose.
Secondary outcome [2] 389132 0
To determine optimal biologic dose (OBD)- The OBD determination will be made based on the safety, PK, and PD data of MAD cohorts.
Outcome for Safety is assessed by Patient report ; PK and PD by Serum Assay.
Timepoint [2] 389132 0
Timepoints for PK and PD: Day 1 predose, at end of infusion (EOI), and at 30 minutes, 1 hour, 6 hours on Day 1 and on Days 2, 8, 11, 15, 22, 29, 32, 36, 43, 57, and 85.
Secondary outcome [3] 390103 0
To determine the regimen of KP104 for the MAD - The precise doses and dose regimen for MAD will be determined based on the safety, PK, and PD results from the SAD portion of the study.
Timepoint [3] 390103 0
Timepoints for PK and PD for SAD (IV doses): Day 1 predose, at end of infusion (EOI), and at 30 minutes, 1, 2, and 6 hours after the end of infusion, and on Days 2, 3, 4, 8, 15, 29, and 57.

Timepoints for PK and PD for SAD (SC doses): Day 1 predose and at 6 hours, and on Days 2, 3, 4, 6, 8,15,29, and 57.
Secondary outcome [4] 390106 0
To assess the pharmacokinetics (PK) (Maximum concentration (Cmax), Area under the concentration-time profile (AUC), Systemic clearance (Cl), Elimination half-life (t½), and Absolute bioavailability of KP104 administered SC (F)) by serum assay of single and multiple doses of KP104 when administered by the IV and SC routes.
Timepoint [4] 390106 0
Timepoints for SAD for PK (IV doses): Day 1 predose, at end of infusion (EOI), and at 30 minutes, 1, 2, and 6 hours after the end of infusion, and on Days 2, 3, 4, 8, 15, 29, and 57.

Timepoints for PK for SAD (SC doses): Day 1 predose and at 6 hours, and on Days 2, 3, 4, 6, 8, 15, 29, and 57.

Timepoints for MAD for PK: Day 1 predose, at end of infusion (EOI), and at 30 minutes, 1 hour, and 6 hours on Day 1, and on Days 2, 8, 11, 15, 22, 29, 32, 36, 43, 57, and 85.
Secondary outcome [5] 390107 0
To assess the pharmacodynamics (PD) and biomarker changes of KP104 (Change from baseline in the C3b activity assay (FH activity), Change from baseline in total and free serum C5 levels, Change from baseline in rabbit RBC assay (AP and TP activity), and Change from baseline in FH serum levels) by serum assay.
Timepoint [5] 390107 0
Timepoints for SAD for PK (IV doses): Day 1 predose, at end of infusion (EOI), and at 30 minutes, 1, 2, and 6 hours after the end of infusion, and on Days 2, 3, 4, 8, 15, 29, and 57.

Timepoints for PK for SAD (SC doses): Day 1 predose and at 6 hours, and on Days 2, 3, 4, 6, 8, 15, 29, and 57.

Timepoints for MAD for PK: Day 1 predose, at end of infusion (EOI), and at 30 minutes, 1 hour, and 6 hours on Day 1, and on Days 2, 8, 11, 15, 22, 29, 32, 36, 43, 57, and 85.
Secondary outcome [6] 390108 0
To assess the PK/PD relationship of KP104 - assessed by serum assay following single and multiple doses of KP104 administered by IV and SC routes.
Timepoint [6] 390108 0
Timepoints for SAD for PK (IV doses): Day 1 predose, at end of infusion (EOI), and at 30 minutes, 1, 2, and 6 hours after the end of infusion, and on Days 2, 3, 4, 8, 15, 29, and 57.

Timepoints for PK for SAD (SC doses): Day 1 predose and at 6 hours, and on Days 2, 3, 4, 6, 8, 15, 29, and 57.

Timepoints for MAD for PK: Day 1 predose, at end of infusion (EOI), and at 30 minutes, 1 hour, and 6 hours on Day 1, and on Days 2, 8, 11, 15, 22, 29, 32, 36, 43, 57, and 85.
Secondary outcome [7] 390109 0
To determine doses and regimens for further study in subjects with paroxysmal nocturnal hemoglobinuria (PNH) and other complement-mediated diseases; the precise doses and dose regimen for PNH subjects will be determined based on the safety, PK, and PD results from the SAD and MAD portions of the study.
Timepoint [7] 390109 0
Timepoints for PK and PD for SAD (IV doses): Day 1 predose, at end of infusion (EOI), and at 30 minutes, 1, 2, and 6 hours after the end of infusion, and on Days 2, 3, 4, 8, 15, 29, and 57.

Timepoints for PK and PD for SAD (SC doses): Day 1 predose and at 6 hours, and on Days 2, 3, 4, 6, 8,15,29, and 57.
Secondary outcome [8] 390110 0
To assess the immunogenicity of KP104 – assessed via serum assay following single and multiple doses of KP104 administered by IV and SC routes; measure binding antibodies with a screening assay, ADA titer using a confirmatory assay, and neutralizing antibodies in subjects with confirmed positive titers in the confirmatory assay (all confirmed ADA-positive subjects will be followed to resolution or stabilization of ADA titer).
Timepoint [8] 390110 0
Timepoints for ADA for SAD for IV doses: Day 1 predose, and on Days 8, 15,29, and 57.

Timepoints for ADA for SAD for SC doses: Day 1 predose, and on Days 8, 15,29, and 57.

Timepoints for ADA for MAD: Day 1 predose, and on Days 29, 57, and 85.

Eligibility
Key inclusion criteria
1. Is male or female, age 18 to 55 years, inclusive, at Screening
2. Weight of > 40 kg and < 120 kg at Screening
3. In good general health, determined by no clinically significant findings in the opinion of the Investigator from medical history, physical examination, 12-lead electrocardiogram (ECG), clinical laboratory findings, and vital signs at Screening and Check-in
4. Hemoglobin, hematocrit, white blood cell count, absolute neutrophil count, and platelet count results within the normal range at the Screening Visit; subjects with Gilbert’s disease with associated abnormalities of liver function tests are eligible for enrollment. Tests may be repeated at the discretion of the Investigator to confirm abnormalities.
5. Creatinine clearance based on the Cockcroft-Gault equation of equals to 80 ml/min
6. Females of childbearing potential and males must practice effective contraception from Screening until 28 days after the EOS visit.
7. Females of childbearing potential must have a negative pregnancy test at Screening and within 24 hours prior to dosing of study drug; for post-menopausal subjects, a blood sample will also be tested for follicle stimulating hormone to confirm post-menopausal status.
8. Males must agree to not donate sperm for 90 days following the last dose of IP
9. Must provide evidence of prior vaccination against Neisseria meningitidis, Streptococcus pneumoniae, and Hemophilus influenzae at least 2 weeks prior to their initial dose of IP (subjects receiving vaccination during Screening and less than 2 weeks prior to their initial dose of IP are required to receive treatment with appropriate antibiotic prophylaxis until 2 weeks after vaccination); if unvaccinated and they decline vaccination, must agree to self-administer oral antibiotic prophylaxis for a total of 6 weeks following their last dose of IP
10. Able to provide Informed Consent
11. Willing and able to comply with this protocol and be available for the entire duration of the study
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Any clinically significant underlying illness in the opinion of the Investigator
2. Any history or sign of significant chronic active or recurrent infection, or screening laboratory evidence consistent with a significant chronic active or recurrent infection requiring treatment with antibacterials, antivirals, or antifungals
3. Treatment of any infection with IV (within 30 days of Screening) or oral (within 14 days of Screening) antibacterials, antivirals, or antifungals
4. History of clinically significant hematologic or bone marrow disease or blood dyscrasias
5. History of meningococcal infection
6. History of tuberculosis
7. History of asplenia (functional or anatomical)
8. Prior exposure to KP104
9. Known allergy to penicillin antibiotics or history of allergy or contraindication to required prophylactic antibiotic therapy to be used during the study
10. Known or suspected complement deficiency during screening
11. Positive serology for HBV, HCV or HIV at Screening
12. History of drug or alcohol abuse within 1 year of Screening in the opinion of the investigator, or a positive test for drugs of abuse or alcohol at Screening or Check-in
13. Received any type of live attenuated vaccine < 1 month prior to Screening or is planning to receive any such live attenuated vaccine over the course of the study
14. Use of any prescription or OTC medications including food supplements and herbal medications (e.g. St. John’s wort), with the exception of contraceptive medications and as needed (prn) paracetamol (not exceeding 2 grams/day) within 7 days prior to IP administration
15. History of malignancy, except adequately treated basal cell carcinoma or in situ carcinoma of the uterine cervix
16. History of drug allergy or drug hypersensitivity, or intolerance of IV or SC injections
17. Smoking greater than 10 cigarettes per week in the 3 months prior to IP administration
18. History of excessive bleeding following trauma or medical/dental procedures
19. Any female who is pregnant or breastfeeding, or any female who is planning to become pregnant during the study and follow-up period
20. Any condition that, in the investigator’s opinion, may compromise study participation, present a safety risk to the subject, or may confound the interpretation of the study results
21. A QT duration corrected for heart rate by Fridericia's formula (QTcF) > 450 millisecond (msec) for males or > 470 msec for females based on either single or averaged QTcF values of triplicate ECGs obtained over a 3-minute interval (at Screening).
22. Currently enrolled in another investigational device or drug study, or less than 30 days have passed since ending another investigational device or drug study

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 computer - generated randomization schedule will be prepared to randomly allocate the subjects to treatment groups in the appropriate ratio according to the cohort. Participants will be randomly assigned to KP104 dosing or placebo based on the randomization scheme.
The pharmacist will dispense the study drug for individual subject dosing according to the randomization code.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomization using a randomization table created by computer software (i.e. computerised sequence generation), creating randomization schedule using SAS.
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
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
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)
SA
Recruitment hospital [1] 17822 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 31675 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 306978 0
Commercial sector/Industry
Name [1] 306978 0
Kira Pharmaceuticals
Address [1] 306978 0
3624 Market Street
Suite 5e
Philadelphia,
PENNSYLVANIA 19104
United States
Country [1] 306978 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Kira Pharmaceuticals
Address
3624 Market Street
Suite 5e
Philadelphia,
PENNSYLVANIA 19104
United States
Country
United States of America
Secondary sponsor category [1] 307540 0
Commercial sector/Industry
Name [1] 307540 0
INCResearch Australia Pty Ltd
Address [1] 307540 0
159 Port Road, Hindmarsh,
South Australia 5007
Country [1] 307540 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307110 0
Bellberry Human Research Ethics Commiittee
Ethics committee address [1] 307110 0
123 Glen
Osmond Road
Eastwood, South Australia 5063
Ethics committee country [1] 307110 0
Australia
Date submitted for ethics approval [1] 307110 0
21/10/2020
Approval date [1] 307110 0
24/11/2020
Ethics approval number [1] 307110 0

Summary
Brief summary
This is phase 1 first-in-human trial evaluating KP-104 to assess safety, tolerability, pharmacokinetics and pharmacodynamics. This study will be conducted in 2 parts - SAD and MAD with target of 64 healthy volunteers.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106066 0
Dr Nicholas Farinola
Address 106066 0
CMAX Clinical Research
Level 5, 18A North Terrace
Adelaide, South Australia
5000
Country 106066 0
Australia
Phone 106066 0
+61 8 7088 7900
Fax 106066 0
Email 106066 0
nicholas.farinola@cmax.com.au
Contact person for public queries
Name 106067 0
Ms Helen Fu
Address 106067 0
Kira Pharmaceuticals (Australia) Pty Ltd
58 Gipps Street,
Collingwood
VIC 3066

Country 106067 0
Australia
Phone 106067 0
+61 3 9419 7607
Fax 106067 0
Email 106067 0
helen.fu@kirapharma.com
Contact person for scientific queries
Name 106068 0
Ms Helen Fu
Address 106068 0
Kira Pharmaceuticals (Australia) Pty Ltd
58 Gipps Street,
Collingwood
VIC 3066

Country 106068 0
Australia
Phone 106068 0
+61 3 9419 7607
Fax 106068 0
Email 106068 0
helen.fu@kirapharma.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
As this is a Phase 1 study, only aggregate data may be posted/published.
What supporting documents are/will be available?
No other documents available
Summary results
No Results