Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617000377336
Ethics application status
Approved
Date submitted
8/03/2017
Date registered
13/03/2017
Date last updated
6/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A double-blind, randomised, placebo-controlled study to determine the safety, pharmacokinetics and maximum tolerated dose of NRP2945 in healthy adult volunteers.
Scientific title
A Double-blind, Randomised, Placebo-controlled Study to Determine the Safety, Pharmacokinetics and Maximum Tolerated Dose of NRP2945 In Healthy Adult Volunteers.
Secondary ID [1] 291317 0
NRP2945-1
Universal Trial Number (UTN)
U1111-1193-6357
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Severe childhood epilepsy (Lennox-Gastaut Syndrome) 302296 0
Condition category
Condition code
Neurological 301878 301878 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
NRP2945 (0.64mg/mL net peptide weight) is formulated in 0.4% PEG (MW 3000-3200), 1% mannitol, 0.5 M D(+)-Trehalose in 20mM sodium citrate (pH 4.5).
In Part 1, it will be administered as a single dose by subcutaneous bolus injection in the lower abdomen (anyone of the 4 quadrants may be used for the injection).
In Part 2, multiple doses will be injected in the 4 quadrants of the lower abdomen over a period of 27 days every second day starting from Day 1. All 4 quadrants will be used for each subject. Two injections will be given if the volume to be administered is more than 2mls.
Part 1: Single ascending dose cohorts; doses to be administered are 1.0, 3.0, 10.0 and 25.0 microgram/kg.
Part 2: Multiple ascending dose cohorts – 3 doses will be administered and will be determined by a data monitoring committee after completion of the SAD cohorts in Part 1.
Intervention code [1] 297343 0
Treatment: Drugs
Comparator / control treatment
Placebo: vehicle only i.e. 0.4% PEG (MW 3000-3200), 1% mannitol, 0.5 M D(+), Trehalose in 20mM sodium citrate (pH 4.5).
Administered by subcutaneous bolus injection in the lower abdomen; multiple doses will be injected in the 4 quadrants of the lower abdomen for each subject; 2 injections will be given if the volume to be administered is more than 2mls.
Part 1: Single ascending dose cohorts; subjects will be administered the same volume as treated subjects in their cohort.
Part 2: Multiple ascending dose cohorts; subjects will be administered the same volume as treated subjects in their cohort on the same days.
Control group
Placebo

Outcomes
Primary outcome [1] 301308 0
To assess the safety of NRP2945 by assessment of adverse events, evaluation of laboratory tests results and vital signs, weight measurement and evaluation of ECGs.
Timepoint [1] 301308 0
Adverse events (including serious adverse events): from randomisation until the follow-up visit.
SAD cohorts: Day 1 to Day 2 (24 hrs) continuous monitoring and at follow-up visit (day 3-6)
MAD cohorts: Day 1 to Day 4 (continuous monitoring); and at visits on Days 5, 7, 9, 11, 13, 15, 17, 19, 21, 23,25, 27 and at the follow up visit (day 29-32)
Laboratory tests: haematology, clinical chemistry and urinalysis:
SAD cohorts: screening visit, Day -1 visit, Day 2 and follow-up visit (Day 3-6)
MAD cohorts: screening visit, Day -1 visit, Days 2, 3, 4 , 5 7, 9, 11, 13, 15, 17, 19, 21, 23,25, 27 and follow-up visit (Day 29-32)
Vital signs:
SAD cohorts: Screening visit, Day -1 visit, Day 1 , Day 2 and follow-up visit (Day 3-6),
MAD cohorts: screening visit, Day -1, Day 1 (10min, 20 min, 30 min, 60 min, 2hr, 3hr, 4 hr, 6hr, 8hr, 10hr, and 12hr post-dose), Days 2, 3 ,4, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and follow up visit (Day 29-32)
Weight: SAD cohorts: screening visit, Day -1 and follow up visit (Day 3-6)
MAD cohorts: screening visit, Day -1 and follow up visit (Day 29-32)
ECG: SAD cohorts: Screening visit, prior to dosing; 15-25 min and 60-70min post-dose (Day 1 visit)
MAD cohorts: :Screening visit, , Day 1 visit (pre-dose) and on Days 1, and 9 and 21 visits (pre-dose and 15-25 min and 60-70min post-dose)
Secondary outcome [1] 332273 0
To document the pharmacokinetic profile of NRP2945 after single dose and multiple doses by subcutaneous bolus injection.
Timepoint [1] 332273 0
For NRP2945 determination, for each dose administered, blood samples will be collected at the following time-points: pre-dose, 5, 10, 15, 20, 30, 45 and 60 minutes post-dose.
The following pharmacokinetic parameters for NRP2945 will be derived for the 1, 3, 10 and 25 microgram/kg SAD and for each of the 3 MAD dose groups:
1. Cmax
2. Tmax
3. Half-life (if possible)
4. AUC (if possible)
Secondary outcome [2] 332274 0
To assess the potential of CXCR4 expression levels to serve as a blood-based biomarker for NRP2945 activity in future studies .
Timepoint [2] 332274 0
Blood samples for CXCR4 gene expression will be collected pre-dose and at 0.5, 1.0, and 4.0 hours post dose on Day 1 of the SAD cohorts and on Days 1, 9 and 21 (at 0.5, 1.0, and 4.0 hours post dose) of the MAD cohorts.
Secondary outcome [3] 332641 0
To determine whether the highest tested SAD-dose of 25 microgram/kg NRP2945 can be classified as maximum tolerated dose.
Timepoint [3] 332641 0
Safety:
Adverse events (including serious adverse events): from randomisation until the follow-up visit.
SAD cohorts: Day 1 to Day 2 (24 hrs) continuous monitoring and at follow-up visit (day 3-6)
MAD cohorts: Day 1 to Day 4 (continuous monitoring); and at visits on Days 5, 7, 9, 11, 13, 15, 17, 19, 21, 23,25, 27 and at the follow up visit (day 29-32)
Laboratory tests: haematology, clinical chemistry and urinalysis:
SAD cohorts: screening visit, Day -1 visit, Day 2 and follow-up visit (Day 3-6)
MAD cohorts: screening visit, Day -1 visit, Days 2, 3, 4 , 5 7, 9, 11, 13, 15, 17, 19, 21, 23,25, 27 and follow-up visit (Day 29-32)
Vital signs:
SAD cohorts: Screening visit, Day -1 visit, Day 1 , Day 2 and follow-up visit (Day 3-6),
MAD cohorts: screening visit, Day -1, Day 1 (10min, 20 min, 30 min, 60 min, 2hr, 3hr, 4 hr, 6hr, 8hr, 10hr, and 12hr post-dose), Days 2, 3 ,4, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and follow up visit (Day 29-32)
Weight: SAD cohorts: screening visit, Day -1 and follow up visit (Day 3-6)
MAD cohorts: screening visit, Day -1 and follow up visit (Day 29-32)
ECG: SAD cohorts: Screening visit, prior to dosing; 15-25 min and 60-70min post-dose (Day 1 visit)
MAD cohorts: :Screening visit, , Day 1 visit (pre-dose) and on Days 1, and 9 and 21 visits (pre-dose and 15-25 min and 60-70min post-dose)
Pharmacokinetic parameters:
For the 25 microgram/kg dose, blood samples will be collected at the following time-points: pre-dose, 5, 10, 15, 20, 30, 45 and 60 minutes post-dose.
The following pharmacokinetic parameters for NRP2945 will be derived for the SAD dose group:
1. Cmax
2. Tmax
3. Half-life (if possible)
4. AUC (if possible)

Eligibility
Key inclusion criteria
1. Provide written informed consent
2. Males aged 18 - 45 years inclusive on the day of consent
3. Healthy on the basis of medical history and screening assessments, in the opinion of the Investigator
4. BMI 20 – 30 kg/m2 inclusive
5. Use of contraception for 90 days from the start of study drug administration. Men not surgically sterile or who are capable of producing offspring must practice abstinence or use a barrier method of birth control, and must agree to continue use of this method for 90 days post treatment.
6. Agree to fulfil all of the requirements of the study
7. No alcohol is to be consumed from 24 hours prior to the time of pre-dose admission until after the final follow-up visit is completed.
8. Participants will be asked to refrain from strenuous exercise the day before screening and during the day prior to admission for dosing.
Minimum age
18 Years
Maximum age
45 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Clinically significant co-existing disease or condition in the opinion of the Investigator (example of an allowable condition is hay fever that does not require regular medication).
2. Self-reported or known seropositivity suggestive of acute or chronic viral infection for human immunodeficiency virus, hepatitis B or hepatitis C;
3. Infection or febrile illness within 5 days prior to first dose
4. Haemoglobin or haematocrit below the laboratory reference range
5. Raised blood pressure (systolic >140 mmHg or diastolic >95 mmHg)
6. Current or previous clinically significant smoking history (i.e. more than 2 cigarettes per day in the last 12 months)
7. Any prescribed medications within 14 days prior to the first dose of study medication
8. Any over-the-counter medications/herbal remedies/vitamins/supplements within 7 days prior to first dose of study medication
9. Use of any investigational drug within 30 days of dosing, or planned use of another investigational drug during the course of this study
10. History of prolonged QT interval, or prolonged QTcF interval at screening, defined as QTcF >450 msec (the average of the triplicate should be used to assess QTcF).
11. Positive results for urine drugs of abuse screen or alcohol breath test at screening
12. Any illegal or non-approved recreational drug use during the last six months.

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)
Randomisation numbers will be allocated sequentially to subjects in the order in which they are enrolled.
Treatment allocation will be provided in a randomisation list generated by the unblinded statistician not otherwise involved in the study. The list will be sent to the unblinded pharmacy team at the site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will only occur once participant eligibility is confirmed for the study and as close as possible prior to administration of Study Drug. A randomisation list for each dose will be computer-generated by an independent unblinded statistician. This list will be provided to the unblinded study pharmacist. The study pharmacist will provide the site with syringes of blinded Study Drug, individually packed and labelled for each study participant. Allocation will be made to NRP2945 or placebo in a 5:2 ratio. Sponsor personnel and study site staff involved in the study conduct and management will remain blinded.
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
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The analysis of study endpoints will be performed using the ITT participant population. Secondary analysis using the Per Protocol Population will also be performed.

Simple summary descriptive statistics, (means, medians, standard deviations, inter-quartile ranges and ranges) and participant data listings will be used to summarize all data.
Primary Analyses:
The primary pharmacokinetic parameters will be summarised with 95% confidence intervals and linear and non-linear regression will be used to determine the form of the dose response curves for both single and multiple doses. If these key variables are not normally distributed then confidence intervals will be derived using the log-normal distribution or failing this, empirical non-parametric intervals will be generated.
Any missing data required for the pharmacokinetic derivations will be interpolated using WinNonlin.

Secondary Analyses
Adverse events and serious adverse events will be listed individually for each subject, and summarised by dose group. Other secondary variables, including laboratory assessments, vital signs and ECG parameters, will be summarised and graphed for each dose group at each time, using means or medians with standard deviations or inter-quartile ranges as appropriate.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
14/03/2017
Actual
14/03/2017
Date of last participant enrolment
Anticipated
17/09/2017
Actual
Date of last data collection
Anticipated
22/10/2017
Actual
Sample size
Target
49
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 7588 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 15486 0
3000 - Melbourne

Funding & Sponsors
Funding source category [1] 295784 0
Commercial sector/Industry
Name [1] 295784 0
CuroNZ Pty. Ltd
Country [1] 295784 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
CuroNZ Pty Ltd
Address
6 Pemberton Close
Stirling, WA 6021
Country
Australia
Secondary sponsor category [1] 294633 0
Commercial sector/Industry
Name [1] 294633 0
Clinical Network Services (CNS) Pty Ltd
Address [1] 294633 0
Level 4, 88 Jephson St,
Toowong QLD 4066
Country [1] 294633 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297082 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 297082 0
Ethics committee country [1] 297082 0
Australia
Date submitted for ethics approval [1] 297082 0
12/12/2016
Approval date [1] 297082 0
09/02/2017
Ethics approval number [1] 297082 0
2-17

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

Contacts
Principal investigator
Name 72914 0
Dr Jason Lickliter
Address 72914 0
Nucleus Network Limited
5th Floor, Burnet Tower, AMREP Precinct
89 Commercial Road
Prahran Vic 3001
Country 72914 0
Australia
Phone 72914 0
+61 3 9076 8960
Fax 72914 0
+61 3 9076 8911
Email 72914 0
[email protected]
Contact person for public queries
Name 72915 0
Frank Sieg
Address 72915 0
CuroNZ Ltd
173 Cames Road
Mangawhai 0975
Country 72915 0
New Zealand
Phone 72915 0
+64 2150 0453
Fax 72915 0
+64 9377 1761
Email 72915 0
[email protected]
Contact person for scientific queries
Name 72916 0
Frank Sieg
Address 72916 0
CuroNZ Ltd
173 Cames Road
Mangawhai 0975
Country 72916 0
New Zealand
Phone 72916 0
+64 2150 0453
Fax 72916 0
+64 9377 1761
Email 72916 0
[email protected]

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