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Trial registered on ANZCTR


Registration number
ACTRN12618001506280
Ethics application status
Approved
Date submitted
29/08/2018
Date registered
7/09/2018
Date last updated
20/08/2019
Date data sharing statement initially provided
20/08/2019
Date results provided
20/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Proof-of-concept clinical intervention study to analyze whether NRP2945 has anti-epileptic properties in 5 adult participants diagnosed with absence epilepsy
Scientific title
A Phase 2a, single-blind, placebo-controlled safety and efficacy study of two doses of NRP2945 in patients showing drug-resistant typical absence epilepsy as a form of their genetic, generalized epilepsy pattern
Secondary ID [1] 295945 0
None
Universal Trial Number (UTN)
U1111-1219-6485
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
absence epilepsy 309450 0
Condition category
Condition code
Neurological 308291 308291 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The design is a single-blind, placebo-controlled, sequential dose study in a cross-over design to assess the safety and efficacy of NRP2945 in patients with known stable absence (spike-and-wave discharges) epilepsy.
Safety will be assessed by determining the incidence and type of adverse events (AEs), the tolerability of NRP2945 at injection site, and review of clinical laboratory tests and assessments. All intervention treatments, clinical observation periods and analysis will be performed at Royal Melbourne Hospital.
Efficacy will be assessed by determining the pharmacodynamics on the cumulative response of the frequency of absence seizures (spike-and-wave discharges) analyzed from the electroencephalogram (EEG) of each subject following the sequential administration of Placebo (Arm 1) and two doses of NRP2945 (5ug/kg and 7ug/kg -- Arm 2 and 3, respectively). The wash-out time in between the three different cohorts is 14 days. The route of administration is subcutaneously and NRp2945 / placebo will be administered as single bolus on day 1 and day 3 of the three treatment regimens, respectively. Subjects will be observed for 8 hrs after each subcutaneous bolus injection and every treatment regimen employs a follow-up visit at 7 days after last dosing.
Additional study assessments will include evaluations of concomitant use of anti-epileptic drugs (AED). A questionnaire will be given to subjects at the follow-up visit. The exploratory biomarker CXCR4 (gene expression profiling) will be performed at pre-determined time-points over the course of the study.
Intervention code [1] 312268 0
Treatment: Drugs
Comparator / control treatment
Placebo-controlled study

The formulation of the placebo is identical to the formulation of the NRP2945 injectable. In brief, placebo vials contain a solution of 255 mg of D(+)-trehalose (170mg/ml) and sterile physiological saline. Final volume is 1.5 ml. The solution is filtered through a PES filter mounted syringe for administration.
Placebo vials must be stored at -20 degree Celsius. Vials are to be brought to room temperature at least 1 hour prior to dose administration, and used within 2 hours of preparation.
Control group
Placebo

Outcomes
Primary outcome [1] 307261 0
To assess the safety and tolerability of two doses of NRP2945 after subcutaneous bolus injection at 48 hours apart in patients with typical absence epilepsy. Injection site reactions will be assessed for possible transient injection-related pain (verbal question put forward to the participant) and will be assessed for possible redness or erythema over the hours after the injection. This clinical assessment will be monitored recorded up the cessation of this respective injection site reaction. There have been stopping rules implemented in case a generalized seizure will occur during or after the dosing regimen.
In clinical phase 1 NRP2945 only encountered mild injection site reactions (N=49 subjects for SAD/MAD configuration).
Timepoint [1] 307261 0
Safety blood samples will be taken pre-dose and 6 hrs after injection while vital signs will be checked pre-dose, at 15 min and 2hrs after injection. A neurological examination will be performed at pre-dose and 4 hrs after injection. Further vital signs and safety blood will be collected at the follow-up visit at 7 days after the last injection.
Secondary outcome [1] 351297 0
1. To evaluate the ability of NRP2945 to suppress the epileptic generalised discharges as compared to Placebo in patients with absence epilepsy. In brief, EEG analysis at 30 min before and for 3 hrs after injection will determine whether NRP2945 has the ability to lower the cumulative frequency of spike-and-wave discharges (the EEG biomarker of absence epilepsy)
Timepoint [1] 351297 0
30 min pre-dose EEG recording followed by NRP2945 or placebo injection and recording for a time frame of 3 hrs for every injection day
Secondary outcome [2] 351298 0
2. To evaluate the effect of NRP2945 on the plasma concentrations of concomitantly taken anti-epileptic drugs following administration of NRP2945 (e.g. valproate, phenytoin and lamotrigine). This PK-analysis of the concomitantly taken drugs will provide information whether NRP2945 displays drug-drug interaction properties with the tested AEDs. Only levels of concentration will be assessed for the concomitantly AED administrations.
Timepoint [2] 351298 0
AED levels will be analyzed at pre-dose and 4 hrs therefafter
Secondary outcome [3] 351299 0
3. To evaluate the pharmacodynamic profile of and effect of NRP2945 on the biomarker CXCR4 compared to Placebo. This biomarker analysis is a surrogate analysis for assessing the pharmacodynamcics effective range of NRP2945 because CXCR4 is the target receptor in the blood stream and the brain for NRP2945. In other words target engagement can be estimated by measuring blood cell CXCR4 gene expression profiles.
Timepoint [3] 351299 0
A pre-dose, 30 min, 60 min and 240 min blood cell sample will be drawn on every injection day.

Eligibility
Key inclusion criteria
Inclusion Criteria
1. Are male or female age 18-65 years.
2. Signed informed consent form (ICF) indicating that the subject has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and discomforts.
3. Males or non-pregnant, non-breastfeeding females 18 to 65 years-of-age
4. Clinical diagnosis of a genetic (idiopathic) generalised epilepsy syndrome (including, but not limited to, childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, or Jeavons syndrome) with absence seizures consistent with the International League against Epilepsy Revised Classification of Seizures (2017).
5. Absence seizures persisting despite at least two documented standard anti-epileptic treatments (drug-resistance). Subjects are resistant to valproate and at least one other AED (e.g. phenytoin).
6. Presence of interictal generalized epileptiform patterns on EEG, including generalized spike-wave or polyspike-wave, generalized polyspike train, generalized paroxysmal fast activity, and generalized low voltage fast activity, within the time frame of 3 hrs of observation period during screening.
7. On no therapy or taking stable doses of one or more anti-epileptic medication(s) for at least 30 days. If a subject is not on medication, adequate documentation justifying lack of therapy is acceptable.
8. Body Mass Index (BMI) of 18-35 at screening.
9. Subjects with reproductive capability including all males and women of child-bearing potential (WOCBP) must agree to practice continuous abstinence or adequate contraception methods (appropriate double barrier method or oral, patch, implant, or injectable contraception) from screening until at least 30 days after the last dose (i.e., intermittent abstinence based on "rhythm", temperature monitoring, or other means of timing is not acceptable).
10. Male subjects with a partner of child-bearing potential must be surgically sterilized or be willing to use condoms with spermicide from screening until at least 30 days after the last dose.
11. Able and willing to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria
1. Have any clinical condition that, in the opinion of the Investigator, might interfere with the results of the study or pose a risk to the subjects due to participation in the study
2. Have a history of alcoholism, drug abuse, or drug addiction within the past 12 months.
3. Have an active CNS infection, demyelinating disease, degenerative neurological disease or any CNS disease deemed to be progressive during the course of the study that may confound the interpretation of the study results.
4. Have any clinically significant psychiatric illness, psychological or behavioral problems which, in the opinion of the Investigator, would make the patient unsuitable to participate in the study.
5. Have a haemoglobin or haematocrit below the site’s lower reference range value.
6. Clinically significant active liver disease, porphyria or have severe hepatic dysfunction indicated by AST and/or ALT greater than 3 x upper limit of normal.
7. Currently taking plerixafor® (AMD3100, a highly specific CXCR4 antagonist), or have stopped taking plerixafor® less than 4 weeks before the day of screening.
8. Participation in another clinical trial or administration of any investigational agent within 8 weeks or 5 half-lives (whichever is longer) prior to Day 1 or intent to participate in another clinical trial during the study.
9. A female who is pregnant or lactating
10. An employee of the sponsor or research site personnel directly affiliated with this study or their immediate family members defined as a spouse, parent, sibling, or child, whether biological or legally adopted.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Not applicable
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Crossover
Other design features
Not applicable
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
This study is a small proof-of-concept study to evaluate the safety of NRP2945 in epileptic patients as well as analyzing the dynamics of human Blood Brain Barrier Penetration of NRP2945 by evaluating the efficacy of the drug candidate for treating drug-resistant absence seizures.
Efficacy Analysis
Descriptive statistics will be presented including the means and standard deviations of number of interictal generalized epileptiform patterns for each subject, for each day of assessment, stratified by duration of the discharge (up to or more than 3 seconds). Graphical displays of the data for each subject will allow exploration of inter- and intra-patient variability. It is expected that at least 5 evaluable subjects will complete the study, which is sufficient to determine whether there is a reduction of the cumulative frequency of absence seizures with the study drug.
Safety and Pharmacodynamic Analysis
Descriptive statistics will be presented for each of the primary safety endpoints and secondary PD endpoints

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
5/11/2018
Actual
11/12/2018
Date of last participant enrolment
Anticipated
26/11/2018
Actual
15/01/2019
Date of last data collection
Anticipated
14/03/2019
Actual
4/04/2019
Sample size
Target
4
Accrual to date
Final
4
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 11748 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 23832 0
3050 - Parkville

Funding & Sponsors
Funding source category [1] 300541 0
Commercial sector/Industry
Name [1] 300541 0
CuroNZ Pty Ltd
Country [1] 300541 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
CuroNZ Pty Ltd
Address
6 Pemberton Close, Stirling, WA-6021, Australia.
Country
Australia
Secondary sponsor category [1] 300026 0
None
Name [1] 300026 0
Address [1] 300026 0
Country [1] 300026 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301334 0
Melbourne Health Human Research Ethics Committee [EC00243]
Ethics committee address [1] 301334 0
Ethics committee country [1] 301334 0
Australia
Date submitted for ethics approval [1] 301334 0
29/08/2018
Approval date [1] 301334 0
02/10/2018
Ethics approval number [1] 301334 0
HREC/45740/MH-2018

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

Contacts
Principal investigator
Name 86658 0
Prof Patrick Kwan, BMedSci, MB, BChir, PhD, FRCP Head of Epilepsy
Address 86658 0
The Royal Melbourne Hospital
Grattan Street
Melbourne VIC 3010
Australia
Country 86658 0
Australia
Phone 86658 0
+61 3 93424426
Fax 86658 0
Email 86658 0
patrick.kwan@unimelb.edu.au
Contact person for public queries
Name 86659 0
Patrick Kwan
Address 86659 0
The Royal Melbourne Hospital
Grattan Street
Melbourne VIC 3010
Australia
Country 86659 0
Australia
Phone 86659 0
+61 3 93424426
Fax 86659 0
Email 86659 0
patrick.kwan@unimelb.edu.au
Contact person for scientific queries
Name 86660 0
Frank Sieg
Address 86660 0
Frank Sieg, 173 Cames Road, Mangawhai 0975, New Zealand
Country 86660 0
New Zealand
Phone 86660 0
+64 21 500 453
Fax 86660 0
Email 86660 0
frank@curonz.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This was a proof-of-concept study only which in the end only enrolled 4 patients with diagnosed genetic generalized absence epilepsy. The clinical site failed to recruit a 5th subject in an acceptable time frame.
Because the clinical study NRP2945-3 (ACTRN: 12618001506280) was mainly an acute study (only two successive placebo/NRP2945 injections per cohort) there are no long-term safety/ tolerability data available justifying full participant data disclosure.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
942Ethical approvalThe human ethical approval for the study NRP2945-3 was granted on the 27th of September 2018 with the following specifics: HREC Reference Number: HREC/45740/MH-2018 Melbourne Health Site Reference Number: 2018.321 Project Title: A Phase 2a, single-blind, placebo-controlled safety and efficacy study of two doses of NRP2945 in patients showing drug-resistant typical absence epilepsy as a form of their genetic, generalized epilepsy pattern Darren.Germaine@mh.org.au The project manager of the clinical study NRP2945-... [More Details] 375900-(Uploaded-14-08-2019-04-12-46)-Study-related document.pdf



Results publications and other study-related documents

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