Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000514808
Ethics application status
Approved
Date submitted
17/12/2020
Date registered
3/05/2021
Date last updated
17/04/2024
Date data sharing statement initially provided
3/05/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of
mEphA4-Fc
Scientific title
A Phase 1, Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD), First-In-
Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of
mEphA4-Fc in Healthy Volunteers and Patients with Amyotrophic Lateral Sclerosis (ALS)
Secondary ID [1] 302998 0
NU-MEPHA4.FC-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Amyotrophic Lateral Sclerosis 320054 0
Condition category
Condition code
Neurological 317980 317980 0 0
Other neurological disorders
Neurological 318354 318354 0 0
Neurodegenerative diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is a First in Human, open label, SAD and MAD study to determine the safety and PK characteristics of mEphA4-Fc in HVs and patients with ALS. Measurements of clinical and lung function endpoints associated with ALS will also be assessed.
There will be two parts:
Part 1 (SAD) of the study will be conducted in five cohorts of 4 subjects each.
The MAD part of the study will be conducted in two cohorts of 4 ALS patients each.

Investigational Product (IP): mEphA4-Fc
Presentation: Liquid in a Glass vial: 10 mL at 10 mg/mL
Mode of administration: Intravenous (IV) infusion

mEphA4-Fc will be administered as an IV infusion in a 0.9% sodium chloride solution (normal saline). Each infusion of mEphA4-Fc administration should be completed within 75-90 minutes.

Part 1 (SAD) in Healthy Volunteers: Each cohort will be comprised of 4 HVs each to receive mEphA4-Fc. mEphA4-Fc will be given in sequential, escalating doses;
Incremental doses starting from a dose selected according to the NOAEL strategy for FIH studies will be administered and the planned increments will not exceed 3 fold. The minimum and maximum doses for each cohort are limited by body weight.
The actual dose level for a cohort will be ultimately decided by the Safety Review Committee based on a review of data from the proceeding cohort/s.

Part 2 (MAD) in ALS Patients: The first multiple dose cohort may be initiated prior to the completion of the fifth SAD cohort and after completion of the fourth SAD cohort. The multiple ascending dose will be comprised of two cohorts of 4 ALS patients each to receive mEphA4-Fc.
The frequency of administration, dose increments and number of cohorts will be reviewed based on review of all data by the Safety Review Committee.

Each cohort will be comprised of 4 subjects each to receive 4 doses of mEphA4-Fc, over 28 days.
The proposed time duration between each dose will be 7 days, but will be reviewed by the Safety Review Committee.

To monitor adherence to the intervention for all SAD/MAD cohorts: Clinical trial management system, laboratory tests, and pharmacy records.

Part 1: 1mg/kg, 3mg/kg, 10mg/kg, 20 mg/kg, 30 mg/kg
Part 2: 15mg/kg, 30mg/kg
Part 3(Extended Access Study) in ALS Patients. Total of 8 ALS patients in 2 cohorts. The study patients will receive 5 cycles of 4 weekly infusions.
Part 3 will involve 4 infusions of 15 / 20 or 30 mg/kg weekly, in a 4-week cycle, for up to 6 months. Each dose of mEphA4-Fc will be given as an IV infusion over 90 to 120 minutes. The 4 infusions will take place 7 days apart, at Day 1, 8,15, 22, or until intolerable toxicity, progression of disease, or withdrawal of consent. Therefore, all subjects will have been dosed for 6 cycles for up to 6 months when they complete the Phase 1b study.

All MAD subjects who want to continue receiving mEphA4-Fc treatment will be directly moved to Part 3. So, the cohorts in Part 2 will be unique cohorts in Part 3. The first dose of Part 3 would be 7 days post the last dose of the MAD part 2.

Part 3 addition was anticipated prior to enrolment commencement for Part 2, but has been implemented post enrolment given the same subjects are involved in Parts 2 and 3.
Intervention code [1] 319281 0
Treatment: Drugs
Comparator / control treatment
No Control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 325985 0
Safety and tolerability of mEphA4-Fc assessed from Incidence and severity of adverse events (AEs), Outcome is assessed through CTCAE v5.
Timepoint [1] 325985 0
Measured daily from baseline to 28 days post-commencement of intervention. Timepoints will be the same for Part 1 and Part 2
Primary outcome [2] 325986 0
To characterize the pharmacokinetics (PK) of mEphA4-Fc.
Parameters: AUC, Tmax, Cmax, AUC0-last, elimination half-life, RCmax and RAUC, CL.
Timepoint [2] 325986 0
Part 1 and 2: Blood samples for PK analysis will be obtained. Part 1: Day 1; Pre-infusion, during infusion, immediately before the EOI (within 5 minutes), 5, 15, 30 and 60 minutes post infusion, 3, 4, 6, 9 and 12 hours post-dose, Day 2 (24h), Day 4 (72h), Day 6 (120h), Day 8 (168h), Day 15 (336h) and Day 29 (672h) post- EOI. Part 2: Day 1 at pre-infusion, during the infusion, immediately before the EOI (within 5 minutes), 30 and 60 minutes post EOI (±5 minutes), and at 3, 4, 6, 9, and 12 hours (±10 minutes), 24 (Day 2), 72 (Day 4), and 120 (Day 6) hours post-EOI (±2 hours). Day 8 dose PK sampling: Day 8 at pre-infusion (within 30 minutes), immediately before the EOI (within 5 minutes), 30 and 60 minutes post EOI (±5 minutes), and at 3 and 6 hours (±10 minutes), 24 (Day 9) and 72 (Day 11) hours post EOI (±2 hours). Day 15 dose PK sampling: Day 15 at pre-infusion (within 30 minutes), immediately before the EOI (within 5 minutes), 30 and 60 minutes post EOI (±5 minutes), and at 3 and 6 hours (±10 minutes), 24 (Day 16) and 72 (Day 18) hours post EOI (±2 hours). Day 22 dose PK sampling: Day 22 at pre-infusion (within 30 minutes), during the infusion (after 25% and 50% of the infusion has been completed), immediately before the EOI (within 5 minutes), 5, 15, 30 and 60 minutes post-EOI (±5 minutes), and at 3, 4, 6, 9, and 12 hours (±10 minutes), 24 (Day 23), 72 (Day 25), 120 (Day 27) and 168 (Day 29) hours post-EOI (±2 hours).
Part 3: Blood samples for PK analysis will be collected at immediately before the EOI (within 5 minutes), 30- and 60 minutes post EOI (±5 minutes) and at 3 hours (±10 minutes).
Secondary outcome [1] 389795 0
To evaluate the potential effects of treatment on ALS function rating score revised (ALSFRS-R).
Measured through ALSFRS-R Score.
Tool: ALS function rating score
Timepoint [1] 389795 0
Part 1 and 2: Monitored on screening (pre-dose), Day 1, Day 22, Day 29, Day 43 post-first dose
Part 3: ALSFRS-R will be conducted on Day 1 pre-dose only at 4th treatment cycle.
Secondary outcome [2] 391066 0
To evaluate the potential effects of treatment on forced vital capacity (FVC).
Measured through FVC.
Tool: Spirometry will be used.
Timepoint [2] 391066 0
Part 1 and 2: Monitored on screening (pre-dose), Day 1, Day 22, Day 29, Day 43 post-first dose
Part 3: FVC will be conducted on Day 1 pre-dose only at 4th treatment cycle.

Eligibility
Key inclusion criteria
Healthy Volunteers:

1. Healthy male or female volunteers aged 18 to 55 years of age (inclusive at the time
of informed consent).
2. Subjects must be in good general health, with no significant medical history, have
no clinically significant abnormalities on physical examination at Screening and/or
before administration of the initial dose of study drug.
3. Subjects must have a minimum body weight of 50 kg and a Body Mass Index
(BMI) between greater than or equal to 18.0 and lesser than or equal to 32.0 kg/m2 at Screening.
4. Subjects must have clinical laboratory values within normal range as specified by
the testing laboratory, unless deemed not clinically significant by the Investigator
or delegate.
5. Subjects who smoke no more than 2 cigarettes or equivalent per week can be
included in the study but must be willing to abstain from smoking during the
confinement period.

ALS Patients;

1. Males and females aged 18 to 70 years of age (inclusive at the time of informed consent).
2. Must have a minimum body weight of 50 kg and a BMI between greater than or equal to 18.0 and less than or equal to 32.0 kg/m2 at Screening.
3. Patients who smoke no more than 2 cigarettes or equivalent per week can be
included in the study but must be willing to abstain from smoking during the
confinement period.
4. Patients with diagnosis of familial or sporadic ALS, defined as meeting the
possible, laboratory-supported probable, probable, or definite diagnosis of ALS
according to modified El Escorial criteria.
5. Onset of muscle weakness within 60 months of study entry.
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Healthy Volunteers:

1. Females of childbearing potential, pregnant (confirmed by serum or urine beta
human chorionic gonadotropin (ßhCG) test at Screening and prior to dosing) or
lactating or planning to become pregnant (self or partner) at any time during the
study, including the follow-up period.
2. Prior or ongoing medical conditions, medical history, physical findings, or
laboratory abnormality that, in the Investigator’s (or delegate’s) opinion, could
adversely affect the safety of the subject.
3. Presence of any underlying physical or psychological medical condition that, in
the opinion of the Investigator, would make it unlikely that the subject will comply
with the protocol or complete the study per protocol.
4. A history of substance abuse or dependency or history of recreational IV drug use
over the last 5 years (by self-declaration).
5. Blood donation or significant blood loss within 60 days prior to the first study
drug administration.

ALS Patients:

1. Patients with other neuromuscular disorders (in addition to their ALS diagnosis),
unless the Investigator determines that such additional disorder will not affect safety or other measures in this study.
2. Patients with frontotemporal dementia (FTD).
3. Patients with evidence of psychiatric illness or impaired cognitive function which,
in the Investigator’s opinion, is likely to prevent them from a full understanding of and/or compliance with the study requirements and procedures.
4. Patients with abnormalities detected during the Screening evaluations which, in the Investigator’s medical judgement, are sufficiently significant to exclude them from participation in the study.
5. Patients with Type I or poorly controlled Type II Diabetes Mellitus (HbA1c greater than 8%).

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
29/03/2021
Date of last participant enrolment
Anticipated
14/02/2022
Actual
29/03/2022
Date of last data collection
Anticipated
26/10/2022
Actual
19/05/2023
Sample size
Target
28
Accrual to date
Final
28
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 18186 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 32243 0
4029 - Herston

Funding & Sponsors
Funding source category [1] 307407 0
Commercial sector/Industry
Name [1] 307407 0
NuNerve Pty. Ltd.
Country [1] 307407 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
NuNerve Pty. Ltd.
Address
UniQuest Pty Ltd, General Purpose South Building, Level 7, 1 Staff House Rd, The University of Queensland 4074, QLD, Australia
Country
Australia
Secondary sponsor category [1] 308070 0
None
Name [1] 308070 0
Address [1] 308070 0
Country [1] 308070 0
Other collaborator category [1] 281570 0
Commercial sector/Industry
Name [1] 281570 0
Novotech (Australia) Pty Limited
Address [1] 281570 0
Level 3, 235 Pyrmont Street, Pyrmont NSW 2009
Country [1] 281570 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307492 0
Alfred Health HREC
Ethics committee address [1] 307492 0
Ethics committee country [1] 307492 0
Australia
Date submitted for ethics approval [1] 307492 0
24/11/2020
Approval date [1] 307492 0
18/12/2020
Ethics approval number [1] 307492 0

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

Contacts
Principal investigator
Name 107426 0
Dr Richard Friend
Address 107426 0
Q-Pharm PTY Limited
Address: Level 5, Clive Berghofer Cancer Research Centre (CBCRC), 300C Herston Road, Herston QLD 4029
Country 107426 0
Australia
Phone 107426 0
+61 403 415 925
Fax 107426 0
Email 107426 0
[email protected]
Contact person for public queries
Name 107427 0
Richard Friend
Address 107427 0
Q-Pharm PTY Limited
Address: Level 5, Clive Berghofer Cancer Research Centre (CBCRC), 300C Herston Road, Herston QLD 4029
Country 107427 0
Australia
Phone 107427 0
+61 403 415 925
Fax 107427 0
Email 107427 0
[email protected]
Contact person for scientific queries
Name 107428 0
Jing Zhao
Address 107428 0
NuNerve Pty Ltd
Address: c/- Uniquest Pty Ltd, General Purpose South Building, Level 7, 1 Staff House Road, The University of Queensland, QLD 4072, Australia
Country 107428 0
Australia
Phone 107428 0
+61 431808615
Fax 107428 0
Email 107428 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseAmyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation.2023https://dx.doi.org/10.1038/s41573-022-00612-2
N.B. These documents automatically identified may not have been verified by the study sponsor.