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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04894240




Registration number
NCT04894240
Ethics application status
Date submitted
5/05/2021
Date registered
20/05/2021
Date last updated
21/12/2023

Titles & IDs
Public title
A Study of Monepantel in Individuals With Motor Neurone Disease
Scientific title
A Phase I Tolerability, Safety, Pharmacokinetics and Preliminary Efficacy Study of Oral Monepantel in Individuals With Motor Neurone Disease
Secondary ID [1] 0 0
MON-2021-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Motor Neuron Disease 0 0
Condition category
Condition code
Neurological 0 0 0 0
Neurodegenerative diseases
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Monepantel

Experimental: Monepantel treatment arm - Monepantel tablets will be administered to participants in this arm daily for 28 days. Dose escalation will occur at the end of each 28 day period according to a modified Fibonacci sequence based upon recommendations from the safety management committee


Treatment: Drugs: Monepantel
Monepantel is provided to individuals living with ALS/MND as a white oval tablet to be administered once a day following meals
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Determination of Phase 2 Dose
Timepoint [1] 0 0
At least 4 weeks
Primary outcome [2] 0 0
Blood Plasma Pharmacokinetics of Monepantel
Timepoint [2] 0 0
0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours and 2, 8, 15, 22 and 29 days after dosing
Primary outcome [3] 0 0
Blood Plasma Pharmacokinetics of Monepantel Sulfone
Timepoint [3] 0 0
0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours and 2, 8, 15, 22 and 29 days after dosing
Secondary outcome [1] 0 0
Treatment related changes in peripheral blood mononuclear cell phosphorylated ribosomal protein S6 kinase B1 (RPS6KB1) levels (pharmacodynamics)
Timepoint [1] 0 0
From admission to discharge, up to 6 months
Secondary outcome [2] 0 0
Treatment related changes in peripheral blood mononuclear cell phosphorylated eukaryotic initiation factor 4 E binding protein 1 (EIF4EBP1) levels (pharmacodynamics)
Timepoint [2] 0 0
From admission to discharge, up to 6 months
Secondary outcome [3] 0 0
Treatment-related changes from Baseline on the ALS Functional Rating Scale (ALSFRS) at Week 4
Timepoint [3] 0 0
From admission to discharge, up to 6 months
Secondary outcome [4] 0 0
Treatment-related changes from Baseline in Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS) at Week 4
Timepoint [4] 0 0
From admission to discharge, up to 6 months
Secondary outcome [5] 0 0
Treatment-related changes from Baseline in slow vital capacity (SVC)
Timepoint [5] 0 0
From admission to discharge, up to 6 months
Secondary outcome [6] 0 0
Treatment-related changes in urinary p75 levels
Timepoint [6] 0 0
From admission to discharge, up to 6 months
Secondary outcome [7] 0 0
Treatment-related changes in 3 Tesla magnetic resonance imaging (MRI)
Timepoint [7] 0 0
From admission to discharge, up to 6 months
Secondary outcome [8] 0 0
Treatment-related changes in serum neurofilament light (NfL) chain levels
Timepoint [8] 0 0
From admission to discharge, up to 6 months
Secondary outcome [9] 0 0
Treatment-related changes in central spinal fluid (CSF) NfL chain levels
Timepoint [9] 0 0
From admission to discharge, up to 6 months

Eligibility
Key inclusion criteria
- Signed informed consent obtained prior to initiation of any study-specific procedures
and treatment

- Familial or sporadic ALS/MND diagnosed as clinically possible, probable, or definite
according to Awaji-shima Consensus Recommendations

- Seated slow vital capacity (SVC) = 3L in males and = 2.5L in females at screening

- Not taking riluzole or on a stable dose of riluzole for at least 4 weeks prior to the
screening visit. While on study, subjects are not allowed to start taking riluzole
during the study

- Patient has a competent caregiver who can support the patient's involvement in the
study, including assisting the administration of study drug

- Adequate bone marrow reserve, renal and liver function:

1. absolute neutrophil count (ANC) =1500/µL;

2. platelet count = 100,000/µL;

3. hemoglobin = 9 g/dL;

4. creatinine clearance = 60 mL/min (Cockroft & Gault formula);

5. alanine aminotransferase ALT, SGPT) and/or aspartate aminotransferase (AST, SGOT)

6. = 2 x upper limit of normal (ULN);

7. total bilirubin = 1.5 x ULN;

8. serum albumin = 2.8 g/dL

- Women and men with partners of childbearing potential must use effective contraception
while on study treatment and women of childbearing potential must have a negative
pregnancy test at screening
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Inability to swallow oral medications or presence of a gastrointestinal disorder
(e.g., malabsorption) deemed to jeopardize intestinal absorption of study drug

- Dependence on mechanical ventilation (invasive or non-invasive, including Continuous
Positive Airway Pressure (CPAP) or Bi-level Positive Airway Pressure (BiPAP) for any
part of day or night prior to the screening visit. Dependence on mechanical
ventilation is defined as being unable to lie flat (supine) without it, unable to
sleep without it, or daytime use

- Exposure to any other investigational agent within 3 months prior to the screening
visit

- Active gastrointestinal disease within 30 days of the screening visit.
Gastro-esophageal reflux disease (GERD) is not considered active gastrointestinal
disease and is not exclusionary

- Known immune compromising illness or treatment

- Presence of any of the following clinical conditions:

1. drug abuse or alcoholism;

2. unstable cardiac, pulmonary, renal, hepatic, endocrine, or hematologic disease;

3. active infectious disease;

4. AIDS or AIDS-related complex;

5. diagnosis of malignancy within 2 years of screening (adequately treated basal
cell or squamous cell carcinoma of skin or non-invasive bladder cancer or
carcinoma in situ of the bladder, breast or cervix are allowed;

6. unstable psychiatric illness defined as psychosis or untreated major depression
within 90 days of the screening visit;

7. neuromuscular disease other than ALS/MND

- Dementia that may affect either outcome measures or patient understanding and/or
compliance with study requirements and procedures

- Women and men of childbearing potential not using effective contraception while on
study treatment

- Women who are breast-feeding

- Patients at risk of or known to carry a SOD1 mutation or VCP mutation

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
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
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
28/06/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
29/11/2023
Sample size
Target
Accrual to date
Final
12
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Macquarie University - Sydney
Recruitment hospital [2] 0 0
Calvary Health Care Bethlehem - Melbourne
Recruitment postcode(s) [1] 0 0
2109 - Sydney
Recruitment postcode(s) [2] 0 0
3195 - Melbourne

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
PharmAust Ltd
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
FightMND
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
Calvary Health Care Bethlehem
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
Macquarie University, Australia
Address [3] 0 0
Country [3] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Amyotrophic lateral sclerosis/ Motor Neurone Disease (ALS/MND) is a rare and invariably fatal
neurological disease. ALS/MND has a terribly high burden on patients, family and carers, and
carries great socioeconomic burden. Current best treatment options are expensive and attempt
to control disease progression and manage symptoms while offering no cure. Better treatments
are wanting.

Monepantel is a well-known veterinary drug, registered as a livestock wormicide in 39
countries. The industry collaborator, PharmAust Ltd, has found that monepantel shows
off-target activity, inhibiting a cellular signaling system controlled by mammalian target of
rapamycin (mTOR). This stops cancer growth and reduces protein accumulation in diseased
cells. PharmAust has already tested monepantel in humans and pet dogs in Phase I and II
anti-cancer clinical trials, respectively, in Australia. Data from these trials show that
monepantel treatment associates with an exceptionally high safety profile, mTOR signaling
inhibition and anticancer activity.

Abnormal protein accumulation within motor neurons of the brain associates with the cause of
ALS/MND. Inhibition of the mTOR signaling pathway slows disease progression in certain
preclinical models of ALS/MND and is suggested to provide synergy with the ALS/MND
standard-of-care drug, riluzole. An alternative mTOR inhibitor, rapamycin, is currently the
subject of an ALS/MND clinical trial in humans investigating control of disease progression.
Monepantel has a different structure to rapamycin and an apparently better safety profile.

This Phase I Clinical Trial hypothesis is that monepantel administration to individuals
living with ALS/MND will safely reduce disease associated protein accumulation in motor
neurons and provide therapeutic benefit. To test this hypothesis, the safety and tolerability
of oral monepantel administration and markers of efficacy will be tested in individuals
living with ALS/MND in a dose escalating Phase I/II Clinical Trial. To mitigate risk, only
patients with sporadic and certain known familial types of ALS will be eligible. To further
mitigate risk, the monepantel starting dose will be reduced a calculated five-fold compared
to that already used in human cancer patients and already demonstrated to be safe and
effective as an mTOR inhibitor. Dependent upon incremental outcomes, three higher doses may
then be tested, each for minimally 28 days with a duration at the optimal dose of at least
six months.
Trial website
https://clinicaltrials.gov/ct2/show/NCT04894240
Trial related presentations / publications
Mislang A, Mollard R, Tapia Rico G, Fairlie WD, Lee EF, Harris TJ, Aston R, Brown MP. A preliminary assessment of oral monepantel's tolerability and pharmacokinetics in individuals with treatment-refractory solid tumors. Cancer Chemother Pharmacol. 2020 Nov;86(5):589-594. doi: 10.1007/s00280-020-04146-5. Epub 2020 Sep 22.
Public notes

Contacts
Principal investigator
Name 0 0
Susan Mathers, MB ChB, MRCP(UK), FRACP
Address 0 0
Calvary Health Care Bethlehem
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT04894240