Motor Neuron DiseasePhase 1NCT04894240
A Study of Monepantel in Individuals With Motor Neurone Disease
A Phase 1 study testing Monepantel in people with Motor Neuron Disease, run by Neurizon Therapeutics Limited at 2 sites in Australia.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Motor Neuron Disease
- What is being tested?
- Monepantel
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 2 sitesAustralia
- Study dates
- 28 Jun 2022to 29 Nov 2023
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
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- absolute neutrophil count (ANC) ≥1500/µL;
- platelet count ≥ 100,000/µL;
- hemoglobin ≥ 9 g/dL;
- creatinine clearance ≥ 60 mL/min (Cockroft \& Gault formula);
- alanine aminotransferase ALT, SGPT) and/or aspartate aminotransferase (AST, SGOT)
- ≤ 2 x upper limit of normal (ULN);
- total bilirubin ≤ 1.5 x ULN;
- 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
Who cannot join
- 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:
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- drug abuse or alcoholism;
- unstable cardiac, pulmonary, renal, hepatic, endocrine, or hematologic disease;
- active infectious disease;
- AIDS or AIDS-related complex;
- 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;
- unstable psychiatric illness defined as psychosis or untreated major depression within 90 days of the screening visit;
- 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
Trial locations and contacts
2 sites in 1 country.
Australia2 sites
Calvary Health Care Bethlehem
Melbourne, Victoria, 3195
Macquarie University
Sydney, New South Wales, 2109
About this study
Official title: A Phase I Tolerability, Safety, Pharmacokinetics and Preliminary Efficacy Study of Oral Monepantel in Individuals With Motor Neurone Disease
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.
Read more
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.
- Conditions
- Motor Neuron Disease
- Being tested
- Monepantel
- Medical subject headings
- Motor Neuron Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MonepantelDrug
Monepantel is provided to individuals living with ALS/MND as a white oval tablet to be administered once a day following meals
| Study group | Role | What they receive |
|---|---|---|
| Monepantel treatment arm | Experimental | 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 Receives: Drug: Monepantel |
What is being measured
The primary outcome is the main question the study is designed to answer.
Determination of Phase 2 Dose
A recommended phase 2 dose will be determined by the number of participants at each dose level recording dose limiting toxicities
Measured: At least 4 weeks
Blood Plasma Pharmacokinetics of Monepantel
Characterise monepantel blood plasma levels following administration to individuals living with ALS/MND
Measured: 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours and 2, 8, 15, 22 and 29 days after dosing
Blood Plasma Pharmacokinetics of Monepantel Sulfone
Characterise monepantel's major metabolite monepantel sulfone blood plasma levels following administration of monepantel to individuals living with ALS/MND
Measured: 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours and 2, 8, 15, 22 and 29 days after dosing
Secondary outcomes (9)
Treatment related changes in peripheral blood mononuclear cell phosphorylated ribosomal protein S6 kinase B1 (RPS6KB1) levels (pharmacodynamics)
Changes RPS6KB1 phosphorylation levels will assist in determining if the proposed targeted mammalian target of rapamycin (mTOR) pathway is being correctly affected (photostimulated luminescence units)
Measured: From admission to discharge, up to 6 months
Treatment related changes in peripheral blood mononuclear cell phosphorylated eukaryotic initiation factor 4 E binding protein 1 (EIF4EBP1) levels (pharmacodynamics)
Changes EIF4EBP1 phosphorylation levels will assist in determining if the proposed targeted mammalian target of rapamycin (mTOR) pathway is being correctly affected (photostimulated luminescence units)
Measured: From admission to discharge, up to 6 months
Treatment-related changes from Baseline on the ALS Functional Rating Scale (ALSFRS) at Week 4
The ALS Functional Rating Scale (ALSFRS) is a validated rating instrument for monitoring the progression of disability in patients with amyotrophic lateral sclerosis (ALS). Measurements include: (1) speech (2) salivation (3) swallowing (4) handwriting (5) cutting food and handling utensils (with or without gastrostomy) (6) dressing and hygiene (7) turning in bed and adjusting bed clothes (8) walking (9) climbing stairs and (10) breathing. Possible scores range from 0 (normal function) to 4 (severe loss of function). Change = (Week 4 score - Baseline score)
Measured: From admission to discharge, up to 6 months
Treatment-related changes from Baseline in Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS) at Week 4
The ECAS-cognitive screen is a validated screen comprises 16 items organized into two sub-scales. An ALS-specific sub-scale taps into the cognitive domains of language, verbal fluency, and executive and social functions. A non-ALS-specific sub-scale specifically assesses memory and visuospatial function. The sub-scales of the ECAS-cognitive screen range, respectively, from 0 to 100 and from 0 to 36. Low scores indicate a greater deficit. Change = (Week 4 score - Baseline score)
Measured: From admission to discharge, up to 6 months
Treatment-related changes from Baseline in slow vital capacity (SVC)
A decline in SVC would indicate a decline in respiratory function and is an important indicator of any clinical progression (L/s)
Measured: From admission to discharge, up to 6 months
Treatment-related changes in urinary p75 levels
Urinary p75 level reflect nerve damage and therefore increased levels would act as a proxy to disease progression (ng/mg creatinine)
Measured: From admission to discharge, up to 6 months
Treatment-related changes in 3 Tesla magnetic resonance imaging (MRI)
MRI is a method used to investigate and exclude conditions that may mimic motor neuron dysfunction (Tesla)
Measured: From admission to discharge, up to 6 months
Treatment-related changes in serum neurofilament light (NfL) chain levels
Serum NfL chain levels correlate with disease progression, so stable NfL levels would correlate with stable disease (pg/ml)
Measured: From admission to discharge, up to 6 months
Treatment-related changes in central spinal fluid (CSF) NfL chain levels
CSF NfL chain levels correlate with disease progression. Levels in individuals living with MND are 5 to 10 fold higher than those of healthy individuals (pg/ml)
Measured: From admission to discharge, up to 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 May 2021
- Study start28 Jun 2022
- Primary completion29 Nov 2023
- Study completion29 Nov 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Motor Neuron DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- Neurizon Therapeutics Limited
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- FightMND, Calvary Health Care Bethlehem, Macquarie University, Australia
- Responsible party
- Sponsor
- Investigators
- Susan Mathers, MB ChB, MRCP(UK), FRACP, Principal investigator, Calvary Health Care BethlehemDominic Rowe, PhD, FRACP, AM, Principal investigator, Macquarie University, Sydney
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04894240
- Sponsor's protocol ID
- MON-2021-001
- Status last verified
- Dec 2023
- First submitted
- 5 May 2021
- Last updated
- 21 Dec 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
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.
PubMed 32960289
Study at a glance
From the registry record, last updated by the sponsor on 21 Dec 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I Tolerability, Safety, Pharmacokinetics and Preliminary Efficacy Study of Oral Monepantel in Individuals With Motor Neurone Disease
- ClinicalTrials.gov ID
- NCT04894240
- Acronym / sponsor ID
- MON-2021-001
- Conditions
- Motor Neuron Disease
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- Neurizon Therapeutics LimitedIndustry (pharma, biotech, devices)
- Collaborators
- FightMND, Calvary Health Care Bethlehem, Macquarie University, Australia
- Study start
- 28 Jun 2022 (actual)
- Primary completion
- 29 Nov 2023 (actual)
- Study completion
- 29 Nov 2023 (actual)
- First posted
- 20 May 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Monepantel treatment arm | Experimental | Drug: MonepantelMonepantel 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 |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- 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
Key exclusion criteria (17 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MonepantelMonepantel is provided to individuals living with ALS/MND as a white oval tablet to be administered once a day following meals | Drug | Monepantel treatment arm |
Primary outcome
Determination of Phase 2 Dose
Time frame: At least 4 weeks
A recommended phase 2 dose will be determined by the number of participants at each dose level recording dose limiting toxicities
Blood Plasma Pharmacokinetics of Monepantel
Time frame: 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours and 2, 8, 15, 22 and 29 days after dosing
Characterise monepantel blood plasma levels following administration to individuals living with ALS/MND
Blood Plasma Pharmacokinetics of Monepantel Sulfone
Time frame: 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours and 2, 8, 15, 22 and 29 days after dosing
Characterise monepantel's major metabolite monepantel sulfone blood plasma levels following administration of monepantel to individuals living with ALS/MND
9 secondary outcomes
Treatment related changes in peripheral blood mononuclear cell phosphorylated ribosomal protein S6 kinase B1 (RPS6KB1) levels (pharmacodynamics)
Time frame: From admission to discharge, up to 6 months
Treatment related changes in peripheral blood mononuclear cell phosphorylated eukaryotic initiation factor 4 E binding protein 1 (EIF4EBP1) levels (pharmacodynamics)
Time frame: From admission to discharge, up to 6 months
Treatment-related changes from Baseline on the ALS Functional Rating Scale (ALSFRS) at Week 4
Time frame: From admission to discharge, up to 6 months
Treatment-related changes from Baseline in Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS) at Week 4
Time frame: From admission to discharge, up to 6 months
Treatment-related changes from Baseline in slow vital capacity (SVC)
Time frame: From admission to discharge, up to 6 months
Treatment-related changes in urinary p75 levels
Time frame: From admission to discharge, up to 6 months
Treatment-related changes in 3 Tesla magnetic resonance imaging (MRI)
Time frame: From admission to discharge, up to 6 months
Treatment-related changes in serum neurofilament light (NfL) chain levels
Time frame: From admission to discharge, up to 6 months
Treatment-related changes in central spinal fluid (CSF) NfL chain levels
Time frame: From admission to discharge, up to 6 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Dec 2023.
- Background: PubMed 32960289Mislang 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Susan Mathers, MB ChB, MRCP(UK), FRACP principal investigator
Calvary Health Care Bethlehem
Dominic Rowe, PhD, FRACP, AM principal investigator
Macquarie University, Sydney
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Monepantel in people with Motor Neuron Disease, run by Neurizon Therapeutics Limited at 2 sites in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Dec 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Determination of Phase 2 Dose (time frame: At least 4 weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04894240, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Dec 2023.