Optic NeuritisPhase 2ACTIONNCT01802489
Amiloride Clinical Trial In Optic Neuritis
A Phase 2 study testing Amiloride in people with Optic Neuritis and Multiple Sclerosis, run by University of Oxford at 1 site in United Kingdom.
Trial summary
Optic neuritis (ON) is a common event in Multiple Sclerosis (MS), and causes significant loss of nerve cells in the eye, resulting in poor vision. Optic neuritis also provides a sensitive way of testing the effectiveness of drugs that may help protect from loss of nerve cells in ON and therefore in MS. Read more about this study
- Who is it for?
- Ages 18 to 55 years
- Conditions the study is for
- Optic Neuritis, Multiple Sclerosis
- What is being tested?
- Amiloride
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 46 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Feb 2013to Nov 2015
- Phase
- Phase 2
- 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 55 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Participants with a first episode of unilateral optic neuritis
- Participants with an existing diagnosis of relapsing remitting MS and new onset of ON are eligible if they have;
- Not had a previous episode of optic neuritis,
- A duration of disease of ≤10 years
- An EDSS (Expanded Disability Status Scale) of ≤3.
- No immune modulating treatment other than β-Interferon or glatiramer acetate at time of recruitment
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- Able to be randomised within 28 days of onset of visual symptoms
- Visual acuity of ≤6/9
- Participant is willing and able to give informed consent for participation in the study and able to comply with study visits
- Male or Female, aged between18 - 55 years.
- Stable dose of current regular medication for at least 4 weeks prior to study entry.
- Participant has clinically acceptable urea and electrolytes and estimated glomerular filtration rate (eGFR) >60
- Able and willing to comply with all study requirements.
- Willing to allow his or her General Practitioner to be notified of participation in the study.
Who cannot join
- Previous diagnosis of optic neuritis
- Any concomitant immune suppressing or immune modulating therapy excluding β-interferon or glatiramer acetate.
- Female participants who are pregnant, lactating or planning pregnancy during the course of the study.
- Concomitant potassium supplements, angiotensin converting enzyme inhibitors, angiotensin II antagonists, cyclosporine, tacrolimus or lithium
- Any contra-indication to MRI - severe claustrophobia, metal implant, pacemaker, etc.
- Participant who is terminally ill or is inappropriate for placebo medication
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- Impaired renal function : eGFR ≤60, anuria, acute or chronic renal insufficiency and evidence of diabetic nephropathy
- Raised serum potassium (K+ >5.5mmol/l)
- Diabetes
- Significant concomitant eye disease in either eye that may affect diseased or fellow eye results.
- Any other significant disease or disorder which, in the opinion of the investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant's ability to participate in the study.
- Participants who have participated in another research study involving an investigational product in the past 12 weeks.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Double Blind Randomised Control Trial on Neuroprotection of Amiloride in Optic Neuritis
Optic neuritis (ON) is a common event in Multiple Sclerosis (MS), and causes significant loss of nerve cells in the eye, resulting in poor vision. Optic neuritis also provides a sensitive way of testing the effectiveness of drugs that may help protect from loss of nerve cells in ON and therefore in MS.
The investigators have identified through laboratory and early clinical research in humans that amiloride (a water tablet already in use) may be a drug that can be of benefit in optic neuritis by protecting from loss of nerves cells, ie a neuroprotective drug.
The purpose of this study is to assess the efficacy of amiloride as a neuroprotective drug in optic neuritis
Read the detailed description
Multiple sclerosis (MS), an inflammatory condition of the nervous system, is the most common cause of disability in people of working age in the western world. In addition to the inflammatory episodes in MS, axonal and neuronal damage occurs. It is this axonal loss which is thought to be the major pathological substrate for disability in MS.
Acute inflammatory demyelinating optic neuritis is a common event in multiple sclerosis. Following optic neuritis there is axonal loss in the optic nerve and retina, which if severe can result in a poor visual recovery. Uniquely amongst central nervous system (CNS) structures, the structural and functional changes in the eye during and following optic neuritis provide a sensitive way of observing neurodegeneration and testing the effectiveness of potential neuroprotective agents. In optic neuritis it has been shown that thinning of the retinal nerve fibre layer takes place, and by 6 months this thinning is established and has largely stabilised. This represents axonal loss in the anterior visual system. The degree of this thinning has been shown to correlate with the amount of vision recovered following optic neuritis, the more thinning that occurs, the poorer the outcome. The thickness of the retinal nerve fibre layer can be measured by the simple scanning techniques of scanning laser polarimetry (GDx) and optical coherence tomography (OCT).
Axonal loss in MS is likely to be multifactorial, but a key end point is the influx of sodium and calcium ions. Recent research suggests that in the inflammatory environment of optic neuritis, the acid sensing ion channel may have an important role in this influx of sodium and calcium, and therefore in axonal loss in MS. The drug amiloride, already in use as a diuretic, is a known blocker of this ion channel. The investigators have identified through laboratory and early clinical research in humans that by blockade of the acid sensing ion channel, amiloride may be neuroprotective in optic neuritis and MS.
The investigators primary objective is to assess the neuroprotective efficacy of amiloride in optic neuritis through the surrogate measure of retinal nerve fibre layer measurement. Secondary objectives are to assess markers of neurodegeneration in ON and the neuroprotective effect of amiloride through non-conventional MRI outcomes, to assess if amiloride improves functional and visual outcome following optic neuritis, and to confirm optic neuritis as a sensitive and efficient model for neuroprotection in a clinical trial framework.
46 Participants will be recruited to receive either amiloride, or an identical placebo capsule for 5 months. The primary outcome will be measured at 6 months, with a further measure at 12 months.
Should this trial show a significant benefit from amiloride in optic neuritis, it will be an important first step in developing neuroprotective therapies in optic neuritis and MS and potentially this could have a significant impact on people with MS and their carers.
- Conditions
- Optic Neuritis, Multiple Sclerosis
- Being tested
- Amiloride, Placebo
- Keywords
- Optic neuritis, Multiple sclerosis, Retinal nerve fibre layer, Axonal loss, Neuroprotection, MRI, Optical coherence tomography, Amiloride, Acid Sensing Ion Channels
- Medical subject headings
- Optic Neuritis, Multiple Sclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AmilorideDrug
Also called Midamor
PlaceboDrug
Placebo capsule identical in appearance to Amiloride 10mg capsule
| Study group | Role | What they receive |
|---|---|---|
| Amiloride | Active comparator | Amiloride capsules 10mg once per day for 5 months Receives: Drug: Amiloride |
| Placebo | Placebo comparator | Placebo capsules one per day for 5 months Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Scanning laser polarimetry determined retinal nerve fibre layer thickness
The primary outcome will be difference in retinal nerve fibre thickness at 6 months between affected eye and non-affected fellow eye at baseline between the amiloride and placebo group.
An additional measure will be made at 12 months
Measured: Baseline, 6 and 12 months
Secondary outcomes (5)
Optical coherence tomography determined difference in retinal nerve fibre layer thickness.
Difference in thickness at 6 months and 12 months between affected eye and non-affected fellow eye at baseline, between the amiloride and placebo group
Measured: Baseline, 6 and 12 months
Differences between the amiloride and placebo groups in non-conventional MRI surrogate marker of white matter and grey matter injury and connectivity by 3T scanning.
- Diffusion weighted imaging (DWI) - measures; fractional anisotropy (FA), mean diffusivity (MD), axial and radial diffusivity (RD) of the posterior visual tracts
- High Resolution T1-weighted image measure of grey matter volume
- Magnetic resonance spectroscopy (MRS) measures of N-acetyl aspartate (NAA) in the visual cortex
- Resting state functional MRI (RS fMRI) patterns of activity
- Magnetisation transfer imaging (MTI) derived magnetisation transfer ratio (MTR) of the white and grey matter
Measured: Baseline, 6 and 12 months
Visual Function
- High and low contrast (2.5% and 1.25%) visual acuity.
- Farnsworth Munsell 100 Hue (FM100) colour vision test.
Measured: Baseline, 6 and 12 months
Visual Electrophysiology
Differences in visually evoked potential and pattern electro-retinogram between the amiloride and placebo groups as additional measures of visual function
Measured: 0 and 6 months
Quality of life questionnaires
- 25 point national institutes for health visual function questionnaire
- 10 point neuro ophthalmic supplement.
Measured: Baseline, 6 and 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Mar 2013 (estimated)
- Study startFeb 2013
- Primary completionNov 2015
- Study completionNov 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Optic NeuritisStudies of the same condition, open and under way.
- More trials run by University of OxfordThe sponsor's other registered studies.
- 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 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 46 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Oxford
- Sponsor type
- University, hospital or other
- Collaborators
- Multiple Sclerosis Society of Great Britain and Northern Ireland
- Responsible party
- Sponsor
- Investigators
- Matthew Craner, MBChB PhD, Principal investigator, University of Oxford
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01802489
- Sponsor's protocol ID
- Amiloride 02
- Acronym
- ACTION
- Status last verified
- May 2018
- First submitted
- 27 Feb 2013
- Last updated
- 17 May 2018
- Results posted
- No
- Data monitoring committee
- Yes
Publications
McKee JB, Cottriall CL, Elston J, Epps S, Evangelou N, Gerry S, Kennard C, Kong Y, Koelewyn A, Kueker W, Leite MI, Palace J, Craner M. Amiloride does not protect retinal nerve fibre layer thickness in optic neuritis in a phase 2 randomised controlled trial. Mult Scler. 2019 Feb;25(2):246-255. doi: 10.1177/1352458517742979. Epub 2017 Nov 27.
PubMed 29172994McKee JB, Elston J, Evangelou N, Gerry S, Fugger L, Kennard C, Kong Y, Palace J, Craner M. Amiloride Clinical Trial In Optic Neuritis (ACTION) protocol: a randomised, double blind, placebo controlled trial. BMJ Open. 2015 Nov 9;5(11):e009200. doi: 10.1136/bmjopen-2015-009200.
PubMed 26553836
Study at a glance
From the registry record, last updated by the sponsor on 17 May 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Double Blind Randomised Control Trial on Neuroprotection of Amiloride in Optic Neuritis
- ClinicalTrials.gov ID
- NCT01802489
- Acronym / sponsor ID
- ACTION / Amiloride 02
- Conditions
- Optic Neuritis, Multiple Sclerosis
- Keywords
- Optic neuritis, Multiple sclerosis, Retinal nerve fibre layer, Axonal loss, Neuroprotection, MRI, Optical coherence tomography, Amiloride
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 46 participants (actual)
- Lead sponsor
- University of OxfordUniversity, hospital or other
- Collaborators
- Multiple Sclerosis Society of Great Britain and Northern Ireland
- Study start
- Feb 2013
- Primary completion
- Nov 2015 (actual)
- Study completion
- Nov 2015 (actual)
- First posted
- 1 Mar 2013 (estimated)
- 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.
Optic neuritis (ON) is a common event in Multiple Sclerosis (MS), and causes significant loss of nerve cells in the eye, resulting in poor vision. Optic neuritis also provides a sensitive way of testing the effectiveness of drugs that may help protect from loss of nerve cells in ON and therefore in MS.
The investigators have identified through laboratory and early clinical research in humans that amiloride (a water tablet already in use) may be a drug that can be of benefit in optic neuritis by protecting from loss of nerves cells, ie a neuroprotective drug.
The purpose of this study is to assess the efficacy of amiloride as a neuroprotective drug in optic neuritis
Detailed description
Multiple sclerosis (MS), an inflammatory condition of the nervous system, is the most common cause of disability in people of working age in the western world. In addition to the inflammatory episodes in MS, axonal and neuronal damage occurs. It is this axonal loss which is thought to be the major pathological substrate for disability in MS.
Acute inflammatory demyelinating optic neuritis is a common event in multiple sclerosis. Following optic neuritis there is axonal loss in the optic nerve and retina, which if severe can result in a poor visual recovery. Uniquely amongst central nervous system (CNS) structures, the structural and functional changes in the eye during and following optic neuritis provide a sensitive way of observing neurodegeneration and testing the effectiveness of potential neuroprotective agents. In optic neuritis it has been shown that thinning of the retinal nerve fibre layer takes place, and by 6 months this thinning is established and has largely stabilised. This represents axonal loss in the anterior visual system. The degree of this thinning has been shown to correlate with the amount of vision recovered following optic neuritis, the more thinning that occurs, the poorer the outcome. The thickness of the retinal nerve fibre layer can be measured by the simple scanning techniques of scanning laser polarimetry (GDx) and optical coherence tomography (OCT).
Axonal loss in MS is likely to be multifactorial, but a key end point is the influx of sodium and calcium ions. Recent research suggests that in the inflammatory environment of optic neuritis, the acid sensing ion channel may have an important role in this influx of sodium and calcium, and therefore in axonal loss in MS. The drug amiloride, already in use as a diuretic, is a known blocker of this ion channel. The investigators have identified through laboratory and early clinical research in humans that by blockade of the acid sensing ion channel, amiloride may be neuroprotective in optic neuritis and MS.
The investigators primary objective is to assess the neuroprotective efficacy of amiloride in optic neuritis through the surrogate measure of retinal nerve fibre layer measurement. Secondary objectives are to assess markers of neurodegeneration in ON and the neuroprotective effect of amiloride through non-conventional MRI outcomes, to assess if amiloride improves functional and visual outcome following optic neuritis, and to confirm optic neuritis as a sensitive and efficient model for neuroprotection in a clinical trial framework.
46 Participants will be recruited to receive either amiloride, or an identical placebo capsule for 5 months. The primary outcome will be measured at 6 months, with a further measure at 12 months.
Should this trial show a significant benefit from amiloride in optic neuritis, it will be an important first step in developing neuroprotective therapies in optic neuritis and MS and potentially this could have a significant impact on people with MS and their carers.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Amiloride | Active comparator | Drug: AmilorideAmiloride capsules 10mg once per day for 5 months |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo capsules one per day for 5 months |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (14 listed)
- Participants with a first episode of unilateral optic neuritis
- Participants with an existing diagnosis of relapsing remitting MS and new onset of ON are eligible if they have;
- Able to be randomised within 28 days of onset of visual symptoms
- Visual acuity of ≤6/9
- Participant is willing and able to give informed consent for participation in the study and able to comply with study visits
Key exclusion criteria (12 listed)
- Previous diagnosis of optic neuritis
- Any concomitant immune suppressing or immune modulating therapy excluding β-interferon or glatiramer acetate.
- Female participants who are pregnant, lactating or planning pregnancy during the course of the study.
- Concomitant potassium supplements, angiotensin converting enzyme inhibitors, angiotensin II antagonists, cyclosporine, tacrolimus or lithium
- Any contra-indication to MRI - severe claustrophobia, metal implant, pacemaker, etc.
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 |
|---|---|---|
| AmilorideAlso: Midamor | Drug | Amiloride |
| PlaceboPlacebo capsule identical in appearance to Amiloride 10mg capsule | Drug | Placebo |
Primary outcome
Scanning laser polarimetry determined retinal nerve fibre layer thickness
Time frame: Baseline, 6 and 12 months
The primary outcome will be difference in retinal nerve fibre thickness at 6 months between affected eye and non-affected fellow eye at baseline between the amiloride and placebo group. An additional measure will be made at 12 months
5 secondary outcomes
Optical coherence tomography determined difference in retinal nerve fibre layer thickness.
Time frame: Baseline, 6 and 12 months
Differences between the amiloride and placebo groups in non-conventional MRI surrogate marker of white matter and grey matter injury and connectivity by 3T scanning.
Time frame: Baseline, 6 and 12 months
Visual Function
Time frame: Baseline, 6 and 12 months
Visual Electrophysiology
Time frame: 0 and 6 months
Quality of life questionnaires
Time frame: Baseline, 6 and 12 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 17 May 2018.
- Derived from this study: PubMed 29172994McKee JB, Cottriall CL, Elston J, Epps S, Evangelou N, Gerry S, Kennard C, Kong Y, Koelewyn A, Kueker W, Leite MI, Palace J, Craner M. Amiloride does not protect retinal nerve fibre layer thickness in optic neuritis in a phase 2 randomised controlled trial. Mult Scler. 2019 Feb;25(2):246-255. doi: 10.1177/1352458517742979. Epub 2017 Nov 27.
- Derived from this study: PubMed 26553836McKee JB, Elston J, Evangelou N, Gerry S, Fugger L, Kennard C, Kong Y, Palace J, Craner M. Amiloride Clinical Trial In Optic Neuritis (ACTION) protocol: a randomised, double blind, placebo controlled trial. BMJ Open. 2015 Nov 9;5(11):e009200. doi: 10.1136/bmjopen-2015-009200.
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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.
Matthew Craner, MBChB PhD principal investigator
University of Oxford
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Amiloride in people with Optic Neuritis and Multiple Sclerosis, run by University of Oxford at 1 site in United Kingdom.
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 14 inclusion and 12 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 17 May 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. 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. Some participants in this study may receive a placebo. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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?
Scanning laser polarimetry determined retinal nerve fibre layer thickness (time frame: Baseline, 6 and 12 months). 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 NCT01802489, which also lists 2 linked publications.
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 17 May 2018.