Amiloride Hydrochlorothiazide as Treatment of Acute Inflammation of the Optic Nerve

A Randomized, Placebo-Controlled, Double-Blind, Phase IIa Study of Amiloride in the Treatment of Acute Autoimmune Optic Neuritis

Following acute inflammation of the optic nerve region, as commonly seen in multiple sclerosis patients, the optic nerve often undergoes atrophy, thus representing permanent damage. Data from animal studies suggest that amiloride may prevent this process. The aim of this study is to assess a potential neuroprotective effect of amiloride in acute autoimmune inflammation of the optic nerve region.

Study Overview

• Status: Unknown
• Conditions: Optic; Neuritis, With Demyelination
• Intervention / Treatment: Drug: Amiloride hydrochlorothiazide; Drug: Sugar pill

Detailed Description

Recent studies have shown that the acid-sensing ion channel 1 (ASIC1) contributes to the axonal degeneration in CNS lesions Physiologically, ASIC1 has been described as a postsynaptic proton receptor on hippocampal neurons influencing the intracellular Ca2+ concentration. In MS, ASIC1 seems to activate under acidic conditions predominating in the inflammatory CNS lesions leading to a Na+ and Ca2+ overload and consecutive damage and apoptosis of axons. Consecutively, in a MS mousemodel axonal damage was significantly less pronounced after administering amiloride, a clinically safe blocker of ASICs. So ASIC1 seems to play a major role in axonal degeneration in MS. To our knowledge no clinical studies have tested those promising in vitro results in humans so far.

Only one retrospective registry-based cohort study was performed. This study showed no difference in the risk of incident MS or hospitalization and death among MS patients using amilorid compared to those using thiazide diuretics. However, this study has numerous limitations with respect to it's retrospective designone and the fact that amilorid users were at the vast majority older individuals. Such a late stage of the MS course does not seem to be the best window of opportunity for interventions with neuroprotective agents. Moreover, death may be a too multifactorial parameter to correspond with axonal damage alone. Consequently, a more sensitive parameter for axonal damage in MS is needed to test the impact of amiloride on neuroprotection and repair.Based on the findings described above we intend to assess the potential neuroprotective effect of amiloride hydrochlorothiazide (Amilostad HCT®) in patients with optic neuritis (ON), which has already been demonstrated in a mouse model. ON is one of the most common manifestations of MS and has already been proven appropiate to test neuroprotective agents.

• Study Type: Interventional
• Enrollment (Anticipated): 78
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Fritz Leutmezer, MD; Phone Number: 3120 +43140400; Email: fritz.leutmezer@meduniwien.ac.at

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Recruiting
    • Medical University of Vienna, Department of Neurology
    • Contact: Fritz Leutmezer, MD; Phone Number: 3120 +43140400; Email: fritz.leutmezer@meduniwien.ac.at
    • Principal Investigator: Fritz Leutmezer

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients between 18 and 50 years of age with a first episode of optic neuritis (ON) and a visual acuity decreased to <0,6 will be eligible for inclusion in the study. Diagnosis of ON has to be confirmed by an ophthalmologist. Onset of symptoms has to be within 10 days prior to inclusion into the study

Exclusion Criteria:

• Known allergy or hypersensitivity to amilostad HCT or any of its ingredients
• Known allergy or hypersensitivity to other sulphonamide-derived drugs
• Impaired renal function or any known renal disease
• Intake of other potassium-conserving diuretics
• Intake of potassium supplements or a special potassium rich diet
• Intake of spironolactone or triamterene
• Moderate to severe hepatic failure
• Morbus Addison
• Known hypercalcaemia
• Intake of lithium therapy
• Blood urea > 10mmol/l
• Diabetes mellitus
• History of ON or any other ocular disease (affected as well as unaffected eye)
• Pregnancy or lactation period
• Treatment with corticosteroids or amiloride within 30 days prior to the inclusion into the study
• Use of any immunomodulatory or immunosuppressive agents anytime in the past
• Dearrangement of serum sodium or potassium levels on the lab

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Amiloride hydrochlorothiazide; 5,68 mg Amiloridhydrochloride 2H20 (analogue 4,32 mg Amilorid) und 50 mg Hydrochlorothiazid. Trade name of the agent: Amilostad HCT 5/50mg tablets Manufacturer: Stada initial dose: 1 x 5/50mg once daily target dose: 2 x 5/50mg once daily Patients will be provided with capsules (size 00) containing one tablet of study medication and instructed to take these capsules once daily in the morning together with breakfast. Visit 2 will be scheduled one week after baseline and at visit 2 patients will be provided with capsules containing two tablets of study medication	Drug: Amiloride hydrochlorothiazide; Blinding will be done by over-encapsulating amiloride HCT tablets and providing corresponding placebo capsules.Patients will be provided with capsules (size 00) containing one tablet of study medication (Amilostad HCT 5/50mg tablet or placebo) and instructed to take these capsules once daily in the morning together with breakfast. Visit 2 will be scheduled one week after baseline and at visit 2 patients will be provided with capsules containing two tablets of study medication. This maintenance dose will not be changed throughout the remaining study period. Placebo will be administered in the exact same manner.; Other Names: Marketing Authorisation number: 1-22734; Trade name: Amilostad HCT
Placebo Comparator: Sugar pill; Patients will be provided with capsules (size 00) containing sugar and instructed to take these capsules once daily in the morning together with breakfast.	Drug: Sugar pill; containing placebo; Other Names: placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in thickness of retinal nerve fiber layer (RNFL)	Baseline versus follow-up at 24 weeks

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Investigators: Principal Investigator: Fritz Leutmezer, MD, Medical University of Vienna

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Anticipated): April 1, 2016
• Study Completion (Anticipated): April 1, 2016

Study Registration Dates

• First Submitted: June 13, 2013
• First Submitted That Met QC Criteria: June 13, 2013
• First Posted (Estimate): June 18, 2013

Study Record Updates

• Last Update Posted (Estimate): May 12, 2015
• Last Update Submitted That Met QC Criteria: May 8, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Eye Diseases; Neuromuscular Diseases; Peripheral Nervous System Diseases; Optic Nerve Diseases; Cranial Nerve Diseases; Neuritis; Optic Neuritis; Demyelinating Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Channel Blockers; Diuretics, Potassium Sparing; Sodium Chloride Symporter Inhibitors; Acid Sensing Ion Channel Blockers; Epithelial Sodium Channel Blockers; Hydrochlorothiazide; Amiloride; Amiloride, hydrochlorothiazide drug combination
• Other Study ID Numbers: SSP-2; 2012-005113-39 (EudraCT Number)