Therapeutic Antioxidant Supplementation

Study Overview
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Brief Summary
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A remotely administered study, non-randomized, non-blinded, controlled parallel assignment phase 2 trial to determine if oral inosine or inositol hexaphosphate will provide an effective long-term therapy to combat or slow neural damage progression either concurrently with existing iron chelation therapy or during the natural course of the disorder. Clinical changes in hearing, balance, and mobility, and cognition will be assessed for 36 months through patient-reported outcomes of study assigned assessments.

Detailed Description
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Capsules containing over-the-counter dietary supplement formulas of inosine 500 mg or 500 mg of inositol hexaphosphate(IP6) will be taken orally, two capsules two times per day for 36 months. Initial screening will determine patient arm assignment. Before dosing begins, patients will submit copies of previous audiogram results (3yrs), radiology reports (3yrs), and MRI series (3yrs) if available and complete baseline assessment activities: Montreal Cognitive Assessment (MoCA) administered remotely, Timed Up, and Go (TUG), 2-Minute Walk Test (2-MWT), The Activities-specific Balance Confidence (ABC) Scale, iSS-QoL (custom) patient outcome reported Assessment will take place four times: baseline, end-of-year 1 (12mo), end-of-year 2 (24mo), end-of-study (36mo).

Official Title
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Therapeutic Antioxidant Supplementation for Enhancement of Neural Protection From Free-iron Toxicity in Superficial Siderosis

Conditions
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Superficial Siderosis

Intervention / Treatment
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* Dietary Supplement: Inosine
* Dietary Supplement: IP6


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of iSS (superficial siderosis of the CNS) No illegal drug use No history of myocardial infarction or stroke No history of severe chronic obstructive pulmonary disease Can safely swallow large capsules Exhibits at least one confirmed iSS related symptom: Hearing Loss, Balance, Memory/Cognitive problems Does not have a known hypersensitivity or intolerance to any study antioxidant Has not taken part in another treatment study for any condition within the last 30 days (about four and a half weeks) Not currently pregnant or breastfeeding Exclusion Criteria: Inosine Arm Exclusion : Diagnosed with urate urolithiasis, or recurrent urolithiasis, all unknown type History of Gout History of Kidney Stones P6 Arm Exclusion Long-term anticoagulant Known or suspected active bleed into the CNS Currently undergoing deferiprone chelation therapy Plan to begin deferiprone chelation therapy within three years -

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 77 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Over-the-Counter Dietary Supplement Inosine<br>capsules containing 500 mg of inosine Two capsules Twice Daily Other Name: hypoxanthine 9-β-D-ribofuranoside 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-hydroxymethyl) oxolan-2-yl]-1H-purin-6-one | Dietary Supplement: Inosine<br>* Patients will be dosed with two 500 mg capsules of Inosine twice daily for 36 months<br>|
| Experimental: Over-the-Counter Dietary Supplement IP6<br>capsules containing 500mg of IP6 Two capsules Twice Daily Other Name: Inositol hexaphosphate (1R,2S,3r,4R,5S,6s)-cyclohexane-1,2,3,4,5,6-hexayl hexakis[dihydrogen (phosphate)] | Dietary Supplement: IP6<br>* Patients will be dosed with two 500 mg capsules of IP6 twice daily for 36 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Slow the Rate of Clinical Decline | Deceleration of clinical decline will be quantified by evaluating three primary areas- hearing, balance and mobility, and cognition. End-of-study quantifiable slowing of the historical and year-1 mean rate of decline across all three study areas with a measurable increase on Year-3 iSS-QOL from Year-1 iSS-QOL scoring. | 36 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Efficacy: Rate of Adverse Event Development [Safety and Tolerability} | Therapeutic use of antioxidants through a safe, effective dose range and schedule to the extent that the risk-benefit relationship is acceptable for the patient. Evaluation will include the overall adverse event (AE) and serious AE (SAE) rate. | 36 Months | 
| Clinical Efficacy: Improved Quality of Life | The rate of change in points on the iSS-QoL(custom) from baseline assessment to end-of-study will be scored based on 16 questions with a point range of 1-5. Higher end-of-study scores indicate greater satisfaction. | 36 Months | 
| Clinical Efficacy: Rate of Change in Montreal Cognitive Assessment (MoCA) | The rate of change in points on the Montreal Cognitive Assessment (MoCA) scale from baseline assessment to end-of-study will be assessed for patients in each treatment group. The MoCA assesses attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. Points (range 0-30) are awarded for the correct completion of MoCA tasks. Cognition decline will be defined as ≥ 3pt decline of total MoCA score from baseline assessment to final 36mo testing assessment. | 36 Months | 
| Clinical Efficacy: Rate of Change in Hearing | The baseline audiogram will be compared to the post-study audiogram for each patient. The hearing levels in decibels against the frequency in hertz will be compared pre-study, baseline, and end-of-study for average rate-of-decline. A paired t-test will be used to determine statistical significance in the average difference in the threshold hearing level at any particular frequency. | 36 Months | 
| Clinical Efficacy: Rate of Change in Mobility and Balance | The Timed Up & Go (TUG), 2-Minute Walk Test (2MWT), and Activities-specific Balance Confidence (ABC) Scale will be scored individually. The baseline score will be compared to the annual and end-of-study scores for each patient. A paired t-test will be used to determine statistical significance in the average difference. | 36 Months | 
| Clinical Efficacy: Hemosiderin Reduction (IP6 Arm) | Visible hemosiderin deposition reduction on MRI series from baseline visit to end-of-study. MRIs will be objectively analyzed for changes in iron deposition. | 36 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hemosiderin, Iron Toxicity, Superficial siderosis of the CNS, Infratentorial superficial siderosis, Neurodegenerative disorder, Subpial