Lipoic Acid Supplement for Cystine Stone

Study Overview
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Brief Summary
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This study evaluates how daily alpha lipoic acid supplementation affects cystine kidney stone recurrence. Half of the subjects will receive 1200 mg alpha lipoic acid orally daily for three years, while the other half will receive a placebo. The funding source for this clinical trial is FDA OOPD.

Detailed Description
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Cystinuria is a rare inherited autosomal recessive disorder of the kidney that is the result of a defect in the dibasic amino acid transporter in the renal proximal tubule and small intestine. Supersaturation of cystine in the urine produces crystals that precipitate and form calculi, which can be a cause of obstruction, infection, and chronic kidney disease (Chillarón 2010). One potential therapeutic is a thiol-containing compound alpha-lipoic acid (thioctic acid, 5-(1,2-dithiolan-3- yl) pentanoic acid, ALA). It is an over-the-counter supplement with antioxidant property. Once ALA is transported into the cell, it is reduced to dihydrolipoic acid (DHLA). Both ALA and DHLA have direct antioxidant activity (Scholich 1989), and they can regenerate endogenous antioxidants including ascorbic acid and vitamin E. It can also increase intracellular coenzyme Q10 and glutathione levels. ALA and DHLA also have additional biochemical effects as metal chelators, reactive oxygen species scavengers, and modulators of signaling transduction of several pathways (Gomes 2014). While the potential therapeutic effects of ALA have been studied in a number of diseases including, for example, Alzheimer's disease, obesity, cardiovascular disease, hypertension, and several cancers (Gomes 2014), the efficacy of ALA has been best studied in type 2 diabetic peripheral neuropathy (Ziegler 2011). In our lab, results from a mouse model of cystinuria show that ALA markedly slows the initiation of cystine stone formation as well as the growth of existing stones. Given this history in clinical medicine and, most importantly, based upon our positive findings of ALA effectiveness in a mouse model of cystinuria, we propose a pilot study on the use of this molecule in cystinuric patients.

Official Title
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The Effect of Lipoic Acid Natural Supplement on Cystine Stone Formation

Conditions
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Cystinuria

Intervention / Treatment
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* Dietary Supplement: Alpha lipoic acid
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented cystinuria on prior 24-hour urine collection and/or stone analysis; history of previous cystine kidney stones. Being able and willing to provide consent. Exclusion Criteria: Poorly controlled diabetes mellitus (hemoglobin A1C > 8.0% for more than 1 year). Current alpha-lipoic acid administration at the time of screening or within the last year prior to screening. Vulnerable populations including incarceration status. Unable to give informed consent. Non-English primary language. Pregnancy, lactation, or child-bearing age without birth control devices. Anticipation of pregnancy during the study period. Serious illness likely to cause death within the next 5 years.

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALA supplement<br>Clinical data including medical history, plain KUB x-ray and renal ultrasound, routine blood work and 24-hour urine collections for all subjects will be collected as part of normal clinical care at routine clinical visit every 4 months. Subjects in this study arm will be taking one supplement tablet containing 1200 mg of alpha lipoic acid orally once daily for three years. At the end of the three years of study drug treatment, all subjects will undergo a low dose non-contrast CT scan to look for a silent change in stone size. | Dietary Supplement: Alpha lipoic acid<br>* Already mentioned in arm/group descriptions.<br>|
| Placebo Comparator: Placebo<br>Clinical data including medical history, plain KUB x-ray and renal ultrasound, routine blood work and 24-hour urine collections for all subjects will be collected as part of normal clinical care at routine clinical visit every 4 months. Subjects in this study arm will be taking one placebo tablet containing 10 mg of sucrose orally once daily for three years. At the end of the three years of study drug treatment, all subjects will undergo a low dose non-contrast CT scan to look for a silent change in stone size. | Drug: Placebo<br>* Already mentioned in arm/group descriptions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cystine stone recurrence | The primary efficacy endpoint will be assessed in two ways: symptomatic stone recurrences, defined as renal colic, stone passage, or surgical removal of a stone; silent stone recurrences, classified as stone growth or new stones, diagnosed on the basis of renal ultrasound, plain KUB x-ray, or if clinically indicated, computed tomography. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary cystine level | The secondary endpoints will be quantitative urinary cystine level determined by 24-hour urine collection. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystinuria, Kidney stone, Alpha lipoic acid