Lipoic Acid Supplement for Cystine Stone (ALA)

• ClinicalTrials.gov Identifier: NCT02910531
• Recruitment Status: Recruiting
• First Posted: September 22, 2016
• Last Update Posted: July 27, 2020
• Sponsor: University of California, San Francisco
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): University of California, San Francisco

Tracking Information

• First Submitted Date: September 20, 2016
• First Posted Date: September 22, 2016
• Last Update Posted Date: July 27, 2020
• Actual Study Start Date: June 19, 2017
• Estimated Primary Completion Date: December 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 20, 2016)

Cystine stone recurrence [ Time Frame: 3 years ]

The primary efficacy endpoint will be assessed in two ways:

1. symptomatic stone recurrences, defined as renal colic, stone passage, or surgical removal of a stone;
2. 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 20, 2016)

Urinary cystine level [ Time Frame: 3 years ]

The secondary endpoints will be quantitative urinary cystine level determined by 24-hour urine collection.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Lipoic Acid Supplement for Cystine Stone
• Official Title: The Effect of Lipoic Acid Natural Supplement on Cystine Stone Formation
• Brief Summary: 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

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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention
• Condition: Cystinuria

Intervention

• Dietary Supplement: Alpha lipoic acid
  Already mentioned in arm/group descriptions.
• Drug: Placebo
  Already mentioned in arm/group descriptions.

Study Arms

• Experimental: ALA supplement

  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.

  Intervention: Dietary Supplement: Alpha lipoic acid
• Placebo Comparator: Placebo

  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.

  Intervention: Drug: Placebo

Publications *

• Chillarón J, Font-Llitjós M, Fort J, Zorzano A, Goldfarb DS, Nunes V, Palacín M. Pathophysiology and treatment of cystinuria. Nat Rev Nephrol. 2010 Jul;6(7):424-34. doi: 10.1038/nrneph.2010.69. Epub 2010 Jun 1. Review.
• Gomes MB, Negrato CA. Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases. Diabetol Metab Syndr. 2014 Jul 28;6(1):80. doi: 10.1186/1758-5996-6-80. eCollection 2014.
• Ziegler D, Low PA, Litchy WJ, Boulton AJ, Vinik AI, Freeman R, Samigullin R, Tritschler H, Munzel U, Maus J, Schütte K, Dyck PJ. Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care. 2011 Sep;34(9):2054-60. doi: 10.2337/dc11-0503. Epub 2011 Jul 20.
• Scholich H, Murphy ME, Sies H. Antioxidant activity of dihydrolipoate against microsomal lipid peroxidation and its dependence on alpha-tocopherol. Biochim Biophys Acta. 1989 Feb 20;1001(3):256-61.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 20, 2016): 50
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2023
• Estimated Primary Completion Date: December 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Thomas Chi, MD; 415-206-2934; tom.chi@ucsf.edu

Contact: Victoria Hogue, MA; Victoria.Hogue@ucsf.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02910531
• Other Study ID Numbers: 16-20523; 2P20DK100863-03 ( U.S. NIH Grant/Contract ); OPD Grant Number 5716 ( Other Grant/Funding Number: US Food and Drug Administration )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: University of California, San Francisco
• Study Sponsor: University of California, San Francisco
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Thomas Chi, MD; University of California, San Francisco

• PRS Account: University of California, San Francisco
• Verification Date: July 2020