Effects of Lipoic Acid on Oxidative, Inflammatory and Functional Markers in Asthmatic Patients

Asthma Clinical Trial

Official title:

Exploratory Study of Lipoic Acid Supplementation on Oxidative Stress, Inflammatory and Functional Markers in Asthmatic Patients: Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Clinical Trial.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01221350
• Other study ID #: UdeG-FSL-2010
• Secondary ID: Salud-2010-C01-1
• Status: Completed
• Phase: N/A
• First received: October 14, 2010
• Last updated: October 16, 2013
• Start date: November 2010
• Est. completion date: August 2012

Study information

• Verified date: October 2013
• Source: Centro Universitario de Ciencias de la Salud, Mexico
• Contact: n/a
• Is FDA regulated: No
• Health authority: Mexico: National Council of Science and TechnologyMexico: Secretaria de Salud
• Study type: Interventional

Clinical Trial Summary

The aim of the study is to use the antioxidant and antiinflammatory effects of lipoic acid to improve the quality of life of patients with asthma.

The investigators will administrate 600 mg lipoic acid orally on a daily basis during two months concurrent with the patient anti-asthmatic therapy and evaluate the effects on resulting pulmonary function, inflammatory and oxidative stress biomarkers and health-related quality of life previous to the initial of the treatment and at 60 days of the supplementary therapy.

Description:

Asthma is an inflammatory disease of high prevalence around the world. During development of asthma the presence of oxidative stress has been related to susceptibility and severity of the disease, thus making the use of antioxidant adjuvant therapy with lipoic acid (LA) an interesting treatment option. The objective of the study is to evaluate the efficacy of LA as an adjuvant treatment on functional, antioxidant, inflammatory, quality and control parameters of asthma in human subjects. The trial design is a randomized, double blind, placebo controlled parallel study.

Adult patients (>18 years) with history of mild intermittent to moderate asthma according to the Global Initiative for Asthma (GINA) guidelines were enrolled. It was required a positive skin prick test (>3 mm) for at least two regional allergens. Patients were randomly assigned to receive lipoic acid or placebo for 60 days. Participants had an intermediate visit to the attending physician one month after initial of treatment to monitor adverse events and to undergo laboratory tests.

1. Introduction. Asthma is an inflammatory disease of high prevalence around the world. During development of asthma the presence of oxidative stress has been related to susceptibility and severity of the disease, thus making the use of antioxidant adjuvant therapy with lipoic acid (LA) an interesting treatment option.

2. Study design. A randomized, double blind, placebo controlled parallel study

3. Methods. Participants and interventions: 55 patients with mild to moderate asthma from Hospital Civil "Juan I. Menchaca" in Guadalajara, Jalisco, México were included and randomized in block of 10 to receive; LA (600 mg/day) or placebo for eight weeks from January to October of 2011.

4. Objective. To evaluate the efficacy of LA as an adjuvant treatment on functional, antioxidant, inflammatory, quality and control parameters of asthma in human subjects. Primary outcome: change on Forced expiratory volume in 1 second (FEV1), secondary outcomes were levels of Oxygen radical absorbance capacity (ORAC), glutathione (GSH), glutathione disulfide (GSSG), protein carbonyls, differential count of sputum cells, interleukin-4 (IL-4) and scores of quality of life and control of asthma questionnaires.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 55
• Est. completion date: August 2012
• Est. primary completion date: August 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Outpatients (=18 and = 75 years of age) female or male

• Willingness to participate and comply with procedures by signing a written informed consent

• Moderate/severe persistent allergic rhinitis according to Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines with a history of intermittent, mild persistent or moderate persistent asthma according to GINA guidelines

• Confirmed allergy to at least one of the following allergen preparations: house dust mite f; house dust mite p; cockroach; bush mix; tree mix; grass mix; weed mix, cat; or dog.

• All prior medication washout times had been observed

• Female volunteers of childbearing potential had to agree to use a medically accepted method of contraception

• Negative urine pregnancy test

• Without a concomitant chronic medical condition (e.g., significant cardiovascular disease, diabetes requiring medication, chronic kidney disease, chronic thyroid disease, or coagulation defects)

• Willingness to adhere to the dosing and visit schedules

Exclusion Criteria:

• Pregnant or breastfeeding

• Female who was or intended to become pregnant during the study or within 12 weeks after study completion

• Taking medications prohibited during the study or had not complied with the requirements for the designated washout periods for any of the prohibited medications

• Anatomical abnormalities of the nose (turbinate hypertrophy, septal deviation, polyps)

• Acute or chronic sinusitis currently being treated with antibiotics and/or topical or oral decongestants

• Upper respiratory tract or sinus infection that required antibiotic therapy and had not had at least a 14-day wash-out period prior to the run-in period

• Patients undergoing a progressive course of immunotherapy. Subjects on a regular maintenance schedule prior to the screening visit are eligible for study inclusion; however, subject could not receive hyposensitization treatment within 24 hours prior to any study visit

• Concomitant medical problem

• In a situation or condition that could interfere with participation in the study

• Allergic or sensitivity to the study drug or its excipients

• History of inadequate adherence to treatment

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Supportive Care

Related Conditions & MeSH terms

• Allergic Rhinitis
• Asthma

Intervention

Dietary Supplement:
• Lipoic acid
Lipoic acid 600 mg dose (two 300 mg capsules) once daily in the morning. All patients continued their asthma treatments given by their primary care physician also they were allowed to use rescue medication on demand consisting in inhaled salbutamol. During basal and 8 weeks visits spirometry with bronchodilator challenge, sputum induction and quality of life questionnaires and asthma control test were performed.
• Placebo
Placebo (two capsules filled with 300 mg vehicle) once daily in the morning during 60 days. All patients continued their asthma treatments given by their primary care physician also they were allowed to use rescue medication on demand consisting in inhaled salbutamol. During basal and 8 weeks visits spirometry with bronchodilator challenge, sputum induction and quality of life questionnaires and asthma control test were performed

Locations

Country	Name	City	State
Mexico	Departamento de Fisiología, CUCS, UdeG	Guadalajara	Jalisco
Mexico	Hospital Civil de Guadalajara "Juan I. Menchaca"	Guadalajara	Jalisco

Sponsors (4)

Lead Sponsor	Collaborator
Centro Universitario de Ciencias de la Salud, Mexico	Hospital Civil Juan I. Menchaca, National Council of Science and Technology, Mexico, University of Guadalajara

Country where clinical trial is conducted

Mexico, 

References & Publications (14)

Biewenga GP, Haenen GR, Bast A. The pharmacology of the antioxidant lipoic acid. Gen Pharmacol. 1997 Sep;29(3):315-31. Review. — View Citation

Brozek JL, Bousquet J, Baena-Cagnani CE, Bonini S, Canonica GW, Casale TB, van Wijk RG, Ohta K, Zuberbier T, Schünemann HJ; Global Allergy and Asthma European Network; Grading of Recommendations Assessment, Development and Evaluation Working Group. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol. 2010 Sep;126(3):466-76. doi: 10.1016/j.jaci.2010.06.047. — View Citation

Cho YS, Lee J, Lee TH, Lee EY, Lee KU, Park JY, Moon HB. alpha-Lipoic acid inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma. J Allergy Clin Immunol. 2004 Aug;114(2):429-35. — View Citation

Comhair SA, Erzurum SC. Redox control of asthma: molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal. 2010 Jan;12(1):93-124. doi: 10.1089/ARS.2008.2425. Review. Erratum in: Antioxid Redox Signal. 2010 Feb;12(2):321. Ghio,Andrew [removed]; Kinnula, Vuokko [removed]; Kliment, Corrine [removed];Montuschi, Paolo [removed]; Reddy, Sekhar [removed]; White, Carl [removed]. — View Citation

Juniper EF, Guyatt GH, Epstein RS, Ferrie PJ, Jaeschke R, Hiller TK. Evaluation of impairment of health related quality of life in asthma: development of a questionnaire for use in clinical trials. Thorax. 1992 Feb;47(2):76-83. — View Citation

Kroegel C. [Global Initiative for Asthma Management and Prevention--GINA 2006]. Pneumologie. 2007 May;61(5):295-304. German. — View Citation

Lee KS, Kim SR, Park SJ, Min KH, Lee KY, Jin SM, Yoo WH, Lee YC. Antioxidant down-regulates interleukin-18 expression in asthma. Mol Pharmacol. 2006 Oct;70(4):1184-93. Epub 2006 Jul 5. — View Citation

Miller AL. The etiologies, pathophysiology, and alternative/complementary treatment of asthma. Altern Med Rev. 2001 Feb;6(1):20-47. Review. — View Citation

Patel BD, Welch AA, Bingham SA, Luben RN, Day NE, Khaw KT, Lomas DA, Wareham NJ. Dietary antioxidants and asthma in adults. Thorax. 2006 May;61(5):388-93. Epub 2006 Feb 7. — View Citation

Rahman I. Oxidative stress, chromatin remodeling and gene transcription in inflammation and chronic lung diseases. J Biochem Mol Biol. 2003 Jan 31;36(1):95-109. Review. — View Citation

Riedl MA, Saxon A, Diaz-Sanchez D. Oral sulforaphane increases Phase II antioxidant enzymes in the human upper airway. Clin Immunol. 2009 Mar;130(3):244-51. doi: 10.1016/j.clim.2008.10.007. Epub 2008 Nov 22. — View Citation

Schatz M, Sorkness CA, Li JT, Marcus P, Murray JJ, Nathan RA, Kosinski M, Pendergraft TB, Jhingran P. Asthma Control Test: reliability, validity, and responsiveness in patients not previously followed by asthma specialists. J Allergy Clin Immunol. 2006 Mar;117(3):549-56. — View Citation

Shay KP, Moreau RF, Smith EJ, Smith AR, Hagen TM. Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochim Biophys Acta. 2009 Oct;1790(10):1149-60. doi: 10.1016/j.bbagen.2009.07.026. Epub 2009 Aug 4. Review. — View Citation

Singh U, Jialal I. Alpha-lipoic acid supplementation and diabetes. Nutr Rev. 2008 Nov;66(11):646-57. doi: 10.1111/j.1753-4887.2008.00118.x. Review. Retraction in: Nutr Rev. 2012 Aug;70(8):482. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Spirometric FVC Values at Baseline	Measurement of spirometric predicted parameters at baseline. Forced vital capacity (FVC) is the volume of air that can forcibly be blown out after full inspiration, measured in liters.	Baseline	No
Primary	Spirometric FVC Values at Endpoint	Measurement of spirometric predicted parameters at the baseline and after 60 days of treatment: Forced vital capacity (FVC) is the volume of air that can forcibly be blown out after full inspiration, measured in liters.	60 days	No
Primary	Spirometric FEV1 Values at Baseline	Measurement of spirometric predicted parameters at baseline: Forced expiratory volume in 1 second (FEV1), volume that has been exhaled at the end of the first second of forced expiration.	Baseline	No
Primary	Spirometric FEV1 Values at Endpoint	Measurement of spirometric predicted parameters after 60 days of treatment. Forced expiratory volume in 1 second (FEV1), volume that has been exhaled at the end of the first second of forced expiration.	60 days	No
Primary	Spirometric FEF Values at Baseline	Measurement of spirometric parameters at baseline: Forced expiratory flow (FEF) is the flow (or speed) of air coming out of the lung during the middle portion of a forced expiration.	Baseline	No
Primary	Spirometric FEF Values at Endpoint	Measurement of spirometric FEF after 60 days of treatment: Forced expiratory flow (FEF) is the flow (or speed) of air coming out of the lung during the middle portion of a forced expiration.	60 days	No
Secondary	Induced Sputum of Glutathione (GSH)/Glutathione Disulfide (GSSG) Ratio at Baseline	Induced sputum of GSH and GSSG levels at baseline. The ratio GSH/GSSG is considered an index of antioxidant status and reductive -SH groups. GSH and GSSG were measured by a microplate fluorescent assay.	Baseline	No
Secondary	Induced Sputum of Glutathione (GSH)/Glutathione Disulfide (GSSG) Ratio at Endpoint	Change in the induced sputum of antioxidant parameters GSH and GSSG levels after 60 days of treatment. The ratio GSH/GSSG is considered an index of antioxidant status and reductive -SH groups. GSH and GSSG were measured by a microplate fluorescent assay.	60 days	No
Secondary	Induced Sputum Carbonylated Proteins at Baseline	Proteins can become modified by a large number of reactions involving reactive oxygen species. Among these, carbonylation is an irreversible and unrepairable oxidative reaction. The main protein modifications originated from oxidative stress comprise direct oxidation of aminoacids with a thiol group, such as cysteine, oxidative glycation, and carbonylation. Oxidative protein carbonylation induce protein degradation in a nonspecific manner. Chemically, oxidative carbonylation preferentially occurs at proline, threonine, lysine, and arginine, presumably through a metal-catalyzed activation of hydrogen peroxide to a reactive intermediate. Carbonylation usually refers to a process that forms reactive ketones or aldehydes that can be reacted by 2,4-dinitrophenylhydrazine (DNPH) to form hydrazones. Direct oxidation of side chains of lysine, arginine, proline, and threonine residues, among other aminoacids, produces DNPH detectable protein products	Baseline	No
Secondary	Induced Sputum Carbonylated Proteins at Endpoint	Proteins can become modified by a large number of reactions involving reactive oxygen species. Among these, carbonylation is an irreversible and unrepairable oxidative reaction. The main protein modifications originated from oxidative stress comprise direct oxidation of aminoacids with a thiol group, such as cysteine, oxidative glycation, and carbonylation. Oxidative protein carbonylation induce protein degradation in a nonspecific manner. Chemically, oxidative carbonylation preferentially occurs at proline, threonine, lysine, and arginine, presumably through a metal-catalyzed activation of hydrogen peroxide to a reactive intermediate. Carbonylation usually refers to a process that forms reactive ketones or aldehydes that can be reacted by 2,4-dinitrophenylhydrazine (DNPH) to form hydrazones. Direct oxidation of side chains of lysine, arginine, proline, and threonine residues, among other aminoacids, produces DNPH detectable protein products.	60 days	No
Secondary	Induced Sputum Eosinophils at Baseline	Eosinophils, a prominent feature of asthma, are found in increased numbers in the circulation and sputum, usually in relation to the severity of asthma.	Baseline	No
Secondary	Induced Sputum Eosinophils at Endpoint	Eosinophils, a prominent feature of asthma, are found in increased numbers in the circulation and sputum, usually in relation to the severity of asthma.	60 days	No
Secondary	Inflammatory Interleukin-4 (IL-4) Sputum Levels at Baseline	Inflammatory IL-4 sputum levels after 60 days of treatment. Sputum induction is a semi-invasive technique used to detect and monitor airway inflammation. IL-4 is a Th2 cytokine that promote airway inflammation in asthma. IL-4 drives the production of immunoglobulin E (IgE) in B cells. IL-4 was measured by ELISA.	Baseline	No
Secondary	Inflammatory IL-4 Sputum Levels at Endpoint	Inflammatory IL-4 sputum levels after 60 days of treatment. Sputum induction is a semi-invasive technique used to detect and monitor airway inflammation. IL-4 is a Th2 cytokine that promote airway inflammation in asthma. IL-4 drives the production of IgE in B cells. IL-4 was measured by ELISA.	60 days	No
Secondary	Measurement of Quality of Life With the ACT (Asthma Control Test) at Baseline	Assessment of Quality of life scores with the ACT (Asthma Control Test). The ACT is a way to determine if the asthma symptoms are well controlled. The Asthma Control Test™ (ACT™) is a five question health survey used to measure asthma control in individuals 12 years of age and older. The survey measures the elements of asthma control as defined by the National Heart, Lung, and Blood Institute (NHLBI). ACT is an efficient, reliable, and valid method of measuring asthma control, with or without, lung functioning measures such as spirometry. Each item includes 5 response options corresponding to a 5-point Likert-type rating scale. In scoring the ACT survey, responses for each of the 5 items are summed to yield a score ranging from 5 (poor control of asthma) to 25 (complete control of asthma).	Baseline	No
Secondary	Measurement of Quality of Life With the ACT (Asthma Control Test) at Endpoint	Assessment of Quality of life scores with the ACT (Asthma Control Test). The ACT is a way to determine if the asthma symptoms are well controlled. The Asthma Control Test™ (ACT™) is a five question health survey used to measure asthma control in individuals 12 years of age and older. The survey measures the elements of asthma control as defined by the National Heart, Lung, and Blood Institute (NHLBI). ACT is an efficient, reliable, and valid method of measuring asthma control, with or without, lung functioning measures such as spirometry. Each item includes 5 response options corresponding to a 5-point Likert-type rating scale. In scoring the ACT survey, responses for each of the 5 items are summed to yield a score ranging from 5 (poor control of asthma) to 25 (complete control of asthma).	60 days	No
Secondary	Measurement of Quality of Life With the AQLQ (Asthma Quality of Life Questionnaire) at Baseline	The Asthma Quality of Life Questionnaire (AQLQ) was developed to measure the functional problems (physical, emotional, social and occupational) that are most troublesome to adults (17-70 years) with asthma.; There are 32 questions in the AQLQ and they are in 4 domains (symptoms, activity limitation, emotional function and environmental stimuli). The activity domain contains 5 'patient-specific' questions. This allows patients to select 5 activities in which they are most limited and these activities will be assessed at each follow-up. Patients are asked to think about how they have been during the previous two weeks and to respond to each of the 32 questions on a 7-point scale (7 = not impaired at all - 1 = severely impaired). The overall AQLQ score is the mean of all 32 responses and the individual domain scores are the means of the items in those domains (http://www.qoltech.co.uk/aqlq.html).	Baseline	No
Secondary	Measurement of Quality of Life With the AQLQ (Asthma Quality of Life Questionnaire) at Endpoint	The Asthma Quality of Life Questionnaire (AQLQ) was developed to measure the functional problems (physical, emotional, social and occupational) that are most troublesome to adults (17-70 years) with asthma.; There are 32 questions in the AQLQ and they are in 4 domains (symptoms, activity limitation, emotional function and environmental stimuli). The activity domain contains 5 'patient-specific' questions. This allows patients to select 5 activities in which they are most limited and these activities will be assessed at each follow-up. Patients are asked to think about how they have been during the previous two weeks and to respond to each of the 32 questions on a 7-point scale (7 = not impaired at all - 1 = severely impaired). The overall AQLQ score is the mean of all 32 responses and the individual domain scores are the means of the items in those domains (http://www.qoltech.co.uk/aqlq.html).	60 days	No

External Links

•   Health Sciences Center, University of Guadalajara
•   Hospital Civil de Guadalajara