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| STUDY PROTOCOL |
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| Year : 2016 | Volume
: 1
| Issue : 3 | Page : 134-140 |
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L-carnitine for reducing cardio-metabolic risk in patients with obstructive sleep apnea: study protocol of a randomized, double-blind, placebo-controlled trial
Marta Stelmach-Mardas1, Paweł Bogdański2, Marcin Mardas3, Monika Szulinska2, Jarosław Walkowiak4, Tomasz Piorunek5
1 Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; Department of Paediatric Gastroenterology and Metabolic Disorders, Poznan University of Medical Sciences, Poznan, Poland
2 Department of Education and Obesity Treatment and Metabolic Disorders, Poznan University of Medical Sciences, Poznan, Poland
3 Department of Human Nutrition and Hygiene, Poznan University of Life Sciences, Poznan, Poland
4 Department of Paediatric Gastroenterology and Metabolic Disorders, Poznan University of Medical Sciences, Poznan, Poland
5 Department of Pulmonology, Alergology and Respiratory Oncology, Poznan University of Medical Sciences, Poznan, Poland
| Date of Web Publication | 13-Oct-2016 |
Correspondence Address:
Marta Stelmach-Mardas
Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; Department of Paediatric Gastroenterology and Metabolic Disorders, Poznan University of Medical Sciences, Poznan, Poland
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2468-5658.191356
Background: Dyslipidemia and insulin resistance are diagnosed very often in obstructive sleep apnea patients; therefore the novel therapies based on the components involved in lipid and carbohydrates metabolism are still being searched for. L-carnitine may play a positive role in energy metabolism and in the reduction of cardio-metabolic risk factors. The present trial aims to investigate the potential role of L-carnitine in lipid and carbohydrates metabolism with precision non-invasive measurements in obstructive sleep apnea patients.
Methods/Design: This ongoing study is a randomized, double-blind, placebo controlled, 2-arm parallel-group trial. A total of 80 eligible patients aged 18-80 with obstructive sleep apnea will be randomized in a 1:1 ratio to receive either placebo (placebo group) or L-carnitine (study group) for 8 weeks. Primary outcome measures are changes in lipid and carbohydrates metabolism. Secondary outcome are changes in non-invasive haemodynamic measurements: central blood pressure, pulse wave velocity and peripheral arterial stiffness (secondary outcome) will be assessed. All outcome measures will be assessed at baseline, 4, 8 weeks, and 6 months post-intervention.
Discussion: The novelty of this randomized controlled trial is the supplementation of L-carnitine connected with a mobile application for measuring medication adherence. Combined application of non-invasive haemodynamic measurement with assessment of lipid and glucose metabolism will allow us to examine the potential merit of routine supplementation of L-carnitine in patients suffering from obstructive sleep apnea.
Trial registration: ClinicalTrials.gov identifier: NCT02645942, registered on 29 December 2015.
Ethics: This trial has been approved by Bioethical Committee at Poznan University of Medical Sciences (approval No. 962/15) and will be performed in accordance with the Declaration of Helsinki, formulated by the World Medical Association.
Informed consent: Signed informed consent will be obtained from each patient prior to the trial. Keywords: clinical trial; risk factors; supplementation; lipid metabolism; carbohydrates metabolism; pulse wave velocity; peripheral arterial stiffness; randomized controlled trial
How to cite this article:
Stelmach-Mardas M, Bogdański P, Mardas M, Szulinska M, Walkowiak J, Piorunek T. L-carnitine for reducing cardio-metabolic risk in patients with obstructive sleep apnea: study protocol of a randomized, double-blind, placebo-controlled trial. Clin Trials Degener Dis 2016;1:134-40 |
How to cite this URL:
Stelmach-Mardas M, Bogdański P, Mardas M, Szulinska M, Walkowiak J, Piorunek T. L-carnitine for reducing cardio-metabolic risk in patients with obstructive sleep apnea: study protocol of a randomized, double-blind, placebo-controlled trial. Clin Trials Degener Dis [serial online] 2016 [cited 2023 Sep 30];1:134-40. Available from: https://www.clinicaltdd.com/text.asp?2016/1/3/134/191356 |
| Introduction | |  |
The role of L-carnitine (L-C) in energy metabolism has been widely investigated. Meat, poultry and dairy products are good sources of L-C in the habitual diet; however L-C can be also synthetized from methionine and lysine (Liedtke et al., 1982; Johri et al., 2014). So far there is a lack of information regarding the potential ability of L-C to ameliorate components of obstructive sleep apnoea (OSA). Currently, OSA is under-recognized cardio-metabolic disorder affecting up to 35% of obese individuals (Ahmed et al., 2010; Mirrakhimov, 2012). OSA is characterized by repetitive partial or complete closure of the upper airway during sleep that results in hypoxemia and hypercapnea and contributes to arousals frequently associated with it and leads to an increase in myocardial oxygen demand (Dorasamy, 2007). Dyslipidemia and insulin resistance are diagnosed very often in OSA patients; therefore the novel therapies based on the components involved in lipid and carbohydrates metabolism are still being searched for.
L-C can act as a cofactor for oxidation of fatty acids and be involved in the transport of long-chain fatty acids (LCFAs) (Mingorance et al., 2012). L-C supplementation has been shown to influence prevention and regression of atherosclerosis by reducing the concentration of triglycerides (TG) and low-density lipoprotein (LDL) in animal models (Johri et al., 2014). Moreover, both ester forms: acetyl-L-carnitine and priopionyl-L-carnitine (PLC) play an important role in glucose metabolism (Broderick et al., 1992; Noland et al., 2009; Muoio et al., 2012). Furthermore, acetyl-L-carnitine may stimulate glucose oxidation and priopionyl-L-carnitine may enhance adenosine triphosphate (ATP) efflux (Migrino et al., 2011). There is also data showing the beneficial influence of L-C on blood pressure in patients with pulmonary hypertension and comorbid OSA (El-Beshlawy et al., 2006). So far, the supplementation of carnitine in the L-C form seems to be a promising therapy with no toxicity up to 2,000 mg per day that is additionally recommended for patients suffering from cardiovascular disease (CVD) (Hathcock and Shao, 2006). Recently, a meta-analysis showed that the supplementation with L-C can reduce all-cause mortality by ~27% in CVD (DiNicolantonio et al., 2013).
Although evidence exists in the potential utility of L-C in CVD treatment, there is a lack of information regarding the metabolic response to L-C treatment in OSA patients. We designed this trial to investigate the potential effect of L-C on lipid and carbohydrates metabolism (total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), TG, fasting blood glucose, insulin), non-invasive measurements of central blood pressure, pulse wave velocity and peripheral arterial stiffness in OSA patients.
| Methods/Design | | |
Study design
This randomized, double-blind, placebo controlled, 2-arm parallel-group trial will be performed at Poznan University of Medical Sciences in Poland. Polish individuals diagnosed with OSA will be eligible for the study. Approximately 200 patients will be screened according to the following eligibility criteria: OSA, signed informed consent in two copies, clinical examination, medical history, drug treatment, polysomnography and biochemical measurements. Screening will take place up to 14 days prior to randomization. Patients will be randomized in a 1:1 ratio to either placebo group or study group. At baseline, 4, 8 weeks, and 6 months post-intervention, lipid and carbohydrates metabolism (primary outcome) including TC, LDL-C, HDL-C, TG, fasting blood glucose, insulin, and non-invasive haemodynamic measurements of central blood pressure, pulse wave velocity and peripheral arterial stiffness (secondary outcome) will be determined.
Inclusion criteria
Patients presenting with all of the following conditions will be considered for admission to this trial: OSA (AHI > 5) (Foster et al., 2009), treatment with continuous positive airway pressure for at least 6 months before study screening, disturbed lipid metabolism (according to the National Health and Nutrition Examination Survey: LDL-C > 100 mg/dL or TG >150 mg/dL (Ford et al., 2003)) or use of hypolipidemic drugs, disturbed glucose metabolism (diabetes mellitus or impaired glucose tolerance or impaired fasting glucose) according to American Diabetes Federation (American Diabetes Association, 2014) or use of hypoglycaemic drugs, age over 18 years, continued habitual diet during the study period, Karnofsky performance status score ≥ 80 (Karnofsky and Burchenal, 1949), and signed written informed consent.
Exclusion criteria
Patients presenting with any one or more of the following will be excluded from this trial: newly diagnosed with OSA and individuals treated with continuous positive airway pressure, in the presence of lung dysfunctions, use of hypoglycaemic and hypolipidemic drugs, modification of hypolipidemic or hypoglycaemic treatment during the study period, pregnancy or lactation, cancer (excluding curatively treated individuals with no evidence of diseases for 5 years), severe liver and kidney diseases (aspartate aminotransferase and alanine aminotransferase > 3 × the upper limit of normal (ULN), bilirubin > 1.5 × ULN, creatinine > 1.5 × ULN), known sensitivity to any component of the study supplement, diagnosed with CVD (myocardial infarct, stroke, angina pectoris). An active drug or alcohol abuse, legal incompetence, limited legal incompetence, any uncontrolled medical condition that may put studied patients at high risk during study period will constitute additional exclusion criteria.
Sample size
We assumed the mean difference in cholesterol will be 0.7 mM with a standard deviation of 1.0 between the two groups. Based on 0.8 power to detect a significant difference (α = 0.05, two-sided), the required sample size will be 80 (40 patients per group) since an overall dropout rate of 10 % was anticipated. Size caculation will be performed using a Statistica Software package (StatSoft Inc., Tulsa, OK, USA)
Recruitment
Caucasian patient will be recruited from the Department of Pulmonology, Allergology and Respiratory Oncology, the Poznan University of Medical Sciences in Poland. The information about recruitment will be posted on the clinic website, via e-mail and directly in outpatient's clinic. The potential interest of individuals and assessment of eligibility will be recorded in our database. The schedule of enrollment is shown in [Figure 1] .
Randomization
After screening, all patients will be randomized in a 1:1 ratio to either placebo group or study group (receiving L-C for 8 weeks). The randomization list will be stratified by age, sex, body mass and severity of OSA by Sealed Envelope Ltd. service (London, UK).
Blinding and unblinding
Study medication will be administered using double-blind procedures. No unblinding will be performed during the study. If unblinding is deemed necessary, the investigator will perform emergency unblinding.
Interventions
Randomized patients will receive orally either placebo or L-C once a day for 8 consecutive weeks. All supplements will be packed in a white box. Because this is a double-blind study, vial labels will contain a unique identification number that will not disclose to the patient or investigator if L-C or matching placebo is included. The daily amount of L-C will be 1,400 mg. The treatment will be administrated under supervision of experienced nutritionist and medical doctor.
Outcome measures
The lipid and carbohydrates metabolism, non-invasive measurements of central blood pressure, pulse wave velocity and peripheral arterial stiffness, and other measurements regarding diet, quality of life and sleep, polysomnography, and anthropometry appraisals will be assessed at baseline, 4, 8 weeks, and 6 months post-intervention.
Primary outcome measures
- Lipid and carbohydrates metabolism: All blood samples will be collected after 12 hours of overnight fasting in the first, fourth and eighth week of the study and at 6-month follow up. The lipid profile containing serum TC, HDL-C and TG will be determined by enzymatic colorimetric methods (Roche Diagnostics Corp., Indianapolis IN) in the studied patients (Allain et al., 1974; Roeschlau et al., 1974; Siedel et al., 1993; Sugiuchi et al., 1995). Cholesterol in LDL-C fraction will be calculated according to Friedewald and Levy (1972). The level of fasting blood glucose will be determined by the routine enzymatic method. Plasma insulin will be determined by immunoassay (DIA Source Immunoassays S.A., Nivelles, Belgium). Insulin resistance in the studied patients will be evaluated according to the homeostasis model assessment-insulin resistance (HOMA-IR) (Matthews et al., 1985). Serum aspartate aminotransferase and alanine aminotransferase concentration will be measured using enzyme immunoassay (R&D System, Inc., Minneapolis, MN, USA). The level of creatinine and bilirubin will be assessed by the routine used methods.
Secondary outcome measures
- Non-invasive haemodynamic and blood pressure measurements: A precision non-invasive measurement and analyses of central blood pressure, pulse wave velocity and peripheral arterial stiffness will be performed by the SphygmoCor XCEL (AtCor Medical, Wes Ryde, Australia), a cuff-based device that meets the criteria of the ARTERY Society guidelines for validation of non-invasive haemodynamic measurement devices (Wilkinsona et al., 2010). This device records the carotid-femoral pulse wave velocity (cfPWV) between the diastolic foot of the carotid waveform, recorded by tonometric applanation, and the diastolic foot of the simultaneously recorded femoral pulse, detected using the volume displacement waveform measured in a cuff placed around the upper thigh, inflated to subdiastolic pressure (Butlin et al., 2013). For each patient the average of the three readings taken with each device will be calculated, and used in the subsequent analysis. We will use the analysis method described by Bland and Altman (1986).
- Blood pressure (BP) will be measured during each study visit with a digital electronic tensiometer (Omron Corp., Kyoto, Japan). Regular or large adult cuffs will be used, depending on arm circumference of the patient. BP measurement will be performed in accordance with the guidelines of the European Society of Hypertension (Mancia et al., 2013).
Other outcome measures
- Sleepiness: assessed by the Epworth Sleepiness Scale (Johns, 1991). Patients will be asked to rate their tendency to become sleepy on a scale of 0, no chance of dozing, to 3, high chance of dozing. Its total score ranges from 0 to 24. The scale will estimate whether patients are experiencing excessive sleepiness.
- Quality of life: assessed by the World Health Organization Quality-of-Life Scale (WHOQOL) (WHOQOL, 1995).
- Polysomnography: used as the standard method for OSA diagnosis. The recommendations of the American Academy of Sleep Medicine recommendations (Iber et al., 2007) regarding filters, sample signal rates and configuration will be used. Flow tracing will be provided by a nasal cannula and thermistor, thoracoabdominal motion by piezoelectric bands. Oxygen saturation will be measured with a pulse oximeter. Polysomnography will be analyzed by experienced pulmonologists.
- Dietary intake: evaluated by 24-hour dietary recalls with a dietician checking the completion of data (Dietetyk, National Institute of Food and Nutrition, Warsaw, Poland). The local tables of food portion sizes and the weights of foods displayed in photos will be used to estimate the amounts of food consumed according to the food records that will be converted to gram weights. Several nutritional factors including total energy, proteins, fats, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, dietary fiber, carbohydrates and cholesterol will be surveyed.
- Anthropometry appraisals: The anthropometrical parameters will include body weight, body height, waist and hip circumferences. Body mass index and waist to hip ratio will be calculated to determine the obesity degree in patients (Cole, 1990).
Safety assessment
Any adverse event will be recorded according to Common Terminology Criteria for Adverse Events v4.0. If clinically significant adverse events, severe laboratory abnormality, intercurrent illness, or other medical condition in occurrence, discontinued administration of study medication will be suggested.
Compliance
The incorporation in the daily practice of a simple tool for measurement of medication non-adherence will improve patient-reported discrepancies between cap openings and actual intakes. We will use technologies of mobile phones with real time feedback facilities to evaluate the feasibility and potential of assessing precisely the change in drugs intake. We will create easy-to-apply smartphone apps to act as a reminder and record drugs intake. This tool will allow the researcher to select the language for the patients and will monitor the frequency and progress of respond. The collected data will be stored in our database and further linked with biochemical data expressed as a change in the concentration at baseline and post-intervention period with statistical algorithms. All data will be finally transferred to the patients. A correct quantification of the drugs intake will allow us to manage more personalized intervention in the future, which will be more reliable in the assessment of obtained results. Furthermore, it can be implemented in different clinical studies and spread out into stakeholders. Nevertheless, we will also use in parallel contemporaneous notes and interview during the study visits in order to assess the reliability of the designed tool.
The compliance of the patients will be checked during the visits and also via telephone during the conduct of the study. All concomitant medications used (including herbal supplements) will be recorded in electronic database. The patients will be asked to continue their habitual diet. Moreover, they are also advised that free withdrawal is available any time, for any reason, and without prejudice. The reason for withdrawal and the date of discontinuation will be recorded in our database.
Statistical analysis
Intention-to-treat and per-protocol analysis will be performed. The results will be given as mean values. The D'Agostino-Pearson omnibus normality test will be performed to assess the normality of data. Comparison of continuous variables between baseline and the last day of intervention will be carried out using analysis of variance or Wilcoxon signed-rank test. The independent-samples t-test or Mann-Whitney U test will be used to evaluate inter-group differences at baseline.
For analysis of central blood pressure, pulse wave velocity and peripheral arterial stiffness, we will use a scatter plot of mean values for each patient that will be further inspected to determine trends in the obtained data. The slope, intercept (with 95% confidence interval), root-mean-square error and correlation coefficient r will be given. The difference between values obtained by the two measurements will be plotted against the mean for both measurements and inspected to determine any bias (Bland and Altman, 1986; Butlin et al., 2013). Additionally, the correlation coefficient r will be calculated to check for bias formally.
Statistical calculations will be carried out using STATISTICA software (SatSoft, Inc., Tulsa, OK, USA).
| Discussion | | |
The novelty of this randomized controlled trial is to investigate the effects of L-C supplementation on obstructive sleep apnea patients with electronic monitoring of medication adherence. This study integrates also additional important components of OSA examination. We will measure and analyze the changes of central blood pressure, pulse wave velocity and peripheral arterial stiffness using a precision non-invasive tool. Moreover, the analysis of biomarkers changes, being associated with lipid and glucose metabolism, during the supplementation, will allow us to examine the benefit and potential merit of routine supplementation of L-C in patients suffering from OSA being recognized also as cardio-metabolic disorder.
Strengths of this study include the randomized controlled trial design, homogenous population being also representative for Eastern Europe. Results of this study will provide evidence regarding the potential benefit of L-C supplementation in OSA patients. The use of simply applying electronic devices in the monitoring of medication non-adherence can be a step forward in routine clinical practice. If the obtained results are positive, taking into account low cost of L-C supplementation, it could be used to reduce the cardio-metabolic risk factors and have a strong influence on the treatment of OSA. In obese individuals the L-C supplementation could also positively influence body weight management. Moreover, we will also assess the intake of L-C with diet, which will help to describe the potential deficiency of L-C in OSA patients.
Limitation of this study include the enrollment of only Caucasian population, therefore the obtained results may not be applicable for other races. We have to take into account possible loss in follow-up; however the sample size was corrected by an additional 10%. Self-assessment of dietary intake, sleepiness and quality of life may lead to bias in the recorded data.
A challenge in the treatment of OSA patients is to provide additional support related to beneficial changes in dietary behaviors. The use of beneficial for health supplements and implementation of non-invasive tools for observation of changes in cardio-metabolic risk factors is of high interest scientific community. Furthermore, development of simple on-line tools for aiding the assessment and management of the medication non-adherence is an advantage in the clinical practice.
Trial status
The study is ongoing at the time of submission.[31]
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Conflicts of interest
None declared.
Author contributions
MSM participated in the design of the study and drafted the manuscript. PB, MM, JW, and TP participated in the design of the study. PB, MM, MS, JW, and TP critically revised the manuscript. All authors read and approved the final manuscript.
Plagiarism check
This paper was screened twice using CrossCheck to verify originality before publication.
Peer review
This paper was double-blinded and stringently reviewed by international expert reviewers.
[Figure 1]
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