The Effect of Magnesium Citrate Supplementation in Restless Legs Syndrome (RLS) (RLS)

The Effect of Magnesium Citrate Supplementation in Patients With Restless Legs Syndrome (RLS) - An Open Label, Prospective, Non Placebo Controlled Pilot Study

The expected results of this study will have a significant impact on the treatment of RLS/WED patients. Magnesium supplementation (if proven to be beneficial) can be utilized as an inexpensive, safer, biologically plausible alternative to dopamine agonists and α2δ calcium-channel ligands.

Study Overview

• Status: Recruiting
• Conditions: Restless Legs Syndrome
• Intervention / Treatment: Dietary supplement: Magnesium Citrate

Detailed Description

This is an open-label, prospective, non-placebo controlled pilot study. 15 subjects with a diagnosis of restless legs syndrome (ICSD-3 diagnostic criteria) will be recruited from OSF Healthcare Saint Francis Medical Center sleep center and Illinois Neurological Institute. RLS/WED patients who meet inclusion and exclusion criteria during the initial clinic visit will be offered study participation. Standard treatment options will be discussed prior to the enrollment. Patients will be reassured that not participating in the study will not affect the future care they receive at OSF HealthCare. The potential risks and benefits of the study will be provided and, if the patient is interested, informed consent will be obtained. If the subject withdraws consent or does not finish both pre and post evaluation, we will replace the subject with another new recruit. The subject will come to the clinic for 2 visits, a pre-magnesium visit and a post-magnesium visit. Following the completion of the pre-magnesium visit, the subject will be given 200 mg elemental magnesium daily (will be instructed to take with food at dinner) for 8 weeks. Both Visits the following study procedures will be performed: magnesium level, (International Restless Legs Syndrome) IRLS scale, Kohnen Restless Legs Syndrome Quality of Life Instrument (KRLS-QOL) scale and (Multiple Suggested Immobilization (MSI) test. The post magnesium visit will be schedule at the completion of the 8 week dose of magnesium.

• Study Type: Interventional
• Enrollment (Anticipated): 15
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Kimberly L Hartwig, RN, BSN; Phone Number: (309) 655-4229; Email: kimberly.hartwig@osfhealthcare.org
• Study Contact Backup: Name: Ashwath R Ravisankar, MBBS; Phone Number: (309) 624-5422; Email: ashwath.r.ravisankar@osfhealthcare.org

Study Locations

• United States
  • Illinois
    • Peoria, Illinois, United States, 61603
      • Recruiting
      • OSF HealthCare Illinois Neurological Institute
      • Contact: Praneeth K Chebrolu, MBBS; Phone Number: 309-624-5419; Email: praneeth.k.chebrolu@osfhealthcare.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 89 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age between 18 and 89.
2. Treatment naïve patients (who are not taking RLS medications for at least 1 year) without coexisting untreated OSA.
3. Diagnosed with RLS based on ICSD -3 criteria
4. INI OSF Sleep medicine outpatient clinic patients.
5. Patients with the ability to provide informed consent.

Exclusion Criteria:

1. Patients who are currently taking magnesium supplements or took magnesium supplements in the last 3 months.
2. Patients not on a stable dosage of medications ( patients requiring dosage changes) that can cause PLMs or worsen RLS will be excluded ( medications include antidepressants such as SSRIs, SNRIs and TCAs and Antihistamines such as Benadryl and Allegra, etc)
3. Patients with a history of chronic kidney disease or end-stage renal disease on Hemodialysis
4. Patients with known allergies to magnesium citrate
5. Patients with congestive heart failure with an ejection fraction less than 40%, bradycardia with a resting heart rate below 60 and systolic blood pressure less than 90 mm of Hg.
6. Patients with diarrhea
7. Patients on gabapentin or pregabalin for pain syndromes
8. Pregnancy. (Absence of pregnancy will be determined via subject self-reporting only. Subject self-reporting of the absence of pregnancy is sufficient screening because the dosage of Magnesium supplement that subjects will be consuming during the study is well below the NIH Tolerable Upper Intake Levels for pregnancy [see "Dietary Recommendations" below], and has been shown to cause no fetal abnormalities or pregnancy complications at the dosage patients will consume for the study. Subjects will be encouraged to practice appropriate measures to avoid pregnancy throughout the entirety of their study participation).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Magnesium Citrate; Magnesium Citrate given orally taken once daily for 8 weeks	Dietary supplement: Magnesium Citrate; Magnesium Citrate 200 mg daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subjective Improvement of Restless Legs Symptoms measured by the International Restless Legs Syndrome Scale (IRLS)	International Restless Leg Syndrome Scale. (IRLS) is a 10 question scale that subjects rate on a scale of 0-4; RLS can be classified as mild, moderate, severe and very severe, if the score is 0-10 (mild), 11-20 (moderate), 21-30 (severe) or 31-40 (very severe) respectively. The lower score reflects less symptom burden. Minimum score is 0 with a Maximum of 40.	Completion of Study participation at 8 weeks
Subjective Improvement of Restless Legs Symptoms measured by the Kohnen Kohnen Restless Legs Syndrome Quality of Life Instrument (KRLS QOL)	Kohnen Restless Legs Syndrome Quality of Life instrument (KRLS QOL) is a self-administered validated patient-reported outcome measure with 12 questions that assess the quality of life in RLS patients. Scores range from 0-60.The lower score represents less impact of RLS symptoms on quality of life.	Completion of Study participation at 8 weeks
Objective Improvement of Restless Legs Symptoms: Multiple Suggested Immobilization test (MSI) Score	Reduction in Multiple Suggested Immobilization test (MSI) discomfort Scores, range: 0-10, with a maximum total sum of 60 per hour. Three 1 hour trials will be conducted. Periodic limb movements during wakefulness will also be measured. Periodic limb movement index (PMLI) reflects periodic limb movements per hour. PMLI value of 0 indicates absence of limb movements and higher scores are often seen in patients with severe RLS	Completion of Study participation at 8 weeks
Correlation of magnesium levels with Kohnen Restless Legs Syndrome Quality of Life Instrument (KRLS) and Multiple Suggested Immobilization test (MSI) scores	Assessment of Magnesium level, lab value will be assess. Normal values range from 1.6 - 2.6 mg/dl. The rationale of measuring serum magnesium level is to analyze whether serum magnesium levels correlate with other subjective and objective RLS outcome measures	Completion of Study participation at 8 weeks

Collaborators and Investigators

• Sponsor: OSF Healthcare System
• Investigators: Principal Investigator: Sasikanth Gorantla, MD, OSF HealthCare Saint Francis Medical Center

Publications and helpful links

General Publications

• Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington (DC): National Academies Press (US); 1997. Available from http://www.ncbi.nlm.nih.gov/books/NBK109825/
• Pratt DP. Restless Legs Syndrome/Willis-Ekbom Disease and Periodic Limb Movements: A Comprehensive Review of Epidemiology, Pathophysiology, Diagnosis and Treatment Considerations. Curr Rheumatol Rev. 2016;12(2):91-112. doi: 10.2174/1573403x12666160223120340.
• Montplaisir J, Boucher S, Poirier G, Lavigne G, Lapierre O, Lesperance P. Clinical, polysomnographic, and genetic characteristics of restless legs syndrome: a study of 133 patients diagnosed with new standard criteria. Mov Disord. 1997 Jan;12(1):61-5. doi: 10.1002/mds.870120111.
• Coleman RM, Miles LE, Guilleminault CC, Zarcone VP Jr, van den Hoed J, Dement WC. Sleep-wake disorders in the elderly: polysomnographic analysis. J Am Geriatr Soc. 1981 Jul;29(7):289-96. doi: 10.1111/j.1532-5415.1981.tb01267.x.
• Scofield H, Roth T, Drake C. Periodic limb movements during sleep: population prevalence, clinical correlates, and racial differences. Sleep. 2008 Sep;31(9):1221-7.
• Garcia-Borreguero D, Guitart X, Garcia Malo C, Cano-Pumarega I, Granizo JJ, Ferre S. Treatment of restless legs syndrome/Willis-Ekbom disease with the non-selective ENT1/ENT2 inhibitor dipyridamole: testing the adenosine hypothesis. Sleep Med. 2018 May;45:94-97. doi: 10.1016/j.sleep.2018.02.002. Epub 2018 Feb 24.
• Leu-Semenescu S, Petiau C, Charley Monaca C, Dauvilliers Y. French consensus: Augmentation syndrome in restless legs syndrome. Rev Neurol (Paris). 2018 Sep-Oct;174(7-8):532-539. doi: 10.1016/j.neurol.2018.06.004. Epub 2018 Jul 25.
• Ito E, Inoue Y. [The International Classification of Sleep Disorders, third edition. American Academy of Sleep Medicine. Includes bibliographies and index]. Nihon Rinsho. 2015 Jun;73(6):916-23. Japanese.
• Ferini-Strambi L, Aarskog D, Partinen M, Chaudhuri KR, Sohr M, Verri D, Albrecht S. Effect of pramipexole on RLS symptoms and sleep: a randomized, double-blind, placebo-controlled trial. Sleep Med. 2008 Dec;9(8):874-81. doi: 10.1016/j.sleep.2008.09.001. Epub 2008 Oct 25.
• Giorgi L, Asgharian A, Hunter B. Ropinirole in patients with restless legs syndrome and baseline IRLS total scores >/= 24: efficacy and tolerability in a 26-week, double-blind, parallel-group, placebo-controlled study followed by a 40-week open-label extension. Clin Ther. 2013 Sep;35(9):1321-36. doi: 10.1016/j.clinthera.2013.06.016. Epub 2013 Aug 9.
• Walters AS, LeBrocq C, Dhar A, Hening W, Rosen R, Allen RP, Trenkwalder C; International Restless Legs Syndrome Study Group. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med. 2003 Mar;4(2):121-32. doi: 10.1016/s1389-9457(02)00258-7.
• Abetz L, Arbuckle R, Allen RP, Garcia-Borreguero D, Hening W, Walters AS, Mavraki E, Kirsch JM. The reliability, validity and responsiveness of the International Restless Legs Syndrome Study Group rating scale and subscales in a clinical-trial setting. Sleep Med. 2006 Jun;7(4):340-9. doi: 10.1016/j.sleep.2005.12.011. Epub 2006 May 19.
• Kohnen R, Martinez-Martin P, Benes H, Trenkwalder C, Hogl B, Dunkl E, Walters AS. Validation of the Kohnen Restless Legs Syndrome-Quality of Life instrument. Sleep Med. 2016 Aug;24:10-17. doi: 10.1016/j.sleep.2016.04.019. Epub 2016 Aug 3.
• Sforza E, Johannes M, Claudio B. The PAM-RL ambulatory device for detection of periodic leg movements: a validation study. Sleep Med. 2005 Sep;6(5):407-13. doi: 10.1016/j.sleep.2005.01.004. Epub 2005 Apr 1.
• Garcia-Borreguero D, Kohnen R, Boothby L, Tzonova D, Larrosa O, Dunkl E. Validation of the Multiple Suggested Immobilization Test: A Test for the Assessment of Severity of Restless Legs Syndrome (Willis-Ekbom Disease). Sleep. 2013 Jul 1;36(7):1101-1109. doi: 10.5665/sleep.2820.
• De Cock VC, Bayard S, Yu H, Grini M, Carlander B, Postuma R, Charif M, Dauvilliers Y. Suggested immobilization test for diagnosis of restless legs syndrome in Parkinson's disease. Mov Disord. 2012 May;27(6):743-9. doi: 10.1002/mds.24969. Epub 2012 Mar 21.
• Marshall NS, Serinel Y, Killick R, Child JM, Raisin I, Berry CM, Lallukka T, Wassing R, Lee RW, Ratnavadivel R, Vedam H, Grunstein R, Wong KK, Hoyos CM, Cayanan EA, Comas M, Chapman JL, Yee BJ. Magnesium supplementation for the treatment of restless legs syndrome and periodic limb movement disorder: A systematic review. Sleep Med Rev. 2019 Dec;48:101218. doi: 10.1016/j.smrv.2019.101218. Epub 2019 Oct 16.
• Hornyak M, Voderholzer U, Hohagen F, Berger M, Riemann D. Magnesium therapy for periodic leg movements-related insomnia and restless legs syndrome: an open pilot study. Sleep. 1998 Aug 1;21(5):501-5. doi: 10.1093/sleep/21.5.501.
• Bartell S, Zallek S. Intravenous magnesium sulfate may relieve restless legs syndrome in pregnancy. J Clin Sleep Med. 2006 Apr 15;2(2):187-8.
• [The unveiling ceremony of the monument of the Unknown Nurse]. Noseleutike. 1992 Jan-Mar;31(139):19-23. No abstract available. Greek, Modern.
• Coudray C, Rambeau M, Feillet-Coudray C, Gueux E, Tressol JC, Mazur A, Rayssiguier Y. Study of magnesium bioavailability from ten organic and inorganic Mg salts in Mg-depleted rats using a stable isotope approach. Magnes Res. 2005 Dec;18(4):215-23.
• Lowenstein FW, Stanton MF. Serum magnesium levels in the United States, 1971-1974. J Am Coll Nutr. 1986;5(4):399-414. doi: 10.1080/07315724.1986.10720143.
• Michaud M, Poirier G, Lavigne G, Montplaisir J. Restless Legs Syndrome: scoring criteria for leg movements recorded during the suggested immobilization test. Sleep Med. 2001 Jul;2(4):317-321. doi: 10.1016/s1389-9457(00)00072-1.

Helpful Links

• Manual used for scoring sleep and associated events

Study record dates

Study Major Dates

• Study Start (Actual): July 10, 2020
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: July 5, 2020
• First Submitted That Met QC Criteria: July 7, 2020
• First Posted (Actual): July 8, 2020

Study Record Updates

• Last Update Posted (Actual): February 17, 2023
• Last Update Submitted That Met QC Criteria: February 15, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: RLS, Magnesium Citrate, Magnesium
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Dyskinesias; Psychomotor Disorders; Parasomnias; Syndrome; Psychomotor Agitation; Restless Legs Syndrome; Gastrointestinal Agents; Cathartics; Magnesium citrate
• Other Study ID Numbers: 1567451

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Plan to share an abstract and data analysis results.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No