Effect of the Administration of L-arginine vs. Placebo in Patients Diagnosed With Presbyvestibulopathy. (L-ARGPRES)

Effect of the Administration of L-arginine vs. Placebo on the vHIT Result, Vestibular Caloric Tests and Symptoms of Patients Diagnosed With Presbyvestibulopathy.

Presbivestibulopathy is defined as a chronic vestibular syndrome characterized by bilateral vestibulopathy verified with vestibular tests. These tests objectively assess vestibular function: video Head Impulse Test (v-HIT) and Vestibular Caloric Tests. Also, there are some questionnaires that serve us for monitoring and prognosis (Dizziness Handicap Inventory). There is currently no specific treatment for presbyvestibulopathy. The objective of this study is to evaluate the effect of L-arginine vs. placebo on symptoms, changes in the results of vHIT tests of patients diagnosed with presbyvestibulopathy. It will be conducted a randomized, double blind, placebo controled clinical trial. Patients will be men and women who meet the diagnostic criteria for Presbyvestibulopathy of the Barany Society. The sample size will be 12 patients per group. The patients in the experimental group will receive L-arginine at a dose of 3 grams divided into three doses of 1 g (capsules) every 8 hours, for 3 months. Patients in the control group will receive placebo at the same dosage. All patients will receive vestibular rehabilitation exercises. At the beginning and the end of the intervention , the following tests will be carried out: vertigo disability questionnaire, vHIT tests, and the Up and Go time test.

Study Overview

• Status: Withdrawn
• Conditions: Presbyvestibulopathy
• Intervention / Treatment: Drug: L-arginine; Other: Placebo

Detailed Description

Vertigo is a common cause in the otorhinolaryngology consultation; a high incidence of this condition has been reported, since there are reports indicating that up to 80% of the world population has presented an episode of vertigo at some stage of their lives.

In Germany, it has been reported a prevalence of moderate to severe vestibular vertigo is reported, calculated using a representative sample of a 22.9% in adults of 18 to 79 years. In a report of the United States Emergency Department, it has been reported that 3.3% of the first-contact consultations are due to dizziness, of which 32.9% wer of otological or vestibular origin.

Vertigo is classified into two categories: vertigo of central origin and peripheral vertigo. Peripheral vertigo, object of study of this investigation, is originated in the vestibular system, located in the inner ear. Among the differential diagnoses of vertigo of peripheral origin we find presbivestibulopathy, which is a condition characterized by bilateral vestibular dysfunction proven with objective diagnostic tests such as video HIT (vHIT), vestibular caloric tests, among others. In addition, the diagnostic must be done in people over 60 years, and other diagnostic criteria established by the diagnostic criteria for Presbyvestibulopathy of the Barany Society.

The treatment of vertigo, as well of the presbyvestibulopathy, is aimed to stabilize the pathological fluctuations in peripheral vestibular function, as well as promoting central compensation in case of a permanent deficit in vestibular function. Therefore, the drugs used for its treatment their purpose is to regulate the decompensated vestibular activity and to improve the symptoms, but not to suppress the cause that originates the pathology since the mechanism of action of the disease is not well established.

Currently, there is not a first-choice medication for the treatment of vertigo in general, much less for presbyvestibulopathy, since none has show high efficacy and low presence of adverse effects.

Some of the drugs used to treat vertigo include anticholinergics, antihistamines, benzodiazepines and calcium channel blockers.

In the same way, some substances have been used that have shown effectiveness despite the fact that their mechanism of action is unknown or not very clear, sus as betahistine and Gingko biloba.

L-arginine is a precursor amino acid fr the endogenous synthesis of nitric oxide (NO), a molecule produced in the vascular endothelium with vasodilatory, antiatherogenic and antiplatelet action.

To date, there is no evidence of the use of L-arginine for the treatment of vertigo, however, its vasodilator effect as a precursor of NO should favor vascular perfusion in the vestibular system, therefore, it is of interest to know the therapeutic effects of L-arginine for ths treatment of pathology.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• Mexico
  • Jalisco
    • Tonalá, Jalisco, Mexico, 45425
      • CUTonalá

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Men and women.
• Age over 60 years.

• That patient meets the diagnostic criteria established for presbyvestibulopathy by the Classification Committee of the Barany Society:

  • Chronic vestibular syndrome (al least 3 months duration) with at least 2 of the following symptoms:

    • Postural imbalance or unsteadiness
    • Gait disturbance
    • Chronic dizziness
    • Recurrent falls

  • Mild bilateral peripheral vestibular hypofunction documented by at leat 1 of the following:

    • VOR gain measured by video-HIT between 0.6 and 0.8 bilaterally
    • VOR gain between 0.1 and 0.3 upon sinusoidal stimulation on a rotatory chair (0.1 Hz, Vmax=50-60°/sec)
    • Reduced caloric response (sum of bithermal saccadic peak velocity (SPV) on each side between 6 and 25°/sec)
  • Age ≥60 years
  • Not better accounted for by another disease or disorder
• Consent under information

Exclusion Criteria:

• Not being able to rule out the use of antivertigo drugs 1 week prior to study entry.
• Use of vasodilator drugs or antihistamines.
• Orthostatic hypotension
• Cognitive deficit of the patient that prevents him from understanding the implications of the study.
• Known uncontrolled liver or kidney disease.
• Known hypersensitivity to study drugs.
• Chronic use of drugs with an anticoagulant effect.
• Bronchial asthma.

Elimination Criteria:

• Treatment adherence <80% evaluated through registration in an adherence diary and capsules count
• Presence of serious adverse events
• Withdrawal of consent under information

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: L-arginine; L-arginine 3 grams per day, divided into doses of 1 g every 8 hours during 90 days.	Drug: L-arginine; L-arginine 2-amino-5-guanidino-pentanoic acid is a proteinogenic amino acid that is a natural constituent of the protein diet.; Other Names: Arginine
Placebo Comparator: Placebo; Starch 1 gr every 8hr, during 90 days.	Other: Placebo; Starch; Other Names: Starch

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline Video Head Impulse Test vHIT	The vHIT is a simple, rapid test to assess vestibular function. It is based on the physiological aspects of the vestibular ocular reflex (VOR). VOR is a rapid reflex with a duration of 7 to 10 milliseconds and consists of the ability to keep the gaze fixed on an object with rapid and unexpected movements of the head. This study has a specificity and sensitivity of 100% to evaluate the VOR.	Pre-intervention
Final Video Head Impulse Test vHIT	The vHIT is a simple, rapid test to assess vestibular function. It is based on the physiological aspects of the vestibular ocular reflex (VOR). VOR is a rapid reflex with a duration of 7 to 10 milliseconds and consists of the ability to keep the gaze fixed on an object with rapid and unexpected movements of the head. This study has a specificity and sensitivity of 100% to evaluate the VOR.	Final (after 90 days of intervention)
Baseline Dizziness Handicap Inventory	Questionnaire that helps us to know the degree of emotional, functional and physical disability of patients diagnosed with presbyvestibulopathy. In addition, it has been used by different authors as a prognostic value, to know the improvement of pre- and post-treatment patients.	Pre-intervention
Final Dizziness Handicap Inventory	Questionnaire that helps us to know the degree of emotional, functional and physical disability of patients diagnosed with presbyvestibulopathy. In addition, it has been used by different authors as a prognostic value, to know the improvement of pre- and post-treatment patients.	Final (after 90 days of intervention)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline Time up and go Test	It is a simple test that consists of a patient being asked to stand up without support while sitting in a chair without armrests and walk forward for 3 meters and back, the time it takes to do so is timed. Most authors consider that if the duration is greater than 10 seconds, there is a greater risk of falls.	Pre-intervention
Final Time up and go Test	It is a simple test that consists of a patient being asked to stand up without support while sitting in a chair without armrests and walk forward for 3 meters and back, the time it takes to do so is timed. Most authors consider that if the duration is greater than 10 seconds, there is a greater risk of falls.	Final (after 90 days of intervention)
Adverse events	Adverse events will be evaluated through a diary in which patients will record any adverse event presented between visits. Also, it will be verified with direct interview.	Final (after 90 days of intervention)
Initial Audiometry	Audiometry aims to make a graphic record of hearing which is called audiogram. This study help us to detect hearing loss and classiffy it according to its site of origin.	Pre-intervention
Final Audiometry	Audiometry aims to make a graphic record of hearing which is called audiogram. This study help us to detect hearing loss and classiffy it according to its site of origin.	Final (after 90 days of intervention)

Collaborators and Investigators

• Sponsor: Centro Universitario de Tonalá
• Investigators: Principal Investigator: Martha de Nuestra Señora de San Juan Rodríguez, MD, CUTonalá

Publications and helpful links

General Publications

• Bai Y, Sun L, Yang T, Sun K, Chen J, Hui R. Increase in fasting vascular endothelial function after short-term oral L-arginine is effective when baseline flow-mediated dilation is low: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2009 Jan;89(1):77-84. doi: 10.3945/ajcn.2008.26544. Epub 2008 Dec 3.
• Dong JY, Qin LQ, Zhang Z, Zhao Y, Wang J, Arigoni F, Zhang W. Effect of oral L-arginine supplementation on blood pressure: a meta-analysis of randomized, double-blind, placebo-controlled trials. Am Heart J. 2011 Dec;162(6):959-65. doi: 10.1016/j.ahj.2011.09.012. Epub 2011 Nov 8.
• Agrawal Y, Zuniga MG, Davalos-Bichara M, Schubert MC, Walston JD, Hughes J, Carey JP. Decline in semicircular canal and otolith function with age. Otol Neurotol. 2012 Jul;33(5):832-9. doi: 10.1097/MAO.0b013e3182545061.
• Agrawal Y, Van de Berg R, Wuyts F, Walther L, Magnusson M, Oh E, Sharpe M, Strupp M. Presbyvestibulopathy: Diagnostic criteria Consensus document of the classification committee of the Barany Society. J Vestib Res. 2019;29(4):161-170. doi: 10.3233/VES-190672.
• Aggarwal NT, Bennett DA, Bienias JL, Mendes de Leon CF, Morris MC, Evans DA. The prevalence of dizziness and its association with functional disability in a biracial community population. J Gerontol A Biol Sci Med Sci. 2000 May;55(5):M288-92. doi: 10.1093/gerona/55.5.m288.
• Alrwaily M, Whitney SL. Vestibular rehabilitation of older adults with dizziness. Otolaryngol Clin North Am. 2011 Apr;44(2):473-96, x. doi: 10.1016/j.otc.2011.01.015.
• Rodrigues DL, Ledesma ALL, Pires de Oliveira CA, Bahmad F Jr. Effect of Vestibular Exercises Associated With Repositioning Maneuvers in Patients With Benign Paroxysmal Positional Vertigo: A Randomized Controlled Clinical Trial. Otol Neurotol. 2019 Sep;40(8):e824-e829. doi: 10.1097/MAO.0000000000002324.
• Rosengren SM, Young AS, Taylor RL, Welgampola MS. Vestibular function testing in the 21st century: video head impulse test, vestibular evoked myogenic potential, video nystagmography; which tests will provide answers? Curr Opin Neurol. 2022 Feb 1;35(1):64-74. doi: 10.1097/WCO.0000000000001023.
• Scholtz AW, Hahn A, Stefflova B, Medzhidieva D, Ryazantsev SV, Paschinin A, Kunelskaya N, Schumacher K, Weisshaar G. Efficacy and Safety of a Fixed Combination of Cinnarizine 20 mg and Dimenhydrinate 40 mg vs Betahistine Dihydrochloride 16 mg in Patients with Peripheral Vestibular Vertigo: A Prospective, Multinational, Multicenter, Double-Blind, Randomized, Non-inferiority Clinical Trial. Clin Drug Investig. 2019 Nov;39(11):1045-1056. doi: 10.1007/s40261-019-00858-6.
• Sokolova L, Hoerr R, Mishchenko T. Treatment of Vertigo: A Randomized, Double-Blind Trial Comparing Efficacy and Safety of Ginkgo biloba Extract EGb 761 and Betahistine. Int J Otolaryngol. 2014;2014:682439. doi: 10.1155/2014/682439. Epub 2014 Jun 25.

Study record dates

Study Major Dates

• Study Start (Actual): May 2, 2023
• Primary Completion (Estimated): November 1, 2023
• Study Completion (Estimated): December 30, 2023

Study Registration Dates

• First Submitted: May 12, 2023
• First Submitted That Met QC Criteria: July 3, 2023
• First Posted (Actual): July 6, 2023

Study Record Updates

• Last Update Posted (Estimated): February 15, 2024
• Last Update Submitted That Met QC Criteria: February 14, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Vertigo; L-arginine; Presbyvestibulopathy; v-HIT
• Other Study ID Numbers: 160/22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No