Oral Vitamin B12 as Potential Treatment of Recurrent Aphthous Stomatitis

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Brief Title

Oral Vitamin B12 as Potential Treatment of Recurrent Aphthous Stomatitis


Brief Summary

      Background:

      Recurrent aphthous stomatitis is a common phenomenon in Primary Medicine.Frequency of the
      phenomenon can be as high as 25% of the general population and the recurrence of the problem
      can be up to 50%.Different approaches for treatment are described: treatment with various
      natural vitamins , local ointments , disinfectant agents for local treatment , local
      antibiotic ointments , NSAID, local cortisone-steroids , and even medication on the basis of
      immune-depressants of the immune system and systematic steroids .

      Methods:

      A double-blind study of daily administration of sublingual Vitamin B12 tablets manufactured
      by Solgar (each tablet containing 1000 mcg. of Vitamin B12) opposed to placebo tablets.

      Purpose of the research:

      To investigate the effect of Vitamin B12 on the frequency of recurrent canker sores of the
      mouth (RAS).

      Study hypothesis:

      Treatment with vitamin B12 will reduce the recurrence rate and will diminish the
      symptomatology of RAS episodes.
    

Detailed Description

      Scientific Background:

      Recurrent painful canker sores within the mouth (Recurrent aphthous stomatitis, RAS) are a
      common phenomenon in Primary Medicine (1,2). The term "aphthai" in Greek means a condition
      within the mouth and is attributed to Hippocrates. (1) RAS is characterized by small,
      recurrent, painful canker sores in the mouth. These sores have characteristic round or
      elliptical ulcerations with sharp edges. The sores have a red halo surrounding them and a
      base with a yellowish or grey color (1,3). Frequency of the phenomenon can be as high as 25%
      of the general population and the recurrence of the problem can be up to 50% (2).

      RAS is idiopathic in most cases. A possible cause is frequently a local injury or stress.
      Other possible causes include systemic illness, nutritional deficiency, sensitivity or
      allergy to certain foods, illness that effect the immune system and medication. Even though
      RAS can be associated with celiac disease or Behcet's disease, most of the cases patients are
      presented with this problem there is no other complaint or symptom and the patient is
      considered healthy.

      Since the cause of the condition is unknown, Diagnosis is based on the patient's history and
      on a physical examination. There is no laboratory test that can substantiate or negate the
      condition (4-7).

      In medical literature different approaches for treatment are described: treatment with
      various natural vitamins (8), local ointments (9), disinfectant agents for local treatment
      (10), local antibiotic ointments (11), non-steroidal anti-inflammatory ointments (NSAID)(12),
      local cortisone-steroids (13), and even medication on the basis of immune-depressants of the
      immune system and systematic steroids (14-16).

      Most of these approaches that have been tried up to now have given temporary relief and only
      some have controlled the pain and healed the sores (16, 9-13).

      In the past we have reported successfully treating three patients suffering from RAS with
      Vitamin B12 (17). We also have data regarding the treatment of 15 RAS patients. (This data
      has not yet been published.) The frequency of sores in this group had been an average of 1.5
      episodes per month before treatment with Vitamin B12. During treatment the frequency
      decreased to 0.1 episode per month. As far as we know, there is no research using a
      double-blind design that investigated Vitamin B12 treatment of patients suffering from RAS.

      Purpose of the research:

      To investigate the effect of Vitamin B12 on the frequency of recurrent canker sores of the
      mouth (RAS).

      Methods:

      A double-blind study of daily administration of sublingual Vitamin B12 tablets manufactured
      by Solgar (each tablet containing 1000 mcg. of Vitamin B12, mannitol, stearic acid, Magnesium
      stearat , natural cherry flavor; weight of each tablet is 100 mcg.) opposed to placebo
      tablets (containing the same ingredients, except the Vitamin B12). The two types of tablets
      will be the same shape, size, color and have the same flavor. The tablets will be purchased
      from the Solgar Company in identical boxes, 30 tablets per box. The boxes will be numbered (1
      or 2) - according to the type of treatment. The patient will receive instructions about daily
      treatment for a period of six (6) months, one tablet before going to sleep).

      Sample Size:

      In a retrospective study which we have done (to be published), we found that 73% of the
      patients who received Vitamin B12 there were no recurrent incidents of canker sores in the
      mouth. Assuming that among the patients that do not receive the Vitamin B12 treatment the
      frequency of the disease will be at least 90%, and that in the study group we expect that not
      more than 60% of the patients will continue to suffer from recurrent canker sores, in order
      to achieve a confidence level of 95% and a power of 80%, we need to recruit about 38 patients
      in the study group and 38 patients in the placebo group. With the assumption that the
      drop-out rate will be 30%, we need to recruit about 50 patients in each group.

      Patients:

      Candidates suffering from RAS who agree to participated in the study will sign a informed
      consent form.

      Inclusion Criterion:

        -  Over 18 years old.

        -  Suffering from RAS as least for one year with a frequency of at least one sore per
           month.

      Exclusion Criterion:

        -  Known systemic diseases concurrent with lesions in the mouth (Behcet's disease,
           Rheumatoid arthritis).

        -  Does not speak Hebrew, Russian, or English.

        -  Patients who have received in the last year Vit. B12 in any form.

        -  Patients who receive other treatment for RAS.

        -  Pregnant or nursing mothers.

        -  Patient known as suffering from Leber's optic atrophy.

        -  Patients suffering from psychosis.

      Measurement for treatment effectiveness:

      Principle measurement:

        -  Number of RAS occurrences during treatment (number of episodes per month).

      Secondary measurements:

        -  Number of sores per RAS occurrence.

        -  Score of severity level according to a pain scale (Visual analog scale, VAS), average at
           time of RAS occurrence.

      Measurement tools:

        -  Occurrence diary

        -  Pain Register

      Research Design :

      After receiving permission from the Helsinki Committee and before beginning the process of
      subject selection, we will register our research study with the International Clinical
      Registration System (/http://prsinfo.clinicaltrials.gov). Then we will recruit 20 primary
      physicians who will volunteer to ask 200 patients each concerning recurrent canker sores in
      the mouth. (These patients will be those who come to the physician for other reasons.) Out of
      these 4000 patients according to the literature, 800 patients suffer from RAS. We expect that
      half of these (about 400 patients) will report that the problem exists and half of those will
      agree to participate in the research study. According to our estimate, about 200 patients
      will adhere to the inclusion/exclusion criteria.

      All the patients who are ready to participate in the study will receive from their physician
      the cell phone number of the Nose Throat and Ear physician (G.Z.) and the physician will ask
      the patient to contact G.Z. when they have a canker sore. In addition the patient's physician
      will also give the patient a written health synopsis, which will include any chronic
      diseases, sensitivity to medication and medical treatment. The patient will give this
      synopsis to one of the investigators ((IV, YP, RP, IR,) when they meet with him. The patient
      will then contact G.Z. and will be examined by him within 48 hours after the canker sore(s)
      appear to ascertain that the condition is actually recurrent aphthous stomatitis.

      If the patient actually suffers from aphthous stomatitis, G.Z. will hand over the patient's
      information to one of the investigators. One of the investigators will contact the patient
      and make an appointment with him the next week.

      Meetings with the patients:

      One hundred (100) of the first patients who are found to suffer from aphthous stomatitis and
      who answer the inclusion/exclusion criteria will receive a detailed explanation in one of the
      languages, Hebrew, Russian, English about the purposes of the study, the research design, the
      risks involved in the research, and possible side effects. Those patients who sign the
      informed consent form will then be included in the study.

      At this meeting the investigator will then fill out a form including socio-demographic data,
      a detailed anamnesis concerning the RAS (including number of years the patient has suffered
      from RAS, frequency of the problem in the past year, treatment that the patient has received
      for RAS in the past). The physician will also take measurements of height, weight and blood
      pressure.

      The subjects will also have a blood test to measure the level of Vit. B12. (The sample will
      undergo centrifuge within the next few hours and the serum will be kept frozen until the test
      is done.) Since in our retrospective study (to be published) we did not find any difference
      in the result of treatment between people with patients having high and low levels of Vit.
      B12 in their blood, the level of Vit. B12 was not included as a criterion for inclusion or
      exclusion in the study.

      The patients will receive instructions concerning filling out the "Canker Sore Diary" and the
      use of VAS. The patients will be given an appointment in another month. They will also
      receive the cell phone number for on of the investigators in order to contact him if and when
      an unexpected side effect occurs.

      The subjects included in the study will be divided randomly into two groups (study group and
      control group).

      Meetings with Research Assistant 1:

      After a month from the time they met with the investigator, each patient will meet with
      Research Assistant 1 (physician), who will collect the "Canker Sore Diary" and will give the
      patient a bottle with 30 tablets of active ingredients or of placebo, according to which
      group he belongs (Control or Study). The patient will receive six (6) more appointments (once
      every month). The whole series of appointments will be decided in advance. A few days before
      each appointment the Research Assistant 1 will telephone the patient and remind him when and
      where the appointment will be.

      During each of the six meetings the patient will give the Research Assistant 1 the "Canker
      Sore Diary", he will report on the new tablets that he has begun to take the last month, and
      the Research Assistant will count how many tablets are left in the bottle and will list the
      side effects, if any. At the end of the meeting the patient will receive the bottle of
      tablets for the next month.

      In order to check the fact that the investigators did not know which patient was given which
      treatment, each investigator will be asked to "guess" which type of treatment each patient
      received.

      Randomization:

      Randomization was done by Research Assistant 2. Upon assigning a serial number for each
      subject, the Research Assistant will flip a coin according to which he will determine to
      which group the subject will belong. This number for the group will then be recorded on the
      form.

      Assurance of "double blind" design: In order that the investigators will not know to which
      group the subject belongs, the code of the randomization will be saved in the computer in a
      protected by user name and the password will be know only to Research Assistant 2
      (responsible for randomization, who will be the only one who knows in which box, No. 1 or No.
      2, has the active ingredient, Vit. B12. The code which were assigned to the boxes for the
      investigators will be revealed only after the data has been processed. The research
      assistants will not take part in data processing.

      Research Assistant 2 (responsible for randomization and knowing the code on the bottles) will
      not meet with the subjects and will not know any information about the subjects.

      Statistical Analysis:

      The data will be entered and processed by Research Assistant 3 in Epi-Info-Data 6.

      Statistical Analysis will be done by the investigators with the aide of another research
      assistant (statistician) using SPSS. For statistical analysis the t-test and 2 will be used
      with a confidence level of P< 0.05.

      References

        1. Ship JA, Chavez EM, Doerr PA, Henson BS, Sarmadi M. Recurrent aphthous stomatitis.
           Quintessence Int 2000; 31:95-112.

        2. Barrons RW. Treatment strategies for recurrent oral aphthous ulcers. Am J Health Syst
           Pharm 2001; 58:41-50.

        3. Porter SR, Hegarty A, Kaliakatsou F, Hodgson TA, Scully C. Recurrent aphthous
           stomatitis. Clin Dermatol 2000; 18:569-78.

        4. Piskin S, Sayan C, Durukan N, Senol M. Serum iron, ferritin, folic acid, and vitamin B12
           levels in recurrent aphthous stomatitis. J Eur Acad Dermatol Venereol 2002; 16:66-7.

        5. Wray D, Ferguson MM, Mason DK, Hutcheon AW, Dagg JH. Recurrent aphthae: treatment with
           vitamin B12, folic acid, and iron. BMJ 1975; 2:490-3.

        6. Barnadas MA, Remacha A, Condomines J, de Moragas JM. [Hematologic deficiencies in
           patients with recurrent oral aphthae]. Med Clin (Barc) 1997; 109:85-7.

        7. Natah SS, Konttinen YT, Enattah NS, Ashammakhi N, Sharkey KA, Hayrinen-Immonen R.
           Recurrent aphthous ulcers today: a review of the growing knowledge. Int J Oral
           Maxillofac Implants 2004; 33:221-34.

        8. Pedersen A, Hougen HP, Klausen B, Winther K. LongoVital in the prevention of recurrent
           aphthous ulceration. J Oral Pathol Med 1990; 19:371-5.

        9. Reznik D, O'Daniels CM. Clinical treatment evaluations of a new topical oral medication.
           Compend Contin Educ Dent Suppl 2001; 32:17-21.

       10. Meiller TF, Kutcher MJ, Overholser CD, Niehaus C, DePaola LG, Siegel MA. Effect of an
           antimicrobial mouthrinse on recurrent aphthous ulcerations. Oral Surg Oral Med Oral
           Pathol Oral Radiol Endod 1991; 72:425-9.

       11. Kerr AR, Drexel CA, Spielman AI. The efficacy and safety of 50 mg penicillin G potassium
           troches for recurrent aphthous ulcers. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
           2003; 96:685-94.

       12. Murray B, McGuinness N, Biagioni P, Hyland P, Lamey PJ. A comparative study of the
           efficacy of Aphtheal in the management of recurrent minor aphthous ulceration. J Oral
           Pathol Med 2005; 34:413-9.

       13. Gonzalez-Moles MA, Morales P, Rodriguez-Archilla A, Isabel IR, Gonzalez-Moles S.
           Treatment of severe chronic oral erosive lesions with clobetasol propionate in aqueous
           solution. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002; 93:264-70.

       14. Hutchinson VA, Angenend JL, Mok WL, Cummins JM, Richards AB. Chronic recurrent aphthous
           stomatitis: oral treatment with low-dose interferon alpha. Mol Biother 1990; 2:160-4.

       15. Katz J, Langevitz P, Shemer J, Barak S, Livneh A. Prevention of recurrent aphthous
           stomatitis with colchicine: an open trial. J Am Acad Dermatol 1994; 31(3 Pt 1):459-61.

       16. Femiano F, Gombos F, Scully C. Recurrent aphthous stomatitis unresponsive to topical
           corticosteroids: a study of the comparative therapeutic effects of systemic prednisone
           and systemic sulodexide. Int J Dermatol 2003; 42:394-7.

       17. Volkov I, Rudoy I, Abu-Rabia U, Masalha T, Masalha R. Recurrent apthous stomatitis
           responsive to vitamin B12 treatment. Can Fam Phys 2005; 51:844-5.
    


Study Type

Interventional




Condition

Recurrent Aphthous Stomatitis

Intervention

daily sublingual tablets Vitamin B12 1000 mcg versus placebo

Study Arms / Comparison Groups

 2
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug


Start Date

March 2006

Completion Date

January 2008

Primary Completion Date

December 2007

Eligibility Criteria

        Inclusion Criteria:

          -  Over 18 years old.

          -  Suffering from RAS as least for one year with a frequency of at least one sore per
             month

        Exclusion Criteria:

          -  Known systemic diseases concurrent with lesions in the mouth (Behcet's disease,
             jaundice, Rheumatism, Aides).

          -  Does not speak Hebrew, Russian, or English.

          -  Patients who have received in the last year Vit. B12 in any form.

          -  Patients who receive other treatment for RAS.

          -  Pregnant or nursing mothers.
      

Gender

All

Ages

65 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Ilia Volkov, MD, , 

Location Countries

Israel

Location Countries

Israel

Administrative Informations


NCT ID

NCT00288769

Organization ID

SOR415705CTIL



Study Sponsor

Soroka University Medical Center


Study Sponsor

Ilia Volkov, MD, Principal Investigator, Ben-Gurion University of the Negev


Verification Date

January 2008