Effectiveness of Saccharomyces Boulardii for Gastrointestinal Bacterial-overgrowth in Systemic Sclerosis
Condition: Systemic Sclerosis; Small Intestinal Bacterial Overgrowth
MeSH terms: Scleroderma, Systemic; Scleroderma, Diffuse; Sclerosis
Study type: Interventional
Phase: Phase 4

Summary: 
      Introduction. Autonomic dysfunction, smooth muscle fibrosis and vascular damage lead to small
      intestinal bacterial overgrowth (SIBO) in Systemic Sclerosis (SSc). SIBO is characterized by
      diarrhea, abdominal pain, bloating, malabsorption and malnutrition.

      Aim. To evaluate the efficacy and safety of Saccharomyces boulardii in combination with
      metronidazole for 2 months for reducing gastrointestinal symptoms (NIH-PROMIS) and preventing
      bacterial overgrowth (hydrogen breath test) versus the standard treatment in patients with
      systemic sclerosis.

      Method. Controlled clinical trial conduct in patients with SSc (ACR-EULAR 2015) who signed
      informed consent. NIH PROMIS®questionarie will be apply to evaluate gastrointestinal symptoms
      and classify in not symptomatic, least, mildy, moderately and most symptomatic. Glucose HBT
      will be apply after 14 hours fast, oral hygiene and 30 days free of antibiotics to evaluate
      SIBO. Patients with negative HBT and symptoms associated to glucose ingestion will repeat
      test with lactulose. Patients will be aleatorized into 1. Saccharomyces boulardii, 2.
      Metronidazole and 3. Metronidazole plus Saccharomyces boulardii.

      All data will be analyzed using SPSS software. It will be used parametric statistics for
      normally distributed variables and nonparametric statistics for free distribution.
    

Detailed description: 
      The study will be carried out with prior authorization from the Local Research and Ethics
      Committee. Patients entitled to our healthcare services and complying with screening criteria
      will be included.

      Patients with scleroderma included in our database will be invited to participate in the
      study through a telephone call. Patients complying with the screening criteria and accepting
      to participate in the study will be given a date for an interview.

      On the day of the interview, they will be given the informed consent form. Once it has been
      signed, they will be asked to complete the NIH PROMIS questionnaire for gastrointestinal
      symptoms. In order to validate the questionnaire, it will be translated from English into
      Spanish, then back-translated from Spanish into English and submitted to a panel of
      gastroenterology experts. Once patients have completed the questionnaire, a Cronbach's alpha
      test will be carried out. Another visit will be scheduled two weeks later to perform the
      hydrogen breath test and patients will be given instructions to help them complete the test.

      On the second visit (two weeks later), the following parameters will be recorded: weight
      (measured with a Seca scale without shoes and wearing a hospital gown), height, abdominal
      girth at the level of the navel (using a measuring tape), and patients will take the hydrogen
      breath test (Gastrolyzer instrument). Patients with a positive result will be randomly
      assigned to one of three groups: group 1 (Saccharomyces boulardii), group 2 (metronidazole)
      or group 3 (metronidazole + Saccharomyces boulardii).

      Group 1. Saccharomyces boulardii 200 mg b.i.d. during 2 weeks, followed by a 2-week rest
      period and then again 200 mg b.i.d. during 2 consecutive months.

      Group 2. Metronidazole 500 mg b.i.d during 1 week, followed by a 3-week rest period and then
      again 500 mg b.i.d during 2 consecutive months.

      Group 3. Metronidazole 500 mg b.i.d during 1 week, plus Saccharomyces boulardii 200 mg b.i.d.
      during 1 week, follow for only Saccharomyces 200 mg b.i.d. for one another week, 2-week rest
      period and then this regimen is repeated for two consecutive months.

      Each group will be given written instructions regarding the drug use. At the end of the first
      cycle, another visit will be scheduled to check for treatment compliance (remaining capsules
      will be counted) and patients will be given a new drug supply for the following month.
      Participants will also be asked to complete a form recording GI symptoms and potential
      adverse events. At the end of each treatment cycle, patients will have to take the hydrogen
      breath test, to complete the NIH PROMIS questionnaire and their weight and height will be
      measured. At the end of the second cycle, the statistical analysis will be carried out.

      If the episodes of diarrhea or abdominal distension persist for more than 2 weeks, the
      probiotic treatment will be withdrawn and the patient will be given the standard treatment.

      - NIH-PROMIS questionnaire

      This questionnaire is used to evaluate gastrointestinal symptoms through 60 questions divided
      into 8 domains:

        1. Heartburn / reflux (13 items)

        2. Disrupted swallowing (7 items)

        3. Diarrhea (5 items)

        4. Fecal incontinence (4 items)

        5. Nausea / vomiting (4 items)

        6. Constipation (9 items)

        7. Belly pain (6 items)

        8. Gas / bloating (12 items)

      Each question has 5 possible answers scored from 1 to 5. The physician will give the
      questionnaire to the patient and will cross out the answer corresponding to symptoms'
      severity. At the end of each domain, individual scores are added to calculate a raw score,
      from which a percentile is obtained. This finally leads to a symptom severity score.

      - Hydrogen breath test

      The patient should prepare for the test by following the instructions from Appendix 3. On the
      day of the test, the patient will blow into the mouthpiece of the breath hydrogen monitor
      after taking a deep breath. First, a baseline sample will be taken. The hydrogen baseline
      level must be under 10 ppm. A baseline hydrogen content over 10 ppm strongly suggests
      bacterial overgrowth. Then, the patient has to ingest, within 3 to 5 minutes, 50 g of glucose
      dissolved in 250 ml of water. Samples of exhaled air (alveolar air) will be taken after 15,
      30, 45, 60, 90, 120 and 150 minutes from the moment the patient has finished taking all the
      glucose. Patients with values under 10 ppm but having symptoms associated to glucose
      ingestion (headache, dizziness, nausea, vomiting, distension, hyperperistalsis, tiredness)
      will have to take the test again using 50 g of lactulose dissolved into 250 ml of water.

      In presence of bacterial overgrowth, carbohydrates used as substrate (glucose or lactulose)
      typically produce two peaks: an early increase of 10 ppm is observed when the substrate comes
      into contact with small intestinal bacteria, and then, after one hour, a second peak (a lot
      larger than the first one) is observed, being produced by normal colonic flora fermenting the
      remaining substrate The two peaks may merge and form an early plateau. The test is positive
      for bacterial overgrowth if the hydrogen level exceeds 10 ppm within 30 minutes of the
      lactulose dose or if baseline hydrogen levels exceed 20 ppm. If there is no response to the
      substrate, a flat curve can be observed and it should be interpreted as an impairment of the
      gut by antimicrobial agents prior to the test, pH changes in the feces at colon level,
      extremely slow intestinal transit and predominance of methane-producing bacteria.
    

Intervention name(s): Saccharomyces Boulardii Oral Tablet; Metronidazole
Intervention type(s): Drug; Drug
Intervention description(s): Saccharomyces boulardii 200 mg b.i.d. during 2 weeks, followed by a 2-week rest period and then again 200 mg b.i.d. during 2 consecutive months.; Metronidazole 500 mg b.i.d during 1 week, followed by a 3-week rest period and then again 500 mg b.i.d during 2 consecutive months
Other intervention name(s): Saccaromyces boulardii; Metronidazole alone
Intervention MeSH terms: Metronidazole
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Open Clinical Trial
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Systemic Sclerosis; Small Intestinal Bacterial Overgrowth; Saccaromyces boulardii