1                                           STUDY TITLE

A randomized, double blind, placebo controlled study to evaluate the efficacy & safety of oral probiotic-Sporlac® in the management of irritable bowel syndrome.

2                                           STUDY RATIONALE

Many probiotics were tested for the management of IBS symptoms but not all probiotic strains are effective for the relief of IBS symptoms, and the mechanisms of action remain unclear. In India whichever probiotics are studied for IBS, either studied in diarrhoea predominant IBS (IBS-D) or constipation predominant IBS (IBS-C), but not in both. Gastrointestinal symptoms of patients with IBS may switch from one type to other. Hence we are undertaking this study to establish the beneficial effects of probiotics in both IBS-D and IBS-C.  

Sporlac® is the widely prescribed probiotic in India. It contains strain Bacillus coagulans. Studies suggest that the probiotic Bacillus coagulans is effective in showing significant improvement in several symptoms of gastrointestinal discomfort¹⁹ and decreases the symptoms of abdominal pain and bloating in subjects with irritable bowel syndrome.²⁰ So, we chose this probiotic for our study.

3                                           STUDY AIM AND OBJECTIVES

3.1      AIM

To evaluate the efficacy and safety of oral probiotic Sporlac® (Bacillus coagulans SNZ 1969) in IBS patients.

3.2      PRIMARY OBJECTIVES 

- To assess the efficacy of oral probiotic Sporlac® against the placebo in IBS, in terms of:

·      The change in severity of symptoms related abdominal pain, bloating, constipation, diarrhoea, and satiety on the the gastrointestinal symptom rating scale-IBS version (GSRS-IBS)²¹ (Annexure 1) at 30, 60, and 75 days compared with baseline.

·      Number of responders to treatment defined by the Subject’s Global Assessment (SGA) of Relief ²² (Annexure 2) at 30 and 60 days.

3.3      SECONDARY OBJECTIVES

- To assess overall health and wellbeing of subjects measured on the SF-8 Health Survey (4-week Recall) questionnaire²³ (Annexure 3) at 30, 60, and 75 days compared to baseline.

-To assess the safety and acceptability of the treatment regimen at 30, 60, and 75 days.

4                                           STUDY SITE AND DURATION

Study site: Gastroenterology Department, Apollo Hospital, Jubilee Hills, Hyderabad

The total study duration is expected to be approximately 8 to 10 months. The total duration of a patient participation will be approximately of 5 months including screening period and treatment period (75 days).

5                                           STUDY POPULATION- SAMPLE SIZE

A sample size of 80 subjects was calculated for each group (n=40 for IBS-D and n=40 for IBS-C) based on a 40 % reduction in severity of clinical symptoms between the two treatment groups with a power of 80% at the 5% level of statistical significance.²⁴ Considering 30% dropout rate increases to 80 subjects (40 subjects in each group).

6                                           TREATMENT ARMS         

A Total of 40 subjects in the age group of 18-50 years with IBS-Diarrhoea and 40 subjects of the same age group and with IBS-Constipation will be selected from study site.

As shown below, all the patients will further be randomized in 2 sub-groups in a 1:1 ratio to receive either of the study medication for 60 days:

Each Sporlac® capsule contains 500 million CFU of Bacillus coagulans SNZ 1969. Placebo capsule will be identical to the Sporlac® capsule in colour and shape of the outer coating. It contains maltodextrin.

Rescue medicine will be provided to subject from any group if symptoms worsens or on demand by patients if symptoms not reduced. Rescue medicine composition will be as per clinical practice/guidelines by study site.

7                                           ELIGIBILITY CRITERIA

7.1      INCLUSION CRITERIA:

All the following criteria must be met at screening prior to randomization and at enrolment:

1.      Male or female subjects ranging in age from 18 to 50 years.

2.      Fulfilling Rome IV diagnostic criteria for functional IBS²⁵ (Annexure 4). Criterion fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.

3.      Having GSRS-IBS pain score (question 1 and 2) between 7 and 12.

4.      Willingness to follow the protocol requirement as evidenced by written, informed consent.

5.      Willingness to complete subject diaries and respond to study questionnaires.

6.      Except study treatment and rescue medicine, if required, agree not to use any other (including vitamins and minerals) medication during the course of the study.

7.      Agree not to use any yogurt during the course of this study.

8.      Subjects whose blood chemistries are within a normal range or not considered clinically significant if outside the normal range.

9.      Subject’s assurance that they have not taken antibiotics or other products whose primary site of action is in the gastro intestinal tract (GIT) for a period up to 1 month prior to the start of the study.

7.2      EXCLUSION CRITERIA:

Any of the following criteria will preclude the participant from being enrolled in the study:

1.      Sufficient criteria for a diagnosis of functional dyspepsia or other functional GI disorder.

2.      Any clinically significant medical history, medical finding or an ongoing medical or psychiatric condition exists which in the opinion of the Investigator could jeopardize the safety of the subject, impact validity of the study results or interfere with the completion of study according to the protocol.

3.      Significant abnormal findings as determined by baseline history, physical examination, vital signs (blood pressure, pulse rate, respiration rate) complete blood count (CBC), Liver Function test (LFT), C-reactive protein (CRP).

4.      History or presence of significant alcoholism or product abuse in the past one year.

5.      Participation in a clinical study during the preceding 75 days.

6.      History of malignancy or other serious disease.

7.      Any contraindication to blood sampling.

8.      Smoking or consumption of tobacco products.

9.      Female subjects on pregnancy and lactating women.

10.  Use of any antibiotics (e.g. neomycin, rifaximin) within 1 month of screening,

11.  Daily use of laxative within one month of screening/current usage, or usage from the past 3 months

7.3      Study Visits and Procedures (Annexure 5):

Newly diagnosed or untreated patients who are not on any other treatment in the past 3 months with IBS will be enrolled into the study. Subjects will be given these study medications on an outpatient basis and were advised to return for clinical evaluation at day 30, day 60, and day 75. The dosing period will be for 60 days.

Before starting treatment each individual will undergo a baseline assessment during which demographic data and IBS symptoms will be recorded. During treatment patients will be required to return to the clinic at day 30, day 60, and day 75 for reassessment of IBS symptoms and to report any adverse events (AE) that had occurred.

Compliance with study supplement will be reviewed at each visit by examination of the returned packets/bottles. The patients will be instructed against the use of any kind of yoghurt during the study duration. The daily food intake of the patients will be recorded in the patient diaries provided to them at visit 1. The same will be verified at subsequent visits by the investigators.

If subject’s symptom worsen or if symptom(s) are not reducing and subject ask for alternate therapy, he will be provided with rescue medicine. Rescue medicine will be as per hospital standards for treatment of IBS.

The gastrointestinal symptom rating scale (GSRS) IBS version²¹ (Annexure 1) is a survey that contains questions about how subject has been feeling and what it has been like during the past week. Subject has to mark the choice that best applies to him and your situation with a cross in the box. All items use the following response scale: 1 = no discomfort at all, 2 = minor discomfort, 3 = mild discomfort, 4 = moderate discomfort, 5 = moderately severe discomfort, 6 = severe discomfort, 7 = very severe discomfort. Subscale structure is composed of pain syndrome (Q 1 and 2), bloating syndrome (Q 3, 4, and 13), constipation syndrome (Q 5 and 8), diarrhoea syndrome (Q 6, 7, 9, and 10), and satiety (Q 11 and 12).

The Subject’s Global Assessment (SGA) of Relief²² (Annexure 2) will be used as a primary assessment of outcome to help identify responders to therapy. Question: “Please consider how you felt this past week in regard to your IBS, in particular your overall wellbeing, and symptoms of abdominal discomfort, pain and altered bowel habit. The scale contains five possible answers: (1) completely relieved, (2) considerably relieved, (3) somewhat relieved, (4) unchanged, or (5) worse. Responders will be defined as patients having score ≤3 at visit Day 30 and score ≤2 at visit Day 60.

Subjects quality of life will be assessed by SF-8 Health Survey (4-week Recall)²³ (Annexure 3). It is 8-item questionnaire measure and each item is scored on a five-six point scale. It contains psychometrically based physical and mental health summary measures. We have slightly modified it to make it more applicable for IBS. In question number 2 and 3 “physical health” is replaced by “gut health” and in question 4 “bodily pain” is replaced by “abdominal pain”. The eight domains include general health, physical functioning, role of gut health, abdominal pain, vitality, social functioning, mental health, and role of emotional problems. The SF-8 questionnaire will be given to each patient before treatment is started; the patient complete the form each month and all data will be recorded and entered onto a data sheet.

8                                           PATIENT WITHDRAWAL AND REPLACEMENT

A study patient will be withdrawn/ discontinued at any time from the study if any of the following situations occur:

1.                  Study patient wants to withdraws voluntarily from the study

2.                  Lost to follow-up

3.                  At the discretion of the Investigator (e.g., rapid clinical deterioration)

4.                  Study termination

5.                  Any treated study participant who has an adverse reaction to study medication that threatens his/her well-being. The study participant should be monitored for resolution of the adverse event.

6.                  Significant deterioration in the study participant’s clinical status

7.                  Failure of study participant for whatever reason to comply with requirements of the protocol

8.                  The study participant dies during the study period

When a study participant is removed from the study, the Investigator will clearly document the reason in the medical record and complete the appropriate case report form page describing the reason for discontinuation. In addition, every effort will be made to complete the appropriate assessments.

9                                           LOST TO FOLLOW-UP

If a trial participant fails to appear for a follow-up examination, extensive effort (i.e., documented phone calls) should be undertaken to locate or recall him/her or at least to determine his/her health status. These efforts should be documented in the trial participants CRF and another pertinent source document.

Any study participant who is not available for the final follow up should be classified as “lost to follow-up” and the classification noted on the CRF together with the reason, if known.

Schedule of events & study flow chart