Efficacy and Safety of Sinquanon for Prevention of Antibiotic-associated Diarrhea in Adults (SPAADA)

Phase 4, Efficacy and Safety of Sinquanon for Prevention of Antibiotic-associated Diarrhea in Adults in the Out-patient Setting: Prospective, Multicenter, Double-blind, Placebo-controlled Randomized Parallel-arm Clinical Study

The purpose of this study is to evaluate the efficacy of a probiotic, SINQUANON, on the reduction of the occurrence of diarrhea associated with antibiotic use in adults.

Study Overview

• Status: Completed
• Conditions: Antibiotic-associated Diarrhea
• Intervention / Treatment: Dietary supplement: Sinquanon; Dietary supplement: Placebo

Detailed Description

The study aims to evaluate the efficacy of a specialized multi-strain probiotic, SINQUANON, on the reduction of the incidence of antibiotic-associated diarrhea in adults and to demonstrate the benefit of administering the specialized multi-strain probiotic as a routine add-on to antibiotic therapy on prevention of antibiotic-associated diarrhea in adults who take antibiotics in the outpatient setting.

• Study Type: Interventional
• Enrollment (Actual): 565
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Bulgaria
  • Plovdiv, Bulgaria, 4002
    • University Hospital "St George"
  • Sofia, Bulgaria, 1431
    • University Hospital for Pulmonary Diseases " St. Sofia"
  • Sofia, Bulgaria, 1527
    • University Hospital "Tsaritsa Yoanna - ISUL"

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female subject aged 18 to 60 years.
• The subject has given written informed consent after being provided orally with information about the study objective and design, including the administration regimen of the studied probiotic and the study procedures, the available safety data, as well as the rights and obligations of a participant.
• The subject initiates oral antibiotic treatment in the ambulatory setting.

• Acceptable antibiotic therapy:

  • Broad-spectrum penicillins
  • Cephalosporins
  • Quinolones
  • Tetracyclines

Sequential administration of two antibiotics from the allowed groups is permitted, if the total duration of the antibiotic treatment does not exceed 10 days.

• Planned duration of the antibiotic treatment of 5 to 10 days.
• Body mass index (BMI) of 18.0 to 29.9 kg/m2
• In the opinion of the Investigator, the subject can adhere to the visit schedule, to be compliant with the trial treatment regimen and to complete the study.
• The patient has a smartphone and can use it.

Exclusion Criteria:

• Antibiotics use within 60 days prior to randomization.
• Daily consumption of probiotics, yogurt with probiotics and inability to stop this consumption.
• Use of antidiarrheal medications, laxatives, enemas, or suppositories within 1 week prior to randomization and for the duration of the trial.
• An episode of diarrhea within 30 days before screening, defined as ≥3 loose or liquid stools over 24 hours, regardless of the cause of the diarrhea.
• Acute or chronic constipation - average number of formed stools <3 per week.
• Allergy or hypersensitivity to any of the ingredients of the trial product.
• Allergy or hypersensitivity to the antibiotic prescribed on Day 1.
• Prior documented infection with Clostridioides difficile ≤3 months before screening.
• History of chronic gastrointestinal conditions, including irritable bowel syndrome, chronic constipation, chronic diarrhea, dyspepsia, gastroesophageal reflux disease, diverticulitis, ulcerative colitis, Crohn's disease or any other abnormality in the absorption or gastrointestinal dysfunction.
• Use of proton-pump inhibitors (PPIs) within 30 days prior to Day 1 and for the duration of the study.
• Surgery to the intestines, artificial heart valve, history of rheumatological heart disease or infectious endocarditis within one year prior to screening.
• Immunosuppressive therapy or any condition causing immunosuppression (including hematologic malignancies, AIDS, long-lasting corticosteroid treatment).
• Planned administration of antibiotics, different from those acceptable for the study.
• Patients in severe condition requiring urgent hospitalization or planned hospitalization during the study.
• Planned administration of antibiotics >10 days.
• BMI ≥ 30 kg/m2.
• Pregnant or lactating women; women who plan to get pregnant during the study.
• Drug abuse or alcohol within the past year.
• Unstable medical conditions, in the judgement of the Investigator.
• Eating disorders (for example, anorexia, bulimia).
• On a vegan diet.
• Participation in a clinical trial within 60 days prior to randomization.
• Inability to comply with the study protocol.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Probiotic; During the antibiotic dosing (from 5 to 10 days): 2 capsules once a day 2 hours before or 2 hours after antibiotic administration. 14 days following completion of antibiotic dosing: 1 capsule a day.	Dietary supplement: Sinquanon; This probiotic food supplement includes fourteen probiotic bacterial strains of Lactobacillus Spp, Bifidobacterium Spp., Bacillus coagulans, Saccharomyces boulardii, three prebiotics and Vitamin-B complex - B1, B2, B3, B6, B7, B9 in an enterosolvent cellulose capsule. The product includes supplementary substances: maltodextrin and magnesium stearate. 2 capsules once a day during the antibiotic dosing. 1 capsule a day for 14 days following completion of antibiotic dosing.
Placebo Comparator: Placebo; During the antibiotic dosing (from 5 to 10 days): 2 capsules once a day 2 hours before or 2 hours after antibiotic administration. 14 days following completion of antibiotic dosing: 1 capsule a day.	Dietary supplement: Placebo; The placebo product will have the same appearance as the active product and the same composition but without the live bacteria, prebiotics, and vitamin-B complex. 2 capsules once a day during the antibiotic dosing. 1 capsule a day for 14 days following completion of antibiotic dosing.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Antibiotic-Associated diarrhea (AAD)	The incidence of AAD is defined as the number of subjects who experience at least one day of diarrhea compared to the total number of subjects enrolled in the given treatment arm. AAD is defined as 3 or more loose or liquid stools (types 5-7 according to Bristol Stool Scale [BSS]) over a period of 24 hours.	By 21+2 days after completion of antibiotic dosing.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severity of AAD	Investigator will assess AAD severity using the following modified scale defining AAD as: severe: ≥7 unformed/loose/liquid stools; moderate: 5-6 unformed/loose/liquid stools; mild: a change in the stool pattern 3-4 unformed/loose/liquid stools a day. Investigator's assessment will take into consideration the 24-hour period presenting with the worst severity.	By 21+2 days after completion of antibiotic dosing.
Duration of diarrhea	Number of sequential days with diarrhea. Defined as the time until the first normalization of the stool form according to BSS: presence of one or two sequential normal stools, i.e. "soft and formed" or "hard and formed" - types 1-4 per BSS (or lack of stool) for a period of 24 hours.	By 21+2 days after completion of antibiotic dosing.
Antibiotic-associated adverse experiences (abdominal pain, bloating, passing gas, nausea)	Presence of abdominal pain, bloating, passing gass, nausea - Yes/No.	By 21+2 days after completion of antibiotic dosing.
Visual-analogue scale for the gastrointestinal quality of life (VAS-QoL)	Measured via Visual-analogue scale for the gastrointestinal quality of life. The subjects will answer the question: "To what extent the abdominal problems impact your quality of life?" This scale has numerical points from 0 to 100. "100" indicates THE WORST quality of life one can imagine, "0" indicates NO problems and THE BEST quality of life one can imagine.	By 21+2 days after completion of antibiotic dosing.
Adverse events (AE)	Incidence of mild (for example, self-resolving), moderate (for example, those requiring medical evaluation) and serious AEs (for example, events requiring lasting hospitalization) adverse events.	By 21+2 days after completion of antibiotic dosing.

Collaborators and Investigators

• Sponsor: Neopharm Bulgaria Ltd.
• Investigators: Principal Investigator: Georgi Momekov, Prof PhD, Department of Pharmacology, Pharmacotherapy and Toxicology, Medical University of Sofia; Principal Investigator: Karen Dzhambazov, Prof, PhD, University hospital for active treatment Sveti Georgi, Medical University-Plovdiv; Principal Investigator: Nikolay Sapundziev, Prof, PhD, Department of Neurosurgery and Otorhinolaryngology, Medical University - Varna; Principal Investigator: Boris Bogov, Prof, PhD, UMHAT "Sveta Anna"; Principal Investigator: Rosen Nikolov, Prof, MD, UMHAT St Ivan Rilski; Principal Investigator: Rumen Benchev, Prof, Hill Clinic; Principal Investigator: Vladimir Hodzhev, Prof, PhD, University Hospital "St George"; Principal Investigator: Spiridon Todorov, Prof, PhD, University Hospital "Tsaritsa Yoanna - ISUL"; Principal Investigator: Vania Youroukova, Prof, PhD, University Hospital for Pulmonary Diseases " St. Sofia"; Principal Investigator: Milena Encheva, MD, PhD, Military Medical Academy, Bulgaria

Publications and helpful links

General Publications

• Konstantinidis T, Tsigalou C, Karvelas A, Stavropoulou E, Voidarou C, Bezirtzoglou E. Effects of Antibiotics upon the Gut Microbiome: A Review of the Literature. Biomedicines. 2020 Nov 16;8(11):502. doi: 10.3390/biomedicines8110502.
• Francino MP. Antibiotics and the Human Gut Microbiome: Dysbioses and Accumulation of Resistances. Front Microbiol. 2016 Jan 12;6:1543. doi: 10.3389/fmicb.2015.01543. eCollection 2015.
• Mekonnen SA, Merenstein D, Fraser CM, Marco ML. Molecular mechanisms of probiotic prevention of antibiotic-associated diarrhea. Curr Opin Biotechnol. 2020 Feb;61:226-234. doi: 10.1016/j.copbio.2020.01.005. Epub 2020 Feb 19.
• Barbut F, Meynard JL. Managing antibiotic associated diarrhoea. BMJ. 2002 Jun 8;324(7350):1345-6. doi: 10.1136/bmj.324.7350.1345. No abstract available.
• Szajewska H, Kolodziej M. Systematic review with meta-analysis: Lactobacillus rhamnosus GG in the prevention of antibiotic-associated diarrhoea in children and adults. Aliment Pharmacol Ther. 2015 Nov;42(10):1149-57. doi: 10.1111/apt.13404. Epub 2015 Sep 13.
• Szajewska H, Kolodziej M. Systematic review with meta-analysis: Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea. Aliment Pharmacol Ther. 2015 Oct;42(7):793-801. doi: 10.1111/apt.13344. Epub 2015 Jul 27.
• Ouwehand AC. A review of dose-responses of probiotics in human studies. Benef Microbes. 2017 Apr 26;8(2):143-151. doi: 10.3920/BM2016.0140. Epub 2016 Dec 23.
• Szajewska H, Canani RB, Guarino A, Hojsak I, Indrio F, Kolacek S, Orel R, Shamir R, Vandenplas Y, van Goudoever JB, Weizman Z; ESPGHAN Working Group for ProbioticsPrebiotics. Probiotics for the Prevention of Antibiotic-Associated Diarrhea in Children. J Pediatr Gastroenterol Nutr. 2016 Mar;62(3):495-506. doi: 10.1097/MPG.0000000000001081.
• Goldenberg JZ, Lytvyn L, Steurich J, Parkin P, Mahant S, Johnston BC. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev. 2015 Dec 22;(12):CD004827. doi: 10.1002/14651858.CD004827.pub4.
• Gao XW, Mubasher M, Fang CY, Reifer C, Miller LE. Dose-response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea prophylaxis in adult patients. Am J Gastroenterol. 2010 Jul;105(7):1636-41. doi: 10.1038/ajg.2010.11. Epub 2010 Feb 9.

Study record dates

Study Major Dates

• Study Start (Actual): November 27, 2022
• Primary Completion (Actual): March 20, 2023
• Study Completion (Actual): April 25, 2023

Study Registration Dates

• First Submitted: October 31, 2022
• First Submitted That Met QC Criteria: October 31, 2022
• First Posted (Actual): November 7, 2022

Study Record Updates

• Last Update Posted (Actual): October 21, 2024
• Last Update Submitted That Met QC Criteria: October 17, 2024
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Probiotics; Antibiotics; Antibiotic-associated diarrhea; High-dose; Multistrain
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Diarrhea
• Other Study ID Numbers: SPAADA202211_001; 2022-002817-40 (EudraCT Number)

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