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| Name | Class |
|---|---|
| University of Urbino "Carlo Bo" | OTHER |
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This multicenter, randomized, double-blind, placebo-controlled clinical trial will evaluate the efficacy and safety of the probiotic Bifidobacterium breve PRL2020 (Brevicillin® gocce) in preventing gastrointestinal side effects associated with antibiotic therapy using amoxicillin or amoxicillin/clavulanic acid in pediatric patients aged 0-12 years. Participants will be randomized 1:1 to receive either the probiotic supplement or placebo during standard antibiotic treatment for 6-10 days, followed by a post-treatment observation period up to day 15 without probiotic or placebo administration. The primary objective is to assess the reduction in the incidence of antibiotic-associated diarrhea (AAD).
Antibiotic therapy with amoxicillin or amoxicillin/clavulanic acid is widely prescribed in pediatric populations but is frequently associated with gastrointestinal adverse effects, particularly diarrhea. These effects are linked to disruption of the gut microbiota and a reduction in bifidobacterial populations. Bifidobacterium breve PRL2020 is a probiotic strain with demonstrated intrinsic, non-transferable resistance to these antibiotics and has been developed to mitigate antibiotic-induced dysbiosis.
This study is a multicenter, prospective, randomized, double-blind, placebo-controlled, non-profit trial conducted in pediatric centers across Italy. The study aims to evaluate the clinical efficacy and safety of Bifidobacterium breve PRL2020 in reducing the incidence and severity of antibiotic-associated diarrhea (AAD) in children receiving amoxicillin or amoxicillin/clavulanic acid.
A total of 1100 participants (550 per group) will be enrolled. Participants will be randomized 1:1 to receive either Brevicillin® gocce (5 drops 2-3 times daily, containing 5 billion CFU of B. breve PRL2020 per dose) or matching placebo only during antibiotic therapy (6-10 days). After completion of antibiotic treatment, participants will enter a follow-up period until day 15 without probiotic or placebo administration.
The primary outcome is the incidence of AAD, defined as ≥3 diarrheal episodes in one day during antibiotic treatment (Bristol Stool Scale 5-7).
Secondary outcomes include the incidence and duration of diarrhea, daily bowel movements, stool consistency, gastrointestinal and extra-intestinal symptoms (such as nausea, vomiting, abdominal pain), treatment compliance, and adverse events.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Brevicillin® gocce (Bifidobacterium breve PRL2020) | Experimental | Participants will receive Brevicillin® gocce, a probiotic food supplement containing Bifidobacterium breve PRL2020 (LMG S-32458), alongside standard antibiotic therapy with amoxicillin or amoxicillin/clavulanic acid. Dosage and administration: 5 drops, 2-3 times per day (depending on antibiotic dosing schedule), administered during the antibiotic treatment period (6-10 days). After completion of antibiotic therapy, participants will enter a follow-up period until day 15 without probiotic administration. |
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| Placebo | Placebo Comparator | Participants will receive a placebo formulation matched in appearance, packaging, and dosing schedule to Brevicillin® gocce, administered alongside standard antibiotic therapy with amoxicillin or amoxicillin/clavulanic acid. The placebo will be given at the same frequency (5 drops, 2-3 times per day) and duration as the experimental product during the antibiotic treatment period (6-10 days). After antibiotic completion, participants will enter a follow-up period until day 15 without placebo administration. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Brevicillin® gocce (Bifidobacterium breve PRL2020) | Dietary Supplement | Brevicillin® gocce is a probiotic dietary supplement in oily drops containing the bacterial strain Bifidobacterium breve PRL2020 (LMG S-32458). Each 5-drop dose contains approximately 5 billion live cells. The supplement is administered orally 2-3 times per day, in parallel with antibiotic therapy (amoxicillin or amoxicillin/clavulanic acid), for 6-10 days only (during the antibiotic course). After completion of antibiotic therapy, participants enter a follow-up period until day 15 without probiotic administration. The product is manufactured by PharmExtracta S.p.A., Pontenure, Italy. |
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of Antibiotic-Associated Diarrhea (AAD) | Evaluation of the efficacy of Bifidobacterium breve PRL2020 (Brevicillin® gocce) in reducing the incidence of antibiotic-associated diarrhea (AAD), defined as ≥3 diarrheal episodes within one day of antibiotic treatment, with stool consistency corresponding to types 5-7 on the Bristol Stool Scale. Data will be collected through a daily diary completed by the parent or legal guardian. | 15 days |
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of children with at least one episode of diarrhea | Number of participants experiencing at least one episode of diarrhea during the study period, as recorded in the daily diary. | 15 days |
| Number of daily defecations |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Davide Sisti, PhD | University of Urbino "Carlo Bo" | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Urbino "Carlo Bo" | Urbino | 61029 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 11821511 | Background | Bartlett JG. Clinical practice. Antibiotic-associated diarrhea. N Engl J Med. 2002 Jan 31;346(5):334-9. doi: 10.1056/NEJMcp011603. No abstract available. | |
| 17449881 | Background | Salvo F, Polimeni G, Moretti U, Conforti A, Leone R, Leoni O, Motola D, Dusi G, Caputi AP. Adverse drug reactions related to amoxicillin alone and in association with clavulanic acid: data from spontaneous reporting in Italy. J Antimicrob Chemother. 2007 Jul;60(1):121-6. doi: 10.1093/jac/dkm111. Epub 2007 Apr 21. |
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Participants are randomized in a 1:1 ratio to receive either Brevicillin® gocce containing Bifidobacterium breve PRL2020 or a matching placebo, both administered only during the antibiotic treatment period (6-10 days, according to physician prescription). After completion of antibiotic therapy, all participants enter a follow-up period through day 15 without probiotic or placebo administration.
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Double-blind design: both participants, care providers, investigators, and outcome assessors are unaware of treatment assignments. The probiotic and placebo products are identical in appearance, packaging, and labeling.
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| Placebo (matching oil drops) | Other | The placebo is a formulation identical in appearance, packaging, and administration schedule to Brevicillin® gocce but without the Bifidobacterium breve PRL2020 strain. It is administered orally 2-3 times per day only during the antibiotic treatment period (6-10 days). After antibiotic completion, participants enter a follow-up period until day 15 without placebo administration. |
|
Average number of daily bowel movements recorded by the parent or guardian during the study period, using the child's daily diary.
| 15 days |
| Number of days with diarrhea | Total number of days in which diarrhea occurs during the observation period, recorded by the parent or guardian. | 15 days |
| Stool consistency | Assessment of stool consistency using the Bristol Stool Scale (BSS) to evaluate changes in bowel habits during and after antibiotic treatment. | 15 days |
| Gastrointestinal and extra-intestinal symptoms | Evaluation of symptoms related to antibiotic use, including abdominal pain, nausea, and vomiting, assessed from daily diary entries completed by the parent or guardian | 15 days |
| Treatment compliance | Assessment of adherence to the probiotic or placebo regimen, graded by the pediatrician on a scale from "poor" to "excellent" at the end of the study period. | 15 days |
| Adverse events | Documentation and evaluation of any adverse events reported during treatment and follow-up, as recorded in the child's daily diary and verified by the study physician. | 15 days |
| 1929247 | Background | Caron F, Ducrotte P, Lerebours E, Colin R, Humbert G, Denis P. Effects of amoxicillin-clavulanate combination on the motility of the small intestine in human beings. Antimicrob Agents Chemother. 1991 Jun;35(6):1085-8. doi: 10.1128/AAC.35.6.1085. |
| 34398323 | Background | Yang L, Bajinka O, Jarju PO, Tan Y, Taal AM, Ozdemir G. The varying effects of antibiotics on gut microbiota. AMB Express. 2021 Aug 16;11(1):116. doi: 10.1186/s13568-021-01274-w. |
| 33483308 | Background | Mancabelli L, Mancino W, Lugli GA, Argentini C, Longhi G, Milani C, Viappiani A, Anzalone R, Bernasconi S, van Sinderen D, Ventura M, Turroni F. Amoxicillin-Clavulanic Acid Resistance in the Genus Bifidobacterium. Appl Environ Microbiol. 2021 Mar 11;87(7):e03137-20. doi: 10.1128/AEM.03137-20. Print 2021 Mar 11. |
| 37512822 | Background | Di Pierro F, Campedelli I, De Marta P, Fracchetti F, Del Casale A, Cavecchia I, Matera M, Cazzaniga M, Bertuccioli A, Guasti L, Zerbinati N. Bifidobacterium breve PRL2020: Antibiotic-Resistant Profile and Genomic Detection of Antibiotic Resistance Determinants. Microorganisms. 2023 Jun 24;11(7):1649. doi: 10.3390/microorganisms11071649. |
| 40558167 | Background | Biasucci G, Capra ME, Giudice A, Monopoli D, Stanyevic B, Rotondo R, Mucci A, Neglia C, Campana B, Esposito S. Use of Probiotics During Antibiotic Therapy in Pediatrics: A Cross-Sectional Survey of Italian Primary Care Pediatricians. Antibiotics (Basel). 2025 Jun 4;14(6):577. doi: 10.3390/antibiotics14060577. |