INTRODUCTION: Berotralstat, the first oral plasma kallikrein inhibitor approved for hereditary angioedema (HAE) prophylaxis, may be associated with gastrointestinal (GI) side effects, particularly during the first three months of therapy. Probiotics have been shown to reduce GI disturbances in several conditions. This pilot study described GI tolerability in patients receiving initiation-phase probiotic co-administration alongside berotralstat and explored whether this supportive strategy merits further controlled evaluation.
MATERIALS AND METHODS: We analyzed 25 adolescents and adults with HAE treated with berotralstat across six Italian centers (December 2023-November 2025). All patients received probiotics during the early treatment phase. Demographic and clinical data, side effects, and monthly HAE attack rates were collected. Severity of complaints was graded using the Common Terminology Criteria for Adverse Events (CTCAE).
RESULTS: Participants were 60% females, and the mean age for the cohort was 45 years (range 12-82). The most common probiotics were Lacteol® , Codex® , and Lactoflorene Plus® . GI complaints occurred in 5/25 patients (20%); only 3/25 (12%) experienced GI side effects while receiving probiotics. 2/25 GI complaints occurred after probiotic discontinuation. No serious side effects were reported. Mean monthly attack rate decreased from 2.6 to 0.8 attacks per month, ~3.3-fold reduction from baseline.
CONCLUSION: Probiotic co-administration during early berotralstat therapy was accompanied by a low incidence of GI side effects, while clinical effectiveness was maintained. These preliminary findings support further controlled studies to validate probiotics as a supportive strategy for improving the tolerability of berotralstat.
Probiotic co-administration during early berotralstat therapy was accompanied by a low incidence of GI side effects, while clinical effectiveness was maintained.
an uncontrolled cohort cannot determine whether probiotics explain the low reported incidence
Mean monthly attack rate decreased from 2.6 to 0.8 attacks per month, ~3.3-fold reduction from baseline.
recorded rates support the descriptive change, although baseline observation and prior-treatment washout were not standardized
2/25 GI complaints occurred after probiotic discontinuation.
routine records establish temporal order in two cases but cannot identify a protective probiotic effect
Derived from the full evaluation — not a separate score.
Strengths
The study examines a concrete supportive strategy for early GI complaints that may affect persistence with oral HAE prophylaxis and identifies a prospective controlled evaluation as the next step.
↳ Introduction, final two paragraphs; Abstract, Conclusion
The Results report probiotic products, treatment durations, event severity, timing relative to discontinuation, and interruption outcomes, allowing the observed clinical course to be broadly reconstructed.
↳ Results, probiotic product mix and GI-event paragraphs; Tables 1–3
The Discussion explains how the missing control group, variable follow-up, residual prior-treatment effects, absent adherence measures, and lack of microbiome data restrict causal and mechanistic conclusions.
↳ Discussion, limitations paragraph
Limitations
All participants received probiotics, so the observed 12% on-treatment GI-event rate cannot establish improvement relative to berotralstat alone. Historical trial and surveillance rates are not exchangeable controls.
↳ Materials and Methods, opening paragraph; Discussion, paragraphs 1 and 4
Probiotic product, duration, adherence, follow-up, and adverse-event collection varied across routine practice, limiting internal comparability and leaving alternative explanations unresolved.
↳ Materials and Methods, opening paragraph; Results, treatment-duration paragraph
The concluding proposal for a standardized 8–12-week starter course is operationally concrete, but the current case series does not identify probiotic efficacy or an optimal product and duration.
↳ Discussion, concluding paragraph
The case series addresses a defined tolerability problem and reports clinically useful detail on probiotic exposure and GI-event timing across six centers. Its quality is constrained chiefly by the absence of a berotralstat-only comparator and by nonstandard exposure, adherence, follow-up, and routine adverse-event ascertainment. The Discussion handles these limitations carefully and generally keeps the conclusions hypothesis-generating, supporting strong clarity and contextualization scores. The proposed clinical starter course is premature because neither probiotic efficacy nor an optimal regimen is identified by the design.
Nabu’s assessment, alongside the field’s view.
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Sound3.4
Confidence highThe series contributes an initial multicenter observational signal on probiotic co-administration during berotralstat initiation and frames it as hypothesis-generating. Its advance remains limited because all 25 patients received probiotics and no comparative effect can be estimated.
These hypothesis-generating data aim to inform the design of prospective, controlled evaluations
Event timing, CTCAE severity, exposure duration, and product mix are documented, but follow-up, probiotic selection, adherence, and baseline attack windows were not standardized. Competing explanations are acknowledged rather than resolved analytically, warranting a moderate incomplete-workup deduction.
The most important limitation is the absence of a contemporaneous control group not receiving probiotics
The paper follows a coherent problem–rationale–observation–validation sequence and generally distinguishes association from causation. The proposed clinical “starter” course is more implementation-oriented than the evidence, but remains conditional and does not materially reverse the paper’s caveats.
If corroborated, an “initiation-phase probiotic” approach could be incorporated into HAE care pathways
The Discussion places the findings against pivotal trials, real-world cohorts, pharmacovigilance data, and HAE microbiome studies while explicitly warning against direct historical comparison. Major limitations are connected to causal inference, adverse-event capture, attack-rate estimation, and mechanism.
these external data provide context only and do not substitute for an internal control
Lower confidence on Methodological Rigour — domain match limited.
Caveats4 of 4 checks
The principal counts and attack-rate figures are internally consistent. The Abstract reports mean age 45 years, whereas the Results reports median age 48 years; these statistics can coexist but the change of summary measure is not explained.
Registry ethics approval and written informed consent are declared, and the article includes a data-availability statement. No supplied-text concern indicates misconduct or a material conduct failure.
Flags: 2 declared / 5 total
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No retraction or expression of concern found in Crossref (includes Retraction Watch).
Sources: Crossref (incl. Retraction Watch) ✓
Where this paper’s evidence sits on the path from initial observation to real-world use.
The intervention is inexpensive and operationally simple, but the evidence remains an uncontrolled clinical observation rather than a validated protocol. Controlled comparison and standardized outcome capture are required before practice adoption.
the absence of a contemporaneous control group not receiving probiotics, which precludes causal inference
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