BACKGROUND: Hereditary angioedema is a bradykinin-mediated disorder characterised by recurrent painful swelling attacks. Treatment relies on medications to prevent attacks and on-demand therapies for attack manifestations. Parenteral administration associated with most available on-demand therapies often leads to treatment being delayed or forgone. Deucrictibant is an orally bioavailable bradykinin B2 receptor antagonist under development for prophylaxis and on-demand treatment of hereditary angioedema attacks. We aimed to investigate the efficacy and safety of deucrictibant for the on-demand treatment of hereditary angioedema attacks. METHODS: RAPIDe-1 was a double-blind, randomised, placebo-controlled, crossover, dose-ranging, phase 2 trial that recruited adults aged 18-75 years with hereditary angioedema type 1 or 2 from 38 sites (eg, university hospitals and accredited angioedema centres) across North America, Europe, and Israel. Participants were required to have experienced two or more attacks within the past 2 months or three or more attacks within the past 4 months before screening. An interactive response technology system randomly assigned eligible patients (1:1:1) to receive a blinded dose of oral deucrictibant (immediate-release capsule) 10 mg, 20 mg, or 30 mg during an attack-free period to assess pharmacokinetics and safety in the part 1 of the study; and, subsequently, to receive a crossover treatment sequence of two administrations of the same deucrictibant dose (10 mg, 20 mg, or 30 mg) and one of placebo to treat three investigator-confirmed angioedema attacks in the part 2. Randomisation was stratified by whether the participant was willing to participate in full pharmacokinetic sampling. Participants, investigators, site personnel, and the sponsor were masked to treatment assignment and capsules of deucrictibant and placebo were identical. For each attack, patients self-administered the oral study drug within 3 h after at least one symptom (skin pain, skin swelling, or abdominal pain) reached a visual analog scale (VAS) individual score of 30 or more out of 100 and within 6 h from symptom onset. The primary endpoint was change in the patient-reported composite VAS-3 score measuring severity of attack manifestations from before treatment to 4 h post-treatment and assessed in the modified intention-to-treat and per-protocol populations. Safety was assessed in all patients who received any dose of study drug. RAPIDe-1 is registered with ClinicalTrials.gov (NCT04618211) and is completed. FINDINGS: Between Feb 3, 2021, and June 23, 2022, 89 patients were screened, of whom 74 were randomly assigned between Feb 23, 2021, and July 26, 2022. For the primary analysis set, the median follow-up was 130·0 (IQR 92·5 to 212·5) days for the deucrictibant 10 mg group, 166·5 (80·0 to 275·0) days for the deucrictibant 20 mg group, and 172·0 (65·0 to 242·0) days for the deucrictibant 30 mg group. The primary efficacy analysis included 147 attacks in 62 patients, of whom 42 (68%) were female and 60 (97%) were White. Least squares mean differences of change in VAS-3 score between deucrictibant and placebo was -16·75 (95% CI -21·52 to -11·97) for 10 mg, -15·02 (-20·22 to -9·81; p<0·0001) for 20 mg, and -16·28 (-21·27 to -11·29; p<0·0001) for 30 mg. In part 1, all treatment-emergent adverse events were grades 1-2, with the most common in two or more patients being headache (two [8%] of 25) and nasopharyngitis (two [8%] of 25) in the deucrictibant 30 mg group. In part 2, no single treatment-emergent adverse event was reported by two or more patients in any treatment group. Most adverse events were considered unrelated to the study drug and there were no grade 3 or worse adverse events. INTERPRETATION: Deucrictibant significantly reduced the severity of hereditary angioedema attacks compared with placebo; these results support continued investigation of antagonism of the bradykinin B2 receptor with an orally available agent as a potentially effective approach, with a safety profile similar to placebo, for on-demand treatment. FUNDING: Pharvaris.
In this phase 2 trial, we found that oral administration of deucrictibant 20 mg and 30 mg significantly reduced the severity of attack manifestations from pre-treatment to 4 h post-treatment.
blinded crossover estimates with multiplicity control and consistent prespecified sensitivity analyses
Deucrictibant treatment also reduced the duration of attacks compared with placebo, with significant reductions in the time to onset of symptom relief and to resolution.
multiplicity-controlled time-to-event endpoints consistently favoured the 20 mg and 30 mg doses
The overall safety profile of deucrictibant was comparable to that of placebo
systematic short-term adverse-event collection in a sample too small for uncommon or long-term harms
Derived from the full evaluation — not a separate score.
Strengths
Interactive-response randomisation, identical capsules, masking of participants, investigators, site personnel, and the sponsor, and within-patient crossover comparisons reduce allocation and measurement bias.
↳ Methods, Randomisation and masking, p e202
The 20 mg and 30 mg doses improved VAS-3 severity, symptom-relief timing, MSCS, TOS, and rescue-medication use, with prespecified sensitivity analyses supporting the primary result.
↳ Table 2; Results, pp e207–09; appendix pp 9–10
The Discussion connects the excess of abdominal attacks and sparse 8–24-hour assessments to the unexpectedly short 10 mg resolution estimate, rather than listing these limitations generically.
↳ Discussion, Limitations, pp e211–12
Limitations
Only 62 patients contributed to the primary efficacy analysis, with 16–21 patients represented in each active-dose cohort. This limits precision for dose selection and subgroup interpretation.
↳ Results, p e207; Table 2
Attacks involving the internal head or neck, including laryngeal attacks, and attacks presenting with vomiting were not treated with study drug. The findings therefore do not establish efficacy for these consequential presentations.
↳ Methods, Procedures, p e202; Discussion, pp e211–12
The efficacy population was 97% White, and adverse events were assessed in a modest sample over short post-attack windows. Rare, long-term, and broadly representative safety cannot be established from this trial.
↳ Summary, p e200; Methods, p e203; Table 3
The primary VAS-3 result is supported by a masked crossover design, prespecified multiplicity control, and sensitivity analyses reported as consistent with the main analysis. Secondary symptom-relief, resolution, and rescue-medication outcomes point in the same direction, supporting a quality score above the competent-publication midpoint. The score remains below the top band because the efficacy analysis included 62 patients, consequential attack presentations were excluded, and the safety dataset cannot identify uncommon or long-term harms. Contextualisation is substantive, although numerical comparisons with other therapies remain informal despite the paper’s explicit caution against direct comparisons.
Nabu’s assessment, alongside the field’s view.
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Strong4.2
Confidence highThe trial meaningfully extends on-demand hereditary-angioedema evidence by evaluating an oral bradykinin B2 receptor antagonist and demonstrating placebo-controlled efficacy. Its contribution remains phase 2 evidence without active-comparator or confirmatory effectiveness data.
“Deucrictibant 20 mg and 30 mg significantly reduced the severity of attack manifestations”
Central randomisation, identical masked capsules, a crossover sequence, prespecified multiplicity control, and several sensitivity analyses support the primary findings. The modest analysis set and exclusion of laryngeal, internal head-or-neck, and vomiting-associated attacks constrain precision and scope.
“Prespecified sensitivity and supplementary analyses yielded results consistent with those of the primary statistical analysis”
The paper moves clearly from treatment burden and oral-therapy rationale to effect estimates, safety findings, limitations, and a phase 3-oriented conclusion. Claims are supported with confidence intervals and calibrated language that calls for continued investigation rather than clinical adoption.
“These phase 2 results support further investigation”
The Research in context section and Discussion engage injectable treatments and oral sebetralstat while warning that trial and instrument differences prevent direct comparisons. Limitations are traced to specific interpretations, particularly attack-location imbalance, sparse later assessments, excluded presentations, and racial representation.
“Variations in trial designs and instruments used across trials…prevent direct outcome comparisons.”
No concerns4 of 4 checks
Unanimous clean assessment: enrolment, analysis-set, attack-level, endpoint, multiplicity, and safety reporting are internally coherent across the paper. No methods–results mismatch, impossible statistic, or material overclaim was identified.
Unanimous clean assessment: ethics approval, consent, prospective registration, sponsor participation, conflicts of interest, and the conditional data-sharing policy are disclosed. Sponsor involvement is extensive but transparent and does not itself establish a conduct concern.
Flags: 4 declared / 5 total
28 of 28 checkable references verified
30 references in manuscript 2 have no canonical index record — counted, but not index-checkable 1 reference confirmed by manual review
References not verified automatically are resolved manually within 24 hours.
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.
Home self-administration during investigator-confirmed attacks approximates intended use and moves the intervention beyond an initial mechanistic demonstration. Phase 3 confirmation and broader safety evidence remain necessary before clinical deployment.
“These phase 2 results support further investigation…in a phase 3 trial”
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Tentative