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BACKGROUND: People with hereditary angioedema (HAE) experience anxiety from the unpredictable nature of attacks and the burden of parenteral on-demand therapies, potentially leading to delays or avoidance of treatment. This analysis assessed factors associated with anxiety during attacks and the impact of oral sebetralstat versus placebo on anxiety in the KONFIDENT trial.
METHODS: Participants in the randomised, double-blind, phase 3 KONFIDENT trial (NCT05259917) treated attacks with sebetralstat 300 mg, 600 mg or placebo as early as possible after onset. Anxiety was recorded at treatment administration, every 0.5 h thereafter through 4 h, hourly from 5 to 12 h and every 2 h from 14 to 24 h using an 11-point modified General Anxiety Numeric Rating Scale (GA-NRS). Prespecified exploratory endpoints assessed in all attacks and in attacks rated as inducing moderate-to-extreme anxiety (GA-NRS ≥ 4) included cumulative GA-NRS score and meaningful reduction in anxiety (defined as ≥ 2-point reduction in GA-NRS for ≥ 2 consecutive timepoints); least squares mean change from treatment administration in GA-NRS at 4 and 12 h was also assessed. This study was sponsored by KalVista Pharmaceuticals.
RESULTS: Overall, 115 (44%) attacks were rated as inducing moderate-to-extreme anxiety. Female sex, shorter time since HAE diagnosis and greater attack severity were associated with greater anxiety at treatment administration. Reduction in cumulative anxiety after sebetralstat use was significantly greater versus placebo. The time to meaningful reduction in anxiety endpoint showed agreement with time to beginning of symptom relief, reduction in attack severity and complete attack resolution endpoints.
CONCLUSION: Moderate-to-extreme anxiety was common in HAE attacks. Reduction in anxiety was significantly greater in attacks treated with sebetralstat compared with placebo.
Reduction in anxiety was significantly greater in attacks treated with sebetralstat compared with placebo
exploratory endpoints were unpowered for group significance testing and uncontrolled for multiplicity
Moderate-to-extreme anxiety was common in HAE attacks
direct descriptive evidence from 115 of 261 attacks with recorded baseline anxiety
Female sex, shorter time since HAE diagnosis and greater attack severity were associated with greater anxiety at treatment administration
stepwise association modelling supports the reported direction, but exploratory testing limits certainty
The time to meaningful reduction in anxiety endpoint showed agreement with time to beginning of symptom relief, reduction in attack severity and complete attack resolution endpoints
reported concordance across efficacy endpoints lacks numerical kappa estimates in the supplied text
Derived from the full evaluation — not a separate score.
Strengths
Anxiety was measured before and repeatedly after treatment as a prespecified exploratory endpoint within a randomized, double-blind, placebo-controlled phase 3 trial.
↳ Introduction, final paragraph; Methods, Anxiety Endpoints
The assessment schedule extended through 24 hours, and the mixed model included treatment, sequence, period, time interaction, baseline anxiety, and participant-level random effects.
↳ Methods, Trial Design and Statistics
The discussion considers assessment burden, anxiety from possible placebo receipt, and selection effects that could increase or decrease baseline anxiety.
↳ Discussion, limitations paragraph
Limitations
The abstract and conclusion emphasize statistically significant anxiety reduction without stating that these exploratory comparisons were unpowered and not controlled for multiplicity.
↳ Abstract, Conclusion; Methods, Statistics
The core outcome is an 11-point modified single-item GA-NRS, and the discussion does not directly address the absence of formal psychometric validation as a limitation.
↳ Methods, Trial Design; Discussion, limitations paragraph
Although derived from a phase 3 trial, the anxiety findings are supplementary to the parent efficacy evidence and require confirmatory, prospectively powered assessment before supporting anxiety-specific practice claims.
↳ Methods, Anxiety Endpoints and Statistics
The contribution is a genuine extension from survey evidence to prospectively collected anxiety outcomes in a blinded phase 3 setting, but it remains a secondary exploratory analysis. Methodological credit comes from the repeated assessments and mixed modelling, while LOCF, absent multiplicity control, and lack of power for treatment-group significance testing constrain inference. The discussion engages meaningfully with prior surveys and several potential trial biases, yet the main statistical caveat is not reflected in the abstract or conclusion. The results therefore support a clinically relevant signal rather than confirmatory evidence of an anxiety-specific treatment effect.
Nabu’s assessment, alongside the field’s view.
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Confidence mediumThe study extends survey-based knowledge by prospectively measuring attack-associated anxiety and treatment-related change within a blinded phase 3 trial. The advance remains bounded because this is a secondary exploratory analysis rather than the parent trial's primary efficacy contribution.
“the first phase 3 trial to include anxiety assessments before and after treatment of attacks”
Repeated anxiety assessments, mixed modelling with participant-level random effects, and the blinded placebo-controlled parent design support the analysis. LOCF and treatment comparisons that were unpowered and not multiplicity-controlled materially limit inferential certainty.
“Analyses were not powered to detect statistical significance between treatment groups for GA-NRS endpoints and were not controlled for multiplicity.”
The paper follows a coherent progression from anxiety burden through endpoints, results, and clinical interpretation. The abstract and conclusion nevertheless present significant treatment effects without carrying forward the exploratory, power, and multiplicity qualifications.
“Reduction in anxiety was significantly greater in attacks treated with sebetralstat compared with placebo.”
The discussion compares the findings with earlier HAE surveys and traces several trial-specific biases, including assessment burden, possible placebo receipt, and selection effects. It does not carry the central statistical qualification through to the strength of the concluding efficacy language.
“is robust for measuring the overall change in attack-associated anxiety”
No concerns4 of 4 checks
The participant, attack, and anxiety-record denominators reconcile, and the reported outcomes correspond to the prespecified exploratory methods. The statistical limitations are disclosed in the Statistics section.
Ethics approval, informed consent, trial registration, sponsor funding, extensive conflicts of interest, and a controlled data-request route are explicitly declared. Sponsor involvement is substantial but transparently reported.
Flags: 4 declared / 5 total
16 of 16 checkable references verified
17 references in manuscript 1 are books, websites or datasets — counted, but not index-checkable
No retraction notice found in Retraction Watch.
Sources: Retraction Watch ✓
Where this paper’s evidence sits on the path from initial observation to real-world use.
The evidence derives from a completed phase 3 randomized, double-blind trial, placing the treatment context near clinical use. Anxiety-specific translation remains limited by the exploratory, unpowered analysis.
“Prespecified exploratory endpoints for anxiety”
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