Adjunctive Pascolizumab in Rifampicin-Susceptible Pulmonary Tuberculosis: Proof-of-Concept, Partially-Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Trial.
J Infect Dis
; 230(3): 590-597, 2024 Sep 23.
Article
em En
| MEDLINE
| ID: mdl-38527849
ABSTRACT
BACKGROUND:
Interleukin 4 (IL-4), increased in tuberculosis infection, may impair bacterial killing. Blocking IL-4 confers benefit in animal models. We evaluated safety and efficacy of pascolizumab (humanized anti-IL-4 monoclonal antibody) as adjunctive tuberculosis treatment.METHODS:
Participants with rifampicin-susceptible pulmonary tuberculosis received a single intravenous infusion of pascolizumab or placebo, and standard 6-month tuberculosis treatment. Pascolizumab dose increased in successive cohorts (1) nonrandomized 0.05â mg/kg (n = 4); (2) nonrandomized 0.5â mg/kg (n = 4); (3) randomized 2.5â mg/kg (n = 9) or placebo (n = 3); and (4) randomized 10â mg/kg (n = 9) or placebo (n = 3). Coprimary safety outcome was study-drug-related grade 4 or serious adverse event (G4/SAE) in all cohorts (1-4). Coprimary efficacy outcome was week 8 sputum culture time-to-positivity (TTP) in randomized cohorts (3-4) combined.RESULTS:
Pascolizumab levels exceeded IL-4 50% neutralizing dose for 8 weeks in 78%-100% of participants in cohorts 3-4. There were no study-drug-related G4/SAEs. Median week-8 TTP was 42 days in pascolizumab and placebo groups (P = .185). Rate of TTP increase was greater with pascolizumab (difference from placebo 0.011 log10 TTP/day; 95% Bayesian credible interval 0.006 to 0.015 log10 TTP/day).CONCLUSIONS:
There was no evidence to suggest blocking IL-4 was unsafe. Preliminary efficacy findings are consistent with animal models. This supports further investigation of adjunctive anti-IL-4 interventions for tuberculosis in larger phase 2 trials. CLINICAL TRIALS REGISTRATION NCT01638520.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Rifampina
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Tuberculose Pulmonar
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Interleucina-4
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Anticorpos Monoclonais Humanizados
Limite:
Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
J Infect Dis
/
J. infect. dis
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Journal of infectious diseases
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Singapura