Adjunctive Pascolizumab in Rifampicin-Susceptible Pulmonary Tuberculosis: Proof-of-Concept, Partially-Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Trial

J Infect Dis. 2024 Sep 23;230(3):590-597. doi: 10.1093/infdis/jiae104.

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 0.05 mg/kg (n = 4); (2) nonrandomized 0.5 mg/kg (n = 4); (3) randomized 2.5 mg/kg (n = 9) or placebo (n = 3); and (4) randomized 10 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.

Keywords: clinical trial; host-directed therapy; interleukin-4; pascolizumab; tuberculosis.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Antibodies, Monoclonal, Humanized* / administration & dosage
  • Antibodies, Monoclonal, Humanized* / adverse effects
  • Antibodies, Monoclonal, Humanized* / therapeutic use
  • Antitubercular Agents / administration & dosage
  • Antitubercular Agents / adverse effects
  • Antitubercular Agents / therapeutic use
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Humans
  • Interleukin-4*
  • Male
  • Middle Aged
  • Placebos / administration & dosage
  • Proof of Concept Study
  • Rifampin* / administration & dosage
  • Rifampin* / therapeutic use
  • Treatment Outcome
  • Tuberculosis, Pulmonary* / drug therapy
  • Young Adult

Substances

  • Rifampin
  • Antibodies, Monoclonal, Humanized
  • Interleukin-4
  • Antitubercular Agents
  • Placebos

Associated data

  • ClinicalTrials.gov/NCT01638520