Study design of a randomised, placebo-controlled trial of nintedanib in children and adolescents with fibrosing interstitial lung disease

Abstract

Childhood interstitial lung disease (chILD) comprises >200 rare respiratory disorders, with no currently approved therapies and variable prognosis. Nintedanib reduces the rate of forced vital capacity (FVC) decline in adults with progressive fibrosing interstitial lung diseases (ILDs). We present the design of a multicentre, prospective, double-blind, randomised, placebo-controlled clinical trial of nintedanib in patients with fibrosing chILD (1199-0337 or InPedILD; ClinicalTrials.gov: NCT04093024). Male or female children and adolescents aged 6-17 years (≥30; including ≥20 adolescents aged 12-17 years) with clinically significant fibrosing ILD will be randomised 2:1 to receive oral nintedanib or placebo on top of standard of care for 24 weeks (double-blind), followed by variable-duration nintedanib (open-label). Nintedanib dosing will be based on body weight-dependent allometric scaling, with single-step dose reductions permitted to manage adverse events. Eligible patients will have evidence of fibrosis on high-resolution computed tomography (within 12 months of their first screening visit), FVC ≥25% predicted, and clinically significant disease (Fan score of ≥3 or evidence of clinical progression over time). Patients with underlying chronic liver disease, significant pulmonary arterial hypertension, cardiovascular disease, or increased bleeding risk are ineligible. The primary endpoints are pharmacokinetics and the proportion of patients with treatment-emergent adverse events at week 24. Secondary endpoints include change in FVC% predicted from baseline, Pediatric Quality of Life Questionnaire, oxygen saturation, and 6-min walk distance at weeks 24 and 52. Additional efficacy and safety endpoints will be collected to explore long-term effects.

FIGURE 1

Study design. EoT: end of treatment; FPE: first patient enrolled; FPI: first patient in; LPI: last patient in.

FIGURE 2

Inclusion criteria for fibrosing interstitial lung disease (ILD). Evidence of fibrosing ILD will be confirmed by central review (lung biopsy and high-resolution computed tomography (HRCT)). NSIP: non-specific interstitial pneumonia; UIP: usual interstitial pneumonia. ^#: Coexisting cystic abnormalities or ground-glass opacity are acceptable; however, coexisting multifocal non-fibrotic, non-dependent consolidations (e.g. organising pneumonia, infection) will not be permitted. ^¶: With or without ground-glass opacification.

FIGURE 3

Key assessments. ^#: Part A comprises visit 2 (week 0), visit 3 (week 2), visit 4 (week 6), visit 5 (week 12), and visit 6 (week 24). Laboratory tests can be performed between visit 5 and 6 (visit 5A) as needed. ^¶: Part B starts at the end of visit 6 and comprises visit 7 (week 26), visit 8 (week 36), visit 9 (week 52), visit X (week 64, then every 12 weeks until end of treatment (EoT)), and EoT. Laboratory tests can be performed between each visit (visit 7A, 8A, 9A and XA as needed). ⁺: Clinically significant disease is assessed by the investigator based on any of the following: Fan score ≥3 or documented evidence of clinical progression over time (either 5–10% relative decline in forced vital capacity (FVC) % predicted accompanied by worsening symptoms, or a ≥10% relative decline in FVC% predicted, or increased fibrosis on high-resolution computed tomography (HRCT), or other measures of clinical worsening attributed to progressive lung disease (e.g. increased oxygen requirement, decreased diffusion capacity)). ^§: The primary endpoints are pharmacokinetics (area under the plasma concentration–time curve at steady state (AUC_τ,ss)) based on sampling at steady state (weeks 2 and 26) and number (%) of patients with treatment-emergent adverse events (week 24). 6MWT: 6-minute walk test; D_LCO: diffusing capacity of the lung for carbon monoxide; ECG: electrocardiogram; ILD: interstitial lung disease; PedsQL: Pediatric Quality of Life Questionnaire; PK: pharmacokinetics; S_pO2: oxygen saturation measured by pulse oximetry.