The clinical efficacy of nintedanib has been studied in patients with SSc-ILD in a randomized, double-blind, placebo-controlled phase 3 trial (Study 4 [NCT02597933]). A total of 580 patients were randomized in a 1:1 ratio to receive either OFEV 150 mg twice daily or matching placebo for at least 52 weeks, of which 576 patients were treated. Randomization was stratified by anti-topoisomerase antibody (ATA) status. Individual patients remained on blinded trial treatment for up to 100 weeks. The primary endpoint was the annual rate of decline in FVC over 52 weeks. The absolute change from baseline in the modified Rodnan skin score (mRSS) at Week 52 was a key secondary endpoint. Mortality over the whole trial was an additional secondary endpoint.

Patients were diagnosed with SSc-ILD based upon the 2013 American College of Rheumatology / European League Against Rheumatism classification criteria for SSc with onset of disease (first non-Raynaud symptom) of less than 7 years and greater than or equal to 10% fibrosis on a chest high resolution computed tomography (HRCT) scan conducted within the previous 12 months. Patients were required to have an FVC greater than or equal to 40% of predicted and a DLCO 30-89% of predicted. Patients with relevant airways obstruction (i.e., pre-bronchodilator FEV1/FVC less than 0.7) or previous or planned hematopoietic stem cell transplant were excluded from the trial. Patients with greater than 1.5 times ULN of ALT, AST, or bilirubin, patients with a known risk or predisposition to bleeding, patients receiving a full dose of anticoagulation treatment, and patients with a recent history of myocardial infarction or stroke were excluded from the study. Patients were excluded if they had significant pulmonary hypertension, more than three digital fingertip ulcers, a history of severe digital necrosis requiring hospitalization, or a history of scleroderma renal crisis. Patients were also excluded if they received other investigational therapy, azathioprine within 8 weeks prior to randomization, cyclophosphamide or cyclosporine A within 6 months prior to randomization, or previous treatment with nintedanib or pirfenidone.

The majority of patients were female (75%). Patients were mostly Caucasian (67%), Asian (25%), or Black (6%). The mean age was 54 years. Overall, 52% of patients had diffuse cutaneous systemic sclerosis (SSc) and 48% had limited cutaneous SSc. The mean time since first onset of a non-Raynaud symptom was 3.49 years. At baseline, 49% of patients were on stable therapy with mycophenolate.

Annual Rate of Decline in FVC 

The annual rate of decline of FVC (in mL) over 52 weeks was significantly reduced by 41 mL in patients receiving OFEV compared to patients receiving placebo, corresponding to a relative treatment effect of 44%. See Table 5.

Figure 7 displays the change from baseline over time in both treatment groups. When the mean observed FVC change from baseline was plotted over time, the curves diverged at all timepoints through Week 52. Separation of the mean values is seen after 12 weeks of treatment.

Figure 7 Mean (SEM) Observed FVC Change from Baseline (mL) Over Time in Study 4

bid = twice daily

In two pre-specified subgroup efficacy analyses, the mean treatment difference in FVC decline at 52 weeks in patients were examined by region and mycophenolate use (Figure 8).

Figure 8 Subgroup Analyses of the Mean Treatment Difference in FVC (mL) Decline at Week 52 by Region and Mycophenolate Use (Study 4)

Percent Change from Baseline in Forced Vital Capacity

Figure 9 presents the percent change from baseline in FVC in mL at Week 52 for Study 4. For the majority of patients, the decline in lung function was less on OFEV than on placebo.

Modified Rodnan Skin Score

No benefit in mRSS was observed in patients receiving OFEV. The adjusted mean absolute change from baseline in mRSS at Week 52 was comparable between the OFEV group (-2.17 (95% CI: -2.69, -1.65)) and the placebo group (-1.96 (95% CI: -2.48, -1.45)). The adjusted mean difference between the treatment groups was -0.21 (95% CI: -0.94, 0.53).

Survival 

No difference in survival was observed in an exploratory analysis of mortality over the whole trial (OFEV: n=10 (3.5%) vs. placebo: n=9 (3.1%)). The analysis of time to death over the whole trial resulted in a HR of 1.16 (95% CI: 0.47, 2.84).