Efficacy and Safety of Nintedanib in Systemic Sclerosis-Associated Interstitial Lung Disease

5 Jan, 21

Introduction

Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis, a rare and heterogenous autoimmune disease, and a leading cause of systemic sclerosis–related mortality. Nintedanib, an intracellular inhibitor of tyrosine kinases, is approved for the treatment of idiopathic pulmonary fibrosis (IPF). The pathophysiological processes associated with IPF and ILD might be similar. Animal studies have demonstrated the antifibrotic and anti-inflammatory effects of nintedanib in systemic sclerosis and ILD.

Aim

The Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial evaluated the efficacy and safety of nintedanib in patients with ILD associated with systemic sclerosis.

Patient Profile

Age >18 years with systemic sclerosis
Onset of the first non-Raynaud’s symptom within the past 7 years before screening
A high-resolution computed tomographic scan, obtained within 12 months before screening, that showed fibrosis affecting at least 10% of the lungs
Patients having forced vital capacity (FVC) of least 40% of the predicted value
A diffusion capacity of the lung for carbon monoxide (DL_CO) that was 30 to 89% of the predicted value.

Method

Study Design

Randomized, double-blind, placebo-controlled, parallel-group trial

Treatment Strategy

The patients were randomized, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo, after a screening period of 12 weeks or less
The primary efficacy assessment was conducted at week 52

End Points

Primary End Point

Annual rate of decline in FVC assessed over a 52-week period.

Secondary End Points

Absolute changes from baseline in the modified Rodnan skin score at week 52
Total score on the St. George’s Respiratory Questionnaire (SGRQ) at week 52.
Adverse events (AEs)

Results

The study population comprised a total of 576 patients who received at least one dose of nintedanib or placebo
The baseline characteristics were similar across the groups
Approximately half of the patients had diffuse cutaneous systemic sclerosis (51.9%) and 48.1% had limited cutaneous systemic sclerosis
The median time since the onset of the first non-Raynaud’s symptom was 3.4 years.
The mean (±SD) age of the patients was 54.0±12.2 years, and the mean FVC and DL_CO were 72.5±16.7% and 53.0±15.1% of the predicted value, respectively.
The high-resolution computed tomography scan findings revealed that the mean extent of fibrosis was 36.0±21.3%.
Almost half (48.4%) of the patients were receiving mycophenolate at baseline.
The nintedanib group had a lower adjusted annual rate of change in FVC as compared to placebo group (p=0.04) as seen in Table 1.
Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10.
Both the groups did not have any significant differences in the modified Rodnan skin score and the total score on the SGRQ at week 52 as compared to baseline as seen in Table 1.

Table 1. Comparison of efficacy parameters at week 52

	Nintedanib group	Placebo group	Difference
Adjusted annual change in FVC	-52.4 ml	-43.3 ml	41.0 ml
Adjusted mean absolute change in FVC	-54.6 ml	-101.0 ml	46.4 ml
Adjusted mean absolute change in modified Rodnan skin score	-2.17	-1.96	-0.21
Adjusted mean absolute change in SGRQ score	0.81	-0.88	1.69

Both the groups had similar percentages of patients having AEs or any serious AE
The most common AE was diarrhea, reported by 75.7% of the patients in the nintedanib group vs 31.6% in the placebo group.

Conclusions

Results of the SENSCIS trial demonstrated that nintedanib had a lower annual rate of decline in forced vital capacity among patients with interstitial lung disease (ILD) associated with systemic sclerosis as compared to placebo
There was no other clinical benefit observed for other manifestations of systemic sclerosis.
Nintedanib treatment had a safety profile similar to that observed in patients with idiopathic pulmonary fibrosis, with diarrhea being the most common adverse event.

N Engl J Med 2019; 380:2518-2528. Doi: 10.1056/NEJMoa1903076.