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Patients with interstitial lung disease (ILD) related to systemic sclerosis continued to see less progression when treated with nintedanib (Ofev) in the pivotal 100-week , researchers said.

Among participants who remained on the drug until the protocol had them stop, forced vital capacity (FVC) declined by 55.1 mL/year, compared with 94.0 mL/year in the trial's placebo group (difference 38.9, 95% CI 5.6-72.1), according to Shervin Assassi, MD, of the University of Texas McGovern Medical School in Houston, and colleagues.

A modified intention-to-treat analysis that also included post-treatment data from patients who discontinued prematurely favored nintedanib as well, the researchers : FVC declined by 54.9 and 88.8 mL/year with the drug and placebo, respectively, for a difference of 34.0 mL/year (95% CI 3.4-64.5).

in September 2019 for this patient population, on the basis of , at which point the drug slowed FVC decline by an average 41 mL/year relative to placebo. The drug was first approved in 2014 to treat idiopathic pulmonary fibrosis (IPF) and also, in March 2020, for .

The new report covers the full 100-week results that were the trial's prespecified goal, though not every patient received the drug for that long.

Nintedanib inhibits tyrosine kinases that drive expression of receptors for fibroblast growth factor, vascular endothelial growth factor, and platelet-derived growth factor. (In fact, the drug was for solid tumor cancers.) Its developers eventually realized that this mode of action could also be effective against processes involved in lung fibrosis, leading to successful trials first in IPF and subsequently ILD.

For SENSCIS, Assassi and colleagues enrolled 576 systemic sclerosis patients, randomized in equal numbers to nintedanib (150 mg orally twice daily) and placebo. Eligibility criteria included having a first non-Raynaud symptom no more than 7 years previously, FVC of at least 40% of predicted, presence of fibrotic ILD of at least 10% on CT scans, and diffusing capacity for carbon monoxide of 30%-89% predicted. Participants taking corticosteroids (no more than 10 mg/day prednisone equivalent) and/or methotrexate or mycophenolate mofetil at stable doses were allowed to stay on them.

FVC was the trial's sole measure of lung function, though analyzed in multiple ways. In addition to the average rate of decline (the primary outcome), the researchers also counted the number of participants showing declines of 5% and 10% over the full 100 weeks. Modified Rodnan Skin Score was also assessed to determine effects, if any, on systemic sclerosis's cutaneous manifestations. No statistically significant differences in these secondary outcomes were observed, though there were numerical trends favoring nintedanib.

The trial's design made the efficacy analyses somewhat complicated. Blinded treatment continued until the last patient enrolled had completed 52 weeks of therapy, such that follow-up varied among participants. Patients who decided to stop before then (74 and 46 in the nintedanib and placebo groups, respectively) were then asked to continue with their scheduled clinic visits, and most did so.

Consequently, the modified intention-to-treat analysis included all data from those who stopped treatment but continued with follow-up, yet post-treatment data from participants whose treatment was stopped according to the protocol (because the last enrollee had reached week 52) were excluded. The on-treatment analysis, as the name implies, included the data obtained on treatment but not findings after patients stopped for any reason.

With regard to safety, the most common adverse effect was diarrhea, which was seen in 76% of the nintedanib group and 33% of those assigned to placebo. About 8% of patients receiving nintedanib discontinued for this reason. Liver enzyme elevations beyond three times the upper limit of normal occurred in 6% of the nintedanib group versus 1% of the placebo group, though no one in either arm met . Other adverse events, including all those rated as serious and those ending in death, were balanced between groups.

Overall, the 100-week safety findings were similar to those from the 52-week analysis. Nintedanib's label includes a warning about the hepatic abnormalities and gastrointestinal effects, and recommends monitoring liver enzymes periodically while patients remain on therapy.

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