ILD maintenance trials Flashcards

Question

what adverse events related to the drug were most common in ASCEND?

Answer 1

rash, nausea, LFTs abnormalities - 15% of pirfenidone patients stopped drug due to an adverse event

Answer 2

INBUILD was a double blind RCT placebo multicenter trial testing nintedanib vs placebo in "progressive pulmonary fibrosis" other than IPF. total study size was 663 group 1 - nintedanib 150 BID - n = 332 group 2 - placebo n = 331

Answer 3

inclusion - - HRCT features of reticular abnormalities w/ traction bcx >10% of lungs "ONE of the following criteria for progression of ILD within 24 months despite standard treatment other than nintedanib or pirfenidone" - FVC decline of 10% - FVC decline of 5% + worsening symptoms or increased disease on HRCT - worsening symotoms and increased disease on HRCT - FVC > 45% - DLCO 30-80% exclusion - - treatment with AZA, cyclosporine, MMF, tacrolimus, ritux, cyclophosphamide, steroids >20 pred - note these were allowed 6 months into therapy - liver enzymes > 1.5 ULN, CrCl < 30, recent cardiovascular - "significant" PAH by TTE or RHC - "RV failure" or CI < 2

Answer 4

primay - annual rate of decline in the FVC assessed over 52 weeks secondary - symptom questoinaire, time until exacerbation or death exacerbation definition: acute worsening or development of dyspnea (typically of <1 month duration), CT with new bilateral ground-glass opacity or consolidation superimposed on a background pattern consistent with fibrosing interstitial lung disease, and deterioration not fully explained by cardiac failure or fluid overload. Infection was not an exclusion criterion for an acute exacerbation.

Answer 5

both groups -- 65 year old, male (53%), 50% former smokers, 62% UIP-like pattern, ~50% enrolled because of FVC > 10%, average FVC ~69% predicted, avearge DLCO 45% by ILDs (both groups) - HP (25%) - auto immune - 25% (RA, SS, MCTDm other) - iNSIP 20% - unclassified 20% - other (sarcoid, exposure, etc) - 12%

Answer 6

- at 52 weeks, the nintedanib group lost 82cc vs 187cc in the placebo group (measured as the adjusted rate of cline per year) - at 52 weeks among the UIP-like patients, nintedanib lost 83 vs 211 - among nonUIP - 79 vs 154 secondary mortality/flare (combined outcome) data at 52 weeks - 7.8% in ninedanib and 9.7 in placebo (not significant) - 8.3 vs 12.1 in UIP, 5.3 vs 7.8 in nonUIP in supplementary data, flare/mortality up to first look - nearly significant benefit (.68 CI .46-1.01) in all patients, significant in the UIP subgroup .61 HR CI .38-.91 -> in both circumstances ?driven by data handling in placebo group d/t stepoff - suspect driven by FLARES because analysis of mortality shows the same trend but HR ~.7 but non significant in all comers and UIP subgroups Compared w/ INPULSIS - rate of placebo decline similar (200cc annually), slightly better "improvment (80cc vs 110cc) - INPULSIS 2 showed decreased rate of exacerbations, INPULSIS 1 did not - all show a trend towards decreased mortality but none are significant

Answer 7

2/3rds have diarrhea (tho 1/3 in placebo), 1/3 have nausea

Answer 8

most subgroups were ~50% male except "other ILDs' age 65-70 UIP-pattern still made up the majority of radiographic findings across all subgroups - 52% HP, 75% autoimmune, iNSIP 57%, unclassified IIP 68%, other 58% baseline FVC is 65-70% DLCO is ~45% all groups relatively even save for the "other ILD"

Answer 9

"other," iNSIP, auto immune, HP, unclassifiable HP and unclassifiable cross 0 with their confidence interval - across all subgroups, the effect is larger if there is a UIP-like HRCT

Answer 10

there were 3 ways to define progression that could be met at any time >24 months a) >10% FVC loss b) 5-10% FVC loss AND progression on scan or symptoms c) progression on scan AND symptoms In the PLACEBO groups - the rate of decline at 52 weeks was HIGHEST in group A at -250cc with groups b and c at 130 and 115 respectively. That trend was consistent among UIP and non UIP alike In the TREATMENT group - the benefit of nintedanib was GREATEST in groups A and C with a relative effect vs placebo of ~60-70 cc. Group A had the highest rate of ILD or death in placebo (22%) vs 17 and 15 respectively - highest rate of deaths 16% v 11% in b and c - highest rate of progression >10% or death - 60% vs 50% in b and c the relative benefit of ninetanib was greatest in group A note that INBUILD was not powered to detect any of this

Answer 11

PART A of INBUILD was a 52 weeks of RCT and ended after the patient finished 52 weeks. PART B was a variable follow up where patients remained in a blinded, placebo controlled RCT in which patients who were past 52 weeks continued in the trial until the last patient had finished their 52 week follow up In the end, this meant average follow up was 19 months (rather than 12) and time on medication was 15 months over this time period: - 65% of patients on ofev and 80% without will experience a decline of >5% FVC - 34% of patients on ofev and 48% witohut will experience a decline of >10% FVC - both signficant those ratios are nearly identical for UIP-pattern - 10% of the nintedanib group died vs 13.6 in the placebo died. not significant. - 14% of ofev would die/exacerbate vs 19.6% in the placebo group. significant.

Answer 12

in order of prevelance - RA-ILD, SSc-ILD, MCTD ILD, other ~80 in each arm baseline PFTs similar - FVC ~70%, DLCO 45% in order of benefit with respect to difference in annualized rate of FVC decline - SSc, RA, other, MCTD. The overall difference was 102, similar to the overall study difference UIP improved more than nonUIP patterns - 124 difference vs 40 (not significant) using DMARDs and/or steroids had a large benefit 130 vs 17 cc (not significant) nonsignificant trend towards benefit with acute exacerbation or death, progression or death, and death alone - all non significant

Answer 13

the supplement of Matteson et al demonstrates a that IN THE PLACEBO GROUP those on DMARDs/steroids at baseline have an anualized FVC decline of 202 vs 108, incidicating that being on a DMARD may indicate disease severity the use of all DMARD/nintedanib vs nothing was 71 vs 108 - small n and underpowered but suggests the treatment groups are different nonetheless, the addition of nintedanib does seem to make a notable difference -202 without vs 71

Answer 14

double blind RCT placebo controlled multi-site trial SSc-ILD assigned 1:1 to get nintedanib 150 BID or placebo for 52 weeks, 288 randomized into each arm

Answer 15

inclusion - systemic sclerosis for <7 years (except raynaulds) - 10% lung fibrosis - FVC >40% - DLCO 30-90% - allowed to be on pred 10, or stable MTX/MMF dosing exclusion - other DMARDS than above (ritux, tac, CsA, AZA) - LFTs > 1.5x ULN, CrCl <30, PAH - bleeding, A/C, A/P, prior MI

Answer 16

75% female, age 55, 50% diffuse cutaneous SS, FVC 72%, DLCO 53%, 50% on MMF

Answer 17

primary - adjusted annual rate of change in FVC -52 vs- 93 - statistically significant secondary - no change in rodnan skin score - no change in symptoms questionnaire mortality - 10 people died w/ ofev, 9 w/ placebo

Answer 18

in terms of adjusted annual rate of FVC at 52 weeks, - MMF + ofev was the best at -40cc - both MMF and ofev alone were second at -63 - no therapy was worse at -120 that pattern was recreated w/ mean absolute change though ofev alone was better with MMF alone this is despite the pre-FVC beting 75% (vs 74% in the no MMF). both groups had a DLCO between 50 and 55%, with MMf being slightly worse

Answer 19

a hedgehog inhibitor under investigation for IPF. phase 2a clinical trial randomized patients with IPF (via ATS guidelines, central review) with FVC >50, DLCO >35 with ~20 patients in each group, 200 mg of env 101 demonstrated at 12 weeks: - IMPROVEMENT by 60 cc in treatment group in FVC - decrease in 47 cc in control group (net delta ~100cc) improvement in TLC as measured by CT side effects = metallic taste, alopecia, muscle cramps