ILD maintenance trials Flashcards
what is the research question of the EVER-ILD study (2023)? what are the two groups (including dosing) and what are the outcomes? how many patients?
Among patients with NSIP pattern ILD, is MMF or MMF + rituximab better in terms of change of FVC at six months (primary outcome).
126 total patients
study: ritux 1 g day 1 and 15 + MMF 2 g daily
control: MMF 2 g daily
who were the eligible and excluded patients for the EVER-ILD study (2023)?
inclusion: CTD-ILD, IPAF, idiopathic w/ NSIP (could be biopsy or CT w/ MDD). Eligible if failed / relapsed on first line steroids
Exclusion: UIP, nonNSIP path, pHTN (>45 on TTE)
what were the notable secondary outcomes of EVER-ILD study (2023)?
PFS at 6 months, QoL questionnaires, cumulative steroid dosing
progression = decline in FVC > 10%, death, transplant listing, exacerbation (worsening dyspnea w/ infiltrate on imaging w/ no other cause)
among the CT-ILD group in the EVER-ILD study (2023), what CTDs were represented?
systemic sclerosis - 53%
inflammatory myositis - 19%
sjogrens - 16%
RA - 7%
MCTD - 2%
in the EVER-ILD study (2023) what were the baseline between groups that were notable?
placebo -
> 3 years older (67),
> 1 year longer on average since diagnosis (3 vs 4),
> 70% predicted FVC v 66%,
> shorter 6MWT 325 v 364,
> 17% on oxygen vs 13%,
> less CTD-ILD (30 vs 40%)
> more on steroids (85%)
what were the major findings of the EVER-ILD study (2023)?
primary outcome - significant difference between groups at 6 months in FVC (translated to 100cc FVC difference)
what were the results of the subgroup analysis (w/ FVC) EVER-ILD study (2023)?
The patients who seemed to benefit more w/ ritux included:
- CTD-ILD/IPAF (barely though, more variability in the idiopathic group)
- >FVC at baseline
patients did:
- worse w/ PASP > 45
- worse w/ O2
- worse w/ UIP
- worse w/ 6MWT <150
all together - sicker patients (lower FVC, more phtn, worse O2, worse 6mwt) benefited less
what were the differences in ADRs in the EVER-ILD study (2023)?
more frequent respiratory tract infections w/ ritux
no difference in fatal adverse events.. equal total adverse events.
what is the question and study design of the SLS-II study (Tashkin et al 2017)? what were the two treatment groups? how large were they
SLS 2 is a RCT double blind trial
arm 1 - MMF 1.5 BID x 2 years > 69 assigned > 53 w/ data at 24 months
arm 2 - CYC x 1 year followed by placebo > 73 assigned > 53 w/ data available at 24 months
what were the inclusion and exclusion criteria of the SLS-II study (Tashkin et al 2017)
inclusion - SSc (limited or diffuse) FVC < 80 but > 45, any GGO on RCT w or w/o fibrosis, onset w/in last 7 years
exclusion: FVC < 45, FEV 1/FVC < 65, pHTN judged to be “significant”, DLCO < 40 or <30 w/o pHTN, smoking w/in 6 months, hematuria, leukopenia <4, TCP < 150, anemia < 10, AST/ALT/bili > 1.5x basleine, Cr > 2, CHF
what were the primary and relevant secondary outcomes of the SLS-II study?
primary - % predicted FVC at 24 months
secondary - dlco, dyspnea scores, HRCT fibrosis scoring
what are the notable finding of the SLS-II study (Tashkin et al 2017 w/ regard to the primary outcome?
the primary outcome is % predicted FVC change
both saw improvements in FVC out to 24 months, not significantly different, approximately ~7% FVC improvement
of those who completed entire treatment, 75-80% improved
what was the most common side effect in each arm of the SLS-II study (Tashkin et al 2017
cytopenias
what were the INPULSIS studies? what was the trial design? what were the treatment arms? how large where they?
phase 3 trials for ofev/ninatinib. published in 2014
RCT (3:2), double blind, multi-site, international
arm 1 - ninatinib 150 bid
arm 2 - placebo
inpulsis 1 - 513, inpulsis 2 - 548
what were the inclusion/exclusion criteria for the INPULSIS trials?
eligibility - 40, IPF dx w/in 5 years, FVC > 50%, DLCO 30 to 79%
HRCT criteria (if no bx) - definite basilar, peripheral honeycombing; reticular opacities and traction BCX basilar and peripheral, lack of GGOs/atypical features
exclusion - starting prednisone w/in 8 weeks or dose greater than 15, other DMARDS, bili > 1.5 ULN or unstable cardiac disease
what were the outcomes for the INPULSIS trials?
primary - annual rate of decline in FVC
secondary - time to exacerbation and survey of symptoms
- exacerbation definition - worsening symptoms within 30 days, new infiltrates, exclusion of other causes
describe the average INPULSIS pt
male (80%), 65, BMI 28, former smoker (70%), 1.7 years since diagnosis, not on steroids (80%), FVC 80% predicted, DLCO 47% predicted
what were the key findings in terms of primary and secondary outcomes for the INPULSIS trials?
primary - rate of change in FVC at 52 weeks -
inpulsis 1 - -114 vs 239; 113 vs 207 > ie in both trials, ofev “saved” 100 ccs
secondary - time to acute exacerbations
- INPULSIS 1 showed no difference
- INPULSIS 2 showed benefit of ofev
secondary - deaths
- no differene in either tho trend towards benefit (5 vs 7%)
what were the notable adverse events in the INPULSIS trials?
1 diarrhea reported in ~95% of ofev recipients
2 LFT abnormalities in 5%
3 1.5% of patients had MI w/ ofev vs .5% in control
what is the structure of the ASCEND trial 2014 (King Jr et al)? what are the treatment groups?
phase 3 trial of pirfenidone
previously CAPACITY 004 and 006 studies had been done - 2/3 showed reduced FVC decline
randomized, double blind, placebo controlled, multi-site, international
treatment groups:
- pirfenidone 2403 mg x 1 year, 261 patients
- placebo x 1 year, 261 patients
what were the inclusion and exclusion criteria for the ASCEND trial 2014 (King Jr et al)?
inclusion: 40-80, definite UIP on HRCT or probably + biopsy, 50-90% FVC, 30-90% diffusion capacity, ratio of 80% or more, 150m 6mwt
exclusion: “significant worsening” between screening and day 1, “not suitable,” obstruction on PFTs, BDR response, smoking w/in 3 months, explanation for ILD (CTD, exposure), active infection, severe liver or kidney disease, cardiac instability (electrical, CHF, ischemic), long QTc
what were the primary outcomes of the ASCEND trial 2014 (King Jr et al)? secondary outcomes?
change from baseline to week 52 in predicted FVC
secondary
- change in 6mwt, progression-free survival
in the NEJM publication there is additional pooled analysis of CAPACITY and ASCEND data for mortality
describe the baseline patient characteristics in the ASCEND trial and the CAPACITY trial. how does it compare to INPULSIS?
ASCEND
- avg age 68, male 80%, 67% US, 66% former smoker, avg FVC ~68%, avg DLCO 44%, 415 m on 6MWT, 1.7 years since diagnosis, overall balanced
CAPACITY
- age 66. 70% male, 75% US, FVC 75% predicted, DLCO 47% predicted, 6MWT ~400m, 1.2 years since diagnosis, 65% former smokers, 75% on oxygen
INPULSIS
- male (80%), 65, BMI 28, former smoker (70%), 1.7 years since diagnosis, not on steroids (80%), FVC 80% predicted, DLCO 47% predicted
what were the results of the ASCEND trial?
primary - mean decrease in FVC by 235 vs 428 at 1 year
secondary - fewer patients w/ >50m 6MWT decrease, trend toward mortality benefit but not significant
pooled w/ CAPACITY - significant decrease in mortality of any cause and IPF 3.5 v 6.7 and 1.1 vs 3.5