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
what adverse events related to the drug were most common in ASCEND?
rash, nausea, LFTs abnormalities - 15% of pirfenidone patients stopped drug due to an adverse event
what was the clinical question of the INBUILD trial (Flaherty et al 2019)? what were the two groups? what was the study design?
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
what were the inclusion and exclusion criteria for the INBUILD trial (Flaherty et al 2019)?
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
what was the primary and secondary endpoint for the INBUILD trial (Flaherty et al 2019)?
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.
describe the overall patient population in the two groups of the INBUILD trial?
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%
what were the primary and secondary results of the INBUILD trial? how do they compare to INPULSIS?
- 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
what rate of people had side effects to ninetadanib in INBUILD?
2/3rds have diarrhea (tho 1/3 in placebo), 1/3 have nausea
across the subgroups studied in the INBUILD trial by Wells et al 2020, what were the baseline characteristics between the different types of ILD?
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”
rank the subgroups in the INBUILD study by the observed magnitude of effect
“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
Maher et al 2022 studied the effects of nintedanib based on the inclusion criteria used to define disease progression. What did they find?
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
what was the INBUILD part B trial published by Flaherty et al 2022? what did it show?
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.
Matteson et al 2022 released a sub-group analysis of CTD-ILD in the INBUILD trial. Which CTDs were highly represented? what was notable about their pre-trial treatment? what were the notable findings?
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
what is notable in the INBUILD sub-group analysis of CTD-ILD about the rates of progression IN THE PLACEBO GROUP between baseline use of steroids/DMARDs vs no use
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
describe the SENSCIS trial et al 2019 design and clinical question
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
what were the key inclusion and exclusion criteria for the SENSCIS trial et al 2019?
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
what did the baseline patients look like in the SENSCIS trial et al 2019?
75% female, age 55, 50% diffuse cutaneous SS, FVC 72%, DLCO 53%, 50% on MMF
what were the key primary and secondary outcomes of SENSCIS trial et al 2019?
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
What are was the subanalysis done by Highland et al 2021 on the SENSCIS trial?
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
What is ENV-101? what are the early study results? what are the side effects?
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
