ILD maintenance trials

Question 1

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?

Answer 1

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

Question 2

who were the eligible and excluded patients for the EVER-ILD study (2023)?

Answer 2

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)

Question 3

what were the notable secondary outcomes of EVER-ILD study (2023)?

Answer 3

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)

Question 4

among the CT-ILD group in the EVER-ILD study (2023), what CTDs were represented?

Answer 4

systemic sclerosis - 53%
inflammatory myositis - 19%
sjogrens - 16%
RA - 7%
MCTD - 2%

Question 5

in the EVER-ILD study (2023) what were the baseline between groups that were notable?

Answer 5

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%)

Question 6

what were the major findings of the EVER-ILD study (2023)?

Answer 6

primary outcome - significant difference between groups at 6 months in FVC (translated to 100cc FVC difference)

Question 7

what were the results of the subgroup analysis (w/ FVC) EVER-ILD study (2023)?

Answer 7

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

Question 8

what were the differences in ADRs in the EVER-ILD study (2023)?

Answer 8

more frequent respiratory tract infections w/ ritux

no difference in fatal adverse events.. equal total adverse events.

Question 9

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

Answer 9

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

Question 10

what were the inclusion and exclusion criteria of the SLS-II study (Tashkin et al 2017)

Answer 10

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

Question 11

what were the primary and relevant secondary outcomes of the SLS-II study?

Answer 11

primary - % predicted FVC at 24 months

secondary - dlco, dyspnea scores, HRCT fibrosis scoring

Question 12

what are the notable finding of the SLS-II study (Tashkin et al 2017 w/ regard to the primary outcome?

Answer 12

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

Question 13

what was the most common side effect in each arm of the SLS-II study (Tashkin et al 2017

Answer 13

cytopenias

Question 14

what were the INPULSIS studies? what was the trial design? what were the treatment arms? how large where they?

Answer 14

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

Question 15

what were the inclusion/exclusion criteria for the INPULSIS trials?

Answer 15

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

Question 16

what were the outcomes for the INPULSIS trials?

Answer 16

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

Question 17

describe the average INPULSIS pt

Answer 17

male (80%), 65, BMI 28, former smoker (70%), 1.7 years since diagnosis, not on steroids (80%), FVC 80% predicted, DLCO 47% predicted

Question 18

what were the key findings in terms of primary and secondary outcomes for the INPULSIS trials?

Answer 18

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%)

Question 19

what were the notable adverse events in the INPULSIS trials?

Answer 19

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

Question 20

what is the structure of the ASCEND trial 2014 (King Jr et al)? what are the treatment groups?

Answer 20

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

Question 21

what were the inclusion and exclusion criteria for the ASCEND trial 2014 (King Jr et al)?

Answer 21

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

Question 22

what were the primary outcomes of the ASCEND trial 2014 (King Jr et al)? secondary outcomes?

Answer 22

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

Question 23

describe the baseline patient characteristics in the ASCEND trial and the CAPACITY trial. how does it compare to INPULSIS?

Answer 23

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

Question 24

what were the results of the ASCEND trial?

Answer 24

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

Question 25

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

Answer 25

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

Question 26

what was the clinical question of the INBUILD trial (Flaherty et al 2019)? what were the two groups? what was the study design?

Answer 26

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

Question 27

what were the inclusion and exclusion criteria for the INBUILD trial (Flaherty et al 2019)?

Answer 27

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

Question 28

what was the primary and secondary endpoint for the INBUILD trial (Flaherty et al 2019)?

Answer 28

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.

Question 29

describe the overall patient population in the two groups of the INBUILD trial?

Answer 29

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%

Question 30

what were the primary and secondary results of the INBUILD trial? how do they compare to INPULSIS?

Answer 30

• 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

Question 31

what rate of people had side effects to ninetadanib in INBUILD?

Answer 31

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

Question 32

across the subgroups studied in the INBUILD trial by Wells et al 2020, what were the baseline characteristics between the different types of ILD?

Answer 32

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”

Question 33

rank the subgroups in the INBUILD study by the observed magnitude of effect

Answer 33

“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

Question 34

Maher et al 2022 studied the effects of nintedanib based on the inclusion criteria used to define disease progression. What did they find?

Answer 34

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

Question 35

what was the INBUILD part B trial published by Flaherty et al 2022? what did it show?

Answer 35

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.

Question 36

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?

Answer 36

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

Question 37

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

Answer 37

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

Question 38

describe the SENSCIS trial et al 2019 design and clinical question

Answer 38

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

Question 39

what were the key inclusion and exclusion criteria for the SENSCIS trial et al 2019?

Answer 39

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

Question 40

what did the baseline patients look like in the SENSCIS trial et al 2019?

Answer 40

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

Question 41

what were the key primary and secondary outcomes of SENSCIS trial et al 2019?

Answer 41

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

Question 42

What are was the subanalysis done by Highland et al 2021 on the SENSCIS trial?

Answer 42

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

Question 43

What is ENV-101? what are the early study results? what are the side effects?

Answer 43

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