SOyour patients can do the activities that bring them joy2,3
INCREASE: EXERCISE CAPACITY (HODGES-LEHMANN)
Change in exercise capacity reached statistical significance as early as week 82*
Change in 6MWD (m) from baseline through week 161,2,4†‡
Hodges-Lehmann placebo-corrected median difference.
In Hodges-Lehmann methodology, imputed walk of 0 m was assigned for death, clinical worsening event, and too ill to perform 6MWT. The last observation was carried forward for all other reasons. MMRM uses all available data at all time points and does not require imputation of individual missing data points.4§
TYVASO improved 6MWD across a range of PH-ILD subgroups.2‖
*At 8 weeks, study participants reached a median dose of 10 breaths, 4x daily (target 9-12 breaths).1,2
†P values were obtained from nonparametric ANCOVA adjusted for baseline 6MWD category.4
‡At week 15 (trough), patients who took TYVASO had a placebo-corrected median difference in 6MWD of 15 m (P=0.04).4
§The INCREASE trial was designed to have a target dose of 9 breaths and a maximum dose of 12 breaths per treatment session. There is no maximum labeled dose for TYVASO or TYVASO DPI.1,2
‖Benefits were observed across several subgroups, including etiology of PH-ILD, disease severity (measured by baseline 6MWD), age, sex, baseline hemodynamics, and dose group.2
INCREASE: EXERCISE CAPACITY (MMRM)
Patients on TYVASO saw improved exercise capacity compared to those on placebo3
Exercise capacity declined for those on placebo3
Change in peak 6MWD (m) from baseline through week 161,3,4*†
MMRM placebo-corrected LS mean difference.
MMRM analysis was a prespecified sensitivity analysis for the primary endpoint.1
Patients who took TYVASO saw a change in exercise capacity as early as week 4 that reached statistical significance by week 8.1‡
*LS mean, P values, and estimated difference were from the MMRM with the change from baseline in peak 6MWD as the dependent variable; treatment, week, and treatment-by-week interaction as the fixed effects; baseline 6MWD as the covariate; and subject as the random effect.1
†At week 15 (trough), patients who took TYVASO had a placebo-corrected LS mean difference in 6MWD of 22 m (P=0.004).3
‡At 8 weeks, study participants reached a median dose of 10 breaths, 4x daily (target 9-12 breaths).1,2
MMRM=mixed-effect model repeat measurement.
INCREASE OLE: EXERCISE CAPACITY
Below is a post hoc analysis of data from a prespecified OLE efficacy endpoint without a control group. Interpret with appropriate caution.
After 1 year, patients on TYVASO who did not have a treatment delay saw a +22.1 m increase compared to a -10.3 m decline for those having a 16-week treatment delay.5*
Change in 6MWD after 1 year on TYVASO5
Patients previously on placebo were considered to have a 16-week treatment delay.5
Study limitations include: small sample sizes and the 1-year time point is defined as treatment week 52 for patients formerly in the TYVASO arm and week 48 for patients formerly in the placebo arm due to the difference in follow-up schedules during INCREASE OLE.5†
Treating patients with PH-ILD earlier may help improve long-term exercise capacity.5
*For this analysis, baseline (treatment week 0) was defined as the start of treatment with TYVASO. For patients formerly assigned to the TYVASO arm of the INCREASE RCT, treatment week 0 corresponds to the baseline of the INCREASE RCT. For patients formerly assigned to the placebo arm of the INCREASE RCT, treatment week 0 corresponds to week 16 of the INCREASE RCT.5
†During the OLE, 6MWD was assessed at weeks 4 and 12 and then every 12 weeks thereafter (ie, overall study weeks 20, 28, 40, 52, 64, etc).5
"I don't have any issues anymore just walking out to the mailbox, or walking around the neighborhood, and it would've been impossible before."
— Catherine, a patient living with PH-ILD and taking TYVASO
TYVASO reduced the risk of a first clinical worsening event by 39%2,3*†
Time to first clinical worsening event2,3
Clinical worsening events included a hospitalization due to a cardiopulmonary indication (11% TYVASO vs 14.7% placebo); a decrease in 6MWD >15% from baseline (8% TYVASO vs 16% placebo); death–all causes (2.5% TYVASO vs 2.5% placebo); or lung transplantation (1.2% TYVASO vs 0% placebo).2
TYVASO can help patients reduce their risk of clinical worsening.2,3
*Overall, incidence of any clinical worsening event was 22.7% for patients who took TYVASO vs 33.1% for those who took placebo (P=0.04).3
†Patients who discontinued from the study early had their time to clinical worsening censored at their last visit. Patients who did not experience a clinical worsening event had their time to clinical worsening censored at the study termination date.4
‡P value was calculated with log-rank test stratified by baseline 6MWD category.4
§HR, 95% CI, and P value were calculated with proportional hazards model with treatment and baseline 6MWD (continuous) as explanatory variables.4
INCREASE: DISEASE PROGRESSION
Data are from a post hoc analysis. Interpret with appropriate caution.
TYVASO vs placebo: Total number of disease progression events6
INCREASE post hoc analysis: An analysis was conducted to determine the number of disease progression events among patients who experienced ≥1 event during the trial.6
Total disease progression events by category6*
A total of 147 events occurred in TYVASO patients (n=89) vs 215 events in placebo patients (n=109).6
Disease progression was defined to include clinical worsening events (secondary endpoint), which included ≥15% decline in 6MWD, cardiopulmonary hospitalization, lung transplantation, and death, as well as safety endpoints, including exacerbation of underlying lung disease and decline in FVC ≥10%.6*
Talk to your appropriate patients about the importance of fewer disease progression events and the impact of treatment with TYVASO.6
*Lung transplantation was also considered to be a disease progression event. There were 2 patients in the TYVASO arm and 1 patient in the placebo arm who received a lung transplant. Exacerbations were investigator reported and were defined as acute, clinically significant respiratory deterioration characterized by evidence of new widespread alveolar abnormality.6
INCREASE: NT-proBNP
At week 16, TYVASO resulted in a 15% reduction in NT-proBNP3
Compared with a 46% increase for placebo3
NT-proBNP: Change from baseline (%)1,3
The role of NT-proBNP in PH-ILD and the clinical significance of changes associated with therapy are unknown.
NT-proBNP is a biomarker associated with RV dysfunction.7
*P value was obtained from the MMRM analysis with the change from baseline in log-transformed NT-proBNP as the dependent variable; treatment, week, and treatment-by-week interaction as the fixed effects; and log-transformed baseline NT-proBNP as the covariate.1
NOTE: Elevated levels of BNP and NT-proBNP are biomarkers that can indicate RV dysfunction. Levels correlate to the severity of cardiac stress and begin to increase before symptoms of severe PH and heart failure (eg, peripheral edema, weight gain) are present.7
6MWD=6-minute walk distance; 6MWT=6-minute walk test; ANCOVA=analysis of covariance; BNP=B-type natriuretic peptide; CI=confidence interval; FVC=forced vital capacity; HR=hazard ratio; LS=least squares; MMRM=mixed-effect model repeat measurement; NT-proBNP=N-terminal pro−B-type natriuretic peptide; OLE=open-label extension; PH-ILD=pulmonary hypertension associated with interstitial lung disease; RCT=randomized controlled trial; RV=right ventricular.
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