INOMAX Efficacy
Established treatment in the NICU

CINRGI Study2,3
- Double-blind, randomized, placebo-controlled, multicenter trial of 186 term and near-term neonates with pulmonary hypertension and hypoxic respiratory failure
- The primary objective of the study was to determine whether INOMAX would reduce the need for ECMO
- INOMAX dose 20 ppm, weaned to 5 ppm
- The most common adverse reaction was hypotension (14% vs 11%; >2% higher incidence on INOMAX than on placebo)

NINOS Study2,4
- The Neonatal Inhaled Nitric Oxide Study (NINOS) was a double-blind, randomized, placebo-controlled, multicenter trial in 235 neonates with HRF
- The primary objective of the study was to determine whether INOMAX would reduce mortality and/or the need for ECMO
- INOMAX dose 20 ppm, with a possible increase to 80 ppm*
- Treatment groups were similar with respect to the incidence and severity of intracranial hemorrhage, Grade IV hemorrhage, periventricular leukomalacia, cerebral infarction, seizures requiring anticonvulsant therapy, pulmonary hemorrhage, or gastrointestinal hemorrhage

INOMAX May Help Prevent the Progression of HRF5
Early INOMAX use (OI 10 to 30) potentially prevents progression of HRF5
- This prospective, randomized, controlled, open-label, 2-center trial in Chile was composed of 56 term/near-term infants (≥35 weeks gestation) with HRF and PPHN
- Infants had an oxygenation index (OI) between 10 and 30 (mild to moderate severity)
- Dosing: 20 ppm, weaned to 5 ppm
- Infants were randomized to early mechanical ventilation + INOMAX or control (mechanical ventilation alone). If OI >40 was reached in the control group, the infant was transitioned to INOMAX. If no response was seen with INOMAX in either group, mechanical ventilation was replaced with high-frequency oscillatory ventilation
- Unlike in the United States, ECMO was not available in Chile during the study period. Therefore, the results of the study should be interpreted with this in mind
- The primary endpoint was treatment failure, defined as a worsening in respiratory status during the first 48 hours based on an increase in the OI to >40
- 17 of the 28 (61%) control infants vs 7 of the 28 (25%) infants receiving early INOMAX treatment (OI 10 to 30) developed an OI >40 within 48 hours (P<0.05)
- Patients treated with INOMAX did not have elevated blood levels of methemoglobin or high levels of NO2 in the ventilatory circuit
- There were no differences between groups in the incidence of other neonatal complications such as bleeding and/or coagulation disorders, hypotension, or infections




Original study for Konduri 2013 analysis7
- Prospective, randomized, controlled, double-masked, multicenter trial
- Patients: 299 infants (≥34 weeks gestation) with respiratory failure who needed assisted ventilation; OI ≥15 and <25 (mild to moderate severity) on FiO2 ≥0.80
- Dosing: INOMAX initiated at 5 ppm or simulated (sham) dose; dose increased to 20 ppm if the increase in PaO2 was ≤20 mm Hg; infants in either group were transitioned to standard INOMAX if OI increased to ≥25
- Due to slow enrollment, the study was stopped after 302 infants were enrolled (3 were excluded)
- The primary outcome, death by day 120 or need for ECMO, was similar between groups: 19.5% of the control group and 16.7% of the INOMAX group (P=0.53)
- Despite failing the primary endpoint, more infants in the early INOMAX group had >20 mm Hg increase in PaO2 in response to study gas initiation compared with the control group (73% vs 37%, P<0.001)
- None of the study infants had study gas weaned or discontinued because of elevated methemoglobin or NO2 levels
- One INOMAX infant and 2 control infants developed severe (grade 3-4) intraventricular hemorrhage and periventricular leukomalacia
- Seizures occurred in 14 INOMAX infants (9.4%) and 11 control infants (7.4%) (P=0.68)

Post hoc analysis indicated that early INOMAX reduced progression of HRF (to OI ≥30)8
- Konduri 2013 is a post hoc subgroup analysis of prospectively collected data from the Konduri 2004 study
- Univariate and multivariate logistic regression analyses were used to determine risk factors for the progression of respiratory failure and ECMO/death
- Statistical analysis determined that an OI of 20 was the optimum cut point for the prediction of ECMO/death risk by OI at the time of enrollment
- Analyses showed that infants randomized to the early INOMAX group who received INOMAX at an OI of 15 to <20 (9/88, 10.2%) experienced a 60% relative reduction in ECMO/death compared to early INOMAX infants who received INOMAX at an OI of 20 to 25 (16/62, 25.8%), P=0.02
- Early INOMAX (OI of 15 to <20 at baseline) resulted in a 41% relative reduction in ECMO/death compared to the control group (10.2% vs 17.4%); however, the difference was not statistically significant, P=0.16


INOMAX Reduced Time on O2 Therapy9
Post hoc analysis of CINRGI demonstrated a significant reduction in days on O2 therapy8
- A novel, prespecified, post hoc analysis of the CINRGI study
- CINRGI was a multicenter, randomized, placebo-controlled trial
- 186 term/near-term infants (>34 weeks) with HRF and PPHN
- Dosing: 20 ppm, weaned to 5 ppm



INOMAX Reduced Median Days on Mechanical Ventilation10
Analysis indicated that INOMAX may help reduce median time on mechanical ventilation
- A retrospective pooled analysis of subjects receiving a starting dose of 20 ppm INOMAX in the CINRGI, NINOS, and I-NO/PPHN phase 3 trials
- There was no censoring based on underlying diagnosis or baseline characteristics
- Across all 3 registration studies (CINRGI, NINOS, and I-NO/PPHN), INOMAX significantly improved PaO2 within 30 minutes vs ventilation alone (P<0.001)
- INOMAX reduced median days on mechanical ventilation (11 vs 14 days, P=0.003)



INOMAX Reduced the Need for ECMO2-4




INOMAX Increased Oxygenation10
Analysis indicated that INOMAX increased oxygenation within 30 minutes10
- A retrospective pooled analysis of subjects receiving a starting dose of 20 ppm INOMAX in the CINRGI, NINOS, and I-NO/PPHN phase 3 trials
- There was no censoring based on underlying diagnosis or baseline characteristics
- INOMAX significantly improved oxygenation across all levels of severity (including mild [OI ≤15, P=0.003], moderate [OI >15 to ≤25, P=0.004], severe [OI >25 to ≤40, P<0.001], and very severe [OI >40, P<0.001]) vs ventilation alone
- Pooled analysis indicated that INOMAX significantly improved oxygenation across all levels of severity (including mild [OI ≤15, P=0.003], moderate [OI >15 to ≤25, P=0.004], severe [OI >25 to ≤40, P=0.001], and very severe [OI >40, P<0.001]) vs ventilation alone


Looking again at oxygenation in the CINRGI study3,9
- Multicenter, randomized, placebo-controlled trial3
- 186 term/near-term infants (>34 weeks) with HRF and PPHN3
- Dosing: 20 ppm, weaned to 5 ppm3
- There was a significant reduction in ECMO in infants treated with INOMAX compared with control infants (31% vs 57%, P<0.001)3
- The incidence of death alone was similar in both groups (3% vs 6%, P=0.48)3
- Combined mortality: placebo (11%); INOMAX (9%)3
- Hypotension was the only adverse reaction with >2% higher incidence on INOMAX than on placebo (14% vs 11%)3
