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Reference: 1. INOMAX. Package insert. Mallinckrodt Pharmaceuticals.

Ventilation and perfusion (V/Q) matching is required for optimal oxygenation of the pulmonary vasculature.1 INOMAX is an inhaled pulmonary vasodilator that can improve V/Q matching.1

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Reference: 1. INOMAX. Package insert. Mallinckrodt Pharmaceuticals.

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*Primary endpoint of INOMAX CINRGI and NINOS registration studies.

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Reference: 1. Data on file. Mallinckrodt Pharmaceuticals

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Home › INOMAX Drug › Efficacy Data

INOMAX Efficacy

Established treatment in the NICU

INOMAX has been studied in over 5000 term and near-term neonates with HRF associated with evidence of pulmonary hypertension.1 View clinical studies below or filter studies by area of focus:
CINRGI Study
(pivotal study)
NINOS Study
(pivotal study)
Progression of HRF
Time on O2 Therapy
Time on Mechanical Ventilation
ECMO*
Oxygenation
*Primary endpoint of INOMAX CINRGI and NINOS registration studies.

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)
CINRGI STUDY: Summary of Clinical Results2,3
aPrimary endpoint.
Abbreviation: ECMO, extracorporeal membrane oxygenation.

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*
*As per INOMAX PI, the recommended dose is 20 ppm; doses greater than 20 ppm are not recommended.
  • 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
NINOS STUDY: Summary of Clinical Results2,4
aPrimary endpoint.
Abbreviation: ECMO, extracorporeal membrane oxygenation.

INOMAX May Help Prevent the Progression of HRF5

Early INOMAX use (OI 10 to 30) potentially prevents progression of HRF5

Study – Randomized controlled trial of early compared with delayed use of inhaled nitric oxide in newborns with moderate respiratory failure and pulmonary hypertension.
Authors – González A, Fabres J, D’Apremont I, et al
Published – 2010
Objective – To evaluate whether early treatment with INOMAX can prevent infants with moderate respiratory failure from developing severe HRF (OI ≥40).
  • 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
Early INOMAX Use (OI 10 to 30) Potentially Prevents Progression of HRF2
González 2010: Mean Oxygenation Index (OI) Over 48 Hours
17 of the 28 control infants reached an OI >40 and were switched to INOMAX as rescue therapy.2
aThe oxygenation indexes were significantly higher over the 48-hour study period in the control group (P<0.01)

Original study for Konduri 2013 analysis7

Study – A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure.
Authors – Konduri GG, Solimano A, Sokol GM, et al
Published – 2004
Objective – To determine whether early INOMAX administration results in additional reduction of the incidence of ECMO or death.
  • 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

Study – Impact of early surfactant and inhaled nitric oxide therapies on outcomes in term/late preterm neonates with moderate hypoxic respiratory failure.
Authors – Konduri GG, Sokol GM, Van Meurs KP, et al
Published – 2013
Objective – Identify associations pertinent to the management of moderate HRF failure in term/late preterm neonates via a post hoc analysis of the Konduri 2004 study.
  • 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
Konduri 2013: Proportions of Patients at Risk of Progression to OI ≥30, by OI at Enrollment and Treatment8,a,b
aPost hoc, subgroup analysis of prospectively collected data from the early INOMAX randomized controlled trials (RCT) to identify factors associated with ECMO/death and progression of HRF.
bAn absolute difference of 15% and a relative difference of 47%.
cThe control group was eligible to receive INOMAX if HRF progressed to OI ≥25.

INOMAX Reduced Time on O2 Therapy9

Post hoc analysis of CINRGI demonstrated a significant reduction in days on O2 therapy8

Study – Effect of inhaled nitric oxide on oxygen therapy, mechanical ventilation, and hypoxic respiratory failure.
Authors – Stewart DL, Vogel PA, Jarret B, Potenziano J
Published – 2017
Objective – To assess the role of INOMAX in reducing the need for oxygen therapy, decreasing time on mechanical ventilatory support, and attenuating probability of hypoxic respiratory failure severity progression.
  • 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
Post Hoc Analysis of CINRGI Demonstrated a Significant Reduction in Days on O2 Therapy9,a
The total length of hospital stay was not different between study groups.b
aMedian oxygen time was defined as the day at which 50% of patients went off oxygen therapy. Patients who died or received extracorporeal membrane oxygenation where censored. Absolute difference of 17 days or 50%.
bCINRGI was not sufficiently powered to show significance in this endpoint.

INOMAX Reduced Median Days on Mechanical Ventilation10

Analysis indicated that INOMAX may help reduce median time on mechanical ventilation

Study – Efficacy of inhaled nitric oxide for hypoxic respiratory failure in term and late preterm infants by baseline severity of illness: a pooled analysis of three clinical trials.
Authors – Golombek SG, Young JN
Published – 2010
Objective – To analyze the effects of INOMAX on measures of oxygenation across a range of illness severity strata and on the duration of 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)
aTrial halted due to slow enrollment.
bMSI included the incidence of ECMO, neurologic injury, and bronchopulmonary dysplasia (BDP) to show significance in this endpoint.
Golombek 2010: Time on Mechanical Ventilation Shown in a Kaplan-Meier Analysis of Retrospectively Pooled Data From 3 Controlled Studies: NINOS, CINRGI, and I-NO/PPHN10,a,b
aMedian ventilation time is defined as the day at which 50% of patients went off the ventilator.
bPatients who died or received ECMO were censored. Total length of hospital stay was not different between study groups; individual studies were not sufficiently powered to show significance in this endpoint.

INOMAX Reduced the Need for ECMO2-4

CINRGI: Prevalence of ECMO Among 186 Infants Receiving Placebo or INOMAX2,3
NINOS: Prevalence of Death and/or ECMO Among 235 Infants Receiving Placebo or INOMAX2,4

INOMAX Increased Oxygenation10

Analysis indicated that INOMAX increased oxygenation within 30 minutes10

Study – Efficacy of inhaled nitric oxide for hypoxic respiratory failure in term and late preterm infants by baseline severity of illness: a pooled analysis of three clinical trials.
Authors – Golombek SG, Young JN
Published – 2010
Objective – To analyze the effects of INOMAX on measures of oxygenation across a range of illness severity strata and on the duration of 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
  • 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
aTrial halted due to slow enrollment.
bMSI included the incidence of ECMO, neurologic injury, and bronchopulmonary dysplasia (BDP).
Golombek 2010: Change in PaO2 at 30 Minutes in 493 Infants Receiving Ventilation Alone vs Ventilation + INOMAX10

Looking again at oxygenation in the CINRGI study3,9

Study – Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn.
Authors – Clark RH, Kueser TJ, Walker MW, et al
Published – 2000
Objective – To reduce the need for ECMO.
  • 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
In a post hoc analysis of the CINRGI study, most responders showed a response within 24 hours.9
Percent Responders to Treatment With INOMAXa
aResponse to treatment defined as either a 10% decrease from baseline OI or a 10% increase from baseline arterial oxygen tension (PaO2).1