Ikaria launched a proprietary drug-delivery system, called INOmax DSIR, in February 2011 for the delivery of INOmax®. The device has improved connectivity, delivery and monitoring components compared with its predecessors. In November 2015, the US FDA cleared INOmax DSIR® Plus MRI device for delivery of INOmax® for inhalation during MRI procedures. The device provides uninterrupted inhaled nitric oxide treatment during diagnostic imaging   .
Bronchopulmonary dysplasia (BPD)
as of June 2015, no recent reports of development for inhaled nitric oxide have been identified for prevention of BPD.
A phase III trial was completed in May 2014. The trial investigated prevention of BPD in preterm infants who require mechanical ventilation or positive pressure support during days 5-14 after birth (IK3001-BPD-301; NCT00931632). The primary endpoint of the randomised, double-blind, placebo-controlled trial was survival of patients without BPD at 36 weeks. The trial was initiated in November 2009 and enrolled 451 patients in the US and Canada   .
A phase III trial of inhaled nitric oxide for the prevention of BPD in 110 ventilated preterm neonates was initiated in the US in January 2008 (NCT00569530). Patient enrolment was completed in January 2010. In December 2015, INO Therapeutics completed a phase III trial that investigated inhaled nitric oxide in premature infants requiring surfactant or continuous positive airway pressure for respiratory distress syndrome within 24 hours of birth (NCT00551642; INOT27). The trial, initiated in May 2005, assessed the safety and efficacy of inhaled nitric oxide in reducing the incidence of BPD in such patients. The trial enrolled 800 infants in Belgium, Finland, France, Germany, Italy, Netherlands, Spain, Sweden and the UK. The long term effects of therapy over seven years were also being evaluated. Ikaria reported disappointing efficacy results in October 2008 from this trial, stating that the dose of nitric oxide that was administered may not have been optimal. The company anticipate that additional studies would clarify the dosage issue   .
In April 2020, Mallinckrodt reported that the company and Novoteris has received approval from Health Canada to evaluate Novoteris' Thiolanox® [see Adis Insight Drug profile 800042955], for the treatment of COVID-2019 infections  .
In April 2020, Mallinckrodt reported that the company is supporting an investigator-initiated clinical study at Massachusetts General Hospital evaluating the potential benefits of inhaled nitric oxide as a treatment for pulmonary complications like acute respiratory distress syndrome in patients with COVID-2019 infections. The trial intends to evaluate the potential efficacy of inhaled nitric oxide to rapidly reverse hypoxemia  .
In March 2020, Mallinckrodt announced that the company is evaluating inhaled nitric oxide for the treatment of coronavirus (SARS-CoV-2) infections. The company has conducted a clinical trial, which evaluated inhaled nitric oxide in the treatment of six patients infected with SARS-CoV. Mallinckrodt has engaged with the US FDA, NIH and BARDA for the same. Mallinckrodt is evaluating inhaled nitric oxide for the treatment of COVID-19 infections. The company intends to file an IND application to support of the potential use of iNO in coronavirus-associated acute respiratory distress syndrome  .
Hypoxic respiratory failure (associated with pulmonary hypertension)
INOmax® has been launched in the EU, the US, Canada, Japan, Australia, Malaysia, Singapore, South Korea and Latin America, for the treatment of hypoxic respiratory failure in neonates.
INO Therapeutics (later Ikaria Holdings) launched INOmax® in the US in the first quarter of 2000 for the treatment of hypoxic respiratory failure in neonates. A clinical trial of INOmax® in neonates with respiratory failure and pulmonary hypertension has shown that use of INOmax® reduces the need for extracorporeal membrane oxygenation. This finding, together with the results of an earlier trial, provided the basis for the FDA's approval of INOmax®. INOmax® is the first and only FDA-approved pulmonary vasodilator. The US FDA cleared the INOvent® delivery system for commercial distribution in the US on 21 January 2000. Datex-Ohmeda has stated that INOvent® is the first delivery system to gain FDA clearance for use in nitric oxide inhalation therapy.
In December 1999, INOmax® received approval from the US FDA for the treatment of full-term and near-term (born at >34 weeks' gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension  . INOmax® is to be used in conjunction with ventilatory support and other appropriate therapeutic agents.
In the third quarter of 2001, INOmax® received approval to be used in the EU, in conjunction with ventilatory support, for the treatment of full-term and near-term (> 34 weeks' gestation) neonates with hypoxic respiratory failure associated with pulmonary hypertension. The product has since been launched in Europe.
In July 2008, Japan's Ministry of Health, Labour and Welfare (MHLW) approved inhaled nitric oxide (INOflo®) for the treatment of hypoxic respiratory failure with concurrent pulmonary hypertension in neonates  . In June 2008, the MHLW's Council on Drugs and Food Sanitation recommended the approval of INOflo®  . The product was granted orphan drug status in Japan, in July 2008  . The product has also been approved in Singapore  .
INOmax® received approval in Australia in November 2007 for the treatment of hypoxic respiratory failure in newborns. The product was launched by BOC Medical in 2008. The product has been granted orphan drug status by the Therapeutic Goods Administration in Australia   .
A phase III clinical trial has been completed in the US in which INOmax® has been used to treat hypoxic respiratory failure in children and adolescents ≤ 16 years old. The trial, which enrolled 350 patients, began in January 2002.
Pulmonary arterial hypertension
In July 2004, INO Therapeutics initiated a phase III trial to compare the number of patients with reversible pulmonary hypertension (vasoreactivity) after treatment with mixture of nitric oxide at 800ppm and 100% oxygen for inhalation as compared to 100% oxygen (INOT22; EudraCT2004-000625-30). The trial is designed to assess pulmonary vaso reactivity during Pulmonary Vasodilator Testing in infants, children and adolescents with idiopathic pulmonary arterial hypertension or chronic heart disease with pulmonary hypertension or cardiomyopathy. The randomised, open-label trial intend to recruit 150 patients in Spain and United Kingdom  .
Pulmonary hypertension (PH)
In April 2019, inhaled nitric oxide was approved in Australia by the Australian Therapeutic Goods Administration (TGA) for perioperative pulmonary hypertension in adults in conjunction with cardiovascular surgery  .
In October 2015, inhaled nitric oxide was approved in Japan by the Ministry of Health, Labour and Welfare (MHLW) for the treatment of peri- and post-operative pulmonary hypertension in conjunction with heart surgery in neonates through adults. It was also approved in Australia by the Australian Therapeutic Goods Administration (TGA) for peri- and post-operative pulmonary hypertension in conjunction with cardiovascular surgery in neonates through adolescents up to age 17  .
In November 2014, nitric oxide was granted orphan drug designation for the treatment of pre-,peri- and postoperative pulmonary hypertension in adults and children (including newborns) in heart surgery in order to selectively decrease pulmonary arterial pressure and improve right ventricular function and oxygenation, by the Pharmaceuticals and Medical Devices Agency (PMDA), Japan (PMDA website, November 2014).
INOmax® therapy was being evaluated by AGA Linde Healthcare for a variety of severe pulmonary hypertension conditions of varied aetiology. While Linde does not appear to be pursuing development, the NIH (NIH Clinical Center and NHLBI) have completed phase I trials with inhaled nitric oxide in this area (NCT00098072, NCT00352430, NCT00023296).
A phase III trial investigating the efficacy of inhaled nitric oxide in patients with pulmonary hypertension associated with cardiac surgery was completed in July 2014. In the open-label trial, 18 patients of different age groups (from neonates to elderly) were enrolled in Japan (NCT01959828)  .
a phase II/III trial of inhaled nitric oxide to prevent ischaemia-reperfusion injury associated with restoration of blood flow after liver transplantation began in the US in April 2008 in approximately 40 subjects (NCT00582010). The trial was completed in October 2012; however the indication is not listed on company pipeline since January 2012 and it appears that the development in this indication has been discontinued  .
A phase III trial in the US was to evaluating the effects of inhaled nitric oxide on short term physiology and the development of ischaemia-reperfusion lung injury post lung transplant (NCT00060450). However, it was terminated because of slow enrolment.
INO Therapeutics (later Ikaria Holdings) completed phase III controlled clinical trials of INOmax® in the treatment of adult respiratory distress syndrome (ARDS). It is unclear whether development is continuing in this indication.
INO Therapeutics completed a phase II trial of inhaled nitric oxide for congestive heart failure in July 2009 (NCT00060840). The trial, conducted in the US and Germany, investigated the agent during left ventricular assist device implantation following cardiopulmonary bypass. It appears that Mallinckrodt is no longer developing inhaled nitric oxide in this indication.
Mallinckrodt terminated a pilot phase I/II trial, due to slow patient enrolment (n = 7), which was designed to evaluate the physiologic efficacy (rather than effect on clinical outcomes) of nitric oxide administered by hood in improving oxygenation of neonates (aged up to 120 hours) with elevated A-a DO2 (CARLW1; NCT00041548). The randomised, double-blind, parallel, US-based trial was initiated in May 2002  .
In February 2014, Bellerophon Therapeutics acquired exclusive worldwide rights to Ikaria Holdings' INOpulse (drug-device) programmes to Bellerophon Therapeutics  . [See RDI profile 800040818].
Ikaria Holdings conducted clinical investigation for use of nitric oxide inhalation delivered via pulsed delivery with the INOpulse DS for the treatment of PH and pulmonary arterial hypertension (PAH).
In July 2016, Bellerophon Therapeutics completed a two-part, randomised, placebo-controlled phase II trial of nitric oxide inhalation using INOpulse DS for the treatment of PAH. The trial was initiated in April 2012 to evaluate the safety and efficacy of inhaled nitric oxide as an add-on therapy in patients with PAH whose disease is progressing on other PAH medications (IK-7001-PAH-201; NCT01457781). The nitric oxide was administered via the company's INOpulse DS, which delivers the compound in a pulsatile manner. This double-blind trial completed enrolment of 80 patients in June 2014 in the US and Canada   .
In January 2012, Ikaria announced that the US FDA granted orphan drug designation for the use of inhaled nitric oxide with the INOpulse DS delivery system as a combination therapy for the treatment of pulmonary hypertension. Ikaria submitted an IND to the FDA in November 2011. Ikaria's PAH development programme is known as IK-7001  .
Chronic obstructive pulmonary disease (COPD)
a phase II trial was planned to investigate inhaled nitric oxide, delivered using the INOpulse device, for the treatment of COPD  .