Nitric oxide - Mallinckrodt
Alternative Names: Ik 7001; IK-3001; IK-7001; INOflo; INOmax; INOmax Total Care; INOMAX® Total Care package; INOtherapy; INOVENTLatest Information Update: 28 May 2023
At a glance
- Originator Massachusetts General Hospital
- Developer AGA Linde Healthcare; Ikaria Holdings; Mallinckrodt plc; Massachusetts General Hospital
- Class Anti-infectives; Anti-inflammatories; Antiacnes; Antiandrogens; Antibacterials; Antibronchitics; Antifibrotics; Antifungals; Antihypertensives; Antineoplastics; Antituberculars; Antivirals; Cardiovascular therapies; Diagnostic agents; Foot disorder therapies; Free radicals; Nitrogen oxides; Non-opioid analgesics; Skin disorder therapies; Small molecules; Vascular disorder therapies; Vasodilators
- Mechanism of Action Androgen receptor antagonists; Angiogenesis inducing agents; Cell death stimulants; Guanylate cyclase stimulants; Nitric oxide donors; Reactive oxygen species modulators
-
Orphan Drug Status
Yes - Hypoxic respiratory failure; Pulmonary hypertension
Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.
- New Molecular Entity No
Highest Development Phases
- Marketed Hypoxic respiratory failure; Pulmonary hypertension
- Phase III Bronchopulmonary dysplasia
- Preclinical SARS-CoV-2 acute respiratory disease
- No development reported Transplant rejection
- Discontinued Heart failure; Pulmonary arterial hypertension; Reperfusion injury
Most Recent Events
- 28 May 2023 No recent reports of development identified for clinical-Phase-Unknown development in SARS-COV-2 acute respiratory disease in USA (Inhalation, Inhalant)
- 28 May 2023 No recent reports of development identified for preclinical development in Transplant-rejection in USA (Parenteral, Liquid)
- 30 Dec 2022 Mallinckrodt Pharmaceuticals has patent protection for INOmax® in USA
Development Overview
Introduction
An inhaled nitric oxide therapy (INOmax®) is being developed by Mallinckrodt for the treatment of hypoxic respiratory failure in neonates. The inhaled formulation is designed for use in conjunction with mechanical ventilation devices. Inhaled nitric oxide was originally being developed by Ohmeda, a subsidiary of the BOC Group, and patents for the use of inhaled nitric oxide in the treatment of pulmonary disease were licensed from Massachusetts General Hospital. Inhaled nitric oxide acts as a selective pulmonary vasodilator by activating guanylate cyclase and thus stimulating cyclic guanosine monophosphate-induced vascular smooth muscle relaxation. The inhaled formulation causes no systemic vasodilation as it is rapidly inactivated by binding to haemoglobin in the bloodstream. The drug is launched for hypoxic respiratory failure in Australia, Canada, Czech Republic, Denmark, France, Germany, Greece, Ireland, Italy, Japan, Latin America, Malaysia, Netherlands, Poland, Portugal, Singapore, South Korea, Spain, Sweden, Switzerland and the US. It is also launched for pulmonary hypertension in Australia and Japan. Clinical development for the prevention of bronchopulmonary dysplasia in pre-term infants is underway in Europe. Clinical and preclinical development is underway for SARS-COV-2 acute respiratory disease in the US and the United Kingdom respectively.
In December 2023, Mallinckrodt announced that the INOmax® EVOLVE™ DS delivery system has been cleared by the U.S. Food and Drug Administration (FDA) for the delivery of INOmax® (nitric oxide) gas, for inhalation. The INOmax EVOLVE DS delivers INOmax into the inspiratory limb of the patient breathing circuit in a way that provides a constant concentration of nitric oxide (NO), as set by the user, to the patient throughout the inspired breath. It uses a specially designed injector module, which enables tracking of the gas delivery system waveforms and the delivery of a synchronized and proportional dose of NO. It may be used with the ventilators and respiratory care devices for which INOmax EVOLVE DS has been validated [1] . Earlier in February 2011, Ikaria launched a proprietary drug-delivery system, called INOmax DSIR, 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 [2] [3] .
Novoteris is developing Thiolanox® [see Adis Insight Drug profile 800042955], using Mallinckrodt's high-concentration, 5000 PPM nitric oxide gas for inhalation canisters, for the treatment of cystic fibrosis, and mycobacterial infections.
As at April 2022, no recent reports of development have been identified for pulmonary arterial hypertension is underway in the US, France, Netherlands, Spain and United Kingdom. The indication is not present on pipeline, it appears that company discontinued the development in these indication.
As of June 2015, no recent reports of development have been identified for nitric oxide inhalation in bronchopulmonary dysplasia in the US and Canada and development in reperfusion injury and heart failure in the US and Germany, respectively, have also been discontinued.
Mallinckrodt also conducted clinical investigations of an inhaled nitric oxide via pulsed delivery by the INOpulse DS delivery system (as a drug-device combination product) in pulmonary arterial hypertension (PAH) and pulmonary hypertension secondary to chronic obstructive pulmonary disease (PH-COPD). The worldwide rights to INOpulse programmes in PAH, PH-COPD and pulmonary hypertension associated with idiopathic pulmonary fibrosis (PH-IPF) were exclusively acquired by Bellerophon Therapeutics as part of Ikaria's spin-out of its some research and development assets and subsidiaries [see Adis Insight Drug profile 800040818].
In April 2014, Ikaria was acquired by Mallinckrodt [4] .
As at May 2023, no recent reports of development had been identified for clinical-Phase-Unknown development in SARS-COV-2 acute respiratory disease in USA (Inhalation, Inhalant), preclinical development in Transplant-rejection in USA (Parenteral, Liquid).
Company Agreements
Lee's Pharmaceutical entered into a strategic partnership agreement with Ikaria in November 2014 for the registration and commercialisation of the INOmax® Total Care package in China, Hong Kong, Macau and Taiwan. The financial terms of the agreement were not disclosed [5] .
Bellerophon Therapeutics acquired exclusive worldwide rights to INOpulse programmes in PAH, PH-COPD and PH-IPF from Ikaria Holdings in February 2014 following Ikaria's decision to spin-out some of its research and development assets and subsidiaries [6] .
In March 2007, Ikaria Holdings acquired INO Therapeutics from the Linde Group and the combined company was renamed Ikaria Holdings. The Linde Group retained equity in the new company and appears to be a market licensee for INOmax® [7] .
BOC Medical, a company within the Linde group, will distribute and market INOmax® in Australia through an alliance with Ikaria [8] .
Ikaria Holdings has an exclusive licence in North America to the INOvent® device.
The Japanese companies Sumitomo Seika Chemicals (Sumitomo Corporation) and Air Water Inc. are licensees for INOmax® in Japan.
In 1998, Ohmeda was sold by the BOC Group. In conjunction with the sale, the Finnish company Instrumentarium Corporation acquired the patent for the INOvent® device which is used for administration of Ohmeda's nitric oxide. INOvent® has been available in certain countries, including some EU countries, since 1998 and is currently available worldwide through the global sales network of Datex-Ohmeda (a subsidiary of Instrumentarium Corporation). INOvent® is developed and manufactured at Datex-Ohmeda's facility in Madison (Wisconsin, USA). Instrumentarium Corporation was acquired by GE Medical Systems (General Electric Company) in October 2003. In April 2004, GE Medical Systems merged with Amersham to form GE Healthcare, a subsidiary of General Electric Company.
Key Development Milestones
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 [9] [10] .
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 [11] [12] .
SARS-COV-2 acute respiratory disease
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 [13] .
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 [14] .
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 [15] .
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 [16] . 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 [17] . In June 2008, the MHLW's Council on Drugs and Food Sanitation recommended the approval of INOflo® [18] . The product was granted orphan drug status in Japan, in July 2008 [17] . The product has also been approved in Singapore [18] .
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 [17] [8] .
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
As at April 2022, the indication is not present on pipeline, it appears that company discontinued the development in this indication (Mallinckrodt pipeline, April 2022).
In February 2010, INO Therapeutics completed a phase III trial that compared 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; NCT00626028). The randomised, open-label trial was initiated in July 2004 and enrolled 136 patients in the US, France, Netherlands , Spain and in the UK [19] .
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 [20] .
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 [21] .
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) [22] .
Pulmonary embolism
In May 2022, Mallinckrodt withdraws phase II trial of Nitric oxide prior to enrollment due to no sponsor support (NCT04996667; 21-000569). The open label trial was planned to be initiated in June 2021 in US [23] .
Ischaemia-reperfusion injury
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 [24] .
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.
Other indications
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 [25] .
INOPulse programmes
In February 2014, Bellerophon Therapeutics acquired exclusive worldwide rights to Ikaria Holdings' INOpulse (drug-device) programmes to Bellerophon Therapeutics [6] . [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 [26] [6] .
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 [27] .
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 [28] .
Patent Information
In December 2022, Mallinckrodt announced that the company has portfolio of US and non-US patents and patent applications for INOMAX® (nitric oxide) gas and related technologies. These include over 100 issued patents, expiring between 2023 to 2039, and numerous pending patent applications in the US and over 700 issued patents, expiring between 2026 to 2037, and numerous pending patent applications in other countries [29]
Mallinckrodt holds total 17 patents listed in the US FDA Orange Book covering gas delivery systems as well as methods of using such systems related to INOMAX® (nitric oxide) gas, for inhalation.
Patent disputes
In September 2016, the U.S. Patent and Trademark Office (USPTO) has confirmed the validity of five of those 17 patents, that expire in 2031; reinforcing Mallinckrodt's intellectual property rights. The USPTO decision was the result of Inter Partes Review (IPR) proceedings, instituted by the Patent Trial and Appeal Board (PTAB) following petitions filed by Praxair Distribution [30] .
In September 2016, a second set of petitions filed by Praxair Distribution for IPR proceedings concerning four of five patents that expire in 2029 and cover use of a drug like INOMAX®, was dismissed by the PTAB. Praxair's first request made in July 2015, to institute IPR proceedings on these four patents was also dismissed by the PTAB [30] .
The PTAB instituted an IPR proceeding for the fifth patent expiring in 2029, U.S. patent no. 8,846,112 (the '112 patent) that relates to distribution of a drug like INOMAX in conjunction with its approved labelling. The validity of the patent was confirmed by the PTAB in July 2016. Further, in August 2016, the PTAB had reached a final decision regarding the validity of the claims of that patent. But, Praxair has filed an appeal of this PTAB decision to the U.S. Court of Appeals for the Federal Circuit, and Mallinckrodt subsequently filed a cross-appeal [30] .
In February and March 2016, the USPTO granted two new US patents protecting delivery of nitric oxide utilizing devices like Mallinckrodt'sINOmax DSIR® delivery system, expiring in 2031, and the third new US patent relating to the use of nitric oxide gas sensors, expiring in 2034. These three INOMAX new patents were listed in the FDA Orange Book for INOMAX and added to the company's pending patent litigation against Praxair in the U.S. District Court for the District of Delaware [30] .
Drug Properties & Chemical Synopsis
- Route of administration Inhalation, Parenteral
- Formulation Inhalant, Liquid
- Class Anti-infectives, Anti-inflammatories, Antiacnes, Antiandrogens, Antibacterials, Antibronchitics, Antifibrotics, Antifungals, Antihypertensives, Antineoplastics, Antituberculars, Antivirals, Cardiovascular therapies, Diagnostic agents, Foot disorder therapies, Free radicals, Nitrogen oxides, Non-opioid analgesics, Skin disorder therapies, Small molecules, Vascular disorder therapies, Vasodilators
- Target Androgen receptor; Cell death; Guanylate cyclase; Reactive oxygen species
- Mechanism of Action Androgen receptor antagonists; Angiogenesis inducing agents; Cell death stimulants; Guanylate cyclase stimulants; Nitric oxide donors; Reactive oxygen species modulators
-
WHO ATC code
C01 (Cardiac Therapy)
C04A (Peripheral Vasodilators)
J05 (Antivirals for Systemic Use)
R07A-X01 (Nitric oxide)
-
EPhMRA code
C1 (Cardiac Therapy)
C4A (Cerebral and Peripheral Vasotherapeutics)
J5 (Antivirals for Systemic Use)
R7X (All Other Respiratory System Products)
- Chemical name Nitric oxide
- Molecular formula N O
- SMILES [N]=O
-
Chemical Structure
- CAS Registry Number 10102-43-9
Biomarkers Sourced From Trials
| Indication | Biomarker Function | Biomarker Name | Number of Trials |
|---|---|---|---|
|
acidosis |
Outcome Measure |
hemoglobin subunit gamma 2 |
|
|
aspergillosis |
Eligibility Criteria |
neurotrimin |
|
|
bacterial infections |
Arm Group Label |
Nitric Oxide (NO) |
|
|
bacterial infections |
Brief Title |
Nitric Oxide (NO) |
|
|
bacterial infections |
Arm Group Description |
Nitric Oxide (NO) |
|
|
bacterial infections |
Eligibility Criteria |
hemoglobin subunit gamma 2 |
|
|
bacterial infections |
Official Title |
Nitric Oxide (NO) |
|
|
bronchiectasis |
Official Title |
Nitric Oxide (NO) |
|
|
bronchiolitis |
Arm Group Label |
Nitric Oxide (NO) |
|
|
bronchiolitis |
Brief Title |
Nitric Oxide (NO) |
|
|
bronchiolitis |
Eligibility Criteria |
phosphogluconate dehydrogenase 6-Phosphogluconic acid |
|
|
bronchiolitis |
Official Title |
Nitric Oxide (NO) |
|
|
bronchopulmonary dysplasia |
Arm Group Label |
Nitric Oxide (NO) |
|
|
bronchopulmonary dysplasia |
Brief Title |
Nitric Oxide (NO) |
|
|
bronchopulmonary dysplasia |
Eligibility Criteria |
Fibrinogen |
|
|
bronchopulmonary dysplasia |
Official Title |
Nitric Oxide (NO) |
|
|
Burkholderia infections |
Eligibility Criteria |
neurotrimin |
|
|
calcinosis |
Official Title |
Nitric Oxide (NO) |
|
|
chronic obstructive pulmonary disease |
Arm Group Description |
Nitric Oxide (NO) |
|
|
chronic obstructive pulmonary disease |
Arm Group Label |
Nitric Oxide (NO) COPD |
|
|
chronic obstructive pulmonary disease |
Brief Title |
Nitric Oxide (NO) COPD |
|
|
chronic obstructive pulmonary disease |
Official Title |
Nitric Oxide (NO) COPD |
|
|
cOVID 2019 infections |
Brief Title |
Nitric Oxide (NO) |
|
|
cOVID 2019 infections |
Eligibility Criteria |
neurotrimin |
|
|
cOVID 2019 infections |
Official Title |
Nitric Oxide (NO) |
|
|
COVID-19 respiratory infection |
Arm Group Label |
Nitric Oxide (NO) |
|
|
COVID-19 respiratory infection |
Brief Title |
Nitric Oxide (NO) |
|
|
COVID-19 respiratory infection |
Eligibility Criteria |
hemoglobin subunit gamma 2 |
|
|
COVID-19 respiratory infection |
Official Title |
Nitric Oxide (NO) |
|
|
cystic fibrosis |
Arm Group Label |
Nitric Oxide (NO) |
|
|
cystic fibrosis |
Brief Title |
Nitric Oxide (NO) |
|
|
cystic fibrosis |
Arm Group Description |
Nitric Oxide (NO) |
|
|
cystic fibrosis |
Eligibility Criteria |
hemoglobin subunit gamma 2 ATPase H+ transporting accessory protein 1 |
|
|
cystic fibrosis |
Official Title |
Nitric Oxide (NO) |
|
|
cystic fibrosis-associated respiratory tract infections |
Arm Group Label |
Nitric Oxide (NO) |
|
|
cystic fibrosis-associated respiratory tract infections |
Brief Title |
Nitric Oxide (NO) |
|
|
cystic fibrosis-associated respiratory tract infections |
Arm Group Description |
Nitric Oxide (NO) |
|
|
cystic fibrosis-associated respiratory tract infections |
Eligibility Criteria |
hemoglobin subunit gamma 2 |
|
|
cystic fibrosis-associated respiratory tract infections |
Official Title |
Nitric Oxide (NO) |
|
|
hypoxaemia |
Outcome Measure |
hemoglobin subunit gamma 2 |
|
|
hypoxic respiratory failure |
Arm Group Description |
serpin peptidase inhibitor, clade H (heat shock protein 47), member 1, (collagen binding protein 1) |
|
|
hypoxic respiratory failure |
Outcome Measure |
Vascular endothelial growth factor A (VEGF) tumor protein, translationally-controlled 1 Malondialdehyde Endothelin 1 8-oxo-7-hydrodeoxyguanosine |
|
|
idiopathic pulmonary fibrosis |
Arm Group Label |
Nitric Oxide (NO) COPD |
|
|
idiopathic pulmonary fibrosis |
Brief Title |
Nitric Oxide (NO) COPD |
|
|
idiopathic pulmonary fibrosis |
Eligibility Criteria |
phenylalanine hydroxylase |
|
|
idiopathic pulmonary fibrosis |
Official Title |
Nitric Oxide (NO) COPD |
|
|
interstitial lung diseases |
Arm Group Label |
Nitric Oxide (NO) |
|
|
interstitial lung diseases |
Brief Title |
Nitric Oxide (NO) |
|
|
interstitial lung diseases |
Official Title |
Nitric Oxide (NO) |
|
|
leg ulcer |
Arm Group Label |
Nitric Oxide (NO) |
|
|
leg ulcer |
Brief Title |
Nitric Oxide (NO) |
|
|
leg ulcer |
Arm Group Description |
Nitric Oxide (NO) |
|
|
leg ulcer |
Official Title |
Nitric Oxide (NO) |
|
|
leg ulcer |
Brief Summary |
Nitric Oxide (NO) |
|
|
liver injury |
Brief Title |
Nitric Oxide (NO) |
|
|
liver injury |
Official Title |
Nitric Oxide (NO) |
|
|
liver injury |
Outcome Measure |
Alkaline phosphatase (ALPL) |
|
|
lung disorders |
Detailed Description |
MPO Interleukin-8 (IL-8) Interleukin-6 (IL-6) Interleukin-10 (IL-10) Endothelin 1 |
|
|
lung disorders |
Outcome Measure |
hemoglobin subunit gamma 2 |
|
|
methicillin-resistant Staphylococcus aureus infections |
Arm Group Description |
Nitric Oxide (NO) |
|
|
methicillin-resistant Staphylococcus aureus infections |
Arm Group Label |
Nitric Oxide (NO) |
|
|
methicillin-resistant Staphylococcus aureus infections |
Brief Summary |
Nitric Oxide (NO) |
|
|
Mycobacterium avium complex infections |
Eligibility Criteria |
neurotrimin |
|
|
myocardial infarction |
Outcome Measure |
phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha Cardiac Troponin T BNP |
|
|
nontuberculous mycobacterium infections |
Brief Title |
Nitric Oxide (NO) |
|
|
nontuberculous mycobacterium infections |
Eligibility Criteria |
neurotrimin |
|
|
nontuberculous mycobacterium infections |
Official Title |
Nitric Oxide (NO) |
|
|
oesophageal motility disorders |
Official Title |
Nitric Oxide (NO) |
|
|
pain |
Official Title |
Nitric Oxide (NO) |
|
|
platelet dysfunction |
Outcome Measure |
Prothrombin (PT) P-selectin hemoglobin subunit gamma 2 C-reactive protein (CRP) |
|
|
pneumonia |
Brief Title |
Nitric Oxide (NO) |
|
|
pneumonia |
Official Title |
Nitric Oxide (NO) |
|
|
postoperative complications |
Arm Group Description |
Nitric Oxide (NO) |
|
|
postoperative complications |
Brief Summary |
NGAL GFAP |
|
|
postoperative complications |
Outcome Measure |
NGAL GFAP |
|
|
pressure ulcer |
Arm Group Description |
Nitric Oxide (NO) |
|
|
pressure ulcer |
Arm Group Label |
Nitric Oxide (NO) |
|
|
pressure ulcer |
Brief Summary |
Nitric Oxide (NO) |
|
|
Pulmonary arterial hypertension |
Arm Group Label |
Nitric Oxide (NO) |
|
|
Pulmonary arterial hypertension |
Outcome Measure |
pyroglutamyl-peptidase I GPI BNP biglycan |
|
|
Pulmonary arterial hypertension |
Brief Title |
Nitric Oxide (NO) |
|
|
Pulmonary arterial hypertension |
Arm Group Description |
Nitric Oxide (NO) |
|
|
Pulmonary arterial hypertension |
Eligibility Criteria |
phenylalanine hydroxylase Cardiac Troponin I |
|
|
Pulmonary arterial hypertension |
Official Title |
Nitric Oxide (NO) |
|
|
pulmonary hypertension |
Arm Group Label |
Nitric Oxide (NO) |
|
|
pulmonary hypertension |
Brief Title |
Nitric Oxide (NO) |
|
|
pulmonary hypertension |
Arm Group Description |
Nitric Oxide (NO) |
|
|
pulmonary hypertension |
Detailed Description |
tissue factor pathway inhibitor (lipoprotein-associated coagulation inhibitor) |
|
|
pulmonary hypertension |
Eligibility Criteria |
tissue factor pathway inhibitor (lipoprotein-associated coagulation inhibitor) phenylalanine hydroxylase |
|
|
pulmonary hypertension |
Official Title |
Nitric Oxide (NO) |
|
|
Raynaud's disease |
Official Title |
Nitric Oxide (NO) |
|
|
reperfusion injury |
Brief Title |
Nitric Oxide (NO) |
|
|
reperfusion injury |
Official Title |
Nitric Oxide (NO) |
|
|
reperfusion injury |
Outcome Measure |
Alkaline phosphatase (ALPL) |
|
|
respiratory insufficiency |
Arm Group Label |
Nitric Oxide (NO) |
|
|
respiratory insufficiency |
Brief Title |
Nitric Oxide (NO) |
|
|
respiratory insufficiency |
Detailed Description |
MPO Interleukin-8 (IL-8) Interleukin-6 (IL-6) Interleukin-10 (IL-10) Endothelin 1 |
|
|
respiratory insufficiency |
Eligibility Criteria |
hemoglobin subunit gamma 2 |
|
|
respiratory insufficiency |
Official Title |
Nitric Oxide (NO) |
|
|
sclerodactyly |
Official Title |
Nitric Oxide (NO) |
|
|
severe acute respiratory syndrome |
Brief Title |
Nitric Oxide (NO) |
|
|
severe acute respiratory syndrome |
Official Title |
Nitric Oxide (NO) |
|
|
telangiectasis |
Official Title |
Nitric Oxide (NO) |
|
|
tinea pedis |
Arm Group Description |
Nitric Oxide (NO) |
|
|
tinea pedis |
Brief Title |
Nitric Oxide (NO) |
|
|
tinea pedis |
Eligibility Criteria |
T-cell surface antigen CD4 |
|
|
tinea pedis |
Official Title |
Nitric Oxide (NO) |
|
|
varicose ulcer |
Arm Group Description |
Nitric Oxide (NO) |
|
|
varicose ulcer |
Brief Title |
Nitric Oxide (NO) |
|
|
varicose ulcer |
Official Title |
Nitric Oxide (NO) |
Biomarker
| Drug Name | Biomarker Name | Biomarker Function |
|---|---|---|
| Nitric oxide - Mallinckrodt | (R)-lipoic acid | Arm Group Description, Arm Group Label, Brief Title, Official Title |
| 16S rRNA | Outcome Measure | |
| 2,3-Diphosphoglyceric acid | Detailed Description, Outcome Measure | |
| 3-Nitrotyrosine | Detailed Description | |
| 8-Isoprostaglandin F2a | Outcome Measure | |
| 8-isoprostane | Outcome Measure | |
| 8-oxo-7-hydrodeoxyguanosine | Outcome Measure | |
| ABL2 | Outcome Measure | |
| Acetylcholine | Arm Group Description | |
| Acetylcysteine | Brief Title, Official Title | |
| Adenosine monophosphate | Official Title | |
| Adiponectin (ADIPOQ) | Outcome Measure | |
| ADMA | Eligibility Criteria, Outcome Measure | |
| aldehyde dehydrogenase 7 family, member A1 | Eligibility Criteria | |
| Aldosterone | Outcome Measure | |
| Alkaline phosphatase (ALPL) | Outcome Measure | |
| Allantoin | Detailed Description, Outcome Measure | |
| Allergic rhinitis | Arm Group Label, Brief Title, Official Title, Outcome Measure | |
| alpha-1 antitrypsin (SERPINA1) | Eligibility Criteria | |
| Alpha-Tocopherol | Arm Group Description | |
| AMH | Eligibility Criteria | |
| Amphiregulin | Detailed Description, Outcome Measure | |
| Angiopoietin 1 | Outcome Measure | |
| Angiotensin II | Outcome Measure | |
| Angiotensinogen (AGT | Outcome Measure | |
| Apelin | Arm Group Description, Arm Group Label, Brief Title, Official Title | |
| Apolipoprotein A1 (APOA1) | Outcome Measure | |
| Apolipoprotein B (AOPB) | Outcome Measure | |
| Arachidonic acid | Detailed Description, Outcome Measure | |
| arginine-glutamic acid dipeptide repeats | Outcome Measure | |
| Argininosuccinic acid | Outcome Measure | |
| Ascorbic acid | Arm Group Description, Official Title, Outcome Measure | |
| ASS1 | Brief Summary | |
| BDNF | Outcome Measure | |
| Beta-Alanine | Arm Group Description, Arm Group Label, Detailed Description, Outcome Measure | |
| biglycan | Detailed Description | |
| BNP | Detailed Description, Outcome Measure | |
| bone morphogenetic protein 15 | Detailed Description, Outcome Measure | |
| Bradykinin | Brief Summary | |
| C-peptide | Outcome Measure | |
| C-reactive protein (CRP) | Arm Group Description, Brief Summary, Brief Title, Detailed Description, Eligibility Criteria, Official Title, Outcome Measure | |
| CA 15-3 | Detailed Description | |
| CALCA | Detailed Description | |
| Cardiac Troponin I | Eligibility Criteria | |
| Cardiac Troponin T | Outcome Measure | |
| CFTR | Brief Summary, Detailed Description | |
| CGA | Outcome Measure | |
| cholecystokinin | Outcome Measure | |
| chorionic gonadotropin beta subunit 5 | Outcome Measure | |
| Citric acid | Arm Group Description | |
| Citrulline | Arm Group Description, Arm Group Label, Brief Summary, Brief Title, Detailed Description, Eligibility Criteria, Official Title, Outcome Measure | |
| Cobalamin | Eligibility Criteria | |
| Coenzyme Q10 | Detailed Description, Outcome Measure | |
| COPD | Arm Group Description, Brief Title, Eligibility Criteria, Official Title | |
| COX1 | Detailed Description, Outcome Measure | |
| COX2 | Arm Group Description, Brief Summary, Detailed Description, Official Title, Outcome Measure | |
| Cyanocobalamin | Eligibility Criteria | |
| Cyclic GMP | Outcome Measure | |
| Cystatin C | Outcome Measure | |
| D-dimer | Outcome Measure | |
| D-Ornithine | Outcome Measure | |
| Deacetyldiltiazem | Arm Group Description, Arm Group Label | |
| decorin | Detailed Description | |
| Dihydrobiopterin | Outcome Measure | |
| dynein, axonemal, assembly factor 3 | Brief Summary, Detailed Description, Eligibility Criteria | |
| dynein, axonemal, heavy chain 5 | Brief Summary, Detailed Description, Eligibility Criteria | |
| dynein, axonemal, intermediate chain 1 | Brief Summary, Detailed Description, Eligibility Criteria | |
| ECP | Outcome Measure | |
| Elastase auto-antibodies | Detailed Description | |
| Elastase, neutrophil | Detailed Description | |
| Endothelin 1 | Arm Group Description, Brief Title, Official Title, Outcome Measure | |
| eNOS | Brief Summary, Brief Title, Detailed Description, Official Title, Outcome Measure | |
| EOS | Outcome Measure | |
| Eotaxin (CCL11) | Outcome Measure | |
| Estradiol-17beta 3-sulfate | Eligibility Criteria | |
| Estrogen receptor alpha (ER alpha) | Eligibility Criteria | |
| eukaryotic translation initiation factor 2 alpha kinase 4 | Arm Group Description, Brief Summary, Brief Title, Eligibility Criteria, Official Title, Outcome Measure | |
| FEV | Eligibility Criteria | |
| Fibrinogen | Brief Summary, Eligibility Criteria, Outcome Measure | |
| Fluticasone | Arm Group Description | |
| Folic acid | Arm Group Description, Arm Group Label, Brief Title, Official Title | |
| FSH | Eligibility Criteria | |
| Gastrin (GAS) | Detailed Description | |
| GCG | Detailed Description, Outcome Measure | |
| GFAP | Brief Summary, Outcome Measure | |
| Ghrelin | Outcome Measure | |
| Glutathione | Detailed Description, Outcome Measure | |
| GPI | Detailed Description | |
| growth differentiation factor 9 | Outcome Measure | |
| Guanosine monophosphate | Outcome Measure | |
| Gut Microbiome | Brief Title | |
| Haptoglobin | Outcome Measure | |
| HCY | Brief Summary, Detailed Description | |
| hemoglobin subunit gamma 2 | Eligibility Criteria, Outcome Measure | |
| Hemopexin | Outcome Measure | |
| HER2/ERBB2 | Eligibility Criteria | |
| histone deacetylase 9 | Brief Summary, Brief Title, Official Title, Outcome Measure | |
| Human Microbiome | Official Title | |
| Hydrocortisone | Outcome Measure | |
| hypertrichosis 2 (generalized, congenital) | Outcome Measure | |
| IGF1 | Outcome Measure | |
| IKAROS family zinc finger 4 | Outcome Measure | |
| immunoglobulin heavy constant epsilon | Brief Summary, Detailed Description, Eligibility Criteria, Outcome Measure | |
| iNOS | Arm Group Description, Brief Summary, Brief Title, Detailed Description, Official Title, Outcome Measure | |
| Insulin | Detailed Description, Outcome Measure | |
| Interferon Gamma (IFNg) | Outcome Measure | |
| Interleukin 1 alpha (IL-1α) | Detailed Description | |
| Interleukin 1 Beta (IL-1β) | Brief Summary, Detailed Description, Outcome Measure | |
| Interleukin-10 (IL-10) | Arm Group Description, Detailed Description, Outcome Measure | |
| Interleukin-12A (IL-12p35) | Outcome Measure | |
| Interleukin-12B (IL-12p40) | Outcome Measure | |
| Interleukin-13 (IL-13) | Arm Group Description, Brief Summary, Detailed Description, Outcome Measure | |
| Interleukin-17 (IL-17) | Arm Group Description, Brief Summary, Detailed Description, Outcome Measure | |
| Interleukin-2 (IL-2) | Detailed Description, Outcome Measure | |
| Interleukin-22 (IL-22) | Detailed Description | |
| Interleukin-4 (IL-4) | Arm Group Description, Brief Summary, Detailed Description, Outcome Measure | |
| Interleukin-5 (IL-5) | Brief Summary, Detailed Description, Outcome Measure | |
| Interleukin-6 (IL-6) | Brief Summary, Detailed Description, Outcome Measure | |
| Interleukin-8 (IL-8) | Brief Summary, Detailed Description, Outcome Measure | |
| Interleukin-9 (IL-9) | Detailed Description | |
| kininogen 1 | Brief Summary | |
| L-Aspartic acid | Eligibility Criteria | |
| L-Cysteine | Detailed Description, Outcome Measure | |
| L-Tryptophan | Brief Title, Official Title | |
| Leptin | Outcome Measure | |
| Lipoxin A4 | Detailed Description | |
| Lp-PLA2 | Outcome Measure | |
| LPA | Outcome Measure | |
| Luteinizing hormone (LH) | Detailed Description, Eligibility Criteria | |
| lymphatic vessel endothelial hyaluronan receptor 1 | Detailed Description | |
| MAFD2 | Arm Group Description, Brief Title, Official Title | |
| Malondialdehyde | Brief Summary, Outcome Measure | |
| Mannitol | Arm Group Description, Arm Group Label | |
| mannose-binding lectin (protein C) 2, soluble | Outcome Measure | |
| Methylcobalamin | Arm Group Description | |
| Methyldopa | Arm Group Label | |
| mitochondrially encoded tRNA leucine 1 (UUA/G) | Eligibility Criteria | |
| MMP9 | Outcome Measure | |
| Monocyte chemoattractant protein-1 (MCP-1/CCL2) | Detailed Description | |
| MPO | Outcome Measure | |
| mucin 2, oligomeric mucus/gel-forming | Detailed Description | |
| mucin 5AC, oligomeric mucus/gel-forming | Detailed Description | |
| mucin 5B, oligomeric mucus/gel-forming | Detailed Description | |
| myelin basic protein | Outcome Measure | |
| myoglobin | Outcome Measure | |
| Neuron-specific enolase (NSE) | Brief Summary, Detailed Description | |
| NFkB | Detailed Description, Outcome Measure | |
| NGAL | Brief Summary, Outcome Measure | |
| Nitric Oxide (NO) | Arm Group Description, Arm Group Label, Brief Summary, Brief Title, Detailed Description, Eligibility Criteria, Official Title, Outcome Measure | |
| Norepinephrine | Detailed Description | |
| Ornithine | Outcome Measure | |
| Osteocalcin (OC) | Outcome Measure | |
| Oxidized glutathione | Brief Summary | |
| P-selectin | Outcome Measure | |
| PAI-1 | Brief Summary | |
| PGE2 | Detailed Description, Outcome Measure | |
| PGR | Eligibility Criteria | |
| phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha | Outcome Measure | |
| pregnancy specific beta-1-glycoprotein 5 | Brief Summary, Detailed Description, Eligibility Criteria | |
| progastricsin | Detailed Description | |
| Progesterone | Eligibility Criteria | |
| proprotein convertase subtilisin/kexin type 9 | Official Title | |
| Prostacyclin | Arm Group Description, Arm Group Label, Brief Title, Detailed Description, Official Title | |
| prostaglandin E receptor 1 | Brief Summary, Detailed Description | |
| prostaglandin-endoperoxide synthase 1 | Detailed Description, Outcome Measure | |
| protease, serine 33 | Outcome Measure | |
| proteoglycan 2, pro eosinophil major basic protein | Outcome Measure | |
| Prothrombin (PT) | Outcome Measure | |
| pterin-4 alpha-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha | Brief Summary, Detailed Description, Eligibility Criteria | |
| pyroglutamyl-peptidase I | Detailed Description | |
| serpin peptidase inhibitor, clade H (heat shock protein 47), member 1, (collagen binding protein 1) | Arm Group Description | |
| SOD1 | Detailed Description, Outcome Measure | |
| SOD2-OT1 | Detailed Description, Outcome Measure | |
| solute carrier family 26 (anion exchanger), member 3 | Brief Summary | |
| Stearic acid | Arm Group Description | |
| Substance P | Outcome Measure | |
| sulfotransferase family 1E member 1 | Brief Summary | |
| superoxide dismutase 2, mitochondrial | Detailed Description, Outcome Measure | |
| surfactant protein B | Outcome Measure | |
| Symmetric dimethylarginine | Outcome Measure | |
| syndecan 4 | Outcome Measure | |
| tachykinin, precursor 1 | Arm Group Description, Outcome Measure | |
| Tetrahydrobiopterin | Outcome Measure | |
| Thromboxane A2 | Detailed Description | |
| Thromboxane B2 | Detailed Description | |
| thymic stromal lymphopoietin | Detailed Description | |
| Thyroid stimulating hormone beta (TSH) | Eligibility Criteria | |
| TIMP-2 | Detailed Description | |
| tissue factor pathway inhibitor (lipoprotein-associated coagulation inhibitor) | Detailed Description, Eligibility Criteria | |
| TLR2 | Detailed Description | |
| Toll-Like Receptor 4 (TLR4) | Detailed Description | |
| Transforming growth factor-beta (TGF-beta) | Detailed Description, Outcome Measure | |
| Trypsin | Detailed Description | |
| Tubulin beta class IVb | Arm Group Description, Official Title | |
| Tumor necrosis factor alpha (TNF-alpha) | Brief Summary, Brief Title, Detailed Description, Outcome Measure | |
| tumor protein, translationally-controlled 1 | Outcome Measure | |
| urocortin | Brief Summary | |
| urocortin 2 | Arm Group Description | |
| urocortin 3 | Arm Group Description | |
| Vascular endothelial growth factor A (VEGF) | Detailed Description, Official Title, Outcome Measure | |
| Vasopressin | Official Title, Outcome Measure | |
| VCAM-1 | Detailed Description, Outcome Measure |
Development Status
Summary Table
| Indication | Qualifier | Patient Segment | Phase | Countries | Route / Formulation | Developers | Event Date |
|---|---|---|---|---|---|---|---|
| Bronchopulmonary dysplasia | - | In neonates, Prevention | Phase III | Belgium, Finland, France, Germany, Italy, Netherlands, Spain, Sweden, United Kingdom | Inhalation / Inhalant | Mallinckrodt plc | 01 May 2005 |
| Bronchopulmonary dysplasia | - | In neonates, Prevention | No development reported (III) | Canada, USA | Inhalation / Inhalant | Mallinckrodt plc | 10 Jun 2015 |
| Heart failure | - | - | Discontinued (II) | Germany, USA | Inhalation / Inhalant | Ikaria Holdings | 29 Dec 2011 |
| Hypoxic respiratory failure | - | In neonates | Marketed | Australia, Czech Republic, Japan, Malaysia, Singapore, South Korea, USA | Inhalation / Inhalant | Mallinckrodt plc | 19 Nov 2014 |
| Hypoxic respiratory failure | - | In neonates | Marketed | Denmark, France, Germany, Greece, Ireland, Italy, Netherlands, Poland, Portugal, Spain, Sweden, Switzerland | Inhalation / Inhalant | AGA Linde Healthcare | 31 Dec 2001 |
| Hypoxic respiratory failure | - | In neonates | Marketed | Canada, Latin America | Inhalation / Inhalant | 30 Nov 2007 | |
| Pulmonary arterial hypertension | Reactivity of the pulmonary vasculature | Combination therapy, In adolescents, In children, In infants | Discontinued (III) | France, Netherlands, Spain, USA, United Kingdom | Inhalation / Inhalant | Mallinckrodt plc | 26 Apr 2022 |
| Pulmonary hypertension | associated with cardiac surgery in neonates through adults | In adolescents, In children, In neonates | Marketed | Australia | Inhalation / Inhalant | Mallinckrodt plc | 02 Nov 2015 |
| Pulmonary hypertension | for perioperative pulmonary hypertension in adults in conjunction with cardiovascular surgery | In adults | Marketed | Australia | Inhalation / Inhalant | Mallinckrodt plc | 12 Apr 2019 |
| Pulmonary hypertension | associated with cardiac surgery in neonates through adults | - | Marketed | Japan | Inhalation / Inhalant | Mallinckrodt plc | 02 Nov 2015 |
| Reperfusion injury | during liver transplantation | Prevention | Discontinued (II/III) | USA | Inhalation / Inhalant | Ikaria Holdings | 12 Jun 2014 |
| SARS-CoV-2 acute respiratory disease | - | - | Preclinical | United Kingdom | Inhalation / Inhalant | Mallinckrodt plc | 12 Mar 2020 |
| SARS-CoV-2 acute respiratory disease | - | - | No development reported (Clinical) | USA | Inhalation / Inhalant | Mallinckrodt plc, Massachusetts General Hospital | 28 May 2023 |
| Transplant rejection | - | - | No development reported (Preclinical) | USA | Parenteral / Liquid | Mallinckrodt plc | 28 May 2023 |
Orphan Status
| Indication | Patient Segment | Country | Organisation | Event Date |
|---|---|---|---|---|
| Hypoxic respiratory failure | In neonates | Australia | Mallinckrodt plc | 27 Nov 2007 |
| Hypoxic respiratory failure | In neonates | Japan | Mallinckrodt plc | 21 Jul 2008 |
| Pulmonary hypertension | In adolescents, In adults, In children, In infants, In neonates | Japan | INO Therapeutics | 20 Nov 2014 |
| Pulmonary hypertension | - | USA | Mallinckrodt plc | 23 Jan 2012 |
Commercial Information
Involved Organisations
| Organisation | Involvement | Countries |
|---|---|---|
| Massachusetts General Hospital | Originator | USA |
| Massachusetts General Hospital | Owner | USA |
| AGA Linde Healthcare | Market Licensee | Australia, European Union |
| Sumitomo Seika Chemicals | Market Licensee | Japan |
| Air Water Inc | Market Licensee | Japan |
| Lee's Pharmaceutical | Market Licensee | China, Hong Kong, Macau, Taiwan |
| Mallinckrodt plc | Licensee | World |
| Novoteris | Collaborator | USA |
Brand Names
| Brand Name | Organisations | Indications | Countries |
|---|---|---|---|
| INOVENT | Mallinckrodt plc | Pulmonary hypertension | Japan |
| INOflo | Mallinckrodt plc | Hypoxic respiratory failure, Pulmonary hypertension | Japan |
| INOmax | AGA Linde Healthcare, Mallinckrodt plc | Hypoxic respiratory failure, Pulmonary hypertension | Australia, European Union, Latin America, USA |
| INOmax Total Care | Lee's Pharmaceutical | Hypoxic respiratory failure | Asia |
| INOtherapy | Mallinckrodt plc | Hypoxic respiratory failure | Canada |
Scientific Summary
Adverse Events
In neonates with hypoxic respiratory failure, inhaled nitric oxide therapy has been well tolerated. No systemic hypotension has been observed but therapy has been associated with an increase in methaemoglobin levels. In one study, the dosage of nitric oxide was reduced in 11/141 patients because of increases in methaemoglobin levels of 5-10% [35] [34] .
Therapeutic Trials
Bronchopulmonary dysplasia
there was no significant difference in efficacy between the treatment and control groups in a phase III trial (INOT27) of inhaled nitric oxide for the treatment of bronchopulmonary dysplasia in preterm infants. 800 such infants (gestational age range 24 to 28 weeks) who were administered surfactant within 24h of birth or received continuous positive airway pressure (CPAP) to maintain oxygen saturation of ≥85%, were assigned to treatment with inhaled nitric oxide or nitrogen gas. Both inhaled therapies were administered as 5 ppm for 7-21 days. The primary endpoint, survival without bronchopulmonary dysplasia, was fulfilled in 65.3% of nitric oxide recipients and 65.5% of nitrogen recipients; the difference was not statistically significant [11] .
Hypoxic respiratory failure
a multicentre US trial showed that inhaled nitric oxide reduced the need for extracorporeal membrane oxygenation among neonates with hypoxic respiratory failure, but did not reduce the mortality rate. In the study, 235 neonates born at ≥ 34 weeks gestation who had hypoxic respiratory failure were randomised to inhaled nitric oxide (800 ppm in nitrogen) in the inspiratory circuit of the ventilator or 100% oxygen. The incidence of the combined outcome of death by 120 days of age or the need for extracorporeal membrane oxygenation was significantly lower among nitric oxide recipients (46% vs 64%). However, the mortality rate was similar in the 2 groups (14% vs 17%). Improvement in arterial oxygen tension and oxygenation index was greater in the active treatment group [35] .
A second US multicentre trial, this time in the subgroup of neonates with hypoxic respiratory failure due to persistent pulmonary hypertension, showed that inhaled nitric oxide improved systemic oxygenation. Neonates who required mechanical ventilation were randomised to nitric oxide (800-1000 ppm in nitrogen) or nitrogen, with the concentration adjusted according to arterial oxygen tension. The trial was stopped early after enrolment of 58 patients when it was found that nitric oxide produced a significant improvement in oxygenation (53% improved vs 7% of controls). Long term nitric oxide therapy sustained systemic oxygenation in 75% of patients who had initial improvement. Significantly fewer nitric oxide recipients than nitrogen-only recipients required extracorporeal membrane oxygenation (40% vs 71%). Mortality was similar in the two groups [34] .
In a study which was supported in part by INO Therapeutics, 248 neonates aged ≤4 days who had persistent pulmonary hypertension of the newborn and severe respiratory failure requiring mechanical ventilation and who were born at a gestational age of >34 weeks, were randomised to receive reducing doses of inhaled nitric oxide (NO; n = 126) or nitrogen (controls) starting at 20 parts per million (ppm). The NO or nitrogen dose was reduced to 5ppm after 4h if the neonate was stable, had an arterial oxygen tension value of ≥60mm Hg and the pH was ≤7.55. Otherwise, study drug was maintained at 20ppm until the criteria were met or 24h had elapsed, then reduced to 5ppm until the inspired oxygen fraction was <0.7, treatment had been administered for 96h, or the neonate was 7 days old. Overall, significantly fewer NO recipients, compared with controls, used extracorporeal membrane oxygenation (38% vs 64% of patients, respectively). Following stratification by diagnosis, only NO recipients with congenital diaphragmatic herniation did not show a reduction in the use of extracorporeal membrane oxygenation. Chronic lung disease developed in significantly fewer NO recipients, compared with controls (7% vs 20% of patients, respectively). 30-day mortality was similar for NO recipients and controls (7% vs 8%, respectively); the between-group difference was not significant [33] .
Neonatal respiratory distress syndrome
in a study funded by INO Therapeutics, low-dose inhaled nitric oxide (NO) therapy was investigated in 207 premature neonates with respiratory distress syndrome aged <72h who were born at <34 weeks' gestation at a bodyweight of <2000g. The neonates were randomised to receive inhaled NO [INOmax®] or oxygen placebo for 7 days, plus either intermittent mandatory ventilation or high-frequency oscillatory ventilation. NO was administered at a dosage of 10 ppm for 12−24h followed by 5 ppm for the remaining 6 days. Compared with oxygen placebo, NO significantly reduced the combined incidence of death or chronic lung disease (63.7% vs 48.6% of neonates). There was no apparent interaction between treatment and birthweight. However, there was a significant interaction between treatment and disease severity. Specifically, compared with oxygen placebo, NO significantly reduced the incidence of death or chronic lung disease in neonates with an initial oxygenation index below the median (67.3% vs 36% of neonates), but not in those with an initial oxygenation index at or above the median (58.3% vs 58.8%, respectively). In addition, NO significantly reduced the incidence of severe intraventricular haemorrhage and periventricular leukomalacia, relative to oxygen placebo [31] .
Pharmacoeconomic studies
a cost-effectiveness analysis was conducted of the Canadian Inhaled Nitric Oxide Study (CINOS), in which 96 neonates of ≥34 weeks gestation requiring ventilation were randomly assigned to receive inhaled nitric oxide (n = 49) or oxygen. Costs and outcomes were assessed from baseline to 18−24 months' follow-up. Twenty neonates died, of which 13 were in the oxygen arm; the between-group difference was not significant. Per-patient costs were greater in the nitric oxide, than the oxygen, arm over the study period ($Can23 907 vs $Can19 105), with the majority of costs in both groups occurring during the initial hospitalisation; again, the between-group difference was nonsignificant. Costs (Canadian dollars; $Can1 = $US0.67) were those related to hospitalisation, medications, neonatal intensive care, extracorporeal membrane oxygenation, physician services, surfactant, air transport and all government and family private costs beyond normal care in the first 18−24 months of life. Costs were calculated using a modified societal perspective and second-year costs were discounted at a rate of 5% per annum. Costs incurred between discharge and follow-up were approximately $Can300 higher among oxygen, than among nitric oxide, recipients. The majority of this cost difference, although not significant, was represented by higher medication costs and costs associated with medical services. The researchers noted that although the overall difference in costs between the two groups was not statistically significant, there was a "general trend toward better outcomes for nitric oxide", with a significant reduction in seizure disorders of around 20%, compared with oxygen therapy [32] .
Future Events
| Expected Date | Event Type | Description | Updated |
|---|---|---|---|
| 07 Sep 2021 | Trial Update | University of California and Mallinckrodt plan a phase II trial in Pulmonary embolism in USA (Inhalation) in September 2021 (NCT04996667) | 24 May 2022 |
Development History
| Event Date | Update Type | Comment |
|---|---|---|
| 28 May 2023 | Phase Change - No development reported | No recent reports of development identified for clinical-Phase-Unknown development in SARS-COV-2 acute respiratory disease in USA (Inhalation, Inhalant) Updated 28 May 2023 |
| 28 May 2023 | Phase Change - No development reported | No recent reports of development identified for preclinical development in Transplant-rejection in USA (Parenteral, Liquid) Updated 28 May 2023 |
| 30 Dec 2022 | Patent Information | Mallinckrodt Pharmaceuticals has patent protection for INOmax® in USA [29] Updated 20 Apr 2023 |
| 18 May 2022 | Trial Update | Mallinckrodt withdraw a phase II trial prior to enrollment in Pulmonary Embolism in USA (Inhalation) (NCT04996667) Updated 24 May 2022 |
| 26 Apr 2022 | Phase Change - Discontinued(III) | Discontinued - Phase-III for Pulmonary arterial hypertension (Combination therapy, In adolescents, In children, In infants) in Netherlands, Spain, United Kingdom, France, USA (Inhalation) (Mallinckrodt pipeline, April 2022) Updated 26 Apr 2022 |
| 30 Mar 2022 | Patent Information | Mallinckrodt Pharmaceuticals has patents pending for INOmax® in USA and other countries [29] Updated 20 Apr 2023 |
| 01 Nov 2021 | Biomarker Update | Biomarkers information updated Updated 03 Nov 2021 |
| 09 Aug 2021 | Trial Update | University of California and Mallinckrodt plan a phase II trial in Pulmonary embolism in USA (Inhalation) in September 2021 (NCT04996667) Updated 24 May 2022 |
| 30 Apr 2020 | Trial Update | Massachusetts General Hospital initiates enrolment in a clinical trial for SARS-COV-2 acute respiratory disease in USA [14] Updated 06 May 2020 |
| 12 Mar 2020 | Phase Change - Preclinical | Preclinical trials in SARS-COV-2 acute respiratory disease in United Kingdom (Inhalation) [15] Updated 18 Mar 2020 |
| 12 Mar 2020 | Regulatory Status | Mallinckrodt intends to submit an IND application to the US FDA for SARS-COV-2 acute respiratory disease [15] Updated 18 Mar 2020 |
| 16 Apr 2019 | Phase Change - Registered | Registered for Pulmonary hypertension (In adults) in Australia (Inhalation) [20] Updated 16 Apr 2019 |
| 12 Apr 2019 | Phase Change - Marketed | Launched for Pulmonary hypertension (In adults) in Australia (Inhalation) [20] Updated 03 May 2019 |
| 01 Apr 2019 | Phase Change - Preclinical | Preclinical trials in Transplant rejection in USA (Parenteral) before April 2019 (Mallinckrodt pipeline, April 2019) Updated 16 Apr 2019 |
| 14 Feb 2019 | Other | Chemical structure information added Updated 14 Feb 2019 |
| 23 Sep 2016 | Patent Information | Mallinckrodt has patent protection for nitric oxide inhalation and gas delivery systems in USA [30] Updated 25 Oct 2016 |
| 23 Sep 2016 | Patent Information | Praxair files an appeal against the Patent Trial and Appeal Board decision related to the US patent no. 8 846 112 in U.S. Court of Appeals for the Federal Circuit and Mallinckrodt also files a cross-appeal [30] Updated 25 Oct 2016 |
| 23 Sep 2016 | Patent Information | The US Patent and Trademark Office confirms the validity of five 2031 patents protecting nitric oxide inhalation [30] Updated 25 Oct 2016 |
| 22 Sep 2016 | Patent Information | The Patent Trial and Appeal Board dismisses a set of petitions filed by Praxair Distribution concerning four nitric oxide inhalation patents that expire in 2029 [30] Updated 25 Oct 2016 |
| 25 Aug 2016 | Patent Information | The Patent Trial and Appeal Board dismisses a petition filed by Praxair Distribution concerning the US patent no. 8 846 112 [30] Updated 25 Oct 2016 |
| 01 Jul 2016 | Trial Update | Bellerophon Therapeutics completes a phase II trial in Pulmonary arterial hypertension in USA and Canada (NCT01457781) Updated 19 Aug 2016 |
| 01 Dec 2015 | Trial Update | Mallinckrodt completes a phase-III trial in Bronchopulmonary dysplasia (In neonates, Prevention) in Belgium, Finland, France, Germany, Italy, Netherlands, Spain, Sweden, United Kingdom (Inhalation) (NCT00551642) Updated 26 Dec 2016 |
| 02 Nov 2015 | Phase Change - Marketed | Launched for Pulmonary hypertension (In adolescents, In children, In neonates) in Australia (Inhalation) [21] Updated 03 May 2019 |
| 02 Nov 2015 | Phase Change - Marketed | Launched for Pulmonary hypertension in Japan (Inhalation) [21] Updated 03 May 2019 |
| 30 Oct 2015 | Phase Change - Registered | Registered for Pulmonary hypertension (In neonates, In children, In adolescents) in Australia (Inhalation) Updated 03 Nov 2015 |
| 30 Oct 2015 | Phase Change - Registered | Registered for Pulmonary hypertension in Japan (Inhalation) Updated 03 Nov 2015 |
| 29 Oct 2015 | Phase Change - Preregistration | Preregistration for Pulmonary hypertension in Australia (Inhalation) Updated 03 Nov 2015 |
| 29 Oct 2015 | Phase Change - Preregistration | Preregistration for Pulmonary hypertension in Japan (Inhalation) Updated 03 Nov 2015 |
| 10 Jun 2015 | Phase Change - No development reported(III) | No recent reports on development identified - Phase-III for Bronchopulmonary dysplasia (In neonates, Prevention) in Canada and USA (Inhalation) Updated 10 Jun 2015 |
| 16 Apr 2015 | Company Involvement | Ikaria Holdings has been acquired by Mallinckrodt plc Updated 20 Apr 2015 |
| 20 Nov 2014 | Regulatory Status | Nitric oxide - Mallinckrodt receives Orphan Drug status for Pulmonary hypertension (In adults, In children, In infants, In neonates, In adolescents) in Japan (PMDA website, November 2014) Updated 17 Mar 2020 |
| 19 Nov 2014 | Licensing Status | Nitric oxide inhalation licensed to Lee's Pharmaceutical in China, Hong Kong, Macau & Taiwan [5] Updated 21 Nov 2014 |
| 19 Nov 2014 | Phase Change - Marketed | Launched prior to this date for Hypoxic respiratory failure (In neonates) in South Korea (Inhalation) Updated 21 Nov 2014 |
| 01 Jul 2014 | Trial Update | INO Therapeutics completes a phase III trial in Pulmonary hypertension in Japan (NCT01959828) Updated 28 May 2015 |
| 12 Jun 2014 | Phase Change - Discontinued(II/III) | Discontinued - Phase-II/III for Reperfusion injury (prevention) in USA (Inhalation) Updated 12 Jun 2014 |
| 23 May 2014 | Trial Update | Ikaria Holdings completes enrolment in its phase II trial for Pulmonary hypertension (INOpulse) in USA and Canada (NCT01457781) Updated 09 Jun 2014 |
| 01 May 2014 | Trial Update | Ikaria Holdings completes a pivotal phase III trial in Bronchopulmonary dysplasia prevention in USA and Canada (NCT00931632) Updated 01 Sep 2015 |
| 28 Feb 2014 | Licensing Status | Bellerophon Therapeutics acquires exclusive worldwide rights from Ikaria to INOpulse programmes in pulmonary arterial hypertension and pulmonary hypertension associated with chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis [6] Updated 20 Jun 2014 |
| 01 Sep 2013 | Phase Change - III | Phase-III clinical trials in Pulmonary hypertension (associated with cardiac surgery) in Japan (Inhalation) Updated 29 Nov 2013 |
| 31 Oct 2012 | Trial Update | Mallinckrodt completes a phase II/III trial for Reperfusion injury prevention (in patients undergoing liver transplantation) in USA (NCT00582010) Updated 05 May 2016 |
| 19 Apr 2012 | Phase Change - II | Phase-II clinical trials in Pulmonary hypertension in Canada (Inhalation, INOpulse) Updated 29 Nov 2013 |
| 19 Apr 2012 | Phase Change - II | Phase-II clinical trials in Pulmonary hypertension in USA (Inhalation; INOpulse) Updated 29 Nov 2013 |
| 28 Feb 2012 | Trial Update | Ikaria Holdings completes patient enrolment in a pivotal phase III trial for Bronchopulmonary dysplasia prevention in USA and Canada (NCT00931632) Updated 28 Feb 2012 |
| 25 Jan 2012 | Phase Change - No development reported(II/III) | No development reported - Phase-II/III for Reperfusion injury (prevention) in USA (Inhalation) Updated 12 Jun 2014 |
| 23 Jan 2012 | Regulatory Status | Nitric oxide inhalation in combination with the INOpulse DS system receives Orphan Drug status for Pulmonary hypertension in USA Updated 25 Jan 2012 |
| 29 Dec 2011 | Phase Change - Discontinued(II) | Discontinued - Phase-II for Congestive heart failure in Germany (Inhalation) Updated 29 Dec 2011 |
| 29 Dec 2011 | Phase Change - Discontinued(II) | Discontinued - Phase-II for Congestive heart failure in USA (Inhalation) Updated 29 Dec 2011 |
| 30 Nov 2011 | Regulatory Status | Ikaria Holdings files an IND application with the FDA in USA for Pulmonary arterial hypertension [27] Updated 25 Jan 2012 |
| 19 Aug 2010 | Active Status Review | A phase II/III trial (NCT00582010) in Reperfusion injury prevention (in patients undergoing liver transplantation) is ongoing in USA Updated 19 Aug 2010 |
| 18 Aug 2010 | Active Status Review | Phase-III development is ongoing for Adult respiratory distress syndrome in USA Updated 19 Aug 2010 |
| 18 Aug 2010 | Active Status Review | Phase-III development is ongoing for Bronchopulmonary dysplasia (Prevention, In neonates) in USA and European Union Updated 18 Aug 2010 |
| 09 Jun 2010 | Trial Update | Mallinckrodt terminates a pilot phase I/II trial for Respiratory disorders (In neonates) in USA due to slow enrolment (Inhalation) before June 2010 (NCT00041548) Updated 02 May 2016 |
| 09 Jun 2010 | Trial Update | INO Therapeutics completes a phase II trial (NCT00060840) in Congestive heart failure in USA and Germany Updated 19 Aug 2010 |
| 28 Feb 2010 | Trial Update | Mallinckrodt completes its phase III trial in Pulmonary arterial hypertension (Combination therapy, In adolescents, In children, In infants) in Spain, USA, Netherlands, France, United Kingdom (NCT00626028) Updated 26 Apr 2022 |
| 11 Jan 2010 | Trial Update | Ikaria Holdings completes enrolment in a phase III (TOLSURF Pilot) study in Bronchopulmonary dysplasia in USA Updated 03 Mar 2010 |
| 30 Nov 2009 | Phase Change - III | Phase-III clinical trials for prevention of Bronchopulmonary dysplasia (in preterm infants) in Canada (Inhalation) Updated 29 Dec 2011 |
| 31 Oct 2009 | Phase Change - Marketed | Launched for Hypoxic respiratory failure in Japan (Inhalation) Updated 19 Aug 2010 |
| 31 Oct 2009 | Phase Change - Marketed | Launched for Hypoxic respiratory failure in Malaysia (Inhalation) Updated 19 Aug 2010 |
| 31 Oct 2009 | Phase Change - Marketed | Launched for Hypoxic respiratory failure in Singapore (Inhalation) Updated 19 Aug 2010 |
| 25 Oct 2008 | Scientific Update | Efficacy data from a Phase-III trial in Bronchopulmonary dysplasia released by Ikaria Holdings [11] Updated 01 Nov 2008 |
| 21 Jul 2008 | Phase Change - Marketed | Launched for Hypoxic respiratory failure in Australia (Inhalation) Updated 10 Feb 2009 |
| 21 Jul 2008 | Phase Change - Registered | Registered for Hypoxic respiratory failure in Japan (Inhalation) Updated 10 Feb 2009 |
| 21 Jul 2008 | Regulatory Status | Nitric oxide inhalation - Ikaria Holdings received Orphan Drug status for Hypoxic respiratory failure in Japan Updated 10 Feb 2009 |
| 23 Jun 2008 | Regulatory Status | Japan's Council on Drugs and Food Sanitation recommends approval of nitric oxide inhalation for newborn children with hypoxic respiratory failure in Japan Updated 23 Jun 2008 |
| 18 Jun 2008 | Phase Change - Registered | Registered for Hypoxic respiratory failure in Singapore (Inhalation) Updated 10 Feb 2009 |
| 30 Apr 2008 | Phase Change - II/III | Phase-II/III clinical trials in Reperfusion injury in USA (Inhalation) Updated 01 Nov 2008 |
| 31 Jan 2008 | Phase Change - III | Phase-III clinical trials in Bronchopulmonary dysplasia in USA (Inhalation) Updated 01 Nov 2008 |
| 30 Nov 2007 | Phase Change - Marketed | Launched for Hypoxic respiratory failure in Latin America (Inhalation) Updated 30 Nov 2007 |
| 28 Nov 2007 | Phase Change - Registered | Registered for Hypoxic respiratory failure in Australia (Inhalation) Updated 30 Nov 2007 |
| 27 Nov 2007 | Regulatory Status | Nitric oxide inhalation - Ikaria Holdings received Orphan Drug status for Hypoxic respiratory failure in Australia Updated 10 Feb 2009 |
| 01 Oct 2007 | Company Involvement | INO Therapeutics has merged with Ikaria to form Ikaria Holdings Updated 01 Oct 2007 |
| 30 Sep 2005 | Phase Change - Marketed | Launched for Hypoxic respiratory failure in Canada (Inhalation) Updated 30 Nov 2007 |
| 01 May 2005 | Phase Change - III | Phase-III clinical trials in Bronchopulmonary dysplasia (In neonates, Prevention) in Belgium, Finland, France, Germany, Italy, Netherlands, Spain, Sweden, United Kingdom (Inhalation) (NCT00551642) Updated 26 Dec 2016 |
| 30 Sep 2004 | Phase Change - III | Phase-III clinical trials in Pulmonary arterial hypertension (Combination therapy, In adolescents, In children, In infants) in Netherlands, France, USA (Inhalation) (NCT00626028) Updated 26 Apr 2022 |
| 21 Jul 2004 | Phase Change - III | Phase-III clinical trials in Pulmonary arterial hypertension (Combination therapy, In infants, In children, In adolescents) in Spain and United Kingdom (Inhalation) (EudraCT2004-000625-30) Updated 06 Sep 2019 |
| 17 Apr 2004 | Company Involvement | GE Medical Systems has merged with Amersham to form GE Healthcare Updated 17 Apr 2004 |
| 30 Dec 2003 | Scientific Update | A study has been added to the Respiratory Tract Disorders therapeutic trials section [31] Updated 30 Dec 2003 |
| 30 Jun 2003 | Phase Change - II | Phase-II clinical trials in Congestive heart failure in Germany (Inhalation) Updated 29 Dec 2011 |
| 30 Jun 2003 | Phase Change - II | Phase-II clinical trials in Congestive heart failure in USA (Inhalation) Updated 30 Nov 2007 |
| 31 May 2003 | Phase Change - III | Phase-III clinical trials in Reperfusion injury in USA (Inhalation) Updated 30 Nov 2007 |
| 31 Dec 2002 | Phase Change - Preregistration | Preregistration for Hypoxic respiratory failure in Japan (Inhalation) Updated 30 Dec 2003 |
| 04 Dec 2002 | Scientific Update | A cost-effectiveness study has been added to the Respiratory Tract Disorders therapeutic trials section [32] Updated 04 Dec 2002 |
| 01 May 2002 | Trial Update | Mallinckrodt initiates a pilot phase I/II trial for Respiratory disorders (In neonates) in USA (Inhalation) (NCT00041548) Updated 02 May 2016 |
| 31 Dec 2001 | Phase Change - Marketed | Launched for Hypoxic respiratory failure (In neonates) in Czech Republic, Netherlands, Ireland, Spain, Portugal, Poland, Italy, Germany, Switzerland, Sweden, Greece, France and Denmark (Inhalation) Updated 10 Jun 2015 |
| 31 Dec 2001 | Phase Change - Marketed | Launched for Hypoxic respiratory failure in European Union (Inhalation) Updated 30 Dec 2003 |
| 31 Aug 2001 | Phase Change - Registered | Registered for Hypoxic respiratory failure in European Union (Inhalation) Updated 31 Aug 2001 |
| 23 Nov 2000 | Other | Sumitomo Seika Chemicals and Air Water Inc. are licensees in Japan for INOmax® Updated 23 Nov 2000 |
| 15 Mar 2000 | Scientific Update | A study in neonates with severe respiratory failure has been added to the Respiratory Tract Disorders therapeutic trials section [33] Updated 15 Mar 2000 |
| 01 Feb 2000 | Phase Change - Marketed | Launched for Hypoxic respiratory failure in USA (Inhalation) Updated 01 Feb 2000 |
| 31 Dec 1999 | Phase Change | Investigation in Adult respiratory distress syndrome in USA (Inhalation) Updated 31 Dec 1999 |
| 31 Dec 1999 | Phase Change | Investigation in Pulmonary hypertension in USA (Inhalation) Updated 31 Dec 1999 |
| 31 Dec 1999 | Phase Change - Registered | Registered for Hypoxic respiratory failure in USA (Inhalation) Updated 31 Dec 1999 |
| 18 Aug 1998 | Other | Nitric oxide inhaled - Ohmeda is now called Nitric oxide inhalation - Datex-Ohmeda/INO Therapeutics Updated 18 Aug 1998 |
| 06 Nov 1997 | Phase Change - Preregistration | Preregistration for Respiratory tract disorders in USA (Inhalation) Updated 06 Nov 1997 |
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