Phase 2 Study to Evaluate the Efficacy and Safety of Inhaled Nitric Oxide Therapy in Patients With Severe Right Heart Failure Associated With Pulmonary Hypertension　― Protocol for the PHiNO Study ―

Abstract

Background: Acute right heart failure (RHF) is a syndrome characterized by sudden right ventricular dysfunction leading to systemic hypoperfusion, which carries a poor prognosis, particularly in patients with pulmonary hypertension (PH). Early reduction of pulmonary vascular resistance (PVR) is crucial for improving RHF and reducing acute mortality. Compared with pulmonary vasodilators approved for pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH), inhaled nitric oxide (iNO) therapy has the advantages of being fast acting, an excellent selective pulmonary vasodilation, and has less effect on systemic blood pressure.

Methods and Results: We describe a phase II, investigator-initiated, randomized, open-label trial (Japan Registry of Clinical Trials jRCT2051220042) to evaluate the efficacy and safety of iNO therapy (INOflo® for inhalation 800 ppm), as an acute-phase treatment for severe RHF associated with PAH or CTEPH over a 1-week course. Thirty patients will be enrolled and randomized to receive the study drug, or not, in addition to conventional therapy. The primary endpoint is the change in PVR from baseline to 30 min after the start of inhalation, measured using right heart catheterization. Secondary endpoints include changes in hemodynamic parameters, arterial blood tests, and echocardiography findings, and the safety of iNO therapy, assessed through blood methemoglobin concentration, blood pressure, and adverse events.

Conclusions: iNO therapy is expected to play a significant role in rapidly improving acute severe RHF associated with PH.

Acute right heart failure (RHF) is a syndrome characterized by the sudden loss of right ventricular function, resulting in systemic hypoperfusion.^1,2 Acute RHF results from various causes, including acute left ventricular failure, acute pulmonary embolism, acute respiratory distress syndrome, and chronic pulmonary hypertension (PH), and is a heterogeneous syndrome; therefore, its varied etiologies require individualized treatment.^1,2 The in-hospital mortality rate of patients with acute RHF ranges from 5% to 17%, but RHF associated with PH – such as acute decompensation of chronic PH, first visit for PH, decompensation of undiagnosed PH, or embolism – has a particularly poor prognosis.^1,3,4 Acute severe RHF, classified as Word Health Organization functional class (WHO-FC) 3 or higher, can be triggered by infections, pregnancy, or other events in PH patients, making management challenging due to the limited treatment options.

The following treatment approaches are recommended to be performed simultaneously and rapidly for acute severe RHF associated with PH: (1) treatment of the triggering factors, such as infection, arrhythmias, pulmonary embolism, and administration of supportive therapy; (2) optimization of fluid status, removal of excess fluids using diuretics or hemofiltration; (3) reduction of right ventricular afterload using pulmonary vasodilators; (4) optimization of cardiac output (CO) using inotropes such as dobutamine and milrinone; and (5) optimization of blood pressure using vasopressors such as norepinephrine and vasopressin.⁵ Among these strategies, reducing the right ventricular afterload is a specific and important treatment for patients with PH. Pulmonary arterial hypertension (PAH) is characterized by increased proliferation of pulmonary artery smooth muscle cells, endothelial cells, and myofibroblasts, and the efficacy of pulmonary vasodilators has been reported.^6,7 Inhaled nitric oxide (iNO) therapy has been reported to be effective as an additional treatment during pregnancy and childbirth or during acute exacerbations in patients with drug-treated PAH.^8–10 Chronic thromboembolic PH (CTEPH) has been implicated in the same microarterial lesions as PAH, and the efficacy of pulmonary vasodilators such as riociguat and selexipag and iNO therapy has been demonstraited.^9–13 Pulmonary vasodilators are potential treatments for acute severe RHF associated with PH but carry risks such as lowering systemic blood pressure and requiring gradual dose escalation. iNO therapy reduces right ventricular afterload similar to vasodilators and improves hemodynamics in acute RHF.^9,14 iNO therapy may be preferable as an acute treatment due to its rapid action, selective pulmonary vasodilation, and minimal systemic blood pressure impact.^15,16 iNO therapy is expected to improve PH in the acute phase of RHF, providing a safe bridge to subsequent chronic phase treatment using oral or intravenous treatment.

In Japan, INOflo® for inhalation 800 ppm (INOflo; Mallinckrodt Manufacturing LLC, NJ, USA; Air Water Medical Inc.,Tokyo, Japan) has been reimbursable as iNO therapy for PH in the following 2 cases: (1) improvement of hypoxic respiratory failure with PH in neonates since 2008; and (2) improvement of PH in the perioperative period of cardiac surgery since 2015. However, it is not approved for acute-phase treatment of adult PH-associated RHF outside of perioperative settings.

This study aims to expand the indication of INOflo to include improving severe RHF associated with PH. Here, we describe an ongoing phase 2 trial evaluating the efficacy and safety of iNO therapy in patients with severe RHF associated with PH (Japan Registry of Clinical Trials jRCT2051220042).

Methods

Study Design

The PHiNO study is a phase II, investigator-initiated, randomized, open-label, parallel-group trial designed to evaluate the efficacy and safety of iNO therapy (INOflo) as an acute-phase treatment in patients with severe RHF associated with PH over a 1-week treatment course. This study is being conducted at the National Cerebral and Cardiovascular Center (NCVC), a leading center for PH in Japan.

Ethics Approval

This study has been approved by the Institutional Review Board of the NCVC (#1203). All procedures comply with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) ‘Guideline for Good Clinical Practice’ and its revised ministerial ordinances and operational notifications in Japan. The study is being conducted in accordance with the Declaration of Helsinki (1964) and the Ministerial Ordinance Concerning Standards for the Conduct of Clinical Trials of Pharmaceuticals. Written informed consent is obtained from all patients before enrollment. If the informed consent form is revised, study physicians re-explain the procedure, update the consent form, and obtain the study participant’s voluntary consent for continued participation.

Enrollment

From October 31, 2022, to December 31, 2025, 30 patients with severe RHF associated with PH will have been recruited at the NCVC in Japan. The key inclusion and exclusion criteria are detailed in Table 1. We defined severe RHF as WHO-FC 3 or higher, with fluid retention (evidenced by physical examination or echocardiography signs of congestion) and low CO (cardiac index <2.5 L/min/m² or the need for inotropic support). Eligible participants are required to have a confirmed diagnosis of PAH or CTEPH with right heart catheterization (RHC) findings, including a mean pulmonary artery pressure ≥25 mmHg at rest, pulmonary artery wedge pressure or left ventricular end-diastolic pressure ≤15 mmHg, and PVR >3 Wood units. We are excluding patients with cardiac conditions who are entirely dependent on a right–left shunt for life support (Eisenmenger’s syndrome), those with PAH eligible for calcium channel blocker (CCB) treatment, and patients with pulmonary veno-occlusive disease (PVOD) or pulmonary capillary hemangiomatosis (PCH). INOflo is contraindicated for patients with cardiac disorders solely depending on right-to-left shunting for sustaining life. Patients with PVOD and PCH are excluded due to the risk of worsening hemodynamics with NO inhalation. All PAH patients have undergone acute vasoreactivity testing (AVT) during RHC, and those who tested positive for AVT are considered eligible for CCB treatment. These patients are excluded owing to the significant impact on the efficacy of iNO therapy compared with conventional treatment.

Table 1.

Eligibility Criteria

Inclusion criteria

Patients aged at least 18 years at the time consent is obtained

Patients with PAH or CTEPH

Patients who meet all of the following criteria for RHC:

mPAP ≥25 mmHg

PAWP or LVEDP ≤15 mmHg

PVR >3 Wood units

WHO-FC III or IV

Patients with fluid retention (fluid retention on physical examination or echocardiography evidence of congestion), low cardiac output (CI <2.5 L/min/m2 or in need of inotropic drugs)

Patients with written consent from the patient

Exclusion criteria

Patients with cardiac disease (Eisenmenger’s syndrome) who are completely dependent on a right-left shunt for life support

Patients with PAH who are eligible for calcium channel blockers

Patients with pulmonary veno-occlusive disease

Patients with pulmonary capillary haemangiomatosis

Patients with pulmonary hypertension due to left heart disease

Patients with pulmonary hypertension due to pulmonary disease and/or hypoxia

Patients with pulmonary hypertension with unclear and/or multifactorial mechanisms

Patients with a history of hypersensitivity to the investigational drug

Pregnant or lactating women, or patients who cannot consent to contraception during the study

Patients who plan to participate in other clinical trials or interventional studies during the period of this study

Patients who are judged by the investigator or subinvestigator to be inappropriate to participate in this clinical trial for other reasons

CI, cardiac index; CTEPH, chronic thromboembolic pulmonary hypertension; LVEDP, left ventricular end-diastolic pressure; mPAP, mean pulmonary artery pressure; PAH, pulmonary arterial hypertension; PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; RHC, right heart catheterization; WFO-FC, World Health Organization functional class.

The PHiNO study scheme and schedule are shown in Figures 1 and 2, respectively. Study participants undergo blood tests, arterial blood gas analysis, echocardiography, chest X-ray, and RHC, and are immediately assessed for eligibility. Computed tomography and perfusion scintigraphy data within 365 days prior to enrollment are analyzed to confirm the diagnosis of PAH or CTEPH. After RHC, eligible participants are randomized in a 1 : 1 ratio to either the iNO therapy with conventional treatment group or the conventional treatment group, using Pocock and Simon’s minimization method,¹⁷ with ‘disease <CTEPH/PAH>’ as a prognostic factor. Participants are enrolled and assigned using an electronic data capture system.

Figure 1.

Study schema. iNO, inhaled nitric oxide; PVR, pulmonary vascular resistance; RHC, right heart catheterization.

Figure 2.

Study schedule. BNP, B-type natriuretic peptide; Met-Hb, methemoglobin; RHC, right heart catheterization; WHO-FC, Word Health Organization functional class.

Intervention

The study drug, INOflo, is provided by Mallinckrodt Manufacturing LLC (NJ, USA) and Air Water Medical Inc. (Tokyo, Japan). Patients assigned to the iNO therapy with conventional treatment group will begin inhalation of INOflo at a concentration of 20 ppm. In addition to intubation, patients are provided with a non-intubated oxygen source, such as nasal high-flow oxygen, nasal continuous positive airway pressure, or a face mask. Released NO is oxidized to NO₂, which is harmful at high concentrations.¹⁸ Hence, it is necessary to consider the desired NO₂ levels and the surrounding environment for iNO therapy. In addition to measuring the desired NO₂ with the administration device, the patient is managed in a private room with a simple negative pressure device attached to the ceiling, and the concentration is continuously monitored during the study. During iNO therapy, methemoglobin (Met-Hb) concentration is also monitored. If the Met-Hb concentration remains below 2%, the dose is increased by 10 ppm every 5 min up to a maximum concentration of 40 ppm. PVR is evaluated 30 min after the start of inhalation, and inhalation therapy continues until day 7. The dosing regimen, dose reduction/withdrawal criteria, and discontinuation criteria for INOflo are based on the pharmaceutical product’s form (provided in the Supplementary File).

The standard treatment is administered according to the patient’s condition, following the Guidelines for the Treatment of Pulmonary Hypertension (2017).³ Standard treatment is initiated when feasible after the evaluation of PVR, which is evaluated 30 min after registration and assignment, in both groups.

Study Endpoints

The primary and secondary endpoints of the PHiNO study are summarized in Table 2. The primary endpoint is change in PVR as determined by RHC from baseline to 30 min after the start of inhalation. The secondary endpoints included changes in hemodynamic parameters, arterial blood test findings, echocardiography findings, and the safety of iNO therapy. Safety is assessed by monitoring Met-Hb concentration, blood pressure, and adverse events throughout the observation period. Details are described in the Supplementary File.

Table 2.

Objectives and Endpoints

Objectives

Primary: Evaluate the acute efficacy of iNO therapy in subjects with severe RHF associated with PH

Secondary: Evaluate the efficacy and the safety of iNO therapy in this population

Endpoints

Primary: Change of PVR from baseline to 30 min later

Secondary:

Change of hemodynamic parameters, arterial blood test findings, echocardiography findings, and blood test findings

Met-Hb concentration, blood pressure, and adverse events

iNO, inhaled nitric oxide; Met-Hb, methemoglobin; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RHF, right heart failure.

Sample Size

Given the rarity of patients with severe RHF associated with PH, the study aims to enroll a maximum of 30 patients, based on the number treated annually at NCVC. Under a conservative scenario, where the mean difference between groups for the primary endpoint is 1.2 with a standard deviation of 0.4, this sample size provides a power greater than 99.9% to detect differences. Even with a standard deviation of 1.2, the power is still 75.3%. Therefore, enrolling 30 patients was considered appropriate for this trial.

Statistical Analysis

Statistical analyses will be conducted according to the intention-to-treat (ITT) principle. For the primary endpoint, the mean difference between treatment groups will be estimated with a 95% confidence interval and tested at the 5% significance level using analysis of covariance, with baseline PVR as a covariate. Per-protocol analyses will be performed to support the conclusions drawn from the ITT analysis. Subgroup analyses will explore the differential effects of interventions based on factors such as disease type (CTEPH vs. PAH). Other efficacy endpoints will be assessed by estimating the change from baseline within each treatment group. Safety data will be analyzed descriptively for the treated set, which includes all randomized patients who receive the study treatments. The detailed statistical analysis plan will be prespecified and finalized prior to the database lock.

Discussion

iNO may be an ideal pulmonary vasodilator for the acute phase of severe RHF associated with PH. Recently, iNO has also been recently reported as an effective treatment for adults with PH-associated RHF.⁹ The study drug, INOflo is currently reimbursable in several countries for improving hypoxic respiratory failure associated with PH in neonates (such as Japan, USA, and the EU) and for managing PH during the perioperative period of cardiac surgery (such as Japan and the EU). However, this drug is not currently approved for the acute-phase treatment of PH-associated RHF outside the perioperative period in adult patients in any country.

PH-associated RHF has a poor prognosis, and patients with PH can develop acute severe RHF due to triggers such as infection, pregnancy, or other events. However, current treatment options are limited in number and effectiveness. Early reduction of right ventricular afterload and PVR may improve the prognosis for patients with severe RHF associated with PH. In unstable hemodynamic conditions during acute exacerbations, administering approved pulmonary vasodilators for PAH is often challenging due to their systemic effects. While extracorporeal membrane oxygenation can be used to reduce right heart preload in RHF, it is highly invasive and poses risks of complications such as infection. Therefore, there is a pressing need for new treatment options for patients experiencing acute deterioration. In this context, iNO therapy emerges as a potentially safe and effective treatment option due to its key features: (1) immediate effectiveness; (2) selective pulmonary vasodilation; (3) improvement in ventilation/perfusion mismatch; and (4) reduction of intrapulmonary shunting.

The significance of this study lies in the potential of iNO therapy to become a crucial treatment for severe RHF associated with PH, a rare and challenging condition. Establishing iNO as a standard treatment modality for RHF could significantly improve patient outcomes.

Acknowledgments

We thank Editage (www.editage.jp) for English language editing.

Disclosures

T.O. is a member of Circulation Reports’ Editorial Team. T.O. reports receiving lecture fees from Nippon Shinyaku Co., Janssen Pharmaceutical K.K., Bayer Yakuhin, Ltd, and Mochida Pharmaceutical Co., Ltd, outside of the submitted work. The other authors declare no conflicts of interest.

Sources of Funding

This study is supported by the Japan Agency for Medical Research and Development and Mallinckrodt Manufacturing LLC.

Author Contributions

T.O. is the guarantor and is responsible for the overall content of the study.

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circrep.CR-24-0125

References

• 1.   Harjola VP, Mebazaa A, Celutkiene J, Bettex D, Bueno H, Chioncel O, et al. Contemporary management of acute right ventricular failure: A statement from the Heart Failure Association and the Working Group on Pulmonary Circulation and Right Ventricular Function of the European Society of Cardiology. Eur J Heart Fail 2016; 18: 226–241.
• 2.   Konstam MA, Kiernan MS, Bernstein D, Bozkurt B, Jacob M, Kapur NK, et al. Evaluation and management of right-sided heart failure: A scientific statement from the American Heart Association. Circulation 2018; 137: e578–e622.
• 3.   Fukuda K, Date H, Doi S, Fukumoto Y, Fukushima N, Hatano M, et al. Guidelines for the treatment of pulmonary hypertension (JCS 2017/JPCPHS 2017). Circ J 2019; 83: 842–945.
• 4.   Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, et al. 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2022; 43: 3618–3731.
• 5.   Hoeper MM, Benza RL, Corris P, de Perrot M, Fadel E, Keogh AM, et al. Intensive care, right ventricular support and lung transplantation in patients with pulmonary hypertension. Eur Respir J 2019; 53: 1801906.
• 6.   Sitbon O, Jais X, Savale L, Cottin V, Bergot E, Macari EA, et al. Upfront triple combination therapy in pulmonary arterial hypertension: A pilot study. Eur Respir J 2014; 43: 1691–1697.
• 7.   Tamura Y, Kumamaru H, Satoh T, Miyata H, Ogawa A, Tanabe N, et al. Effectiveness and outcome of pulmonary arterial hypertension-specific therapy in Japanese patients with pulmonary arterial hypertension. Circ J 2017; 82: 275–282.
• 8.   Bhorade S, Christenson J, O’Connor M, Lavoie A, Pohlman A, Hall JB. Response to inhaled nitric oxide in patients with acute right heart syndrome. Am J Respir Crit Care Med 1999; 159: 571–579.
• 9.   Tremblay JA, Couture EJ, Albert M, Beaubien-Souligny W, Elmi-Sarabi M, Lamarche Y, et al. Noninvasive administration of inhaled nitric oxide and its hemodynamic effects in patients with acute right ventricular dysfunction. J Cardiothorac Vasc Anesth 2019; 33: 642–647.
• 10.   Kitamukai O, Sakuma M, Takahashi T, Nawata J, Ikeda J, Shirato K. Hemodynamic effects of inhaled nitric oxide using pulse delivery and continuous delivery systems in pulmonary hypertension. Intern Med 2002; 41: 429–434.
• 11.   Perez-Penate GM, Julia-Serda G, Ojeda-Betancort N, Garcia-Quintana A, Pulido-Duque J, Rodriguez-Perez A, et al. Long-term inhaled nitric oxide plus phosphodiesterase 5 inhibitors for severe pulmonary hypertension. J Heart Lung Transplant 2008; 27: 1326–1332.
• 12.   Ogo T, Shimokawahara H, Kinoshita H, Sakao S, Abe K, Matoba S, et al. Selexipag for the treatment of chronic thromboembolic pulmonary hypertension. Eur Respir J 2022; 60: 2101694.
• 13.   Simonneau G, D’Armini AM, Ghofrani HA, Grimminger F, Hoeper MM, Jansa P, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: A long-term extension study (CHEST-2). Eur Respir J 2015; 45: 1293–1302.
• 14.   Perez-Penate GM, Julia-Serda G, Galvan-Fernandez H, Aleman-Segura D, Leon-Marrero F, Garcia-Quintana A, et al. Safety of inhaled nitric oxide withdrawal in severe chronic pulmonary hypertension. Pulm Circ 2024; 14: e12344.
• 15.   Frostell CG, Blomqvist H, Hedenstierna G, Lundberg J, Zapol WM. Inhaled nitric oxide selectively reverses human hypoxic pulmonary vasoconstriction without causing systemic vasodilation. Anesthesiology 1993; 78: 427–435.
• 16.   Griffiths MJ, Evans TW. Inhaled nitric oxide therapy in adults. N Engl J Med 2005; 353: 2683–2695.
• 17.   Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 1975; 31: 103–115.
• 18.   Hashimoto K, Hashimoto A, Kishimoto M, Sugawara K, Funahashi H, Nakano K, et al. Operator safety zone during the nitric inhalation vasoreactivity test for pulmonary hypertension patients. Adv Biomed Eng 2017; 6: 88–94.