TITLE:
`
`DRUG: (cid:9)
`
`INDICATION: (cid:9)
`
`SPONSOR: (cid:9)
`
`APPENDIX 3
`
`Comparison of Supplemental Oxygen and
`Nitric Oxide for Inhalation Plus Oxygen in
`the Evaluation of the Reactivity of the
`Pulmonary Vasculature During Acute
`Pulmonary Vasodilator Testing
`
`INOmax® (nitric oxide) for inhalation
`
`Diagnostic Use
`
`INO Therapeutics
`6 Route 173
`Clinton, NJ 08809
`
`PROTOCOL: (cid:9)
`
`INOT22
`
`DRUG DEVELOPMENT PHASE:
`
`Phase 3
`
`VERSION: (cid:9)
`
`Amendment II
`
`DOCUMENT DATE:
`
`STUDY INITIATION:
`
`STUDY DURATION: (cid:9)
`
`2 years
`
`MEDICAL MONITOR: (cid:9)
`
`REGULATORY CONTACT: (cid:9)
`
`STUDY CONTACT:
`
`GCP:
`
`Version: Amendment II
`
`James S. Baldassarre, MD
`Senior Director of Research & Development
`Phone (908) 238-6363
`Fax (908) 238-6634
`
`Sandra Cottrell
`VP-Global Regulatory Affairs
`
`Mary Ellen Zamstein
`U.S. & Canadian Regulatory Affairs
`
`Jodee Newman, RN
`Project Leader
`Phone (908) 238-6317
`Fax (908) 238-6634
`
`These studies will be performed in compliance
`with good clinical practices (GCP) guidelines.
`All essential documents will be archived.
`
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`Protocol INOT22
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`2. SYNOPSIS
`
`Sponsor: NO Therapeutics, LLC
`
`Name of Finished Product: INOmax®
`(nitric oxide) for inhalation
`
`Name of Active Ingredient: Nitric Oxide
`for Inhalation
`
`Protocol Number: INOT22
`
`Title of Study: Comparison of Supplemental Oxygen and Nitric Oxide for Inhalation
`Plus Oxygen in the Evaluation of the Reactivity of the Pulmonary Vasculature During
`Acute Pulmonary Vasodilator Testing
`
`Investigators: Pr. Daniel Sidi, Dr. Alain Fraisse, Dr. Federico Larraya, Dr. Jose Luis
`Zunzunegui, Dr. Joaquin Jose Bartrons, Prof Dr. Rolf Berger, Dr. Alan Magee, Dr.
`Mary Mullen, Dr. Robyn Barst, et al. TBD
`
`Study Centers: Hopital Necker, Paris, France; CHU la Timone-Hopital d'enfants,
`Marseille, France; Hospital Matemo-Infantil XII de Octubre, Madrid, Spain; Hospital
`Gregorio Maranon, Madrid Spain; Hospital Sant Joan de Deu, Barcelona, Spain; Beatrix
`Children's Hospital, Univ. Hospital Groningen, Amsterdam, Netherlands; The Royal
`Brampton Hospital, London, UK; Boston Children's Hospital, Boston, MA, US;
`Columbia Presbyterian Hosptital, New York, NY, US, et al. TBD
`
`Study Period:
`
`Phase of development: III
`
`Objectives: Compare utility and side effects of oxygen versus nitric oxide for
`inhalation plus oxygen in determining pulmonary vasoreactivity.
`
`Methodology: An open, prospective, randomized, multi-center, controlled diagnostic
`trial.
`
`Number of patients planned: Enrollment will proceed until at least 25 patients per
`entry diagnosis and at least 150 patients have been enrolled.
`
`Anticipated duration of trial: 2 years
`
`Version: Amendment 11
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`Diagnosis and main criteria for inclusion: Patients between the ages of 4 weeks
`and eighteen years undergoing diagnostic right heart catheterization scheduled to include
`acute pulmonary vasodilation testing to assess pulmonary vasoreactivity. The expected
`population will be patients with:
`1) Idiopathic Pulmonary Arterial Hypertension
`2) Congenital heart disease with pulmonary hypertension;
`3) Cardiomyopathies;
`Patients who are either under general anesthesia or awake sedation will be included in
`this protocol. Patients will be stratified based on entry diagnosis.
`
`Test product, dose and mode of administration: Nitric oxide for inhalation 800
`ppm, administered at a dose of 80 ppm, nitric oxide for inhalation plus 100% 02 and
`100% 02, via facemask or endotracheal tube.
`
`Duration of treatment: 10 minutes of nitric oxide for inhalation at 80 ppm and 10
`minutes of 80 ppm nitric oxide for inhalation plus 100% 02, and 10 minutes of 100% 02;
`delivered via facemask or endotracheal tube.
`
`Criteria for evaluation:
`
`Primary endpoint:
`Number of patients receiving a combination of NO and 02 versus the number of patients
`receiving 02 alone that meet response criteria. The response criteria are as follows:
`Patients with Idiopathic Pulmonary Arterial Hypertension or patients with CHD who do
`not have an unrestricted shunt at the level of the ventricle or ductus arteriosus, response
`will be defined as:
`1) a decrease in PAPm > 20% and no decrease in cardiac index (within 5%)
`
`Patients with cardiomyopathy or patients with CHD who have an unrestricted shunt at the
`level of the ventricle or ductus arteriosus, response will be defined as:
`1) a decrease in PAPin > 20% and no decrease in cardiac index (within 5%)
`
`or
`
`2) a decrease in PVRI > 25% and no decrease in cardiac index (within 5%)
`
`Secondary endpoints:
`1) Number of patients receiving NO versus the number of patients receiving 02 that
`meet response criteria, as defined above.
`2) Number of patients receiving a combination of NO and 0, versus the number of
`
`Version: Amendment 11
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`patients receiving NO alone that meet response criteria, as defined above.
`
`3) PVRI, PAPm and Cardiac Index readings in Room Air versus NO alone, 02 alone
`and the combination of NO and 02
`
`4) Change in the ratio of PAPm to SAPm by treatment
`
`5) Survival at 1 year and 3 years by response
`
`Safety endpoints:
`I) Incidence and types of reported serious adverse events.
`
`2) Incidence and types of drug related adverse events.
`
`Version: .4mendinen1
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`Protocol 1NOT22
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`3. TABLE OF CONTENTS
`
`1. TITLE PAGE
`
`2. SYNOPSIS (cid:9)
`
`3. TABLE OF CONTENTS (cid:9)
`4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS (cid:9)
`
`5. ETHICS (cid:9)
`
`1
`
`4
`
`6
`
`11
`
`5.1 INSTITUTIONAL REVIEW BOARD (IRB) / INDEPENDENT ETHICS COMMITTEE (TEC) 11
`11
`5.2 ETHICAL CONDUCT OF THE STUDY (cid:9)
` 11
`5.3 PATIENT INFORMATION AND INFORMED CONSENT (cid:9)
`12
`5.4 FINANCIAL INTEREST STATEMENT (cid:9)
`
`6. INVESTIGATORS AND STUDY ADMINISTRATION STRUCTURE (cid:9)
`
`6.1 INVESTIGATORS (cid:9)
`6.2 ADMINISTRATIVE STRUCTURE (cid:9)
`6.3 STEERING COMMITTEE MEMBERS (cid:9)
`6.4 DATA SAFETY AND MONITORING BOARD MEMBERS (cid:9)
`
`7. INTRODUCTION (cid:9)
`
`8. STUDY OBJECTIVES (cid:9)
`
`9. INVESTIGATIONAL PLAN (cid:9)
`
`9.1 OVERALL STUDY PLAN AND DESIGN (cid:9)
`9.2 DISCUSSION OF STUDY DESIGN (cid:9)
`9.3 SELECTION OF STUDY POPULATION (cid:9)
`9.3.1 Inclusion Criteria (cid:9)
`9.3.2 Exclusion Criteria (cid:9)
`9.3.3 Removal of Patients from Therapy or Assessment (cid:9)
`9.4 TREATMENTS (cid:9)
`9.4.1 Treatments Administered (cid:9)
`9.4.2 Identity of Investigational Product (cid:9)
`9.4.3 Method ofAssigning Patients to Treatment Groups (cid:9)
`9.4.4 Selection of Doses in the Study (cid:9)
`9.4.5 Selection and Timing of Dose for Each Patient (cid:9)
`9.4.6 Treatment Group Assignment Blinding (cid:9)
`9.4. 7 Prior and Concomitant Therapy (cid:9)
`9.4.8 Treatment Compliance (cid:9)
`9.5 EFFICACY AND SAFETY VARIABLES (cid:9)
`9.5.1 Efficacy and Safety Schedule of Assessments (cid:9)
`9.5.2 Data Collection (cid:9)
`9.5.3 Ventilator Weaning and Extubation Strategy (cid:9)
`9.5.4 Appropriateness of Measurements (cid:9)
`9.5.5 Efficacy Variables (cid:9)
`9.5.6 Safety Variables (cid:9)
`
`Version: Amendment II
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`13
`
`13
`13
`13
`13
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`15
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`17
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`18
`
`18
` 19
` 19
` 19
`20
`20
`21
`21
`21
`22
`22
` 22
`22
`23
`23
`24
`24
`25
`31
`31
` 32
` 33
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`9.5.7 Drug Concentration Measurements (cid:9)
`9.6 DATA QUALITY ASSURANCE (cid:9)
`9.7 STATISTICAL METHODS PLANNED AND DE (cid:9)TERMINATION OF THE SAMPLE SIZE (cid:9)
`9.71 Sample Size Determination (cid:9)
`9.7.2 Interim Analysis (cid:9)
`9.8 CHANGES IN CONDUCT OF THE STUDY OR PLANNED ANALYSES (cid:9)
`
`10. ADMINISTRATIVE DETAILS (cid:9)
`10.1 ACCOUNTABILITY OF STUDY DRUG AND EQUIPMENT (cid:9)
`10.2 CASE REPORT FORMS (cid:9)
`10.3 INVESTIGATOR REQUIREMENTS (cid:9)
`10.4 RECORDING OF ADVERSE EVENTS (cid:9)
`10.4.1 Study Drug Relationship (cid:9)
`10.4.2 Serious Adverse Events (cid:9)
`10.4.3 Unexpected Adverse Events (cid:9)
`10.5 RECORDS RETENTION (cid:9)
`10.6 MONITORING AND AUDITS... (cid:9)
`10.7 AMENDMENTS TO "TIE PROTOCOL (cid:9)
`10.8 TERMINATION OF TRIAL (cid:9)
`
`11. REFERENCE LIST (cid:9)
`
`APPENDIX I. PROTOCOL VERSIONS (cid:9)
`
`APPENDIX 2. ANALYTIC PLAN (cid:9)
`
`A. ANALYSIS POPULATIONS (cid:9)
`B. ANALYSES OF BASELINE CHARACTERISTICS (cid:9)
`C. PRIMARY EFFICACY ANALYSIS (cid:9)
`D. SECONDARY EFFICACY ANALYSIS (cid:9)
`E. SAFETY ANALYSIS (cid:9)
`F. ADDITIONAL ANALYSES (cid:9)
`G. INTERIM ANALYSES (cid:9)
`APPENDIX 3. LISTING OF AMENDMENT 1 CHANGES (cid:9)
`
`Synopsis (cid:9)
`Page 19 Section 9.1 (cid:9)
`Section 9.5.1 Table 1 - Footnote (cid:9)
`9.5.5 Efficacy Variables (cid:9)
`10.4.2 Serious Adverse Events (cid:9)
`Appendix 2. Analytic Plan (cid:9)
`APPENDIX 4. LISTING OF AMENDMENT II CHANGES (cid:9)
`
`INVESTIGATOR AGREEMENT (cid:9)
`
`Version.- Amendment 11
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`33
`33
`33
`33
`34
`34
`
`35
`
`35
`35
`35
`36
`37
`38
`39
`39
`40
`40
`40
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`41
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`42
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`43
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`43
`43
`43
`44
`49
`50
`50
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`51
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`51
`52
`52
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`53
`54
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`55
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`60
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`4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
`
`Below is a list of abbreviations that are used in this clinical protocol.
`
`AE (cid:9)
`
`ABG (cid:9)
`
`Adverse events
`
`Arterial Blood Gas
`
`APVT (cid:9)
`
`Acute pulmonary vasodilator testing
`
`BSA (cid:9)
`
`CFR (cid:9)
`
`CHD (cid:9)
`
`CHF (cid:9)
`
`CI (cid:9)
`
`CO (cid:9)
`
`Body Surface Area
`
`Code of Federal Regulations
`
`Congenital heart disease
`
`Congestive heart failure
`
`Cardiac index
`
`Cardiac output
`
`CVPm (cid:9)
`
`Mean central venous pressure
`
`DAP (cid:9)
`
`Diastolic arterial blood pressure
`
`FDA 1572 (cid:9)
`
`Statement of Investigator
`
`Food and Drug Administration
`
`Fraction of inspired oxygen concentration
`
`Hemoglobin
`
`Heart rate
`
`Hypertension
`
`Investigational new drug (application)
`
`FDA (cid:9)
`
`Fi02 (cid:9)
`
`Hgb (cid:9)
`
`HR (cid:9)
`
`HTN (cid:9)
`
`IND (cid:9)
`
`Version: Amendment II
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`Protocol !NO T22
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`Page 7
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`INO (cid:9)
`
`IPAH (cid:9)
`
`IRB (cid:9)
`
`MAP (cid:9)
`
`Nitric Oxide for Inhalation
`
`Idiopathic Pulmonary Arterial Hypertension
`
`Institutional Review Board
`
`Mean arterial pressure
`
`MetHgb (cid:9)
`
`Methemoglobin
`
`mmHg (cid:9)
`
`Millimeters of mercury
`
`n (cid:9)
`
`N2 (cid:9)
`
`NO (cid:9)
`
`NO2 (cid:9)
`
`02 (cid:9)
`
`PAP (cid:9)
`
`Total number of patients (sample size)
`
`Nitrogen
`
`Nitric oxide
`
`Nitrogen dioxide
`
`Oxygen
`
`Pulmonary artery pressure
`
`PAPd (cid:9)
`
`Diastolic pulmonary artery pressure
`
`PAPm (cid:9)
`
`Mean pulmonary artery pressure
`
`PAPs (cid:9)
`
`Systolic pulmonary artery pressure
`
`PAWPrn (cid:9)
`
`Mean pulmonary artery wedge pressure
`
`PA Sat (cid:9)
`
`Pulmonary artery oxygen saturation
`
`PCWP (cid:9)
`
`Pulmonary capillary wedge pressure
`
`PH (cid:9)
`
`PPH (cid:9)
`
`Pulmonary hypertension
`
`Primary pulmonary hypertension
`
`Version: Amendment II
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`Protocol INOT22
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`ppm
`
`PVR
`
`PVRI
`
`Parts per million, by volume (40 ppm = 0.004% of the inhaled gas)
`
`Page 8
`
`Pulmonary vascular resistance
`
`Pulmonary vascular resistance index
`
`PV Sat
`
`Pulmonary vein oxygen saturation
`
`Sa02
`
`SAP
`
`Arterial oxygen percent saturation
`
`Systolic arterial blood pressure
`
`SAPm
`
`Mean Systolic arterial blood pressure
`
`SOP
`
`Sp02
`
`Sv02
`
`Standard operating procedure
`
`Oxygen saturation by pulse oximeter
`
`Mixed venous oxygen saturation
`
`Definition of Terms
`Below is a list of terms, and their respective definition, used in this report
`
`Body Surface Area (BSA)
`
`Cardiac Index (CI)
`
`Cardiac Output (CO)
`
`Version: Amendment H
`
`Uses the patient's height and weight to
`calculate the surface area.
`M2— SqRt[(cm*kg)/3600]
`Normal range: 2.5 to 4 Umin/m2
`The CI assess overall cardiac performance
`(eliminates body size as a variable).
`CI — CO/BSA
`
`Normal range: 4 to 8 Umin
`The cardiac output is the product of stroke
`volume and heart rate and can be measured by:
`thermo dilution if no shunts or the Fick
`equation (using measured VO2 for patients
`with our without shunts).
`
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`Protocol 1NOT22
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`Fick Equation:
`
`Page 9
`
`By measuring the amount of oxygen consumed
`by the tissues and the arterial-venous oxygen
`content difference, the cardiac output can be
`determined.
`Fick equation:
`CO = V02/min / Ca02 — Cv02
`V02/min = total tissue extraction of
`oxygen per minute
`Ca02 = arterial content of oxygen
`(mL/L)
`Cv02 = venous content oxygen (mL/L)
`(Ca02 may be Sa02 and Cv02 may be Sv02)
`
`Pulmonary Vascular Resistance (cid:9)
`(PVR): (cid:9)
`
`PVR (dynes/sec/cm5)
`(PAPm — PAWP)/CO
`
`Pulmonary Vascular Resistance
`Index (PVRI):
`
`Pulmonary Hypertension:
`
`Normal range: ( 2 units. The PVR is a useful
`parameter in assessing right ventricular
`afterload.
`(dynes/sec/cm' = Woods unit
`(Hg/L/min)/80)
`Normal range: ( 3u•rn2
`The PVRI utilizes the cardiac (CI) instead of
`the cardiac output (CO)
`
`PVRI = (PAPm — PAWP)/CI
`
`A condition characterized by elevated
`pulmonary artery pressure, associated with
`changes in the pulmonary vascular bed. PAPm
`is greater than 25 mmHg at rest or 30 mmHg
`during exercise.
`
`Version: Amendment 11
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`Reversible Pulmonary Hypertension Patients with Idiopathic Pulmonary Arterial
`Hypertension or patients with CHD who do not
`have an unrestricted shunt at the level of the
`ventricle or ductus arteriosus, response will be
`defined as:
`1) a decrease in PAPm > 20% and no
`decrease in cardiac index (within
`5%)
`
`Patients with cardiotnyopathy or patients with
`CHD who have an unrestricted shunt at the
`level of the ventricle or ductus arteriosus,
`response will be defined as:
`1) a decrease in PAPm > 20% and no
`decrease in cardiac index (within 5%)
`or
`
`2) a decrease in PVRI > 25% and no
`decrease in cardiac index (within 5%)
`
`Version: Amendment II
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`5. ETHICS
`
`5.1 Institutional Review Board (IRB) /Independent Ethics Committee (IEC)
`
`The protocols and local Informed Consent Forms must be reviewed and approved by
`
`each of the participating institutions' Institutional Review Board (IRB) I Independent
`
`Ethics Committee (IEC) prior to the initiation of patient accrual. The IRB/IEC must be
`
`notified of all subsequent protocol amendments. In addition, progress reports will be
`
`submitted to the IRB/IEC by the investigator as indicated by IRB/IEC' s guidelines. Each
`
`Institutional Review Board / Independent Ethics Committee must meet the United States
`
`Food and Drug Administration's (FDA's) and/or ICH requirements for composition,
`
`documentation, and operational procedures.
`
`The Investigator shall provide the Sponsor with the IRB/JEC's written notification of
`
`approval along with the IRB/IEC membership list and/or statement that the IRB/IEC
`
`operates in accordance with GCPs.
`
`5.2 Ethical Conduct of the Study
`
`The study will be conducted in accordance with the principles that have their origins in
`
`the Declaration of Helsinki, as well as International Conference on Harmonization Good
`
`Clinical Practices Guidelines (ICH GCP) and applicable regulatory requirements.
`
`5.3 Patient Information and Informed Consent
`
`The informed consent must contain all elements required by the FDA under 21 CFR part
`
`50 and/or ICH Guidance for Good Clinical Practice — E6 section 4.8 as well as any other
`
`elements required by local and institutional policies. All patients, (or legally authorized
`
`representative) must provide written consent after having had adequate time to consider
`
`their participation in the study. Consent must be obtained prior to any protocol related
`
`procedures that are not part of the patient's normal care. Written documentation of
`
`consent must be provided via the signature page. The patient or their legal representative
`
`must receive a signed copy of the consent form according to ICH GCP guidelines. The
`
`exact definition of legal representative should be determined for a hospital by its
`
`Version: Amendment II
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`Institutional Review Board / Independent Ethics Committee in compliance with local and
`
`state statutes.
`
`5.4 Financial Interest Statement
`
`In anticipation of utilizing this study for US regulatory submission, each investigator will
`
`complete and submit a Financial Interest Disclosure statement detailing all financial
`
`involvement with the Sponsor (including other research grants, stock, consultation fees,
`
`etc.) as required by FDA 21 CFR 54.4.
`
`Version: Amendment II
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`6. INVESTIGATORS AND STUDY ADMINISTRATION
`
`STRUCTURE
`
`6.1 Investigators
`
`Approximately 18 sites will participate in the trial with an expected total enrollment of a
`
`minimum of 150 patients (approximately 9 patients per site).
`
`6.2 Administrative Structure
`
`This study was established by the WO Therapeutics (the sponsor). A steering committee
`
`will review the contents of the protocol and subsequent amendments, monitor the
`
`progress of the trial, and provide recommendations to the sponsor on changes in the
`
`procedures and conduct of the trial.
`
`6.3 Steering Committee Members
`
`David Wessel, MD
`
`Boston Children's Hospital, Massachusetts,
`
`USA
`
`Robyn Barst, MD
`
`Columbia Presbyterian Hospital, New
`
`Duncan Macrae, MD
`
`Royal Brompton Hospital, London,
`
`England
`
`York, USA
`
`6.4 Data Safety and Monitoring Board Members
`
`The NIH and many other institutions require that the study protocol specify a plan for the
`
`data and safety monitoring of the trial. Typically, the level of oversight is determined by
`
`the risks, complexity and duration of the proposed investigation, and the plan must be
`
`approved by the appropriate IRBs.
`
`DSIVIBs have not been commonly established for short-term studies of interventions to
`
`relieve symptoms or to confirm diagnoses. Because the primary endpoints of such studies
`
`are not serious irreversible events, as in a major outcome study, the ethical issues for
`
`Version: Amendment II
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`monitoring are different. Early termination for effectiveness is rarely appropriate in such
`
`studies.
`
`Given the nature of the proposed investigation, the very short duration of exposure, the
`
`endpoints being studied, the number of patients and the duration of treatment, no interim
`
`analysis for efficacy will be conducted. Although the adverse event profile of inhaled NO
`
`has been well characterized in newborn infants, and to a lesser extent in the target
`
`population for this investigation, all possible risks cannot be predicted with certainty. To
`
`ensure the well being of patients enrolled in the trial, safety of all patients will be
`
`monitored on an ongoing basis. All adverse events and serious adverse events will be
`
`reviewed with the steering committee on a regular basis, and will be reported to the
`
`appropriate health authorities, and IRBs/lEC as per ICH GCP and as required by local
`
`regulations.
`
`Version: Amendment 11
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`Protocol INOT22
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`Page 15
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`7. INTRODUCTION
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`Pulmonary hypertension (PH) is a condition characterized by elevated pulmonary artery
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`pressures. Pulmonary hypertension may be idiopathic (i.e., without an identified cause),
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`or secondary to other disease processes (e.g. intrinsic heart or lung disease, collagen-
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`vascular disease, toxins or infections). In either case, it is associated with changes in the
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`pulmonary vascular bed such as vasoconstriction, vascular-wall remodeling and
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`thrombosis in situ resulting in increased vascular resistance. Abnormal production of
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`vasorelaxants and vasoconstrictors by the pulmonary endothelium may also play a role.
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`Endothelium-derived metabolite imbalances of the vasorelaxant prostacyclin and
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`vasoconstrictor thromboxane have been linked to PH, as have impaired synthesis of
`vasorelaxant nitric oxide and enhanced production of vasoconstrictor endothelin. i,2' 3
`Conventional medical treatments consisting of vasodilators, inotropes, anticoagulants,
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`diuretics or oxygen, are aimed at decreasing mean pulmonary artery pressure (PAPm)
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`and pulmonary vascular resistance (PVR). In patients with primary pulmonary
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`hypertension and symptomatic right ventricular failure, the median survival time is less
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`than 3 years. Surgical intervention such as heart or heart/lung transplantation may have to
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`be considered.9
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`For patients with right ventricular failure and lung disorders, the prognosis and course of
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`treatment are determined by acute pulmonary vasodilation testing (APVT). A reduction
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`in the mean pulmonary artery pressure (PAPm) and pulmonary vascular resistance (PVR)
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`with acute vasodilator treatment may be used to predict therapeutic efficacy of long-term
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`vasodilator medication. Acute pulmonary vasodilation testing is also used to evaluate
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`patients being considered for heart or heart/lung transplantation; elevated pulmonary
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`artery pressures and pulmonary vascular resistance place a strain on the right ventricle
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`leading to an increased risk of perioperative morbidity and mortality due to right heart
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`failure post heart transplant. 4' 5' 6
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`Version: Amenchnent II
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`IKARIA EXHIBIT 2002
`Praxair v. INO Therapeutics
`IPR2015-00524
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`(cid:9)
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`Protocol 1NOT22
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`Page 16
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`Administration of 100% supplemental 02 has been a standard in acute pulmonary
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`vasodilation testing, especially in pediatrics. However, some patients with reactive
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`pulmonary vasculature fail to respond to acute treatment with 100% supplemental 02. It
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`has been shown that combination testing with inhaled nitric oxide and oxygen provides
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`additional pulmonary vasodilation in patients with a reactive vascular bed.'
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`Nitric oxide (1NOmax6) is FDA approved for use in term newborns with pulmonary
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`hypertension and hypoxic respiratory failure in conjunction with mechanical ventilation
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`and other supportive measures to allow more blood to circulate in the lung, which helps
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`increase blood oxygen levels. (Investigators Brochure, INO Therapeutics) Nitric oxide
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`(NO), the endothelial-derived relaxing factor is a major physiologic regulator of
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`endothelial smooth muscle tone. In published studies, nitric oxide for inhalation has been
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`shown to reduce pulmonary artery pressures in patients with the adult respiratory distress
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`syndrome, chronic obstructive lung disease, pulmonary hypertension, and congenital
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`heart disease.45'7'8. In primary and secondary forms of pulmonary hypertension, studies
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`have shown that short-term nitric oxide for inhalation can selectively reduce both PAPm.
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`and PVR with minimal side effects4'7 Nitric oxide for inhalation has a short half-life. as
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`it quickly binds to hemoglobin within the pulmonary capillary lumen to form
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`methemoglobin, rendering it inactive, and the systemic vasodilation effects are minimal.
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`Potential risks of nitric oxide are rebound pulmonary hypertension, increased nitrogen
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`dioxide levels (a lung irritant), and methemoglobinemia. However, due to the short
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`duration of delivery in this study, it is unlikely these events will occur.
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`This study will test the hypothesis that a combination of inhaled nitric oxide and oxygen
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`is more sensitive than 100% supplemental oxygen alone in detecting pulmonary
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`vasoreactivity in patients with pulmonary hypertension.
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`Version: Amendment II
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`IKARIA EXHIBIT 2002
`Praxair v. INO Therapeutics
`IPR2015-00524
`
`(cid:9)
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`Protocol 1NOT22
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`Page 17
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`8. STUDY OBJECTIVES
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`The primary objective of the trial is to compare the number of patients with reversible
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`pulmonary hypertension (vasoreactivity) due to nitric oxide for inhalation and oxygen as
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`compared to 100% oxygen. The criteria for response are:
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`Patients with Idiopathic Pulmonary Arterial Hypertension or patients with CHD who do
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`not have an unrestricted shunt at the level of the ventricle or ductus arteriosus, response
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`will be defined as:
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`1) a decrease in PAPm > 20% and no decrease in cardiac index (within 5%)
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`Patients with cardiomyopathy or patients with CHD who have an unrestricted shunt at the
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`level of the ventricle or ductus arteriosus, response will be defined as:
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`1) a decrease in PAPm > 20% and no decrease in cardiac index (within 5%)
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`or
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`2) a decrease in PVRI > 25% and no decrease in cardiac index (within 5%)
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`The additional objectives of the trial are to compare the incidence and types of drug
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`related and serious adverse events as well as the number of patients with reversible
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`pulmonary hypertension due to nitric oxide for inhalation alone compared to 100%
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`oxygen and to oxygen with nitric oxide for inhalation.
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`Version: Amendment 11
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`IKARIA EXHIBIT 2002
`Praxair v. INO Therapeutics
`IPR2015-00524
`
`(cid:9)
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`Protocol /NO T22 (cid:9)
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`Page 18
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`9. INVESTIGATIONAL PLAN
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`9.1 Overall Study Plan and Design
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`This trial will be an open, prospective, multi-center, randomized, controlled trial that will
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`compare the utility and side effects of oxygen, nitric oxide and a combination of nitric
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`oxide and 02 in determining pulmonary reactivity. Each patient will be screened for
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`enrollment and fulfill all entry criteria described in section 9.3. Upon obtaining informed
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`consent approved by the institution's IRB/IEC, patients will be randomly assigned, using
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`a randomization table, to receive either nitric oxide for inhalation at 80 ppm or 100% 02
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`as their initial dose. The patients will either be under general anesthesia or awake
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`sedation (mild sedation). Once the study drug delivery equipment is prepared, baseline
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`data will be collected. Using a calibrated INOvent®, either nitric oxide for inhalation at
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`80 ppm or 100% 02 will be continuously administered to the patient for ten minutes
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`followed by data collection. The second dose will be the same as the first dose with the
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`addition of either 80 ppm nitric oxide for patients receiving 02, or 100% 02 for patients
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`receiving nitric oxide. This dose of 80 ppm NO and 100% 02 will be delivered for ten
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`minutes followed by data collection. There will be a ten-minute wash out period
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`following this administration. Baseline data will again be collected followed by a ten
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`minute administration of either 80 ppm nitric oxide or 100% 02. The study drug
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`delivered for this third administration will be the one that was not randomly assigned for
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`the initial study drug administration.
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`For each patient, NO2 levels will be monitored throughout the treatment period.
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`Treatment with study gas will be discontinued if NO2 levels exceed 3 ppm. Treatment
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`can also be discontinued at the discretion of the attending physician or following the
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`presentation of an adverse response to study drug. All adverse reactions will be recorded
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`while on study gas. Serious adverse events will continue to be recorded during the
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`treatment period through day 1 or discharge from the hospital, whichever comes first.
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`Qualification and reporting of all serious adverse events will occur as per the Code of
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`Federal Regulations (CFR) and ICH guidelines.
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`Version: Amendment II
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`IKARIA EXHIBIT 2002
`Praxair v. INO Therapeutics
`IPR2015-00524
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`Protocol INOT22
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`Page 19
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`One appointed clinical staff member at each site will be responsible for the set up and use
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`of the treatment gas delivery system. This individual may also be responsible for
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`maintaining drug accountability records for the sponsor.
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`Following the acute diagnostic procedure, a brief follow up contact will be made on each
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`patient to determine the vital status 1 year after the diagnostic procedure.
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`9.2 Discussion of Study Design
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`This is an open, randomized, prospective, multi-center, controlled trial to demonstrate
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`which diagnostic treatment is most capable of identifying patients with a reactive
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`pulmonary vascular bed. Each patient will serve as his/her own control, receiving all
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`three treatment regimens: 80 ppm nitric oxide for inhalation, 80 ppm nitric oxide and
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`100% 02, and the comparison treatment, 100% 02. Due to the short half-life of NO, a 10
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`minute washout period following the nitric oxide for inhalation and 100% 02 treatment
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`will allow sufficient time for elimination of the drug effect before the administration of
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`the comparison treatment.
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`9.3 Selection of Study Population
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`The expected population to be enrolled in this study will include patients with Idiopathic
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`Pulmonary Arterial Hypertension, CHO (with or without intravascular shunt) with
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`pulmonary hypertension, and cardiomyopathies. Patients will be stratified based on entry
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`diagnosis. Patients who are either under general anesthesia or awake sedation will be
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`included.
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`9.3.1 Inclusion Criteria
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`The patient must meet the following criteria:
`1. Have any one of the three disease categories:
`a. Idiopathic Pulmonary Arterial Hypertension
`i. PAPm > 25mmHg at rest, PCWP < 15rnmlig, and PVRI > 3 u•
`m2 or diagnosed clinically with no previous catheterization.
`b. CHD with pulmonary hypertension repaired and unrepaired,
`i. PAPm > 25mmHg at rest, and PVRI > 3 u• m2 or diagnosed
`clinically with no previous catheterization
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`Version: Amendment II
`
`IKARIA EXHIBIT 2002
`Praxair v. INO Therapeutics
`IPR2015-00524
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`(cid:9)
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`Protocol INOT22 (cid:9)
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`Page 20
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`c. Cardiomyopathy
`i. PAPm > 25mmHg at rest, and PVRI > 3 u•m2 or diagnosed
`clinically with no previous catheterization.
`2. Scheduled to undergo right heart catheterization to assess pulmonary
`vasoreactivity by acute pulmonary vasodilation testing.
`3. Males or females, ages 4 weeks to 18 years, inclusive
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`4. Signed IRB/IEC approved informed consent (and assent if applicable).
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`9.3.2 Exclusion Criteria
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`The patient will be excluded from enrollment if any of the following are true:
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`1. Focal pulmonary infiltrates on chest radiograph.
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`Diagnosed with severe obstructive or restrictive pulmonary disease that is
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`significantly contributing to the patient's pulmonary hypertension.
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`3. Received treatment with nitric oxide for inhalation within 30 days prior to study
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`initiation, are on other investigational medications, nitroglycerin, sodium
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`nitroprusside, sildenafil, other PDE-5 inhibitors, or prostacyclin.
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`4. Pregnant (urine HCG +).
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`5. Baseline PCWP > 20 mmHg
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`9.3.3 Removal of Patients from Therapy or Assessment
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`Study gas will be discontinued if NO2 levels exceed 3 ppm. Alarms on the INOvent®
`exist to alert clinical personnel when NO2 levels > 3 ppm. Treatment may also be
`discontinued if the patient (or legal representative) withdraws their consent or the
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`investigator deems it in the best medical interest of the patient.
`
`Version: Amendment II
`
`IKARIA EXHIBIT 2002
`Praxair v. INO Therapeutics
`IPR2015-00524
`
`

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`Protocol IN0T22
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`9.4 Treatments
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`9.4.1 Treatments Administered
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`Page 21
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`After obtaining a signed informed consent form, each patient will receive either nitric
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`oxide for inhalation administered using an NOvent® delivery system, or 100% 02. The
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`INOvent® is designed to add nitric oxide at preset levels to a ventilator circuit so that
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`inspired NO concentrations remain unchanged despite changes in ventilation modes.
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`n Patients who are under general anesthesia will be intubated and receive nitric oxide
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`for inhalation, 100% 02 or a combination of NO and 02 The NO will be administered
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`using an INOvent® delivery system through a t-connector downstream of the
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`inspiratory limb of a mechanical ventilator.
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`n Patients who are under awake sedation (mild sedation) will receive nitric oxide for
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`inhalation, 100% 02 or a combination of NO and 02. The NO will be administered
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`using an INOvent® delivery system through a properly fitted, sealed facemask.
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`Each patient will be randomized as to which study drug (80 ppm NO or 100%02) they
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`will receive as the initial dose. The second dose administration will be 80ppm NO for
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`inhalation with 100% 02 (set - approximate oxygen delivery 90%) and the third dose
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`administration will be whichever study drug was not initially administered (NO or 100%
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`02). There will be a ten-minute was