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    Summary
    EudraCT Number:2021-005032-30
    Sponsor's Protocol Code Number:2021-PDNO-003
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-12-29
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSweden - MPA
    A.2EudraCT number2021-005032-30
    A.3Full title of the trial
    An open-label, multicenter study to evaluate the DOSE, efficacy, safety and tolerability of PDNO (Nitrosooxypropanol) infusion in patients with pulmonary hypertension after cardiopulmonary bypass (CPB) surgery for Coronary artery bypass grafting (CABG) or mitral or Aortic valve repair or replacement with or without CABG
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to evaluate the efficacy and potential side effects of intravenous PDNO (that releases nitric oxide into the blood stream) in patients with high blood pressure in the lung circulation after heart surgery
    A.4.1Sponsor's protocol code number2021-PDNO-003
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAttgeno AB
    B.1.3.4CountrySweden
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAttgeno AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationScandinavian CRO
    B.5.2Functional name of contact pointAnna Runeson
    B.5.3 Address:
    B.5.3.1Street AddressSkolgatan 8
    B.5.3.2Town/ cityUppsala
    B.5.3.3Post code750 15
    B.5.3.4CountrySweden
    B.5.4Telephone number+460703033508
    B.5.6E-mailanna.runeson@scro.se
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code PDNO
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInfusion (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPDNO
    D.3.9.1CAS number 950478-73-6
    D.3.9.2Current sponsor codePDNO
    D.3.9.3Other descriptive name2-(nitrosooxy)propan-1-ol
    D.3.9.4EV Substance CodeSUB12540MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10.5 to 63.1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboInfusion (Noncurrent)
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acute Pulmonary Hypertension
    E.1.1.1Medical condition in easily understood language
    Increased blood pressure in the pulmonary circulation
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10037401
    E.1.2Term Pulmonary hypertensions
    E.1.2System Organ Class 100000004855
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objective:
    To evaluate the dose-range efficacy of PDNO on pulmonary vascular resistance (PVR) in patients undergoing CPB surgery with post-operative aPH.
    E.2.2Secondary objectives of the trial
    Secondary objectives:
    To evaluate the selectivity and dose-range of PDNO as a pulmonary vasodilator.
    To explore the effects of PDNO right ventricular function.
    To evaluate safety and tolerability of PDNO in patients undergoing CPB surgery.
    To assess the exposure of PD.

    Exploratory objectives:
    To explore potential biomarkers and to explore PD metabolites.
    To assess levels of fractional exhaled NO (FeNO) before and during iv infusion of PDNO.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Ability to understand and willing to sign an ICF after information at the pre-op screening visit.
    2. Male and female patients, age ≥ 18 years on the date of the informed consent at the time of the pre-op screening visit.*
    3. Planned to undergo elective cardiopulmonary bypass (CPB) for CABG, AVR or MVR w
    or w/o CABG. Non-elective (emergency) surgery patients are not eligible. Concomitant
    CryoMaze procedure and/or surgical left atrial appendix occlusion as a treatment for
    atrial fibrillation is routinely performed in some of these patients and may be done.
    4. Diagnosed with echocardiographic signs of pulmonary artery systolic pressure (PASP) >40 mmHg, as estimated by doppler defined echocardiography using a modified Bernoulli equation: PASP ≈ 4 (tricuspid regurgitant jet velocity)2 + CVP.
    *evaluated from medical history
    E.4Principal exclusion criteria
    Patients must not enter the study if any of the following exclusion criteria are fulfilled:
    1. History of chronic PH (WHO group 1, 3, 4 or 5), not group 2 due to left heart disease, as judged by the Investigator.*
    2. Patients with contraindications for PAC.
    3. History of severe chronic obstructive pulmonary disease, as judged by the Investigator.*
    4. Left heart failure with ejection fraction (EF) <35%.
    5. Non-ST elevation myocardial infarction [non-STEMI] or ST elevation myocardial infarction [STEMI] within 1 months prior to informed consent.*
    6. Stroke (CVL), transient ischemic attack (TIA), AV block III within 3 months prior to informed consent or QTcF >450ms at the time of screening.*
    7. High inotropic requirement (No more than one inotrope treatment and the vasopressor norepinephrine at time of screening/postoperative evaluation).
    8. (Increased) mediastinal bleeding >100 mL/hour in mediastinal drainage at postoperative evaluation.
    9. Mechanical circulatory assistance (IABP or R/L VAD).
    10. Echocardiographic evidence of significant tricuspid insufficiency as judged by the Investigator at screening.*
    11. Body Mass Index (BMI) >40 kg/m2.*
    12. Estimated glomerular filtration rate (eGFR) < 30 mL/min preoperative value.
    13. Methemoglobin >3%.
    14. Indication of liver disease, defined by serum levels of either alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP) above 3 x upper limit of normal (ULN) (preoperative value).
    15. Preoperative haemoglobin <10 g/dL, postoperative: Hb < 9 g/dL.
    16. Thrombocytopenia (platelet count <100,000/mm3), preoperative value.
    17. Prothrombin time International ratio (INR) > 1.3, preoperative value.
    18. Pregnant or lactating women, or with a positive pregnancy test at screening (for fertile women only).
    19. Ongoing daily treatment the last 3 days with non-steroidal anti-inflammatory drugs (NSAIDs, excluding low dose, i.e. 75 mg, acetylsalicylic acid), new oral anticoagulants (NOACs), warfarin, heparin, clopidogrel (last 5 days). Low molecular weight heparin (LMWH) is not an exclusion criterion. Any use of PDE5 inhibitors (sildenafil, tadalafil, vardenafil and avanafil) within 48 hours prior to the administration of PDNO.
    20. Known active malignancy within the past 3 years except for localized prostate cancer, cervical carcinoma in situ, breast cancer in situ, or nonmelanoma skin cancer that has been definitively treated.*
    21. History of allergy/hypersensitivity to PD or ongoing allergy/hypersensitivity or history of hypersensitivity to drugs with a similar chemical structure or class to PDNO.*
    22. History of any other clinically significant disease or disorder which, in the opinion of the investigator, may either put the patient at increased risk because of participation in the study, or influence the results or the ability to participate in the study.*
    23. Participation in any interventional clinical study or has been treated with any investigational research products within 30 days or 5 half-lives, whichever is longer, prior to the initiation of screening.*
    *evaluated from medical history
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint:
    Mean change in PVR from baseline (mean of T0 and T1) to time point T2, T3, T4, T5 and T6, respectively.
    PVR, will be derived as the mean pulmonary artery pressure (MPAP) - pulmonary capillary wedge pressure (PCWP) divided by cardiac output (CO), (PVR=(MPAP-PCWP)/CO), as measured with a pulmonary artery catheter (PAC) including thermodilution-determined cardiac output.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Assessments will be done at the following timepoints:
    T0 (-15 min) and T1 (0 min) with placebo
    T2 (15 min), T3 (30 min), T4 (45 min), T5 (60 min), and T6 (75 min) with 3, 10, 30, 45, 60 nmol/kg/min with PDNO respectively
    T7 (85 min) and T8 (95 min) with placebo
    E.5.2Secondary end point(s)
    Mean change in PVR/SVR ratio from baseline (mean of T0 and T1) to time point T2, T3, T4, T5 and T6, respectively.
    Ratio PVR / systemic vascular resistance (SVR). SVR is determined from (MAP-CVP)/CO.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Assessments will be done at the following timepoints:
    T0 (-15 min) and T1 (0 min) with placebo
    T2 (15 min), T3 (30 min), T4 (45 min), T5 (60 min), and T6 (75 min) with 3, 10, 30, 45, 60 nmol/kg/min with PDNO respectively
    T7 (85 min) and T8 (95 min) with placebo)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 4
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state24
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-05-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-05-03
    P. End of Trial
    P.End of Trial StatusOngoing
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