Clinical Trials Register

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

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A. Protocol Information

A.1

Member State Concerned

Sweden - MPA

A.2

EudraCT number

2021-005032-30

A.3

Full 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.3.1

Title 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.4.1

Sponsor's protocol code number

2021-PDNO-003

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Attgeno AB
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Attgeno AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Scandinavian CRO
B.5.2	Functional name of contact point	Anna Runeson
B.5.3	Address:
B.5.3.1	Street Address	Skolgatan 8
B.5.3.2	Town/ city	Uppsala
B.5.3.3	Post code	750 15
B.5.3.4	Country	Sweden
B.5.4	Telephone number	+460703033508
B.5.6	E-mail	anna.runeson@scro.se

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	PDNO
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Infusion (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PDNO
D.3.9.1	CAS number	950478-73-6
D.3.9.2	Current sponsor code	PDNO
D.3.9.3	Other descriptive name	2-(nitrosooxy)propan-1-ol
D.3.9.4	EV Substance Code	SUB12540MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10.5 to 63.1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Infusion (Noncurrent)

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute Pulmonary Hypertension

E.1.1.1

Medical condition in easily understood language

Increased blood pressure in the pulmonary circulation

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10037401
E.1.2	Term	Pulmonary hypertensions
E.1.2	System Organ Class	100000004855

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Primary objective:
Part I: To evaluate the dose-range efficacy of PDNO on pulmonary vascular resistance (PVR) in patients undergoing CPB surgery with post-operative aPH.
Part II: To evaluate the dose titration efficacy of PDNO on PVR in patients undergoing CPB surgery with post-operative aPH.

E.2.2

Secondary objectives of the trial

Secondary objectives Part I:
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.

Secondary objectives Part II:
Evaluate the selectivity and dose titration of PDNO as a pulmonary vasodilator.
Valuate safety and tolerability of PDNO in patients undergoing CPB surgery.
To assess the exposure of PD.

Exploratory objectives Part I:
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.2.3

Trial contains a sub-study

E.3

Principal 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.4

Principal 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.5.1

Primary end point(s)

Primary endpoint Part I:
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.

Primary endpoint Part II:
Mean change in PVR from baseline (mean of T0 and T1) to time point T2.
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.5.1.1

Timepoint(s) of evaluation of this end point

Assessments will be done at the following timepoints for Part I:
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

Assessments are done at the following timepoints for Part II:
T0 (-15 min) and T1 (0 min) with placebo.
T2 (ca 30min) with titrated dose for the infusion with PDNO.
T3 and T4 with placebo).

E.5.2

Secondary end point(s)

For Part I:
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.

Part II:
Mean change in PVR/SVR ratio from baseline (mean of T0 and T1) to time point T2.
Ratio PVR / systemic vascular resistance (SVR). SVR is determined from (MABP-CVP)/CO.

E.5.2.1

Timepoint(s) of evaluation of this end point

Assessments will be done at the following timepoints for Part I:
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)

Assessments will be done at the following timepoints for Part II:
Assessments will be done at the following timepoints
T0 (-15 min) and T1 (0 min) with placebo
T2 (ca30 min) with PDNO
T4 and T5 with placebo)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-05-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-05-03

P. End of Trial
P.	End of Trial Status	Ongoing

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