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| ID | Type | Description | Link |
|---|---|---|---|
| 2021-005032-30 | EudraCT Number |
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| Name | Class |
|---|---|
| Aurevia | INDUSTRY |
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This is an open-label, multicenter study evaluating the dose, effect, safety and tolerability of intravenous PDNO infusion given to patients undergoing cardiopulmonary bypass (CPB) surgery with post-operative acute pulmonary hypertension (aPH).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment with PDNO (placebo during baseline and washout observation periods before & after PDNO) | Experimental | PDNO will be administered as an incremental intravenous infusion of respectively 15 minutes with the planned dosage: 3, 10, 30, 45 and 60 nmol/kg/min. If no effect on MPAP/PVR is seen at 60 nmol/kg/min in the first patients treated, further dose escalation up to 120 nmol/kg/min is possible, if recommended by the Internal Safety Review Committe (iSRC) following careful review of collected safety data. The iSRC will in any case review all collected data after 4, 8 and 12 patients (if applicable also after 16 and 20 patients). PDNO is administered together with a carrier buffer (NaHCO3-) flow into a central venous catheter. Placebo (NaCl, commercially available dilution solution for parenteral use, 9 mg/mL) will be administered during the baseline and washout observation periods before and after start of IMP infusion. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| PDNO | Drug | PDNO consists of propylene glycol (1,2-propanediol, PD) chemically combined with NO (to be donated). The drug substance is formulated as an inherent mixture of 4 structure analogues. The mixture consists of an equilibrium of the 2 regioisomers 1-(nitrosooxy) propan-2-ol and 2-(nitrosooxy) propan-1-ol. In addition, each regioisomer is a racemic mixture. |
| Measure | Description | Time Frame |
|---|---|---|
| Mean change in pulmonary vascular resistance (PVR) | 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. Assessments will be done at the following timepoints: T0 (-15 minutes) and T1 (0 minutes) with placebo; T2 (15 minutes), T3 (30 minutes), T4 (45 minutes), T5 (60 minutes), and T6 (75 minutes) with 3, 10, 30, 45, 60 nmol/kg/min with PDNO, respectively; and T7 (85 minutes) and T8 (95 minutes) with placebo. | From baseline (mean of -15 minutes and 0 minutes) to time point 15, 30, 45, 60, and 75 minutes with PDNO, respectively; and 85 and 95 minutes with placebo. |
| Measure | Description | Time Frame |
|---|---|---|
| Mean change in the pulmonary vascular resistance/systemic vascular resistance ratio (PVR/SVR ratio) | 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. SVR is determined from mean pulmonary artery pressure - central venous pressure divided by cardiac output (CO), (SVR=(MABP-CVP)/CO). Assessments will be done at the following timepoints: T0 (-15 minutes) and T1 (0 minutes) with placebo; T2 (15 minutes), T3 (30 minutes), T4 (45 minutes), T5 (60 minutes), and T6 (75 minutes) with 3, 10, 30, 45, 60 nmol/kg/min with PDNO, respectively; and T7 (85 minutes) and T8 (95 minutes) with placebo. |
| Measure | Description | Time Frame |
|---|---|---|
| Assess the levels of the following biomarkers: nitrite and nitrate in plasma (µM) | Explore potential biomarkers. | Change from baseline T0 (-15 minutes; placebo) to time point T6 (75 minutes; PDNO). |
| Assess the levels of the following biomarkers: 1,2-propanediol (PD) metabolites in serum |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Christofer Adding, MD/PhD | Contact | +46 (0) 70 788 67 66 | christofer.adding@attgeno.com |
| Name | Affiliation | Role |
|---|---|---|
| Cecilia Kemi, PhD | Attgeno AB | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Sahlgrenska University Hospital, Anaesthesiology and Intensive Care | Recruiting | Gothenburg | SE-413 45 | Sweden |
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| Sodium chloride (placebo) | Drug | Placebo (NaCl, commercially available dilution solution for parenteral use, 9 mg/mL) |
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| From baseline (mean of -15 minutes and 0 minutes) to time point 15, 30, 45, 60, and 75 minutes with PDNO, respectively; and 85 and 95 minutes with placebo. |
| Mean change in fractional area change (FAC) | Assessments will be done at the following timepoints: T0 (-15 minutes) and T1 (0 minutes) with placebo; T2 (15 minutes), T3 (30 minutes), T4 (45 minutes), T5 (60 minutes), and T6 (75 minutes) with 3, 10, 30, 45, 60 nmol/kg/min with PDNO, respectively; and T7 (85 minutes) and T8 (95 minutes) with placebo. | From baseline (mean of -15 minutes and 0 minutes) to time point 15, 30, 45, 60, and 75 minutes with PDNO, respectively; and 85 and 95 minutes with placebo. |
| Mean change in tricuspidannular plane systolic excursion (TAPSE) | Assessments will be done at the following timepoints: T0 (-15 minutes) and T1 (0 minutes) with placebo; T2 (15 minutes), T3 (30 minutes), T4 (45 minutes), T5 (60 minutes), and T6 (75 minutes) with 3, 10, 30, 45, 60 nmol/kg/min with PDNO, respectively; and T7 (85 minutes) and T8 (95 minutes) with placebo. | From baseline (mean of -15 minutes and 0 minutes) to time point 15, 30, 45, 60, and 75 minutes with PDNO, respectively; and 85 and 95 minutes with placebo. |
| Mean change in right ventricular (RV) free wall strain | Assessments will be done at the following timepoints: T0 (-15 minutes) and T1 (0 minutes) with placebo; T2 (15 minutes), T3 (30 minutes), T4 (45 minutes), T5 (60 minutes), and T6 (75 minutes) with 3, 10, 30, 45, 60 nmol/kg/min with PDNO, respectively; and T7 (85 minutes) and T8 (95 minutes) with placebo. | From baseline (mean of -15 minutes and 0 minutes) to time point 15, 30, 45, 60, and 75 minutes with PDNO, respectively; and 85 and 95 minutes with placebo. |
| Safety and tolerability of PDNO in patients undergoing Cardiopulmonary Bypass (CPB) surgery | Measured by incidence of: treatment-emergent adverse events (AEs), treatment-emergent serious AEs (SAEs), treatment-emergent AEs of special interest (AESI), treatment-emergent changes in vital signs (blood pressure, pulse, oxygen saturation, respiratory frequency, body temperature), treatment-emergent electrocardiogram (ECG) abnormalities, and treatment-emergent laboratory abnormalities. | Until study end (i.e., end of Day 1 [95 minutes]). All AEs (including SAEs) will be collected from the initiation of any study specific procedure, starting when postoperative preparatory preparations are performed on Day 1 and until the end of the study. |
| Exposure parameters for 1,2-propanediol (PD): estimated area under the curve from time 0 to time t (AUC0-t) | To assess the exposure of PD. | Assessments at time points T0 (-15 minutes; placebo), T6 (75 minutes; PDNO), and T8 (95 minutes; placebo). |
| Exposure parameters for 1,2-propanediol (PD): estimated area under the curve from time 0 to infinity (AUC0-inf) | To assess the exposure of PD. | Assessments at time points T0 (-15 minutes; placebo), T6 (75 minutes; PDNO), and T8 (95 minutes; placebo). |
| Exposure parameters for 1,2-propanediol (PD): maximum plasma concentration (Cmax) | To assess the exposure of PD. | Assessments at time points T0 (-15 minutes; placebo), T6 (75 minutes; PDNO), and T8 (95 minutes; placebo). |
| Exposure parameters for 1,2-propanediol (PD): estimated elimination half life (t½) | To assess the exposure of PD. | Assessments at time points T0 (-15 minutes; placebo), T6 (75 minutes; PDNO), and T8 (95 minutes; placebo). |
Explore PD metabolites. |
| Change from baseline T0 (-15 minutes; placebo) to time point T6 (75 minutes; PDNO). |
| Örebro University Hospital, Vascular and Thoracic Department (Kärl-Thoraxkliniken) | Recruiting | Örebro | SE-701 85 | Sweden |
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| ID | Term |
|---|---|
| D006976 | Hypertension, Pulmonary |
| ID | Term |
|---|---|
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D006973 | Hypertension |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| C000717227 | 1-(nitrosooxy)propan-2-ol and 2-(nitrosooxy)propan-1-ol drug combination |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |
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