2021-PDNO-003

Attgeno AB

Fogdevreten 2, Solna, Sweden, 17165

Christofer Adding, Attgeno AB, +46 70 788 67 66, christofer.adding@attgeno.com

Christofer Adding, Attgeno AB, +46 70 788 67 66, christofer.adding@attgeno.com

No

No

No

Final

29 Apr 2024

Yes

29 Apr 2024

Yes

29 Apr 2024

No

Primary objective: To evaluate the dose-range efficacy of PDNO on pulmonary vascular resistance (PVR) in patients undergoing CPB surgery with post-operative aPH. The primary objective of "Part I" of the study is reported, as the sponsor decided to run "Part II" as a seperate Phase 2b study.

Safety data from the pre-clinical studies and the completed Phase I study did not reveal any safety issues that would outweigh the expected benefits of the study. The clinical benefit of this hemodynamic study was to identify the dose range of PDNO that is safe and have potential beneficial efficacy in patients with aPH that undergo cardiac surgery. The direct benefit for participating patients was limited to possible advantages from extended investigations and potential benefit from reduced pulmonary blood pressure during the short infusion time. This dose finding study would provide vital hemodynamic data which would aid in the design of the continued clinical development program, including the phase III study. Thus, the clinical benefit of the use of PAC would outweigh the potential complications of the PAC insertion and expected drug related adverse events. The Principal Investigator at each clinic ascertained that adequate facilities, procedures and skilled personnel were available to handle emergency situations should they have occurred during the study. An internal iSRC monitored emerging safety data over the course of the study. Study assessments were considered sufficient to meet the scientific and medical goals for the study. Overall, it was concluded that the potential benefits from the study outweighed the potential risks for the treated patients.

14 Jun 2022

No

Yes

Sweden: 21

21

21

0

0

0

0

0

0

6

15

0

Overall trial (overall period)

Not applicable

PDNO (Nitrosooxypropanol)

Solution for injection/infusion

Infusion

Prior to IMP infusion, a 15-minute placebo (NaCl) and a sodium bicarbonate buffer was given. Thereafter, the patients were planned to be dosed with up to five consecutively incrementing doses of IMP. Initial start dose of IMP was infused for 10-20 minutes. If no effect (decrease of MPAP or PVR) was seen or any stopping criteria developed, the dose was titrated up to the next dose level for 10-20 minutes and again evaluated for effect and safety. This was repeated for up to five dose levels. After the highest IMP infusion had been stopped, a 20-minute placebo (NaCl) and carrier buffer infusion were infused. The initial dose levels were (cohort 1): 3; 10; 30; 45; and 60 nmol/kg/min of PDNO. Based on analyses of emerging data the iSRC decided on adjusted dose levels: Cohort 2 doses: 5; 10; 15; 20; 25 nmol/kg/min (PDNO), and Cohort 3 doses: 2.5; 5; 10; 15; 20 nmol/kg/min (PDNO).

Overall trial

Full-analysis set (FAS)

All patients who were included and received at least one dose of IMP and have observed PVR data (primary endpoint data) after IMP dosing. Here, observed PVR data is defined as at least one PVR observation during PDNO infusion

Modified full analysis set (MFAS)

All FAS patients who were judged as “evaluable” by the iSRC, i.e., to have generated conclusive data for efficacy response.

Safety analysis set (SAS)

All patients who received at least one dose of placebo or PDNO.

Experimental

Full-analysis set (FAS)

All patients who were included and received at least one dose of IMP and have observed PVR data (primary endpoint data) after IMP dosing. Here, observed PVR data is defined as at least one PVR observation during PDNO infusion

Modified full analysis set (MFAS)

All FAS patients who were judged as “evaluable” by the iSRC, i.e., to have generated conclusive data for efficacy response.

Safety analysis set (SAS)

All patients who received at least one dose of placebo or PDNO.

The primary estimand for the primary endpoint was based on the individual dose-range relationship. Individually functions were estimated for the exponential decay curve y(PVR)=Caᵡ, where ᵡ=dose, y=PVR, C=constant, and where a < 1 was interpreted as a decreasing PVR curve by dose. The estimates for C and for each participant were based on actual dosing schedule and observed PVR values. The mean of all individual a:s was tested for H0: a=1 (no decrease by dose). If H0 is rejected, there is a proof for a declining dose-range relationship. The test was one-sided using the type-I error rate of 0.10. The dose schedule for the established timepoints T2-T6 was changed during the study (decision from the iSRC). PDNO was initially given at 3, 10, 30, 45 and 60 nmol/kg/min at T2-T6. After the first three evaluable patients, doses changed to 5, 10, 15, 20, 25 nmol/kg/min at T2-T6, and further after additional three patients to 2.5, 5, 10, 15, 20 nmol/kg/min at T2-T6.

Primary

Periods of assessments: T0: start of placebo infusion (approx. after 2-5 min placebo), T1: end of placebo infusion (approx. after 8-10 min placebo), T2-T6: during PDNO infusion (each PDNO dose is approx. 15 min).

From initiation of any study specific procedure until termination of placebo infusion (T8). From CSP v3.0, for patients collecting post-infusion blood samples (T9-T11) only AEs judged by investigator to be directly caused by the sampling were reported.

25.0

Safety analysis set (SAS)