0135-0347

Boehringer Ingelheim

Binger Strasse 173, Ingelheim am Rhein, Germany, 55216

Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com

Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com

No

No

No

Final

16 Aug 2022

Yes

19 Jul 2022

Yes

25 Jul 2022

No

To evaluate the efficacy and safety of intravenous alteplase in ARDS triggered by COVID-19.

Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all subjects as required.

25 Jan 2021

No

Yes

Austria: 10

Belgium: 20

France: 38

Germany: 9

Italy: 6

Netherlands: 4

Russian Federation: 6

Spain: 8

Brazil: 1

Mexico: 2

104

95

0

0

0

0

0

0

59

42

3

Overall Study (overall period)

Randomised - controlled

This was an open-label study.

Yes

Alteplase

Powder and solvent for solution for infusion

Intravenous use

0.3 milligram/kilogram (mg/kg) over 2 hours (Day 1) immediately followed by daily infusion of 0.02 mg/kg/hour over 12 hours (starting on Day 1 and up to Day 5), plus Standard of Care (SOC). One optional additional infusion of 0.3 mg/kg over 2 hours could be given once on Days 2 to 5 in case of clinical worsening, per investigator judgement.

Alteplase

Powder and solvent for solution for infusion

Intravenous use

0.6 milligram/kilogram (mg/kg) over 2 hours (Day 1) immediately followed by daily infusion of 0.04 mg/kg/hour over 12 hours (starting on Day 1 and up to Day 5), plus Standard of Care (SOC). One optional additional infusion of 0.6 mg/kg over 2 hours could be given once on Days 2 to 5 in case of clinical worsening, per investigator judgement.

No investigational medicinal product assigned in this arm

Alteplase

Powder and solvent for solution for infusion

Intravenous use

0.6 milligram/kilogram (mg/kg) over 2 hours (Day 1) immediately followed by daily infusion of 0.04 mg/kg/hour over 12 hours (starting on Day 1 and up to Day 5), plus Standard of Care (SOC). One optional additional infusion of 0.6 mg/kg over 2 hours could be given once on Days 2 to 5 in case of clinical worsening, per investigator judgement.

No investigational medicinal product assigned in this arm

Alteplase

Powder and solvent for solution for infusion

Intravenous use

0.6 milligram/kilogram (mg/kg) over 2 hours (Day 1) immediately followed by daily infusion of 0.04 mg/kg/hour over 12 hours (starting on Day 1 and up to Day 5), plus Standard of Care (SOC). One optional additional infusion of 0.6 mg/kg over 2 hours could be given once on Days 2 to 5 in case of clinical worsening, per investigator judgement.

No investigational medicinal product assigned in this arm

Part 1: Alteplase low dose

Part 1: Alteplase high dose

Part 1: Standard of Care

Part 2: Alteplase high dose - NIV patients

Part 2: Standard of Care - NIV patients

Part 2: Alteplase high dose - IMV patients

Part 2: Standard of Care - IMV patients

Part 1: Alteplase low dose

Part 1: Alteplase high dose

Part 1: Standard of Care

Part 2: Alteplase high dose - NIV patients

Part 2: Standard of Care - NIV patients

Part 2: Alteplase high dose - IMV patients

Part 2: Standard of Care - IMV patients

From randomisation to either an improvement of 2 points on the 11-point World Health Organization (WHO) Clinical Progression Scale (from 0 to 10, a low score indicates a better outcome) or discharge from the hospital, whichever comes first. 0=Uninfected; no viral RNA detected 1=Asymptomatic; viral RNA detected 2=Symptomatic; independent 3=Symptomatic; assistance needed 4=Hospitalised; no oxygen therapy 5=Hospitalised; oxygen by mask or nasal prongs 6=Hospitalised; oxygen by NIV or high flow 7=Intubation and mechanical ventilation, PaO2/FiO2=150 or SpO2/FiO2=200 8=Mechanical ventilation PaO2/FiO2<150 (SpO2/FiO2<200) or vasopressors 9=Mechanical ventilation PaO2/FiO2<150 and vasopressors, dialysis, or ECMO 10=Dead Patients that not met the endpoint were censored (Day 28) if they died prior to Day 28. Patients receiving bail out therapy without having first met the endpoint, were censored on the day of bail-out (hypothetical estimand). FAS.

Primary

Up to 28 days.

Unadjusted Hazard Ratio: Cox proportional hazard model containing fixed effect for treatment. The confidence intervals was determined using the Wald method to determine the variance. 

Part 1: Alteplase low dose v Part 1: Standard of Care

42

Pre-specified

1.01

2-sided

Unadjusted Hazard Ratio: Cox proportional hazard model containing fixed effect for treatment. The confidence intervals was determined using the Wald method to determine the variance. 

Part 1: Alteplase high dose v Part 1: Standard of Care

42

Pre-specified

1.75

2-sided

Adjusted Hazard Ratio: Cox proportional hazard model containing fixed effect for treatment, ventilation status at baseline and age. The confidence intervals was determined using the Wald method to determine the variance.

Part 1: Alteplase low dose v Part 1: Standard of Care

42

Pre-specified

1.23

2-sided

Adjusted Hazard Ratio: Cox proportional hazard model containing fixed effect for treatment, ventilation status at baseline and age. The confidence intervals was determined using the Wald method to determine the variance.

Part 1: Alteplase high dose v Part 1: Standard of Care

42

Pre-specified

2.04

2-sided

Unadjusted Hazard Ratio: Cox proportional hazard model containing fixed effect for treatment. The confidence intervals was determined using the Wald method to determine the variance. 

Part 2: Alteplase high dose - NIV patients v Part 2: Standard of Care - NIV patients

25

Pre-specified

1.13

2-sided

Adjusted Hazard Ratio: Cox proportional hazard model containing fixed effect for treatment, ventilation status at baseline and age. The confidence intervals was determined using the Wald method to determine the variance.

Part 2: Alteplase high dose - NIV patients v Part 2: Standard of Care - NIV patients

25

Pre-specified

1.19

2-sided

Number of subjects with major bleeding events (MBE). Major bleeding events (MBE) according to International Society on Thrombosis and Haemostasis [ISTH] definition until Day 6. Definition of a major bleed: •Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, and/or •Bleeding associated with a reduction in hemoglobin of at least 2 gram/deciliter (1.24 millimole/Liter), or leading to transfusion of two or more units of blood or packed cells and/or •Fatal bleed The Treated Set (TS) consisted of all patients who were randomised and, for patients in the alteplase groups, treated with at least one dose of trial drug.

Secondary

From start of treatment (Alteplase) or randomisation (SOC) (day 1) till Day 6, up to 6 days.

Chan and Zhang exact confidence interval.

Part 1: Alteplase low dose v Part 1: Standard of Care

42

Pre-specified

5

2-sided

Chan and Zhang exact confidence interval.

Part 2: Alteplase high dose - NIV patients v Part 2: Standard of Care - NIV patients

25

Pre-specified

11.76

2-sided

Chan and Zhang exact confidence interval.

Part 1: Alteplase high dose v Part 1: Standard of Care

42

Pre-specified

20

2-sided

All cause mortality at Day 28. If it is unknown whether the patient was dead at end of Day 28, then it will be assumed that the patient did not die up to Day 28, regardless of the reason. This unfavorable endpoint is met if: - the last known status of the patient is 10 on the WHO clinical progression scale by the end of Day 28, or - vital status is dead within 28 days Full Analysis Set (FAS) consisted of all randomised patients with at least one baseline and one post baseline assessment relating to the primary endpoint.

Secondary

Up to 28 days.

Adjusted risk difference and 95% confidence interval is based upon average marginal effect Delta method, adjusting for baseline ventilation status, age and treatment.

Part 1: Alteplase low dose v Part 1: Standard of Care

42

Pre-specified

-16.6

2-sided

Adjusted risk difference and 95% confidence interval is based upon average marginal effect Delta method, adjusting for baseline ventilation status, age and treatment.

Part 1: Alteplase high dose v Part 1: Standard of Care

42

Pre-specified

-11.8

2-sided

Unadjusted risk difference and 95% CI is based upon average marginal effect Delta method, adjusting for treatment.

Part 2: Alteplase high dose - NIV patients v Part 2: Standard of Care - NIV patients

25

Pre-specified

-19.1

2-sided

Treatment failure defined as all cause mortality or mechanical ventilation at Day 28. Full Analysis Set (FAS) consisted of all randomised patients with at least one baseline and one post baseline assessment relating to the primary endpoint.

Secondary

Up to 28 days.

Adjusted risk difference and 95% confidence interval is based upon average marginal effect Delta method, adjusting for baseline ventilation status, age and treatment.

Part 1: Alteplase low dose v Part 1: Standard of Care

42

Pre-specified

-9

2-sided

Adjusted risk difference and 95% CI is based upon average marginal effect Delta method, adjusting for baseline D-dimer status, age, days of NIV support and treatment.

Part 2: Alteplase high dose - NIV patients v Part 2: Standard of Care - NIV patients

25

Pre-specified

14.5

2-sided

Adjusted risk difference and 95% confidence interval is based upon average marginal effect Delta method, adjusting for baseline ventilation status, age and treatment.

Part 1: Alteplase high dose v Part 1: Standard of Care

42

Pre-specified

-9.1

2-sided

Number of ventilator-free days (VFDs) from start of treatment to Day 28. ‘Ventilator’ is defined as ‘assisted breathing’ but it refers to mechanical invasive ventilation. The number of VFDs starts from when the patient has a ‘lasting’ value on the WHO clinical progression scale of ≤ 6, and ends on Day 28. A lasting value of ≤ 6 means that the value cannot exceed 6 at a later timepoint. If the patient is liberated from the ventilator on Day x, then the number of VFDs is 28-x. If a patient has withdrawn consent prior to day 28 then he will have a missing value for VFD. In any case, if the status of the patient at Day 28 is death, as determined from the vital status page then the VFD=0. Full Analysis Set (FAS) consisted of all randomised patients with at least one baseline and one post baseline assessment relating to the primary endpoint. The endpoint was only planned for subjects in Part 1.

Secondary

Up to 28 days.

Parameters included in model: treatment,ventilation status at baseline, and age.

Part 1: Alteplase low dose v Part 1: Standard of Care

42

Pre-specified

3.1

2-sided

Standard error of the mean

3.7

Parameters included in model: treatment,ventilation status at baseline, and age.

Part 1: Alteplase high dose v Part 1: Standard of Care

42

Pre-specified

4.3

2-sided

Standard error of the mean

3.7

Number of subjects with improvement of Sequential (sepsis-related) Organ Failure Assessment (SOFA) score by ≥2 points from baseline to end of Day 6. The Sequential Organ Failure Assessment (SOFA) scores six variables: respiratory, coagulation, liver, Cardiovascular, central nervous system and renal. Each variable is score from 0 (best outcome) to 4 (worst outcome) with a total score calculated as the sum of all six variables ranging from 0 (best outcome) to 24 (worst outcome). Full Analysis Set (FAS) consisted of all randomised patients with at least one baseline and one post baseline assessment relating to the primary endpoint. The endpoint was only planned for subjects in Part 1.

Secondary

Baseline (Day 0) and Day 6 of treatment

Adjusted risk difference and 95% confidence interval is based upon average marginal effect Delta method, adjusting for baseline ventilation status, age and treatment.

Part 1: Alteplase high dose v Part 1: Standard of Care

42

Pre-specified

-15.2

2-sided

Adjusted risk difference and 95% confidence interval is based upon average marginal effect Delta method, adjusting for baseline ventilation status, age and treatment.

Part 1: Alteplase low dose v Part 1: Standard of Care

42

Pre-specified

-4.9

2-sided

Daily average PaO2/FiO2 ratio (or inferred PaO2/FiO2 ratio from SpO2) change from baseline to Day 6. This was measured 3-times daily. All available values of these days, regardless of the position of the patient when being measured, were averaged to determine the daily average PaO2/FiO2 ratio for that patient. The higher the value the better the health status of the patient. If patient was still in hospital during day 6 then the day 6 daily average value was used, if available. If the patient was discharged from hospital prior to day 6 then the daily average at the time of hospital discharge was used as a surrogate for day 6, if available. If the patient died prior to day 6 then there was no imputation but handled as failure in the determination of the difference in medians and CI. Based upon this, the change from baseline for each patient was calculated. FAS. Only subjects with non-missing endpoint data were included. The endpoint was only planned for subjects in Part 1.

Secondary

Up to 6 days.

Based upon Hedges-Lehmann estimator handling deaths as failure and Wilcoxon rank sum test methodology.

Part 1: Alteplase low dose v Part 1: Standard of Care

41

Pre-specified

17.193

2-sided

Based upon Hedges-Lehmann estimator handling deaths as failure and Wilcoxon rank sum test methodology.

Part 1: Alteplase high dose v Part 1: Standard of Care

41

Pre-specified

54.436

2-sided

Length of hospital stay up to day 28 was determined based upon the first hospital discharge date, or discharge to another care facility. If the patient died within the first 28 day period, then length of hospital stay was 28. Full Analysis Set (FAS) consisted of all randomised patients with at least one baseline and one post baseline assessment relating to the primary endpoint. The endpoint was only planned for subjects in Part 2.

Secondary

Up to 28 days.

Unadjusted mean difference: A restricted maximum likelihood (REML) based Analysis of Covariance (ANCOVA) was used. Adjustment was made for treatment.

Part 2: Alteplase high dose - NIV patients v Part 2: Standard of Care - NIV patients

25

Pre-specified

0.1

2-sided

Standard error of the mean

3.6

Adjusted mean difference: A restricted maximum likelihood (REML) based Analysis of Covariance (ANCOVA) was used. Adjustment was made for treatment, the number of days under NIV support, baseline D-Dimer level and age.

Part 2: Alteplase high dose - NIV patients v Part 2: Standard of Care - NIV patients

25

Pre-specified

-0.6

2-sided

Standard error of the mean

3.8

Number of oxygen-free days (OFD) up to Day 28. Oxygen-free is defined as free from assistance from oxygen support. The number of oxygen-free days starts from when the patient has a ‘lasting’ value on the WHO clinical progression scale of ≤ 4 and ends on Day 28. A lasting value of ≤ 4 means that the value cannot exceed 4 at a later timepoint. If the patient is liberated from oxygen on Day x, then the number of OFDs is 28-x. If a patient has withdrawn consent prior to day 28 then he will have a missing value for OFD. In any case, if the status of the patient at Day 28 is death, as determined from the vital status page then the OFD=0. Full Analysis Set (FAS) consisted of all randomised patients with at least one baseline and one post baseline assessment relating to the primary endpoint. The endpoint was only planned for subjects in Part 2.

Secondary

Up to 28 days.

Worst PaO2/FiO2 ratio (or inferred PaO2/FiO2 ratio from SpO2) change from baseline to day 6. This assessment was planned to be measured on each of days 0 to 6. but only whilst the patients was still in hospital. The worst (lowest) daily measurement will be used and the higher the value the better the health status of the patient. • If the patient was still in hospital during day 6 then the day 6 value was used • If the patient was discharged from hospital prior to day 6 then the value at the time of hospital discharge was used • If the patient died prior to day 6 then the last value prior to death was used • If day 6 value was missing but Day 5 value available, the day 5 value was used • If day 6 value was missing, no Day 5 value available, but day 7 available, then day 7 value was used • Otherwise value was set to missing for that patient. Based upon this, the change from baseline for each patient was calculated and used for the analysis. FAS

Secondary

Up to 7 days.

Adjusted mean difference: A restricted maximum likelihood (REML) based Analysis of Covariance (ANCOVA) was used. Adjustment was made for treatment, the number of days under NIV support, baseline D-Dimer level, baseline PaO2/FiO2 ratio and age.

Part 2: Alteplase high dose - NIV patients v Part 2: Standard of Care - NIV patients

25

Pre-specified

87.2

2-sided

Standard error of the mean

38.5

Unadjusted mean difference: A restricted maximum likelihood (REML) based Analysis of Covariance (ANCOVA) was used. Adjustment was made for treatment.

Part 2: Alteplase high dose - NIV patients v Part 2: Standard of Care - NIV patients

25

Pre-specified

70.9

2-sided

Standard error of the mean

35.8

treated set (TS) including all patients who were randomised and for the alteplase groups, treated with at least one dose.

Treated Set (TS), included all patients who were randomised and, for patients in the alteplase groups, treated with at least one dose of trial drug.

25.0

Part 1: Alteplase low dose

Part 1: Alteplase high dose

Part 1: Standard of Care

Part 2: Standard of Care - IMV patients

Part 2: Standard of Care - NIV patients

Part 2: Alteplase high dose - IMV patients

Part 2: Alteplase high dose - NIV patients