Trial Outcomes & Findings for Standard-dose Apixaban AFtEr Very Low-dose ThromboLYSis for Acute Intermediate-high Risk Acute Pulmonary Embolism (NCT NCT03988842)

NCT ID: NCT03988842

Last Updated: 2021-06-11

Results Overview

Change in percentage of clot lysis in the experimental arm only as measured using the Refined Modified Miller Score (RMMS) from the baseline CTA to the 24 hour CTA after 24mg of systemic (IV) tPA + standard anticoagulation therapy (experimental arm).

• Recruitment status: TERMINATED
• Study phase: PHASE4
• Target enrollment: 4 participants
• Primary outcome timeframe: Baseline, 24 hours
• Results posted on: 2021-06-11

Participant Flow

The study was terminated early and never unblinded. Arm/Group randomization information is not available.

Participant milestones

Measure	All Study Participants Participants were randomly assigned to either: 1. Alteplase \& Unfractionated Heparin \& Apixaban Alteplase 24mg intravenous infusion for 20 minutes followed by unfractionated heparin intravenous infusion over 24 hours followed by apixaban 10mg tablet twice-daily for one week followed by apixaban 5mg tablet twice-daily for at least 6 months. Alteplase: Lyophilized powder for reconstitution in 50mg vials Unfractionated heparin: Heparin sodium in 0.45% sodium chloride injection for intravenous use Apixaban: Apixaban tablet OR 2. Placebo \& Unfractionated Heparin \& Apixaban Alteplase placebo solution 24mg intravenous infusion for 20 minutes followed by unfractionated heparin intravenous infusion over 24 hours followed by apixaban 10mg tablet twice-daily for one week followed by apixaban 5mg tablet twice-daily for at least 6 months. Unfractionated heparin: Heparin sodium in 0.45% sodium chloride injection for intravenous use Placebo: Saline solution reconstituted to mimic Alteplase 50mg vial Apixaban: Apixaban tablet
Overall Study STARTED	4
Overall Study COMPLETED	3
Overall Study NOT COMPLETED	1

Reasons for withdrawal

Measure

All Study Participants Participants were randomly assigned to either: 1. Alteplase \& Unfractionated Heparin \& Apixaban Alteplase 24mg intravenous infusion for 20 minutes followed by unfractionated heparin intravenous infusion over 24 hours followed by apixaban 10mg tablet twice-daily for one week followed by apixaban 5mg tablet twice-daily for at least 6 months. Alteplase: Lyophilized powder for reconstitution in 50mg vials Unfractionated heparin: Heparin sodium in 0.45% sodium chloride injection for intravenous use Apixaban: Apixaban tablet OR 2. Placebo \& Unfractionated Heparin \& Apixaban Alteplase placebo solution 24mg intravenous infusion for 20 minutes followed by unfractionated heparin intravenous infusion over 24 hours followed by apixaban 10mg tablet twice-daily for one week followed by apixaban 5mg tablet twice-daily for at least 6 months. Unfractionated heparin: Heparin sodium in 0.45% sodium chloride injection for intravenous use Placebo: Saline solution reconstituted to mimic Alteplase 50mg vial Apixaban: Apixaban tablet

Overall Study Death

1

Baseline Characteristics

Standard-dose Apixaban AFtEr Very Low-dose ThromboLYSis for Acute Intermediate-high Risk Acute Pulmonary Embolism

Baseline characteristics by cohort

Measure	All Study Participants n=4 Participants Participants were randomly assigned to either: Alteplase \& Unfractionated Heparin \& Apixaban Alteplase 24mg intravenous infusion for 20 minutes followed by unfractionated heparin intravenous infusion over 24 hours followed by apixaban 10mg tablet twice-daily for one week followed by apixaban 5mg tablet twice-daily for at least 6 months. Alteplase: Lyophilized powder for reconstitution in 50mg vials Unfractionated heparin: Heparin sodium in 0.45% sodium chloride injection for intravenous use Apixaban: Apixaban tablet OR Placebo \& Unfractionated Heparin \& Apixaban Alteplase placebo solution 24mg intravenous infusion for 20 minutes followed by unfractionated heparin intravenous infusion over 24 hours followed by apixaban 10mg tablet twice-daily for one week followed by apixaban 5mg tablet twice-daily for at least 6 months. Unfractionated heparin: Heparin sodium in 0.45% sodium chloride injection for intravenous use Placebo: Saline solution reconstituted to mimic Alteplase 50mg vial Apixaban: Apixaban tablet
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	2 Participants n=5 Participants
Age, Categorical >=65 years	2 Participants n=5 Participants
Age, Continuous	62.5 years n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants
Sex: Female, Male Male	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants
Race (NIH/OMB) White	2 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Region of Enrollment United States	4 participants n=5 Participants
Gender Female	3 Participants n=5 Participants
Gender Male	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, 24 hours

Population: The study was terminated early and never unblinded. Data was not analyzed.

Change in percentage of clot lysis in the experimental arm only as measured using the Refined Modified Miller Score (RMMS) from the baseline CTA to the 24 hour CTA after 24mg of systemic (IV) tPA + standard anticoagulation therapy (experimental arm).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 24 hours

Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.

Change in percentage of clot lysis between the experimental arm and the active comparator arm as measured using the Refined Modified Miller Score (RMMS) from the baseline CTA to the 24 hour CTA after 24mg of systemic (IV) tPA + standard anticoagulation therapy (experimental arm) compared to 24mg of systemic (IV) placebo + standard anticoagulation therapy (active comparator arm).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 24 hours

Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.

RV/LV ratio as measured by chest CTA from baseline to 24 ± 6 hours after the infusion of very low dose systemic (IV) tPA in patients with acute intermediate-high risk PE compared with placebo.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 24 hours and 30 days

Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.

Change from baseline in echocardiographic parameters as measured by the RV/LV ratio within 24 hours ± 6 hours and at 30 ± 5 days after the end of the systemic (IV) tPA infusion compared with placebo.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 24 hours and 30 days

Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.

Change from baseline in echocardiographic parameters as measured by the tricuspid annular plane systolic excursion (TAPSE) within 24 hours ± 6 hours and at 30 ± 5 days after the end of the systemic (IV) tPA infusion compared with placebo.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 24 hours and 30 days

Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.

Change from baseline in echocardiographic parameters as measured by the estimated right ventricular systolic pressure (RVSP) within 24 hours ± 6 hours and at 30 ± 5 days after the end of the systemic (IV) tPA infusion compared with placebo.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 24 hours and 30 days

Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.

Change from baseline in echocardiographic parameters as measured by the collapse of the inferior vena cava (IVC) with respiration within 24 hours ± 6 hours and at 30 ± 5 days after the end of the systemic (IV) tPA infusion compared with placebo.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 30 days, 60 days, and 1 year

Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.

6MWT distance as measured by the requirement for oxygen therapy at 30 day, 60 day and one year ± 14 days clinic follow-up compared with placebo.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 30 days, 60 days, and 1 year

Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.

6MWT distance as measured by the Borg Dyspnea Scale score (Borg score) at 30 day, 60 day and one year ± 14 days clinic follow-up compared with placebo. The Borg Scale measures self-reported intensity and severity of breathlessness (dyspnea) and fatigue before, during, and after a 6MWT. Each item is scored 0 - 10 (0 = no breathlessness at all; 10 = most severe breathlessness that you have ever experienced), yielding a total between 0 and 20.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 30 days, 6 months, and 1 year

Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.

Quality of life (QOL) as measured by the PROMIS PF-6at 30 days, 6 months and one year ± 14 days clinic follow-up compared with placebo. The PROMIS PF-6 measures self-reported physical function for everyday tasks (i.e., yard work, shopping, walking up/down stairs). Each item is score 1 - 5 (1 = unable to do/cannot do; 5 = without any difficulty/not at all), yielding a total between 6 and 30.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 30 days, 6 months, and 1 year

Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.

Quality of life (QOL) as measured by the PEmb-QOL at 30 days, 6 months and one year ± 14 days clinic follow-up compared with placebo. The PEmb-QOL measures self-reported QOL after a Pulmonary Embolism. The PEmb-QOL has nine sub-scales with higher scores indicating worse outcomes. Each item is score 1 - 5 (1 = unable to do/cannot do; 5 = without any difficulty/not at all), yielding a total between 6 and 30.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 30 days, 60 days, 6 months, and 1 year

Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.

Measured as the number of recurrent DVT and/or PE events in patients at 30 days, 60 days, 6 months, and 1 year compared to placebo.

Outcome measures

Outcome data not reported

Adverse Events

All Study Participants

Serious events: 2 serious events

Other events: 1 other events

Deaths: 1 deaths

Serious adverse events

Measure	All Study Participants n=4 participants at risk Participants were randomly assigned to either: Alteplase \& Unfractionated Heparin \& Apixaban Alteplase 24mg intravenous infusion for 20 minutes followed by unfractionated heparin intravenous infusion over 24 hours followed by apixaban 10mg tablet twice-daily for one week followed by apixaban 5mg tablet twice-daily for at least 6 months. Alteplase: Lyophilized powder for reconstitution in 50mg vials Unfractionated heparin: Heparin sodium in 0.45% sodium chloride injection for intravenous use Apixaban: Apixaban tablet OR Placebo \& Unfractionated Heparin \& Apixaban Alteplase placebo solution 24mg intravenous infusion for 20 minutes followed by unfractionated heparin intravenous infusion over 24 hours followed by apixaban 10mg tablet twice-daily for one week followed by apixaban 5mg tablet twice-daily for at least 6 months. Unfractionated heparin: Heparin sodium in 0.45% sodium chloride injection for intravenous use Placebo: Saline solution reconstituted to mimic Alteplase 50mg vial Apixaban: Apixaban tablet
Renal and urinary disorders AKI and Anemia	25.0% 1/4 • Number of events 1 • Adverse events were collected up to 8.5months given patient safety concerns due to the COVID-19 pandemic. The original Adverse Event assessment per the protocol was 1 year from baseline. Study was not unblinded. All data was entered in the treatment fields.
Respiratory, thoracic and mediastinal disorders Respiratory Failure	25.0% 1/4 • Number of events 1 • Adverse events were collected up to 8.5months given patient safety concerns due to the COVID-19 pandemic. The original Adverse Event assessment per the protocol was 1 year from baseline. Study was not unblinded. All data was entered in the treatment fields.
Blood and lymphatic system disorders Anemia	25.0% 1/4 • Number of events 1 • Adverse events were collected up to 8.5months given patient safety concerns due to the COVID-19 pandemic. The original Adverse Event assessment per the protocol was 1 year from baseline. Study was not unblinded. All data was entered in the treatment fields.

Other adverse events

Measure	All Study Participants n=4 participants at risk Participants were randomly assigned to either: Alteplase \& Unfractionated Heparin \& Apixaban Alteplase 24mg intravenous infusion for 20 minutes followed by unfractionated heparin intravenous infusion over 24 hours followed by apixaban 10mg tablet twice-daily for one week followed by apixaban 5mg tablet twice-daily for at least 6 months. Alteplase: Lyophilized powder for reconstitution in 50mg vials Unfractionated heparin: Heparin sodium in 0.45% sodium chloride injection for intravenous use Apixaban: Apixaban tablet OR Placebo \& Unfractionated Heparin \& Apixaban Alteplase placebo solution 24mg intravenous infusion for 20 minutes followed by unfractionated heparin intravenous infusion over 24 hours followed by apixaban 10mg tablet twice-daily for one week followed by apixaban 5mg tablet twice-daily for at least 6 months. Unfractionated heparin: Heparin sodium in 0.45% sodium chloride injection for intravenous use Placebo: Saline solution reconstituted to mimic Alteplase 50mg vial Apixaban: Apixaban tablet
Nervous system disorders Headache	25.0% 1/4 • Number of events 1 • Adverse events were collected up to 8.5months given patient safety concerns due to the COVID-19 pandemic. The original Adverse Event assessment per the protocol was 1 year from baseline. Study was not unblinded. All data was entered in the treatment fields.
Eye disorders Eye pain	25.0% 1/4 • Number of events 1 • Adverse events were collected up to 8.5months given patient safety concerns due to the COVID-19 pandemic. The original Adverse Event assessment per the protocol was 1 year from baseline. Study was not unblinded. All data was entered in the treatment fields.
Gastrointestinal disorders Stomach pain	25.0% 1/4 • Number of events 1 • Adverse events were collected up to 8.5months given patient safety concerns due to the COVID-19 pandemic. The original Adverse Event assessment per the protocol was 1 year from baseline. Study was not unblinded. All data was entered in the treatment fields.
Blood and lymphatic system disorders Suspected bleed	25.0% 1/4 • Number of events 1 • Adverse events were collected up to 8.5months given patient safety concerns due to the COVID-19 pandemic. The original Adverse Event assessment per the protocol was 1 year from baseline. Study was not unblinded. All data was entered in the treatment fields.
Blood and lymphatic system disorders Bruising on chest	25.0% 1/4 • Number of events 1 • Adverse events were collected up to 8.5months given patient safety concerns due to the COVID-19 pandemic. The original Adverse Event assessment per the protocol was 1 year from baseline. Study was not unblinded. All data was entered in the treatment fields.
Respiratory, thoracic and mediastinal disorders increased shortness of breath	25.0% 1/4 • Number of events 1 • Adverse events were collected up to 8.5months given patient safety concerns due to the COVID-19 pandemic. The original Adverse Event assessment per the protocol was 1 year from baseline. Study was not unblinded. All data was entered in the treatment fields.
Musculoskeletal and connective tissue disorders back pain	25.0% 1/4 • Number of events 1 • Adverse events were collected up to 8.5months given patient safety concerns due to the COVID-19 pandemic. The original Adverse Event assessment per the protocol was 1 year from baseline. Study was not unblinded. All data was entered in the treatment fields.
Musculoskeletal and connective tissue disorders worsening back pain	25.0% 1/4 • Number of events 1 • Adverse events were collected up to 8.5months given patient safety concerns due to the COVID-19 pandemic. The original Adverse Event assessment per the protocol was 1 year from baseline. Study was not unblinded. All data was entered in the treatment fields.
Respiratory, thoracic and mediastinal disorders Dyspnea	25.0% 1/4 • Number of events 1 • Adverse events were collected up to 8.5months given patient safety concerns due to the COVID-19 pandemic. The original Adverse Event assessment per the protocol was 1 year from baseline. Study was not unblinded. All data was entered in the treatment fields.
Musculoskeletal and connective tissue disorders left groin pain	25.0% 1/4 • Number of events 1 • Adverse events were collected up to 8.5months given patient safety concerns due to the COVID-19 pandemic. The original Adverse Event assessment per the protocol was 1 year from baseline. Study was not unblinded. All data was entered in the treatment fields.
Respiratory, thoracic and mediastinal disorders palpitations	25.0% 1/4 • Number of events 1 • Adverse events were collected up to 8.5months given patient safety concerns due to the COVID-19 pandemic. The original Adverse Event assessment per the protocol was 1 year from baseline. Study was not unblinded. All data was entered in the treatment fields.

Additional Information

Victor Tapson

Cedars-Sinai Medical Center

Phone: 919-971-6441

Email: Victor.Tapson@cshs.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place