PEITHO-3 - A reduced dose of thrombolytic treatment for patients with intermediate high-risk acute pulmonary embolism: a randomized controlled trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

4 Aug 2021 → ongoing

Decision date (initial)

2024-07-30

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Spanish Ministry of Science and Innovation, Instituto De Salud Carlos III (ISCIII) · French Ministry of Health: Programme hospitalier de Recherche Clinique – PHRC 2016 · Canadian Venous Thromboembolism Research Network (CanVECTOR) · D. Collen Research Foundation · Boehringer Ingelheim · Canadian Institutes of Health Research (CIHR) · German Research Foundation (Deutsche Forschungs-gemeinschaft) · International Network of VENous Thromboembolism Clinical Research Networks (INVENT)

External identifiers

EU CT number

2024-511321-54-00

EudraCT number

2018-000816-96

ClinicalTrials.gov

NCT04430569

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

To assess the efficacy of reduced dose thrombolytic therapy in patients with acute intermediate-high-risk pulmonary embolism at day 30.

Secondary objectives 5

1. To assess the safety of reduced dose thrombolytic therapy in patients with intermediate-high-risk acute pulmonary embolism at day 30
2. To assess the net clinical benefit of reduced dose thrombolytic therapy in patients with intermediate-high-risk acute pulmonary embolism at day 30
3. To assess the effect of reduced dose thrombolytic therapy on overall mortality of patients with intermediate-high-risk acute pulmonary embolism at 2 years
4. To assess the effect of reduced dose thrombolytic therapy on long-term mortality, functional impairment, residual right ventricular (RV) dysfunction and chronic thromboembolic pulmonary hypertension at 2 years
5. To assess the effect of reduced-dose thrombolytic therapy on utilization of health care resources at day 30 and day 180

Conditions and MedDRA coding

intermediate-high-risk acute pulmonary embolism

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Age 18 years or older
2. Objectively confirmed acute PE with first symptoms occurring 2 weeks or less before randomization. Objective confirmation is based on at least one of the following criteria: a. at least one segmental ventilation-perfusion mismatch on lung scanning b. a computed tomography pulmonary angiography (CTPA) or selective pulmonary angiography showing a filling defect or an abrupt obstruction of a segmental or more proximal pulmonary artery;
3. Acute PE confirmed within 24 hours prior to randomization;
4. Elevated risk of early death, or of hemodynamic collapse, or PE recurrence, indicated by at least one of the following criteria:  systolic blood pressure ≤ 110 mm Hg over at least 15 minutes upon enrolment  temporary need for fluid resuscitation and/or treatment with low dose catecholamines because of arterial hypotension at presentation, provided that the patient could be stabilized within 2 hours of admission and maintains SBP of ≥ 90 mm Hg and adequate organ perfusion without catecholamine infusion  respiratory rate > 20/min or oxygen saturation on pulse oximetry (SpO2) < 90% (or partial arterial oxygen pressure < 60 mm Hg) at rest while breathing room air  documented history of chronic symptomatic heart failure, defined as previous diagnosis of heart failure (i.e. heart failure with reduced, moderately reduced or preserved ejection fraction) or treatment for heart failure at any time during the past 12 months;
5. RV dysfunction indicated by RV/LV diameter ratio > 1.0 on echocardiography apical four-chamber or subcostal four-chamber view or on CTPA (transverse plane);
6. Serum troponin I or T concentration above the upper limit of local normal using a high sensitivity assay
7. Ability to randomize the patient within 6 hours after the investigator receives the result of the second of the two criteria for RV dysfunction (RV/LV diameter ratio >1.0) and myocardial injury (serum troponin I or T concentration above the upper limit of local normal), whichever comes the latest.
8. Signed informed consent form.
9. [France] Patient insured under a social security system

Exclusion criteria 29

1. Hemodynamic instability, defined by at least one of the following criteria [1] - cardiac arrest; - obstructive shock, defined as: (i) systolic BP < 90 mm Hg, or vasopressors required to achieve a SBP ≥90 mm Hg despite an adequate filling status; and (ii) end-organ hypoperfusion (altered mental status; cold, clammy skin; oliguria/anuria; increased serum lactate); - isolated persistent hypotension (systolic BP < 90 mm Hg, or a systolic pressure drop ≥ 40 mm Hg for > 15 min), if not caused by new-onset arrhythmia, hypovolemia, or sepsis
2. Platelet count < 100 x 109/L
3. INR > 1.4. If INR not available: prothrombin time ratio < 60%. If both INR and prothrombin time ratio are measured, INR is relevant for the assessment of this criterion.
4. Treatment with antiplatelet agents other than a. acetylsalicylic acid (ASA) ≤ 100 mg once daily or b. clopidogrel 75 mg once daily or c. a single loading dose of ASA or clopidogrel Dual anti-platelet therapy (ASA + clopidogrel) is not allowed.
5. Known significant bleeding risk according to the investigator’s judgement
6. Administration of thrombolytic agents within the previous 4 days
7. Vena cava filter insertion or pulmonary thrombectomy within the previous 4 days
8. [Italy and the Netherlands] Participation in another interventional clinical study within 30 days from the inclusion
9. [All countries except Italy and the Netherlands] Current participation in another interventional clinical study
10. Previous enrolment in this study
11. Known hypersensitivity to alteplase, gentamicin (a residue of the Actilyse®/Activase® (only for Canada) manufacturing process present in trace amounts), any of the excipients of Actilyse®/Activase® (only for Canada), or low-molecular weight heparin
12. Any direct oral anticoagulant within 12 hours of inclusion
13. Uncontrolled hypertension defined by SBP > 180 mm Hg at the time of inclusion
14. Known pericarditis or endocarditis
15. Active bleeding
16. History of non-traumatic intracranial bleeding, any time
17. Acute ischemic stroke or transient ischemic attack (TIA) within the previous 6 months
18. Known central nervous system neoplasm/metastasis
19. Neurologic, ophthalmologic, abdominal, cardiac, thoracic, vascular or orthopedic surgery or trauma within the previous 3 weeks
20. Known previous immune heparin-induced thrombocytopenia
21. Known severe liver disease (grade ≥ 3)1 including liver failure, cirrhosis, portal hypertension (esophageal varices) and active hepatitis
22. Acute symptomatic pancreatitis
23. Gastrointestinal ulcers or esophageal varices, documented within the past 3 months
24. Known arterial aneurysm, arterial or venous malformations
25. Pregnancy or parturition within the previous 30 days or current breastfeeding.
26. Women of childbearing potential who do not have a negative pregnancy test at the inclusion visit and do not use one of the following methods of birth control: hormonal contraception or intrauterine device or bilateral tubal occlusion
27. Any other condition that in the investigator’s opinion would place the patient at increased risk upon start of the investigational treatment
28. Life expectancy of less than 6 months or inability to complete 6-month follow-up.
29. Patient under legal protection

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary outcome is the composite of (1) death from any cause, or (2) hemodynamic decompensation, or (3) objectively confirmed recurrent PE at day 30.

Secondary endpoints 3

1. Fatal or GUSTO severe or life-threatening bleeding within 30 days
2. Net clinical benefit defined as the composite of the primary efficacy outcome and GUSTO severe or life-threatening bleeding within 30 days
3. All-cause mortality within 30 days

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Prof. Olivier SANCHEZ

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Prof. Olivier SANCHEZ

Third parties 1

Locations

8 EU/EEA countries · 56 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 40 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications