PEITHO Pulmonary Embolism Thrombolysis Study

• Clinical composite endpoint of all-cause mortality or haemodynamic collapse within 7 days [ Time Frame: Day 7 ] [ Designated as safety issue: Yes ]
• Haemodynamic collapse is defined as: need for cardiopulmonary resuscitation; or systolic blood pressure < 90 mm Hg for at least 15 min or drop of syst [ Time Frame: Day 7 ] [ Designated as safety issue: Yes ]

• Clinical composite endpoint of all-cause mortality or haemodynamic collapse within 7 days [ Time Frame: select one ] [ Designated as safety issue: No ]
• Haemodynamic collapse is defined as: need for cardiopulmonary resuscitation; or systolic blood pressure < 90 mm Hg for at least 15 min or drop of syst [ Time Frame: select one ] [ Designated as safety issue: No ]

• Death within 7 days [ Time Frame: Day 7 ] [ Designated as safety issue: Yes ]
• Haemodynamic collapse within 7 days [ Time Frame: Day 7 ] [ Designated as safety issue: Yes ]
• Confirmed symptomatic pulmonary embolism recurrence within 7 days [ Time Frame: Day 7 ] [ Designated as safety issue: Yes ]
• Death within 30 days [ Time Frame: Day 30 ] [ Designated as safety issue: Yes ]
• Total strokes (intra cranial haemorrhage or ischaemic stroke) within 7 days [ Time Frame: Day 7 ] [ Designated as safety issue: Yes ]
• Major bleeding (other intracranial haemorrhage or ischaemic stroke) [ Time Frame: Day 7 ] [ Designated as safety issue: Yes ]

• Death within 7 days [ Time Frame: select one ] [ Designated as safety issue: Yes ]
• Haemodynamic collapse within 7 days [ Time Frame: select one ] [ Designated as safety issue: Yes ]
• Confirmed symptomatic pulmonary embolism recurrence within 7 days [ Time Frame: select one ] [ Designated as safety issue: Yes ]
• Death within 30 days [ Time Frame: select one ] [ Designated as safety issue: Yes ]
• Total strokes (intra cranial haemorrhage or ischaemic stroke) within 7 days [ Time Frame: select one ] [ Designated as safety issue: Yes ]
• Major bleeding (othe [ Time Frame: select one ] [ Designated as safety issue: Yes ]

Heparin is the reference therapy for most patients with pulmonary embolism. Some patients with sub-massive pulmonary embolism defined by normal blood pressure and dysfunction of the right ventricle have a higher mortality risk. It has been suggested that thrombolytic treatment, a drug that dissolves blood clots more rapidly, may reduce the mortality in those patients. The studies reported to date were unable to confirm or refute this hypothesis because the number of patients included in those studies is too low. The aim of the study is to compare thrombolytic treatment with heparin (which is the reference therapy for pulmonary embolism) in a large group of patients with sub-massive pulmonary embolism.

A prospective, randomized, double-blind, placebo-controlled, international, multicentre, parallel-group comparison trial evaluating the efficacy and safety of single i.v. bolus tenecteplase plus standard anticoagulation as compared with standard anticoagulation in normotensive patients with acute pulmonary embolism and with echocardiographic and laboratory evidence of right ventricular dysfunction.Patients suffering from acute pulmonary embolism (first symptoms occurring within 15 days) confirmed by lung scanning or a positive spiral computed tomogram, or a positive pulmonary angiogram, presenting with right ventricular dysfunction on echocardiography and tested troponin I or T positive will be included in the study if they have no exclusion criteria.Patients in the investigational group will receive: Ø Tenecteplase as a single body-weight (known or estimated) adjusted IV bolus administered over 5 - 10 seconds not later than 30 minutes after randomization, and not later than 2 hours after the diagnosis of RV dysfunction Weight (kg) Dose in mg Dose in units Dose in ml<60 30 mg 6000 U 6 ml>60 to <70 35 mg 7000 U 7 ml>70 to <80 40 mg 8000 U 8 ml>80 to <90 45 mg 9000 U 9 ml>90 50 mg 10000 U 10 mlØ and: concomitant therapy-Unfractionated heparin at a dose of 80 IUxKg-1 as an intravenous bolus, followed by an infusion of 18 IUxKg-1xh-1, to be administered immediately after randomization in all patients for at least 48 hours following randomization. Beyond this period, intravenous UFH may be substituted with subcutaneous heparin (LMWH) treatment. The bolus will be omitted when heparin was started before randomisation.Patients in the control group will receive Ø placebo as a single body-weight (known or estimated) adjusted IV bolus administered over 5 - 10 seconds not later than 30 minutes after randomization, and not later than 2 hours after the diagnosis of RV dysfunction. Weight (kg) Dose in ml<60 6 ml>60 to <70 7 ml>70 to <80 8 ml>80 to <90 9 ml>90 10 mlØ and concomitant therapy with Unfractionated heparin

• Drug: placebo ( group B)
  placebo ( group B)
  Other Name: placebo ( group B)
• Drug: tenecteplase (group A)
  tenecteplase (group A)
  Other Name: tenecteplase (group A)

• Experimental: group A
  tenecteplase (group A)
  Intervention: Drug: tenecteplase (group A)
• Placebo Comparator: group B
  placebo ( group B)
  Intervention: Drug: placebo ( group B)

• Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation. 2004 Aug 10;110(6):744-9. Epub 2004 Jul 19.
• Steering Committee. Single-bolus tenecteplase plus heparin compared with heparin alone for normotensive patients with acute pulmonary embolism who have evidence of right ventricular dysfunction and myocardial injury: rationale and design of the Pulmonary Embolism Thrombolysis (PEITHO) trial. Am Heart J. 2012 Jan;163(1):33-38.e1.

Inclusion Criteria:

• Age 18 years or older
• Acute PE (first symptoms occurring 15 days or less before randomisation) confirmed by lung scan, or a positive spiral computed tomogram, or a positive pulmonary angiogram
• Right ventricular dysfunction confirmed by echocardiography or spiral computed tomography of the chest and a positive troponin I or T test

Exclusion criteria:

• Haemodynamic collapse at presentation as defined above
• Known significant bleeding risk
• Administration of thrombolytic agents within the previous 4 days
• Vena cava filter insertion or pulmonary thrombectomy within the previous 4 days
• Uncontrolled hypertension defined as systolic BP >180 mm Hg and/or diastolic BP >110 mm Hg at randomisation
• Treatment with an investigational drug under another study protocol in the previous 7 days or greater, according to local requirements
• Previous enrolment in this study
• Known hypersensitivity to tenecteplase, alteplase, unfractionated heparin, or to any of the excipients
• Pregnancy, lactation or parturition within the previous 30 days. Women of childbearing age must have a negative pregnancy test or use a medically accepted method of birth control
• Known coagulation disorder (including vitamin K antagonists)
• Any other condition that the investigator feels would place the patient at increased risk if the investigational therapy is initiated

• German Federal Ministry of Education and Research
• Boehringer Ingelheim Pharmaceuticals