Clinical Trial Results:
RE-SPECT CVT: a randomised, open-label, exploratory trial with blinded endpoint adjudication (PROBE), comparing efficacy and safety of oral dabigatran etexilate versus oral warfarin in patients with cerebral venous and dural sinus thrombosis over a 24-week period
Summary
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EudraCT number |
2015-004412-38 |
Trial protocol |
PT NL ES DE IT |
Global end of trial date |
27 Jun 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Jun 2019
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First version publication date |
23 Jun 2019
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
1160.248
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Boehringer Ingelheim
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Sponsor organisation address |
Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
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Public contact |
QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
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Scientific contact |
QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
08 Aug 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
27 Jun 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
27 Jun 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective was to compare the net clinical benefit of the treatment arms, as measured by the composite of venous thrombotic event (VTE) (recurring cerebral venous thrombosis [CVT]; deep vein thrombosis [DVT] of any limb, pulmonary embolism [PE], or splanchnic vein thrombosis) or major bleeding events (MBEs) according to ISTH (International Society on Thrombosis and Haemostasis) criteria, after up to 24 weeks. Secondary objectives included a comparison of additional efficacy and safety parameters. A substudy at selected trial centres looked at the development of dural fistulas during the 24-week treatment period following the qualifying CVT.
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Protection of trial subjects |
Only participants that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All participants were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all participants was adhered to throughout the trial conduct. Rescue medication was allowed for all participants as required.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
20 Dec 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 13
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Country: Number of subjects enrolled |
India: 20
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Country: Number of subjects enrolled |
Italy: 14
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Country: Number of subjects enrolled |
Netherlands: 10
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Country: Number of subjects enrolled |
Poland: 10
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Country: Number of subjects enrolled |
Portugal: 22
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Country: Number of subjects enrolled |
France: 8
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Country: Number of subjects enrolled |
Russian Federation: 22
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Country: Number of subjects enrolled |
Spain: 4
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Worldwide total number of subjects |
123
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EEA total number of subjects |
81
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
110
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From 65 to 84 years |
13
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85 years and over |
0
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Recruitment
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Recruitment details |
This is a randomised, open-label, exploratory trial with blinded endpoint adjudication (PROBE [prospective, randomised, open-label, blinded endpoint] design), comparing efficacy and safety of oral dabigatran etexilate versus oral warfarin in patients with cerebral venous and dural sinus thrombosis over a 24-week period. | |||||||||||||||||||||
Pre-assignment
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Screening details |
All participants were screened for eligibility to participate in the trial. Participants attended specialist sites which would then ensure that they (all participants) met all inclusion/exclusion criteria. Participants were not to be randomised to trial treatment if any one of the specific entry criteria were not met. | |||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||
Blinding implementation details |
This was a randomised, open-label, exploratory trial with blinded endpoint adjudication.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Dabigatran etexilate | |||||||||||||||||||||
Arm description |
Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Dabigatran etexilate
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Investigational medicinal product code |
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Other name |
Pradaxa®
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.
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Arm title
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Warfarin | |||||||||||||||||||||
Arm description |
Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks. | |||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||
Investigational medicinal product name |
Warfarin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks.
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Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same. Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication. |
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Baseline characteristics reporting groups
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Reporting group title |
Dabigatran etexilate
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Reporting group description |
Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Warfarin
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Reporting group description |
Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Dabigatran etexilate
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Reporting group description |
Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks. | ||
Reporting group title |
Warfarin
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Reporting group description |
Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks. |
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End point title |
Percentage of participants with composite of Venous Thrombotic Event (VTE) or major bleeding event (MBE) according to International Society on Thrombosis and Haemostasis (ISTH) criteria in full observation period [1] | ||||||||||||
End point description |
Composite of the percentage of participants with MBE according to ISTH criteria and VTE (recurring cerebral venous thrombosis (CVT); deep venous thrombosis (DVT) of any limb, pulmonary embolism (PE), splanchnic vein thrombosis) in full observation period. All components were adjudicated in a blinded manner. Major bleeds were defined according to the ISTH definition of a major bleed, as follows: -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 haemoglobin of at least 2 grams/deciLitre (1.24 millimole/Litre) within 24 h, or leading to transfusion of 2 or more units of blood or packed cells and/or -Fatal bleed.
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End point type |
Primary
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End point timeframe |
From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks.
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. |
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Notes [2] - Full analysis set (FAS) [3] - FAS |
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No statistical analyses for this end point |
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End point title |
Percentage of participants with recurring cerebral venous and dural sinus thrombosis; DVT of any limb, PE or splanchnic vein thrombosis in full observation period | ||||||||||||||||||||||||
End point description |
VTE criteria: -New neurological signs/symptoms or worsening of previous signs/symptoms with new CVT on neuroimaging. -DVT of any limb was documented by: Abnormal compression ultrasonography; An intraluminal filling defect on venography; At autopsy -Splanchnic vein thrombosis: The presence of endoluminal material/absence of flow in the extrahepatic portal veins/mesenteric veins as shown by duplex-Doppler ultrasound/contrast-enhanced CT scan/MRI. -PE was documented by: An intraluminal filling defect in segmental/more proximal branches on spiral CT scan; An intraluminal filling defect/an extension of an existing defect/a sudden cut-off of vessels>2.5 mm in diameter on the pulmonary angiogram; Perfusion defect of at least 75% of a segment with a local normal ventilation result on ventilation/perfusion lung scan; Inconclusive spiral CT, pulmonary angiography/lung scintigraphy with demonstration of DVT in the lower extremities by compression ultrasonography/venography; At autopsy.
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End point type |
Secondary
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End point timeframe |
From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks.
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Notes [4] - FAS [5] - FAS |
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No statistical analyses for this end point |
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End point title |
Cerebral venous recanalisation as measured by the change in number of occluded cerebral veins and sinuses at week 24 | ||||||||||||
End point description |
Cerebral venous recanalisation was assessed by imaging and was adjudicated. Occlusion of cerebral veins and sinuses was scored as: 1 = full occlusion; 0 = no occlusion/partial occlusion. This score was applied using the below conventions: Superior sagittal, straight, cavernous sinuses, left and right jugular veins each scored individually as either 0 or 1; Right lateral transverse and sigmoid sinus were scored together, Left lateral transverse and sigmoid sinus were scored together, Superior petrous sinus and inferior petrous sinus were scored together, these were scored together as 0 = neither was fully occluded and 1 = at least 1 of them was fully occluded; Deep venous system, Superficial cortical veins, Cerebellar veins were scored as systems with conventions as 0 = none was fully occluded and 1 = at least 1 was fully occluded. For each patient a total score was calculated at baseline and at EOT and the recanalisation score was calculated as EOT - baseline total scores.
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End point type |
Secondary
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End point timeframe |
Baseline and week 24
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Notes [6] - FAS - Patients with missing/not analysable MRI scan at EOT are excluded from the analysis [7] - FAS - Patients with missing/not analysable MRI scan at EOT are excluded from the analysis |
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No statistical analyses for this end point |
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End point title |
Percentage of participants with major bleeding according to ISTH criteria in full observation period | ||||||||||||
End point description |
Major bleeds were defined according to the ISTH definition of a major bleed, as follows: -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 haemoglobin of at least 2 grams/deciLitre (1.24 millimole/Litre) within 24 h, or leading to transfusion of 2 or more units of blood or packed cells and/or -Fatal bleed
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End point type |
Secondary
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End point timeframe |
From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks.
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Notes [8] - TS [9] - TS |
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No statistical analyses for this end point |
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End point title |
Composite endpoint of percentage of participants with new Intracranial haemorrhage or worsening of the haemorrhagic component of a previous lesion after up to 24 weeks | ||||||||||||
End point description |
Intracranial haemorrhage (ICH) comprised the subtypes of intracerebral bleeds, subdural bleeds, epidural bleeds and subarachnoid bleeds that were recorded.
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End point type |
Secondary
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End point timeframe |
From first administration of trial medication until end of treatment visit, up to 24 weeks.
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Notes [10] - TS - Patients with missing/not analysable MRI scan at baseline or EOT are excluded from the analysis [11] - TS - Patients with missing/not analysable MRI scan at baseline or EOT are excluded from the analysis |
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No statistical analyses for this end point |
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End point title |
Percentage of participants with clinically relevant non-major bleeding events in full observation period | ||||||||||||
End point description |
A clinically relevant non-major bleeding event (CRNMBE) was a clinically overt bleed that did not meet the criteria for a major bleed but prompted a clinical response, in that it led to at least 1 of the following: A hospital admission (i.e. overnight stay in the hospital) for bleeding / A physician guided medical or surgical treatment for bleeding / A physician guided change, interruption or discontinuation of trial medication.
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End point type |
Secondary
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End point timeframe |
From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks.
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Notes [12] - TS [13] - TS |
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No statistical analyses for this end point |
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End point title |
Percentage of participants with major bleeding according to ISTH criteria or CRNMBEs after up to 24 weeks | ||||||||||||
End point description |
Percentage of participants with major bleeding according to ISTH criteria or CRNMBEs after up to 24 weeks.
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End point type |
Secondary
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End point timeframe |
From first administration of trial medication until end of treatment visit, up to 24 weeks.
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Notes [14] - TS [15] - TS |
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No statistical analyses for this end point |
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End point title |
Percentage of participants with any bleeding event after up to 24 weeks | ||||||||||||
End point description |
Percentage of participants with any bleeding event after up to 24 weeks where any bleeding event is the sum of all major and non-major bleeding events.
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End point type |
Secondary
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End point timeframe |
From first administration of trial medication until end of treatment visit, up to 24 weeks.
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Notes [16] - TS [17] - TS |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks.
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Adverse event reporting additional description |
TS
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.0
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Reporting groups
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Reporting group title |
Warfarin
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Reporting group description |
Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Dabigatran etexilate
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Reporting group description |
Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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10 Feb 2017 |
The number of planned patients was changed from a total of 180 to 120 (and from 90 to 60 patients planned in each treatment arm). The anticipated drop-out rate was changed from 15-20% to 10%, resulting in an estimated 108 evaluable patients (54 per treatment arm). It was clarified that all women of childbearing potential (WOCBP) should perform a pregnancy test every 4 weeks. A list of acceptable contraception methods was added and tubal ligation was removed from the list of procedures to render a woman not of childbearing potential. It was also specified that WOCBP should use effective methods of birth control from the moment of signing informed consent for the trial until completion of the follow-up visit (Visit 6). It was clarified that the primary objective did not require 24 weeks of treatment.
The set up of the adjudication committee (AC) was performed by BI and not by a third party. A caution statement was added regarding treatment with warfarin in patients with known protein C or protein S deficiency. The requirements for confirmation of DVT, PE and splanchnic vein thrombosis were changed to require images and/or reports (instead of both) to be provided to the AC.
An additional patient population, Screened Set (SCR), was defined, i.e. All patients who signed informed consent and completed at least some screening procedures. The list of documents and images that would be made available for adjudication purposes was removed. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
Full analysis set (FAS): All patients randomised were analysed in the treatment group to which they were randomised regardless of whether they took study medication. This followed the intent-to-treat principle. |