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A Clinical Trial Comparing Efficacy and Safety of Dabigatran Etexilate With Warfarin in Patients With Cerebral Venous and Dural Sinus Thrombosis (RE-SPECT CVT)

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ClinicalTrials.gov Identifier: NCT02913326
Recruitment Status : Completed
First Posted : September 23, 2016
Results First Posted : August 15, 2019
Last Update Posted : August 15, 2019
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Thromboembolism
Interventions Drug: Dabigatran etexilate
Drug: Warfarin
Enrollment 120
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 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.
Arm/Group Title Dabigatran Etexilate Warfarin
Hide Arm/Group Description Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks. 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.
Period Title: Overall Study
Started 60 60
Completed 59 58
Not Completed 1 2
Reason Not Completed
Reason not listed             0             1
Lost to Follow-up             0             1
Adverse Event             1             0
Arm/Group Title Dabigatran Etexilate Warfarin Total
Hide Arm/Group Description Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks. 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. Total of all reporting groups
Overall Number of Baseline Participants 60 60 120
Hide Baseline Analysis Population Description
Treated set (TS): The set includes patients who received at least one dose of study medication and were analysed according to the treatment they received.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 60 participants 60 participants 120 participants
44.4  (14.06) 46.0  (13.64) 45.2  (13.82)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 60 participants 60 participants 120 participants
Female
33
  55.0%
33
  55.0%
66
  55.0%
Male
27
  45.0%
27
  45.0%
54
  45.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 60 participants 60 participants 120 participants
Hispanic or Latino
4
   6.7%
11
  18.3%
15
  12.5%
Not Hispanic or Latino
52
  86.7%
43
  71.7%
95
  79.2%
Unknown or Not Reported
4
   6.7%
6
  10.0%
10
   8.3%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 60 participants 60 participants 120 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
12
  20.0%
7
  11.7%
19
  15.8%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
White
45
  75.0%
49
  81.7%
94
  78.3%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
3
   5.0%
4
   6.7%
7
   5.8%
1.Primary Outcome
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.
Hide 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
Time Frame From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Dabigatran Etexilate Warfarin
Hide Arm/Group Description:
Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.
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.
Overall Number of Participants Analyzed 60 60
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
1.7
(0.0 to 8.9)
3.3
(0.4 to 11.5)
2.Secondary Outcome
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
Hide Description

VTE criterions:

  • 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.
Time Frame From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks.
Hide Outcome Measure Data
Hide Analysis Population Description

FAS,

Magnetic resonance imaging (MRI), Computed tomography (CT)

Arm/Group Title Dabigatran Etexilate Warfarin
Hide Arm/Group Description:
Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.
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.
Overall Number of Participants Analyzed 60 60
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
Recurring CVT
0.0
(0.0 to 6.0)
0.0
(0.0 to 6.0)
DVT of any limb
0.0
(0.0 to 6.0)
0.0
(0.0 to 6.0)
PE
0.0
(0.0 to 6.0)
0.0
(0.0 to 6.0)
Splanchnic vein thrombosis
0.0
(0.0 to 6.0)
0.0
(0.0 to 6.0)
3.Secondary Outcome
Title Cerebral Venous Recanalisation as Measured by the Change in Number of Occluded Cerebral Veins and Sinuses at Week 24
Hide 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; Deep venous system, Superficial cortical veins, Cerebellar veins were scored as systems.

For each patient a total score was calculated at baseline and at EOT and the recanalisation score was calculated as EOT - baseline total scores with conventions as 0 = no cerebral veins or sinuses fully occluded and 11 = all cerebral veins and sinuses fully occluded; the lower the score, the better.

Time Frame Baseline and week 24
Hide Outcome Measure Data
Hide Analysis Population Description
FAS - Patients with missing/not analysable MRI scan at baseline or end of treatment (EOT) are excluded from the analysis
Arm/Group Title Dabigatran Etexilate Warfarin
Hide Arm/Group Description:
Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.
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.
Overall Number of Participants Analyzed 55 52
Mean (Standard Deviation)
Unit of Measure: Units on scale
-0.8  (0.78) -1.0  (0.92)
4.Secondary Outcome
Title Percentage of Participants With Major Bleeding According to ISTH Criteria in Full Observation Period
Hide 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
Time Frame From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks.
Hide Outcome Measure Data
Hide Analysis Population Description
TS
Arm/Group Title Dabigatran Etexilate Warfarin
Hide Arm/Group Description:
Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.
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.
Overall Number of Participants Analyzed 60 60
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
1.7
(0.0 to 8.9)
3.3
(0.4 to 11.5)
5.Secondary Outcome
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
Hide Description Intracranial haemorrhage (ICH) comprised the subtypes of intracerebral bleeds, subdural bleeds, epidural bleeds and subarachnoid bleeds that were recorded.
Time Frame From first administration of trial medication until end of treatment visit, up to 24 weeks.
Hide Outcome Measure Data
Hide Analysis Population Description
TS - Patients with missing/not analysable MRI scan at baseline or EOT are excluded from the analysis
Arm/Group Title Dabigatran Etexilate Warfarin
Hide Arm/Group Description:
Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.
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.
Overall Number of Participants Analyzed 56 53
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
1.8
(0.0 to 9.6)
3.8
(0.5 to 13.0)
6.Secondary Outcome
Title Percentage of Participants With Clinically Relevant Non-major Bleeding Events in Full Observation Period.
Hide 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.
Time Frame From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks.
Hide Outcome Measure Data
Hide Analysis Population Description
TS
Arm/Group Title Dabigatran Etexilate Warfarin
Hide Arm/Group Description:
Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.
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.
Overall Number of Participants Analyzed 60 60
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
0.0
(0.0 to 6.0)
1.7
(0.0 to 8.9)
7.Secondary Outcome
Title Percentage of Participants With Major Bleeding According to ISTH Criteria or CRNMBEs After up to 24 Weeks
Hide Description Percentage of participants with major bleeding according to ISTH criteria or CRNMBEs after up to 24 weeks.
Time Frame From first administration of trial medication until end of treatment visit, up to 24 weeks.
Hide Outcome Measure Data
Hide Analysis Population Description
TS
Arm/Group Title Dabigatran Etexilate Warfarin
Hide Arm/Group Description:
Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.
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.
Overall Number of Participants Analyzed 60 60
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
1.7
(0.0 to 8.9)
5.0
(1.0 to 13.9)
8.Secondary Outcome
Title Percentage of Participants With Any Bleeding Event After up to 24 Weeks
Hide 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.
Time Frame From first administration of trial medication until end of treatment visit, up to 24 weeks.
Hide Outcome Measure Data
Hide Analysis Population Description
TS
Arm/Group Title Dabigatran Etexilate Warfarin
Hide Arm/Group Description:
Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.
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.
Overall Number of Participants Analyzed 60 60
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
20.0
(10.8 to 32.3)
20.0
(10.8 to 32.3)
Time Frame From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks.
Adverse Event Reporting Description TS
 
Arm/Group Title Dabigatran Etexilate Warfarin
Hide Arm/Group Description Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks. 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.
All-Cause Mortality
Dabigatran Etexilate Warfarin
Affected / at Risk (%) Affected / at Risk (%)
Total   0/60 (0.00%)   0/60 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
Dabigatran Etexilate Warfarin
Affected / at Risk (%) Affected / at Risk (%)
Total   8/60 (13.33%)   6/60 (10.00%) 
Blood and lymphatic system disorders     
Evans syndrome  1  1/60 (1.67%)  0/60 (0.00%) 
Eye disorders     
Glaucoma  1  1/60 (1.67%)  0/60 (0.00%) 
Gastrointestinal disorders     
Gastrointestinal necrosis  1  1/60 (1.67%)  0/60 (0.00%) 
Intestinal haematoma  1  1/60 (1.67%)  0/60 (0.00%) 
Vomiting  1  1/60 (1.67%)  0/60 (0.00%) 
Infections and infestations     
Pyelonephritis  1  0/60 (0.00%)  1/60 (1.67%) 
Severe fever with thrombocytopenia syndrome  1  0/60 (0.00%)  1/60 (1.67%) 
Urinary tract infection  1  0/60 (0.00%)  1/60 (1.67%) 
Injury, poisoning and procedural complications     
Subdural haematoma  1  0/60 (0.00%)  2/60 (3.33%) 
Upper limb fracture  1  0/60 (0.00%)  1/60 (1.67%) 
Investigations     
International normalised ratio fluctuation  1  0/60 (0.00%)  1/60 (1.67%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Meningioma  1  1/60 (1.67%)  0/60 (0.00%) 
Nervous system disorders     
Cerebral haemorrhage  1  1/60 (1.67%)  0/60 (0.00%) 
Cerebral infarction  1  1/60 (1.67%)  0/60 (0.00%) 
Epilepsy  1  1/60 (1.67%)  0/60 (0.00%) 
Intracranial aneurysm  1  1/60 (1.67%)  0/60 (0.00%) 
Intracranial pressure increased  1  0/60 (0.00%)  1/60 (1.67%) 
Intracranial venous sinus thrombosis  1  1/60 (1.67%)  0/60 (0.00%) 
Paraesthesia  1  1/60 (1.67%)  0/60 (0.00%) 
Seizure  1  1/60 (1.67%)  0/60 (0.00%) 
Vascular disorders     
Raynaud's phenomenon  1  0/60 (0.00%)  1/60 (1.67%) 
1
Term from vocabulary, MedDRA 21.0
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Dabigatran Etexilate Warfarin
Affected / at Risk (%) Affected / at Risk (%)
Total   21/60 (35.00%)   17/60 (28.33%) 
Gastrointestinal disorders     
Diarrhoea  1  4/60 (6.67%)  2/60 (3.33%) 
Dyspepsia  1  4/60 (6.67%)  0/60 (0.00%) 
Nervous system disorders     
Headache  1  10/60 (16.67%)  8/60 (13.33%) 
Psychiatric disorders     
Depression  1  2/60 (3.33%)  4/60 (6.67%) 
Insomnia  1  0/60 (0.00%)  4/60 (6.67%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  5/60 (8.33%)  0/60 (0.00%) 
1
Term from vocabulary, MedDRA 21.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI’s intellectual property rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim, Call Center
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02913326     History of Changes
Other Study ID Numbers: 1160.248
2015-004412-38 ( EudraCT Number )
First Submitted: September 21, 2016
First Posted: September 23, 2016
Results First Submitted: June 3, 2019
Results First Posted: August 15, 2019
Last Update Posted: August 15, 2019