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Trial to Evaluate the Effect of Secondary Prophylaxis With rFVIII Therapy in Severe Hemophilia A Adult and/or Adolescent Subjects Compared to That of Episodic Treatment (SPINART)

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ClinicalTrials.gov Identifier: NCT00623480
Recruitment Status : Completed
First Posted : February 26, 2008
Results First Posted : August 7, 2013
Last Update Posted : November 17, 2014
Sponsor:
Information provided by (Responsible Party):
Bayer

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Hemophilia A
Intervention Biological: Recombinant Factor VIII (Kogenate FS, BAY14-2222)
Enrollment 84
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Recombinant Factor VIII Prophylaxis Treatment Recombinant Factor VIII On-demand Treatment
Hide Arm/Group Description Participants received 25 IU/kg of Recombinant Factor VIII (Kogenate FS, BAY14-2222) intravenously (IV), 3 times per week. Dose escalation steps by 5 IU/kg (to 30 IU/kg or 35 IU/kg maximum) for patients exhibiting a bleeding frequency of 12 bleeding episodes per year or greater. Participants received Recombinant Factor VIII (Kogenate FS, BAY14-2222) IV for bleeds in accordance with package insert instructions and study physician recommendations.
Period Title: Overall Study
Started 42 42
Completed 35 35
Not Completed 7 7
Reason Not Completed
Lost to Follow-up             0             1
Withdrawal by Subject             2             4
Lack of Efficacy             1             0
Non-compliant with study medication             4             0
Protocol Violation             0             1
Site closed by sponsor             0             1
Arm/Group Title Recombinant Factor VIII Prophylaxis Treatment Recombinant Factor VIII On-demand Treatment Total
Hide Arm/Group Description Participants received 25 IU/kg of Recombinant Factor VIII (Kogenate FS, BAY14-2222) intravenously (IV), 3 times per week. Dose escalation steps by 5 IU/kg (to 30 IU/kg or 35 IU/kg maximum) for patients exhibiting a bleeding frequency of 12 bleeding episodes per year or greater. Participants received Recombinant Factor VIII (Kogenate FS, BAY14-2222) IV for bleeds in accordance with package insert instructions and study physician recommendations. Total of all reporting groups
Overall Number of Baseline Participants 42 42 84
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 42 participants 42 participants 84 participants
30.6  (8.8) 30.7  (9.7) 30.6  (9.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 42 participants 42 participants 84 participants
Female
0
   0.0%
0
   0.0%
0
   0.0%
Male
42
 100.0%
42
 100.0%
84
 100.0%
Number of bleeds during last 6 months  
Mean (Standard Deviation)
Unit of measure:  Bleeds
Number Analyzed 42 participants 42 participants 84 participants
10.0  (4.4) 12.2  (5.1) 11.1  (4.8)
Number of patients with target joints, Yes/No   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 42 participants 42 participants 84 participants
Yes 28 31 59
No 14 11 25
[1]
Measure Description: A ‘target joint’ is a particular joint that has experienced repeated bleeds or at least four bleeds into one joint within a six month period.
1.Primary Outcome
Title Bleeding Frequency (Number of Total Bleeds)
Hide Description [Not Specified]
Time Frame After the last enrolled patient has been in the study for 1 year. At the cut-off, the median follow-up duration was 616 days (minimum was 111 days and maximum was 1109 days)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT (Intent-to-treat) Population
Arm/Group Title Recombinant Factor VIII Prophylaxis Treatment Recombinant Factor VIII On-demand Treatment
Hide Arm/Group Description:
Participants received 25 IU/kg of Recombinant Factor VIII (Kogenate FS, BAY14-2222) intravenously (IV), 3 times per week. Dose escalation steps by 5 IU/kg (to 30 IU/kg or 35 IU/kg maximum) for patients exhibiting a bleeding frequency of 12 bleeding episodes per year or greater.
Participants received Recombinant Factor VIII (Kogenate FS, BAY14-2222) IV for bleeds in accordance with package insert instructions and study physician recommendations.
Overall Number of Participants Analyzed 42 42
Median (Full Range)
Unit of Measure: Bleeds
0
(0 to 57)
54.5
(0 to 149)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Recombinant Factor VIII Prophylaxis Treatment, Recombinant Factor VIII On-demand Treatment
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Negative Binomial Regression Model
Comments Adjusted for time of follow-up
Method of Estimation Estimation Parameter Ratio (On-Demand vs. Prophylaxis)
Estimated Value 14.7
Confidence Interval (2-Sided) 95%
8.1 to 26.5
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change From Baseline to 3 Years in the MRI (Magnetic Resonance Imaging) Scale.
Hide Description The Extended MRI Scale total score has a range between 0 (normal unaffected joint) to 45 (maximal joint damage) points. It is composed of 2 domains, the soft tissue domain with a maximum of 9 points and the osteochondral domain with a maximum of 36 points. A single score for each subject was to be calculated from the sum of both domains and the average over all joints for the Extended MRI endpoint. Higher MRI score denotes greater joint structure damage thus a positive change from baseline means worsening.
Time Frame Baseline and 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set
Arm/Group Title Recombinant Factor VIII Prophylaxis Treatment Recombinant Factor VIII On-demand Treatment
Hide Arm/Group Description:
Participants received 25 IU/kg of Recombinant Factor VIII (Kogenate FS, BAY14-2222) intravenously (IV), 3 times per week. Dose escalation steps by 5 IU/kg (to 30 IU/kg or 35 IU/kg maximum) for patients exhibiting a bleeding frequency of 12 bleeding episodes per year or greater.
Participants received Recombinant Factor VIII (Kogenate FS, BAY14-2222) IV for bleeds in accordance with package insert instructions and study physician recommendations.
Overall Number of Participants Analyzed 41 38
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Scores on a scale
0.79
(0.27 to 1.32)
0.96
(0.34 to 1.58)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Recombinant Factor VIII Prophylaxis Treatment, Recombinant Factor VIII On-demand Treatment
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6614
Comments [Not Specified]
Method Based on cLDA model
Comments Adjusted for presence/absence of target joint and prior 6 month bleeding frequency
Method of Estimation Estimation Parameter estimated diff (prohylaxis vs. OD)
Estimated Value -0.17
Confidence Interval (2-Sided) 95%
-0.92 to 0.59
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change From Baseline to 3 Years in the Colorado Adult Joint Assessment Scale
Hide Description The total joint score is derived for each of six joints: left and right sides for knees (score: 0-25), ankles (score: 0-25), and elbows (score: 0-21). Higher CAJAS (Colorado Adult Joint Assessment Scale) score denotes greater joint structure damage thus a positive change from baseline means worsening. CAJAS total score is the sum of all 6 joints, ranging from 0 (best possible outcome) to 142 (worst possible outcome).
Time Frame Baseline and 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set
Arm/Group Title Recombinant Factor VIII Prophylaxis Treatment Recombinant Factor VIII On-demand Treatment
Hide Arm/Group Description:
Participants received 25 IU/kg of Recombinant Factor VIII (Kogenate FS, BAY14-2222) intravenously (IV), 3 times per week. Dose escalation steps by 5 IU/kg (to 30 IU/kg or 35 IU/kg maximum) for patients exhibiting a bleeding frequency of 12 bleeding episodes per year or greater.
Participants received Recombinant Factor VIII (Kogenate FS, BAY14-2222) IV for bleeds in accordance with package insert instructions and study physician recommendations.
Overall Number of Participants Analyzed 42 42
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Scores on a scale
-0.31
(-0.79 to 0.18)
0.63
(0.08 to 1.18)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Recombinant Factor VIII Prophylaxis Treatment, Recombinant Factor VIII On-demand Treatment
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0072
Comments [Not Specified]
Method Based on cLDA model
Comments Adjusted for presence/absence of target joint and prior 6 month bleeding frequency
Method of Estimation Estimation Parameter estimated diff (prohylaxis vs. OD)
Estimated Value -0.94
Confidence Interval (2-Sided) 95%
-1.61 to -0.26
Estimation Comments [Not Specified]
4.Other Pre-specified Outcome
Title Change From Baseline to 3 Years in the Physical Functioning Domain of the Haemo-QoL-A
Hide Description The Haemo-QoL-A total score as well as each of its domains have a range between 0 (worst Quality of Life) and 100 (best Quality of Life) points. Therefore, a higher Haemo-QoL-A score denotes greater Quality of Life.
Time Frame Baseline and 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set
Arm/Group Title Recombinant Factor VIII Prophylaxis Treatment Recombinant Factor VIII On-demand Treatment
Hide Arm/Group Description:
Participants received 25 IU/kg of Recombinant Factor VIII (Kogenate FS, BAY14-2222) intravenously (IV), 3 times per week. Dose escalation steps by 5 IU/kg (to 30 IU/kg or 35 IU/kg maximum) for patients exhibiting a bleeding frequency of 12 bleeding episodes per year or greater.
Participants received Recombinant Factor VIII (Kogenate FS, BAY14-2222) IV for bleeds in accordance with package insert instructions and study physician recommendations.
Overall Number of Participants Analyzed 41 42
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Scores on a scale
7.86
(1.79 to 13.92)
-5.30
(-11.97 to 1.37)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Recombinant Factor VIII Prophylaxis Treatment, Recombinant Factor VIII On-demand Treatment
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments no p-values computed
Method Based on cLDA model
Comments Adjusted for presence/absence of target joint and prior 6 month bleeding frequency
Method of Estimation Estimation Parameter estimated diff (prohylaxis vs. OD)
Estimated Value 13.15
Confidence Interval (2-Sided) 95%
5.23 to 21.08
Estimation Comments [Not Specified]
Time Frame From randomization until Month 37.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Recombinant Factor VIII Prophylaxis Treatment Recombinant Factor VIII On-demand Treatment
Hide Arm/Group Description Participants received 25 IU/kg of Recombinant Factor VIII (Kogenate FS, BAY14-2222) intravenously (IV), 3 times per week. Dose escalation steps by 5 IU/kg (to 30 IU/kg or 35 IU/kg maximum) for patients exhibiting a bleeding frequency of 12 bleeding episodes per year or greater. Participants received Recombinant Factor VIII (Kogenate FS, BAY14-2222) IV for bleeds in accordance with package insert instructions and study physician recommendations.
All-Cause Mortality
Recombinant Factor VIII Prophylaxis Treatment Recombinant Factor VIII On-demand Treatment
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Recombinant Factor VIII Prophylaxis Treatment Recombinant Factor VIII On-demand Treatment
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   9/42 (21.43%)      11/42 (26.19%)    
Blood and lymphatic system disorders     
Anaemia * 1  0/42 (0.00%)  0 1/42 (2.38%)  1
Congenital, familial and genetic disorders     
Phimosis * 1  0/42 (0.00%)  0 1/42 (2.38%)  1
Gastrointestinal disorders     
Peritoneal haemorrhage * 1  1/42 (2.38%)  1 0/42 (0.00%)  0
Retroperitoneal haematoma * 1  1/42 (2.38%)  1 0/42 (0.00%)  0
Tooth impacted * 1  1/42 (2.38%)  1 0/42 (0.00%)  0
Infections and infestations     
Appendicitis * 1  2/42 (4.76%)  2 1/42 (2.38%)  1
Device related infection * 1  1/42 (2.38%)  1 0/42 (0.00%)  0
Peritonsillar abscess * 1  1/42 (2.38%)  1 0/42 (0.00%)  0
Pilonidal cyst * 1  1/42 (2.38%)  1 0/42 (0.00%)  0
Injury, poisoning and procedural complications     
Fibula fracture * 1  0/42 (0.00%)  0 1/42 (2.38%)  1
Humerus fracture * 1  0/42 (0.00%)  0 1/42 (2.38%)  1
Meniscus injury * 1  1/42 (2.38%)  1 0/42 (0.00%)  0
Stab wound * 1  0/42 (0.00%)  0 1/42 (2.38%)  1
Tibia fracture * 1  0/42 (0.00%)  0 1/42 (2.38%)  1
Metabolism and nutrition disorders     
Dehydration * 1  0/42 (0.00%)  0 1/42 (2.38%)  1
Musculoskeletal and connective tissue disorders     
Haemarthrosis * 1  0/42 (0.00%)  0 2/42 (4.76%)  2
Joint contracture * 1  1/42 (2.38%)  1 0/42 (0.00%)  0
Joint lock * 1  0/42 (0.00%)  0 1/42 (2.38%)  1
Joint range of motion decreased * 1  0/42 (0.00%)  0 1/42 (2.38%)  1
Muscle haemorrhage * 1  0/42 (0.00%)  0 1/42 (2.38%)  1
Osteoarthritis * 1  0/42 (0.00%)  0 1/42 (2.38%)  1
Nervous system disorders     
Migraine * 1  1/42 (2.38%)  1 0/42 (0.00%)  0
Psychiatric disorders     
Suicidal ideation * 1  1/42 (2.38%)  1 0/42 (0.00%)  0
Reproductive system and breast disorders     
Balanitis * 1  0/42 (0.00%)  0 1/42 (2.38%)  1
Vascular disorders     
Haematoma * 1  1/42 (2.38%)  1 0/42 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (16.1)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Recombinant Factor VIII Prophylaxis Treatment Recombinant Factor VIII On-demand Treatment
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   11/42 (26.19%)      28/42 (66.67%)    
Gastrointestinal disorders     
Dental caries * 1  0/42 (0.00%)  0 3/42 (7.14%)  3
Dyspepsia * 1  0/42 (0.00%)  0 3/42 (7.14%)  3
Toothache * 1  3/42 (7.14%)  3 2/42 (4.76%)  3
General disorders     
Pyrexia * 1  1/42 (2.38%)  2 5/42 (11.90%)  6
Infections and infestations     
Influenza * 1  2/42 (4.76%)  2 7/42 (16.67%)  7
Nasopharyngitis * 1  2/42 (4.76%)  2 7/42 (16.67%)  8
Pharyngitis * 1  0/42 (0.00%)  0 3/42 (7.14%)  4
Upper respiratory tract infection * 1  1/42 (2.38%)  1 3/42 (7.14%)  5
Metabolism and nutrition disorders     
Vitamin D deficiency * 1  0/42 (0.00%)  0 3/42 (7.14%)  3
Musculoskeletal and connective tissue disorders     
Arthralgia * 1  5/42 (11.90%)  7 5/42 (11.90%)  6
Back pain * 1  0/42 (0.00%)  0 4/42 (9.52%)  5
Myalgia * 1  3/42 (7.14%)  3 1/42 (2.38%)  1
Nervous system disorders     
Headache * 1  2/42 (4.76%)  2 7/42 (16.67%)  12
Respiratory, thoracic and mediastinal disorders     
Cough * 1  0/42 (0.00%)  0 3/42 (7.14%)  3
Oropharyngeal pain * 1  0/42 (0.00%)  0 3/42 (7.14%)  3
Vascular disorders     
Hypertension * 1  0/42 (0.00%)  0 3/42 (7.14%)  3
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (16.1)
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.
The Investigator must send a draft manuscript of the publication or abstract to the Sponsor sixty days in advance of submission in order to obtain written approval prior to submission of the final version for publication. In case of a difference of opinion between the Sponsor and the Investigator(s), the contents of the publication will be discussed in order to find a solution which satisfies both parties.
Results Point of Contact
Name/Title: Therapeutic Area Head
Organization: BAYER
Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT00623480     History of Changes
Other Study ID Numbers: 12800
2008-000985-21 ( EudraCT Number )
First Submitted: February 4, 2008
First Posted: February 26, 2008
Results First Submitted: May 2, 2013
Results First Posted: August 7, 2013
Last Update Posted: November 17, 2014