Clinical Trial Results:
A Phase 2/3, multicenter, open-label clinical study to assess the safety and efficacy of BAY86-6150 in subjects with hemophilia A or B with inhibitors, composed of 2 Parts (A & B). Part A: Sequential cohorts of four dose levels of the modified rFVIIa BAY86-6150 assessed in a non-controlled dose response design in acutely bleeding subjects and for PK/ PD in an intra-individual crossover design compared with one fixed dose of eptacog alfa (activated) in non-bleeding subjects. Part B: Confirmatory study to further investigate the efficacy and safety of BAY86-6150.
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Summary
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EudraCT number |
2011-000323-33 |
Trial protocol |
DE HU PL DK IT |
Global end of trial date |
24 Mar 2014
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Results information
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Results version number |
v1 |
This version publication date |
12 Jul 2016
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First version publication date |
26 Jul 2015
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Other versions |
v2 |
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 |
BAY86-6150/15534
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Additional study identifiers
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ISRCTN number |
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US NCT number |
NCT01625390 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Bayer HealthCare AG
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Sponsor organisation address |
Kaiser-Wilhelm-Allee, D-51368, Leverkusen, Germany,
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Public contact |
Therapeutic Area Head, Bayer HealthCare AG, clinical-trials-contact@bayerhealthcare.com
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Scientific contact |
Therapeutic Area Head, Bayer HealthCare AG, clinical-trials-contact@bayerhealthcare.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 |
24 Jul 2014
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
24 Mar 2014
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
Part A:
- To identify the recommended dose by conducting a risk-benefit assessment of four different dose levels of BAY86-6150 based on safety and dose response assessments in acutely bleeding subjects with hemophilia A or B with inhibitors.
Part B:
- To further investigate the safety and efficacy of the recommended dose of BAY86-6150 in acutely bleeding subjects with hemophilia A or B with inhibitors.
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Protection of trial subjects |
The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
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Background therapy |
- | ||
Evidence for comparator |
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Actual start date of recruitment |
21 Jun 2012
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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 |
Bulgaria: 3
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Country: Number of subjects enrolled |
Singapore: 2
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Country: Number of subjects enrolled |
South Africa: 5
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Worldwide total number of subjects |
10
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EEA total number of subjects |
3
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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) |
1
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Adults (18-64 years) |
9
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 8 study centers in Bulgaria, Korea, Poland, Singapore, Turkey, Ukraine, and South Africa. Overall, subjects enrolled in 3 countries (Bulgaria, Singapore and South Africa) were assigned to treatment. The study was conducted between 21 June 2012 (first subject first visit) and 24 March 2014 (last subject last visit). | ||||||||||||
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Pre-assignment
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Screening details |
Study was composed of Part A: 4 dose levels were to be evaluated sequentially, Part B: subjects were to be treated with the recommended dose level of BAY86-6150. However, the study was prematurely discontinued due to safety reasons and only 10 out of 20 enrolled subjects were treated with an initial dose of 6.5 microgram per kilogram. | ||||||||||||
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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 |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Arm title
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Experimental, modified rFVIIa (BAY86-6150) | ||||||||||||
Arm description |
Subjects received targeted intravenous injection of modified recombinant human Factor VIIa (rFVIIa) (BAY86-6150) at an initial dose of 6.5 microgram per kilogram. Dose was escalated as per investigator’s discretion or until the highest dose level was completed. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Modified recombinant human Factor VIIa (rFVIIa)
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Investigational medicinal product code |
BAY86-6150
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received targeted intravenous injection of modified rFVIIa (BAY86-6150) at an initial dose of 6.5 microgram per kilogram. Dose was escalated as per investigator’s discretion or until the highest dose level was completed.
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Baseline characteristics reporting groups
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Reporting group title |
Overall Study
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Reporting group description |
Subjects received targeted intravenous injection of modified recombinant human Factor VIIa (rFVIIa) (BAY86-6150) at an initial dose of 6.5 microgram per kilogram. Dose was escalated as per investigator’s discretion or until the highest dose level was completed. | ||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Experimental, modified rFVIIa (BAY86-6150)
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Reporting group description |
Subjects received targeted intravenous injection of modified recombinant human Factor VIIa (rFVIIa) (BAY86-6150) at an initial dose of 6.5 microgram per kilogram. Dose was escalated as per investigator’s discretion or until the highest dose level was completed. | ||
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End point title |
Number of Subjects with Successful Treatments of Bleeding Episodes [1] | ||||||
End point description |
The successful treatment was defined by "No rescue medication administered".
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End point type |
Primary
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End point timeframe |
Baseline up to the last injection of BAY86-6150
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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: Data was not analysed as the study was terminated due to safety reasons and hence, statistical analysis was not performed. |
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| Notes [2] - Data was not analysed as the study was terminated due to safety reasons. |
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| No statistical analyses for this end point | |||||||
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End point title |
Proportion of Successful Treatments of Bleeding Episodes on Subject Level [3] | ||||||||
End point description |
The individual success rate was calculated as the number of bleeding episodes treated successfully (without rescue medication) divided by the total number of bleeding episodes experienced on a dose level. A responder was defined as at least 70% of bleeding episodes treated without rescue medication.
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End point type |
Primary
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End point timeframe |
Baseline up to the last injection of BAY86-6150
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| Notes [3] - 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: Data was not analysed as the study was terminated due to safety reasons and hence, statistical analysis was not performed. |
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| Notes [4] - Data was not analysed as the study was terminated due to safety reasons. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Injections Needed to Stop the Bleeding Episode | ||||||
End point description |
The number of injections needed to stop the bleeding episodes were calculated as total number of injections given divided by the total number of bleeds. In case rescue medication was given, the number of injections was set to 3, regardless of how many applications of rescue medication were applied.
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End point type |
Secondary
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End point timeframe |
Baseline up to the last injection of BAY86-6150
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| Notes [5] - Data was not analysed as the study was terminated due to safety reasons. |
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| No statistical analyses for this end point | |||||||
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End point title |
Time to Stop the Bleed | ||||||||
End point description |
The time to stop a bleeding episode was assessed as the period between the onset of bleeding and the complete cessation of the bleeding episode as assessed by the subject. Analyses were decided to perform using life table methods.
Subjects assessed the cessation of a bleeding episode based on their long-term experiences coping with bleeds since childhood.
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End point type |
Secondary
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End point timeframe |
Baseline up to the last injection of BAY86-6150
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| Notes [6] - Data was not analysed as the study was terminated due to safety reasons. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Subject’s Efficacy Assessment | ||||||||
End point description |
The effective response to treatment as rated by the subject’s assessment was determined according to: “Please rate the effectiveness (for example, cessation of bleed, pain, tenderness, size of hemorrhage, swelling and joint mobility) of the treatment as per your assessment: Very effective; Effective; Partially effective; Not effective".
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End point type |
Secondary
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End point timeframe |
After every acute bleeding episode or every other week up to 14 days after last exposure to BAY 86-6150
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| Notes [7] - Data was not analysed as the study was terminated due to safety reasons. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Euro Quality of Life-5 Dimension (EQ-5D) | ||||||||
End point description |
Health related quality of life (HRQoL) was assessed using the self administered Euro-QoL (EQ-5D). EQ-5D is a participant answered questionnaire scoring 5 dimensions - mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The EQ-5D is a validated, generic preference based measure of health widely used in health economic calculations. Subjects rated their general health using the EQ-5D. The EQ-5D total score ranges from 0 (worst imaginable health state) to 100 (best imaginable health state which is also the best possible outcome).
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End point type |
Secondary
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End point timeframe |
Baseline up to 14 days after last exposure to BAY86-6150
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| Notes [8] - Data was not analysed as the study was terminated due to safety reasons. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Brief Pain Inventory (BPI) Score | ||||||||
End point description |
Brief Pain Inventory - Short Form (BPI-SF) allows subjects to rate the severity of their pain and the degree to which their pain interferes with common dimensions of feeling and function (e.g., general activity, walking, work, mood, enjoyment of life, relations with others, and sleep). BPI-SF was a 15-item, self-administered, clinically valid, reliable and responsive measure developed to assess pain. BPI-SF was typically scored by averaging the pain severity score and overall pain interference score. Scores range from 0-10 and a higher score indicates a higher level of pain/interference.
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End point type |
Secondary
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End point timeframe |
Baseline up to 14 days after last exposure to BAY86-6150
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| Notes [9] - Data was not analysed as the study was terminated due to safety reasons. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Brief Pain Inventory (BPI) Score: Item 3 and 6 | ||||||||
End point description |
The effectiveness of BAY 86-6150 in alleviating the subject's pain through bleed resolution was assessed by the subjects using Items 3 and 6 of the BPI-SF measure.
Item 3: “Please rate your pain by circling the one number that best describes your pain at its worst in the last 24 hours.” Score range from 0-10 and a higher score indicates a higher level of pain. It was completed by the subject in an e-diary prior to the first injection of BAY 86-6150 and every night for 7 days following the start of the bleed that was treated with BAY 86-6150.
Item 6: “Please rate your pain by circling the one number that tells how much pain you have right now.” Score range from 0-10 and a higher score indicates a higher level of pain. It was completed by the subject in an e-diary prior to the first injection of BAY 86-6150. Item 6 was then completed at every hour for 6 hours following an injection of BAY 86-6150 but before the use of rescue medication (that is, if rescue medication was required).
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End point type |
Secondary
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End point timeframe |
Pre-injection, every night for a week after any BAY86-6150 injection for Item 3
Pre-injection, 1, 2, 3, and 4 hours after administration of BAY86-6150 for Item 6
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| Notes [10] - Data was not analysed as the study was terminated due to safety reasons. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Work Productivity and Activity Impairment (WPAI) Questionnaire | ||||||||
End point description |
The effect of hemophilia on the subject’s ability to work and perform regular activities was evaluated by determination of a WPAI in adult subjects only.
Six-items that assess impairment in work productivity and daily activity during the 7 days before the assessment. It measures the percentage of overall impairment in work productivity and daily activity due to hemophilia. A WPAI score of 0% = no impairment and a score of 100% = total loss of work productivity or activity.
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End point type |
Secondary
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End point timeframe |
Baseline, within 24 to 48 hours after the 2nd treatment with BAY86-6150, after every 5th exposure day to BAY86-6150, 14 days after last exposure to BAY86-6150
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| Notes [11] - Data was not analysed as the study was terminated due to safety reasons. |
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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 |
Baseline up to 14 days after last exposure to BAY86-6150
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.1
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Reporting groups
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Reporting group title |
Experimental, modified rFVIIa (BAY86-6150)
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Reporting group description |
Subjects received targeted intravenous injection of modified recombinant human Factor VIIa (rFVIIa)(BAY86-6150) at an initial dose of 6.5 microgram per kilogram. Dose was escalated as per investigator'sdiscretion or until the highest dose level was completed. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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24 Aug 2012 |
The amendment was prepared in response to the comments by the Medical and Healthcare Products Regualtory Agency (MHRA) in the United Kingdom. The required changes led to modifications of the stopping rules for subjects in the study who experienced drug related adverse events.
- The Common Terminology Criteria for Adverse Events (CTCAE) grading has been removed and replaced with more specific description of relevant clinical conditions.
- Exclusion criterion was modified to clarify that besides activated Prothrombin Complex Concentrates (“aPCC”) also non-activated Prothrombin Complex Concentrates (“PCC”) were allowed to be administered during the study period.
- The text was added as, hypersensitivity adverse events that could occur with any injected protein under definition of serious adverse event.
- The dose of study medication for a subject would be de-escalated to the next lower level or withdrawn from the study if two or more drug-related severe adverse events or or a single drug-related serious adverse event occurred in a subject. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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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. | |||||||
| Results for primary or secondary endpoints were not able to be reported as the study was prematurely terminated due to safety reasons. | |||||||
