Clinical Trial Results:
Multicentre, Non-controlled, Prospective, Post-Marketing Safety Study Following Long-Term Prophylactic Optivate® Treatment in Subjects with Severe Haemophilia A.
|
Summary
|
|
EudraCT number |
2012-004606-10 |
Trial protocol |
DE GB PL |
Global end of trial date |
31 Aug 2017
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
23 Mar 2018
|
First version publication date |
23 Mar 2018
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
8VWF07
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT01811875 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Bio Products Laboratory Limited
|
||
Sponsor organisation address |
Dagger Lane, Elstree, United Kingdom, WD6 3BX
|
||
Public contact |
Medical Department, Bio Products Laboratory Limited (BPL), +44 (0)2089572297, lisa.wilson@bpl.co.uk
|
||
Scientific contact |
Medical Department, Bio Products Laboratory Limited (BPL), +44 (0)2089572297, lisa.wilson@bpl.co.uk
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
26 Oct 2017
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
31 Aug 2017
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
31 Aug 2017
|
||
Was the trial ended prematurely? |
Yes
|
||
|
General information about the trial
|
|||
Main objective of the trial |
To assess post-marketing immunogenicity of Optivate® by monitoring plasma inhibitor levels for at least 100 Exposure Days (EDs) for each subject.
|
||
Protection of trial subjects |
For each of the five recovery assessments the patients had to give blood samples a number of times over the course of 1 hour. Collection of blood samples may lead to bruising or tenderness at the site where blood is collected. Therefore, to minimise distress the subjects were offered a cannula which could be used to take repeated blood samples.
|
||
Background therapy |
There were no comparator tests or products used in this trial. | ||
Evidence for comparator |
Not applicable. | ||
Actual start date of recruitment |
01 Jul 2014
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
No
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Poland: 2
|
||
Country: Number of subjects enrolled |
Germany: 1
|
||
Country: Number of subjects enrolled |
Colombia: 4
|
||
Worldwide total number of subjects |
7
|
||
EEA total number of subjects |
3
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
1
|
||
Adults (18-64 years) |
6
|
||
From 65 to 84 years |
0
|
||
85 years and over |
0
|
||
|
|||||||||||
|
Recruitment
|
|||||||||||
Recruitment details |
First patient first visit: 21-Nov-2014 Last patient first visit: 02-Mar-2017 Last patient last visit: 31-Aug-2017 4 patients recruited in Colombia 2 patients recruited in Poland 1 patient recruited in Germany | ||||||||||
|
Pre-assignment
|
|||||||||||
Screening details |
Screening took place within 4 weeks before the Baseline Visit (V1). A three day wash-out period was required. A brief physical and medical examination was performed and the medical history recorded. Blood samples were taken for viral serology; CD4 count; to measure inhibitor status and FVIII recovery. | ||||||||||
|
Period 1
|
|||||||||||
Period 1 title |
Screening period
|
||||||||||
Is this the baseline period? |
No | ||||||||||
Allocation method |
Not applicable
|
||||||||||
Blinding used |
Not blinded | ||||||||||
Blinding implementation details |
Not applicable
|
||||||||||
|
Arms
|
|||||||||||
|
Arm title
|
Screening | ||||||||||
Arm description |
Following a 3 day washout period, eligible subjects provided a blood sample to test for FVIII inhibitors (pre-bolus only). Subjects also underwent a recovery assessment at this visit using the subject’s current FVIII concentrate (30 IU/kg dose). Blood samples were collected at the following timepoints: - pre-dose (if not already collected) - 15 minutes post-infusion (+5 minutes [mins]) - 30 minutes post-infusion (+5 mins) - 1 hour post-infusion (+10 mins) | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Current FVIII Product
|
||||||||||
Investigational medicinal product code |
|||||||||||
Other name |
|||||||||||
Pharmaceutical forms |
Powder and solvent for solution for injection/infusion
|
||||||||||
Routes of administration |
Intravenous bolus use
|
||||||||||
Dosage and administration details |
Subjects underwent a recovery assessment at this visit using the subject’s current FVIII concentrate (30 IU/kg dose).
|
||||||||||
|
|||||||||||
|
Period 2
|
|||||||||||
Period 2 title |
Baseline( V1)/ Treatment period (V1-V4)
|
||||||||||
Is this the baseline period? |
Yes [1] | ||||||||||
Allocation method |
Not applicable
|
||||||||||
Blinding used |
Not blinded | ||||||||||
Blinding implementation details |
Not applicable
|
||||||||||
|
Arms
|
|||||||||||
|
Arm title
|
Optivate 500IU | ||||||||||
Arm description |
- | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Optivate 500IU
|
||||||||||
Investigational medicinal product code |
B02BD02
|
||||||||||
Other name |
|||||||||||
Pharmaceutical forms |
Concentrate and solvent for solution for infusion
|
||||||||||
Routes of administration |
Intravenous bolus use
|
||||||||||
Dosage and administration details |
- Bolus dose study visits 1-4: 30 IU/kg
- Routine prophylaxis: 20-40 IU/kg to be administered 3 times a week for at least 100 exposure days.
- Preventative therapy: single dose of 20-40 IU/kg to be administered.
- Minor bleeds: 8-15 IU/kg ( Repeated every 12 to 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing was achieved)
- More extensive haemarthrosis, muscle bleeding or haematoma: 12-23 IU/kg (Repeat infusion every 12 to 24 hours for 3 to 4 days or more until pain and acute disability are resolved).
- Life-threatening haemorrhages: 23-37IU/kg (Repeat infusion every 8 to 24 hours until threat resolved).
|
||||||||||
| Notes [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period. Justification: Period 1 is the screening period. Subjects must complete the screening period before entering Period 2(baseline period). |
|||||||||||
|
|||||||||||
|
Period 3
|
|||||||||||
Period 3 title |
Follow-up period
|
||||||||||
Is this the baseline period? |
No | ||||||||||
Allocation method |
Not applicable
|
||||||||||
Blinding used |
Not blinded | ||||||||||
Blinding implementation details |
Not applicable
|
||||||||||
|
Arms
|
|||||||||||
|
Arm title
|
Follow-up period | ||||||||||
Arm description |
Follow-up period was conducted by telephone call 28 days after the last Optivate® infusion to allow follow-up of any AEs. | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Optivate 500IU
|
||||||||||
Investigational medicinal product code |
B02BD02
|
||||||||||
Other name |
|||||||||||
Pharmaceutical forms |
Concentrate and solvent for solution for infusion
|
||||||||||
Routes of administration |
Intravenous bolus use
|
||||||||||
Dosage and administration details |
- Bolus dose study visits 1-4: 30 IU/kg
- Routine prophylaxis: 20-40 IU/kg to be administered 3 times a week for at least 100 exposure days.
- Preventative therapy: single dose of 20-40 IU/kg to be administered.
- Minor bleeds: 8-15 IU/kg ( Repeated every 12 to 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing was achieved)
- More extensive haemarthrosis, muscle bleeding or haematoma: 12-23 IU/kg (Repeat infusion every 12 to 24 hours for 3 to 4 days or more until pain and acute disability are resolved).
- Life-threatening haemorrhages: 23-37IU/kg (Repeat infusion every 8 to 24 hours until threat resolved).
|
||||||||||
|
|||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Baseline( V1)/ Treatment period (V1-V4)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Screening
|
||
Reporting group description |
Following a 3 day washout period, eligible subjects provided a blood sample to test for FVIII inhibitors (pre-bolus only). Subjects also underwent a recovery assessment at this visit using the subject’s current FVIII concentrate (30 IU/kg dose). Blood samples were collected at the following timepoints: - pre-dose (if not already collected) - 15 minutes post-infusion (+5 minutes [mins]) - 30 minutes post-infusion (+5 mins) - 1 hour post-infusion (+10 mins) | ||
Reporting group title |
Optivate 500IU
|
||
Reporting group description |
- | ||
Reporting group title |
Follow-up period
|
||
Reporting group description |
Follow-up period was conducted by telephone call 28 days after the last Optivate® infusion to allow follow-up of any AEs. | ||
Subject analysis set title |
Protocol population
|
||
Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Subjects who completed at least 100 exposure days with Optivate.
|
||
Subject analysis set title |
Safety population
|
||
Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Subjects who took at least part of one dose of Optivate
|
||
|
|||||||||||||
End point title |
To assess post-marketing immunogenicity of Optivate by monitoring plasma inhibitor levels for at least 100 Exposure Days for each subject. | ||||||||||||
End point description |
FVIII inhibitor status at any of the study visits was measured by a Nijmegen Bethesda assay and inhibitor screens. A result of ≥ 0.6 BU confirmed that the subject had developed inhibitors to FVIII. If this occurred, the test was repeated on a separate sample; if both tests were confirmed to be ≥ 0.6 BU, this was to be reported by the Investigator as a serious adverse event (SAE).
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Over a period of 12 months
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Primary efficacy endpoint | ||||||||||||
Statistical analysis description |
The primary efficacy endpoint is the assessment of immunogenicity of Optivate® by monitoring plasma inhibitor levels for at least 100 EDs for each subject.
|
||||||||||||
Comparison groups |
Optivate 500IU v Protocol population
|
||||||||||||
Number of subjects included in analysis |
10
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other [1] | ||||||||||||
Method |
|||||||||||||
Parameter type |
Quantitative inhibitor levels of ≥0.6BU | ||||||||||||
Point estimate |
0
|
||||||||||||
Confidence interval |
|||||||||||||
level |
0% | ||||||||||||
sides |
1-sided
|
||||||||||||
lower limit |
- | ||||||||||||
upper limit |
0 | ||||||||||||
| Notes [1] - Shift tables cross-tabulating positive/negative status (based on the Nijmegen-Bethesda assay) at the Baseline Visit (Visit 1) against those at Visits 2, 3, and 4 were analysed. |
|||||||||||||
|
|||||||||||||
End point title |
To assess efficacy of Optivate by monitoring prior FVIII recovery (Screening Visit) versus first dose with Optivate® (Visit 1). | ||||||||||||
End point description |
Recovery with prior FVIII concentrate (Screening Visit) versus first dose with Optivate® (Visit 1).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Over a period of 12 months
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Optivate® Recovery Over Time (Recovery at 1 Exposure Day [ED, Visit 1], 10 to15 EDs [Visit 2], 50 to 75 EDs, [Visit 3], and 100 EDs [Visit 4]) for the Protocol Population. | ||||||||||||
End point description |
A recovery assessment was conducted at each study visit. Recovery assessments were only conducted after a 3-day washout period and when the subject was not actively bleeding.
At the Screening Visit, subjects who had completed a 3-day washout period and were not actively bleeding were dosed with 30 IU/kg of their prior FVIII concentrate. The dose was measured to the nearest 0.1 mL. Blood samples for the recovery assessment were to be collected at the following time points:
• Predose
• 15 minutes postinfusion (±5 minutes).
• 30 minutes postinfusion (±5 minutes).
• 1 hour postinfusion (±10 minutes).
Actual times of sample collection were to be recorded in the CRF
At visits 1, 2, 3 and 4 subjects were dosed with 30 IU/kg of Optivate and blood samples for recovery assessments were taken at the same timepoints as specified above.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Over a period of 12 months
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Optivate® therapy to treat breakthrough bleeds per subject per year in the protocol population. | ||||||||||||
End point description |
Number of breakthrough bleeds per subject per year in the protocol population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Over a period of 12 months
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Overall consumption of Optivate®: Number of exposure days for each subject per year/subject in the per protocol population. | ||||||||||||
End point description |
Number of exposure days for each subject per year/subject in the per protocol population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Over a period of 12 months
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Overall consumption of Optivate®: Total dose in IU/kg of Optivate® per subject for prophylactic use. | ||||||||||||
End point description |
Total dose in IU/kg of Optivate® per subject for prophylactic use
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Over a period of 12 months
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Overall consumption of Optivate®: Total dose in IU/kg of Optivate® per subject to treat a bleed in the protocol population. | ||||||||||||
End point description |
Total dose in IU/kg of Optivate® per subject to treat a bleed in the protocol population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Over a period of 12 months
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Overall consumption of Optivate®: Total number of infusions for prophylactic use per subject in the protocol population. | ||||||||||||
End point description |
Total number of infusions for prophylactic use per subject in the protocol population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Over a period of 12 months
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Overall consumption of Optivate®: Total number of infusions to treat a bleed per subject in the protocol population. | ||||||||||||
End point description |
Total number of infusions to treat a bleed per subject in the protocol population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Over a period of 12 months
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Overall consumption of Optivate®: Overall mean dose in IU/kg of Optivate® per subject/year for prophylactic use in the protocol population. | ||||||||||||
End point description |
Overall mean dose in IU/kg of Optivate® per subject/year for prophylactic use in the protocol population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Over a period of 12 months
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Treatment emergent adverse events (non-serious) in the safety population | ||||||||||||
End point description |
|||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Over a period of 12 months
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Treatment emergent adverse events (serious) in safety population | ||||||||||||
End point description |
Treatment emergent adverse events (serious) in safety population
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Over a period of 12 months
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Inhibitor Development: Positive FVIII inhibitor status in safety population (measured by ≥0.6 Bethesda units) | ||||||||||||
End point description |
Inhibitor Development: Positive FVIII inhibitor status in safety population measured by ≥0.6 Bethesda units (this was a safety measurement but was assessed as a primary efficacy endpoint).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Over a period of 12 months
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Over a period of 12 months
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Patients had an electronic diary where they could enter any adverse events they experienced in between study visits. Adverse events were assessed at each study visit otherwise.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Safety Population
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Safety population includes all subjects who took at least part of one dose of Optivate. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
02 Dec 2014 |
Update to responsible medical officer. |
||
23 Mar 2015 |
Update to Responsible Medical Officer. |
||
30 Nov 2015 |
- Protocol to clarify that the end of trial will be when the 10th patient has completed their follow-up visit.
- Third exclusion criterion updated to clarify and to be consistent with routine clinical practice and the patient information sheet that subjects will be excluded if they have symptomatic liver or renal disease. In addition, section updated to state that historical lab results for ALT and creatinine (within the last 12 months) would be acceptable instead of a new sample being taken at screening. If historical results are not available, then an ALT and creatinine sample is not required at screening as long as the patient is asymptomatic.
- Product Presentation updated to state that a field for batch specific potency was not included on the approved product label in error. Protocol updated to provide clarification on where actual vial content can be established from i.e. certificate of analysis.
- Dosage to treat breakthrough bleeds updated to clarify what dose may be taken in the event that a bleed occurs on the same day as the routine prophylactic dose.
- Screening Procedures Before Dosing updated to state that all bleeds regardless of severity, from the past 12 months should be recorded in the eCRF. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
