Clinical Trial Results:
An exploratory phase IIa study to evaluate the safety and immunological effects of intravenous interferonβ-1a (IFNβ-1a, Rebif®) therapy in the induction of tolerance to IFNβ in MS patients with neutralising antibodies (NAbs) to subcutaneous IFNβ-1a (Rebif® or Avonex®)
Summary
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EudraCT number |
2008-000256-26 |
Trial protocol |
GB |
Global end of trial date |
12 Feb 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
25 Apr 2019
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First version publication date |
25 Apr 2019
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Other versions |
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Summary report(s) |
NAb Anergy End of STudy Report Feb 2015 |
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 |
006114QM
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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 |
Queen Mary University of London
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Sponsor organisation address |
5 Walden Street, London, United Kingdom, E1 2EF
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Public contact |
Prof Gavin Giovannoni, Queen Mary University of London, +44 02078822579, g.giovannoni@qmul.ac.uk
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Scientific contact |
Prof Gavin Giovannoni, Queen Mary University of London, +44 02078822579, g.giovannoni@qmul.ac.uk
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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 |
11 Feb 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
12 Feb 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Feb 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 |
Perform a “proof-of-concept” phase IIa clinical trial to induce tolerance to IFNβ in subjects with NAbs to IFNβ-1a.
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Protection of trial subjects |
AEs were monitored throughout the trial. Laboratory (haematology and biochemistry) tests, and physical examinations were performed at screening and thereafter at regular intervals throughout the trial.
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Background therapy |
Investigational Medicinal Product (IMP) Rebif® New Formulation EU/1/98/063/004, EU/1/98/063/005, EU/1/98/063/006 Mitoxantrone PL 04515/0127 | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
22 May 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 |
United Kingdom: 1
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Worldwide total number of subjects |
1
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EEA total number of subjects |
1
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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) |
1
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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 |
One patient was consented and enrolled the study, out of the planned 15. It was difficult to recruit as new treatments were available once the trial started. This was an open label, UK study involving 1 site. | ||||||
Pre-assignment
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Screening details |
Male and female subjects with MS, aged 18 to 65 years (inclusive), who have been on IFNβ-1a for at least 12 months and have at least one significant relapse in the last 12 months and are considering switching therapy. Subjects with a positive NAb (neutralising antibody) titre of 20U will then be invited to continue in the study. | ||||||
Pre-assignment period milestones
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Number of subjects started |
1 | ||||||
Number of subjects completed |
1 | ||||||
Period 1
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Period 1 title |
Baseline - Visit 1 and Visit 2
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
Blinding implementation details |
N/A
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Arms
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Arm title
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Patient 1 | ||||||
Arm description |
- | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Interferon Rebif New Formulation
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
(Rebif® New Formulation) 44mcg for injection. Rebif® New Formulation was administered via the IV route, under medical supervision, commencing with a dose of 44mcg. As this dose was tolerated, the subject received a further 88mcg IV on the same day followed by 132mcg IV daily for subsequent 4 days; the total intravenous dose administered will be 660mcg over 5 days.
As the patient developed neutropenia WHO grave 4, the 5th day of treatment was suspended and the total dose was 528mcg over 4 days.
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Period 2
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Period 2 title |
Visit 3
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Is this the baseline period? |
No | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
Blinding implementation details |
Mitoxantrone infusion
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Arms
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Arm title
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Patient 1 | ||||||
Arm description |
- | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Interferon Rebif New Formulation
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
(Rebif® New Formulation) 44mcg for injection. Rebif® New Formulation was administered via the IV route, under medical supervision, commencing with a dose of 44mcg. As this dose was tolerated, the subject received a further 88mcg IV on the same day followed by 132mcg IV daily for subsequent 4 days; the total intravenous dose administered will be 660mcg over 5 days.
As the patient developed neutropenia WHO grave 4, the 5th day of treatment was suspended and the total dose was 528mcg over 4 days.
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Period 3
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Period 3 title |
Visit 4
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Is this the baseline period? |
No | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
Blinding implementation details |
N/A
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Arms
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Arm title
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Patient 1 | ||||||
Arm description |
- | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Interferon Rebif New Formulation
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
(Rebif® New Formulation) 44mcg for injection. Rebif® New Formulation was administered via the IV route, under medical supervision, commencing with a dose of 44mcg. As this dose was tolerated, the subject received a further 88mcg IV on the same day followed by 132mcg IV daily for subsequent 4 days; the total intravenous dose administered will be 660mcg over 5 days.
As the patient developed neutropenia WHO grave 4, the 5th day of treatment was suspended and the total dose was 528mcg over 4 days.
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Period 4
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Period 4 title |
Visit 5 to Visit 9
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Is this the baseline period? |
No | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
Arms
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Arm title
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Patient 1 | ||||||
Arm description |
- | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Interferon Rebif New Formulation
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
(Rebif® New Formulation) 44mcg for injection. Rebif® New Formulation was administered via the IV route, under medical supervision, commencing with a dose of 44mcg. As this dose was tolerated, the subject received a further 88mcg IV on the same day followed by 132mcg IV daily for subsequent 4 days; the total intravenous dose administered will be 660mcg over 5 days.
As the patient developed neutropenia WHO grave 4, the 5th day of treatment was suspended and the total dose was 528mcg over 4 days.
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Period 5
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Period 5 title |
Visit 10 and Visit 11
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Is this the baseline period? |
No | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
Arms
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Arm title
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Patient 1 | ||||||
Arm description |
- | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Mitoxantrone
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Suspension for suspension for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Mitoxantrone12mg/m2 /single dose
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Period 6
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Period 6 title |
Visit 12 to Visit 15
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Is this the baseline period? |
No | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
Arms
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Arm title
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Patient 1 | ||||||
Arm description |
- | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Interferon Rebif New Formulation
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
(Rebif® New Formulation) 44mcg for injection. Rebif® New Formulation was administered via the IV route, under medical supervision, commencing with a dose of 44mcg. As this dose was tolerated, the subject received a further 88mcg IV on the same day followed by 132mcg IV daily for subsequent 4 days; the total intravenous dose administered will be 660mcg over 5 days.
As the patient developed neutropenia WHO grave 4, the 5th day of treatment was suspended and the total dose was 528mcg over 4 days.
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Baseline characteristics reporting groups
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Reporting group title |
Baseline - Visit 1 and Visit 2
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
patient 1
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
There was a SAE as for Grade 4 laboratory results that caused the last dose of interferon not to be injected, as per protocol. There were no other relevant safety issues with the trial’s only participant.
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End points reporting groups
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Reporting group title |
Patient 1
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Reporting group description |
- | ||
Reporting group title |
Patient 1
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Reporting group description |
- | ||
Reporting group title |
Patient 1
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Reporting group description |
- | ||
Reporting group title |
Patient 1
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Reporting group description |
- | ||
Reporting group title |
Patient 1
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Reporting group description |
- | ||
Reporting group title |
Patient 1
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Reporting group description |
- | ||
Subject analysis set title |
patient 1
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
There was a SAE as for Grade 4 laboratory results that caused the last dose of interferon not to be injected, as per protocol. There were no other relevant safety issues with the trial’s only participant.
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End point title |
Safety [1] | ||||||||
End point description |
There was a SAE as for Grade 4 laboratory results that caused the last dose of interferon not to be injected, as per protocol. There were no other relevant safety issues with the trial’s only participant.
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End point type |
Primary
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End point timeframe |
From Visit 5, when treatment starts, to Visit 15, last visit.
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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: Descriptive statistics only |
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No statistical analyses for this end point |
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End point title |
NAb titre at 3, 6, 9 and 12 months post intravenous IFN -1a relative to baseline [2] | ||||||||||||||||||||||||||||||||
End point description |
NAb titre for Interferon-beta is a biological assay and reports in TRU/mL units
Visit 4. 171
Visit 12. 180
Visit 13. <20
Visit 14. <20
Visit 15. <20
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End point type |
Primary
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End point timeframe |
NAb titre at 3 (Visit 12), 6 (Visit 13), 9 (Visit 14) and 12 (Visit 15) months post intravenous IFN -1a relative to baseline (Visit 4)
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Notes [2] - 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: Descriptive statistics only |
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No statistical analyses for this end point |
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End point title |
Immunological tests | ||||||||
End point description |
T-cell proliferative response to rhuIFN -1a compared to baseline, change in T-and B-cell cytokine production in response to rhu-IFN -1a, as assessed using Elispot assays, intracellular cytokine staining, protein and mRNA levels, every 3 months post intravenous IFN-1a relative to baseline and the antigen-specific response will be compared to the changes in control antigen (tetanus toxoid) were not tested as only one patient was enrolled and completed and no significant value would be added with these analyses for one patient only.
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End point type |
Other pre-specified
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End point timeframe |
Baseline and Visit 12, Visit 13, Visit 14 and Visit 15.
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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 baseline Visit 4 to Visit 15
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Assessment type |
Systematic | ||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
SNOMED CT | ||||||||||||||||||||||
Dictionary version |
1
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Reporting groups
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Reporting group title |
Patient 1
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Reporting group description |
AEs: neutropenia grade IV (1), lymphopenia grade III (1), hypotension moderate (1), mild alopecia (1), cold sores (1), back pain (1), numbness of fingers (1) and rigors (1) | ||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 1% | |||||||||||||||||||||||
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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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08 Apr 2011 |
(a)AMENDMENT - (b)DATE APPROVED BY ETHICS - (c)DATE APPROVED BY MHRA - (d)DATE APPROVED BY R&D - (e)Study Documents Included - (f)Comments
(a1)Initial Submission - (b1)Rejected - (c1)Rejected - (d1)N/A - (e1)Protocol Version 1.0; PIS Version 1.0/Version 2.0; ICF Version 1.0; GP Letter Version 1.0; Investigators Brochure IFN-Beta- 1a; SmPC Mitoxantrone; SmPC Rebif-44mcg - (f1)Resubmission to MHRA made on 9 September as initial submission not valid.
(a2)Resubmission - (b2)16 Feb 2009 - (c2)24 Nov 2008 - (d2)20 Feb 2009 - (e2)Protocol Version 2.0; GP Letter Version 2.0; PIS Version 3.0; ICF Version 1.0; Tissues for Future Use ICF 1.0; Investigators Brochure IFN-Beta- 1a; SmPC Mitoxantrone; SmPC Rebif-44mcg; IMP Labels - (f2)Updates based on rejection by both MHRA and REC
(a3)Substantial Amendment 1 - (b3)Rejected 12 Mar 2010; Modified Amendment Sent Approved 26 Aug 2010 - (c3)Acknowledged 11 Mar 2010 - (d3)8 Apr 2011 - (e3)Protocol Version 3.0 and PIS Version 4.0 - (f3)Clarification of IMP name Rebif: New Formulation (RNF); Use of algorithm to calculate dose of IFNbeta; Introduction of ECG Monitoring at dosing; More study visits; PIS Updated with new Rebif algorithm for administration.
(a4)Minor Amendment 1 - (b4)29 Jun 2013 - (c4)N/A Minor - (d4)12 Sep 2012 - (e4)ICF Version 2.0; Tissues for Future Use ICF 2.0 and PIS Version 5.0 - (f4)Update to Barts Health
(a5)Minor Amendment 2 - (b5)11 Sep 2012 - (c5)N/A Minor - (d5)17 Sep 2012 - (e5)Protocol Version 4.0 - (f5)Update of mitoxantrone administration guidelines; Extension of trial to August 2014; Update to details of where patients are seen
(a6)Amendment 3 - (b6)13 Nov 2013 - (e6)Protocol Version 5.0 - (f6)Update to DSMB charter as the previous charter had not been followed correctly and was not proportionate to the study risks |
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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. | |||||||
Only 1 out of 15 planned patients were recruited, which limits the analysis and conclusions |