Clinical Trial Results:
ITT-PMS Extension
An extension study of intrathecal therapy with monoclonal antibodies in progressive multiple sclerosis
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Summary
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EudraCT number |
2012-000721-53 |
Trial protocol |
SE |
Global end of trial date |
07 Jun 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
07 Oct 2018
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First version publication date |
07 Oct 2018
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Other versions |
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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 |
ITT-PMSExt
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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 |
County council of Västerbotten
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Sponsor organisation address |
University Hospital of Umeå, Umeå, Sweden, 90185
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Public contact |
Anders Svenningsson, Dept of Neurology, University Hospital of Umeå, Umeå, Sweden, 46 702415852, anders.svenningsson@ki.se
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Scientific contact |
Anders Svenningsson, Dept of Neurology, University Hospital of Umeå, Umeå, Sweden, 46 702415852, anders.svenningsson@ki.se
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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 |
15 Sep 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
07 Jun 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
07 Jun 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess long-term stabilising effects of on neurological symptoms by regular IT administered monoclonal antibodies in MS.
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Protection of trial subjects |
1. Development of allergic and anaphylactic reactions.
Before each injection antihistamine and corticosteroids were administered to prevent any allergic reaction precipitated by the study drug. Continuous observations was done of the patient during the first hour after each injection of study drug and emergency equipment was available for immediate use in case of signs of allergic reactions. Standard treatm. with epinephrine, fluids, antihistamine and steroids were used; intensive care specialist was consulted when necessary.
2. Symptoms related to cytokine release from the lysis of B lymphocytes.
This was anticipated to demonstrate as increase in neurological symptoms and possibly also as diffuse cerebral symptoms. Our experience from the first study, this does not to appear as a problem in this population but rather belonged to treatment with Rituximab in CNS lymphoma patients.
3. Development of opportunistic CNS infections.
In the period immediately in relation with the intrahtecal injections, the major risk is contaminating bacterial infections. Precautions were taken to make the injections sterile. CSF samples were drawn for bacterial cultures at each Rituximab injection in the Rickham reservoir. If any sign of infection occured, infectious disease specialist was consulted. In our first study (EudraCT number 2008-002626-11), one case of low virulent meningitis with propionebacteriae occurred which was treated successfully with standard antibiotics and removal of the Rickham reservoir. The patient recovered fully from the infection. In the longer perspective, special attention will be paid regarding PML. Any type of neurological deterioration that may raise the suspicion of PML will lead to emergent MRI and CSF examination regarding signs of PML/JC virus infectin. Further potential dosing of Retuximab will be halted until PML is ruled out
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Background therapy |
- | ||
Evidence for comparator |
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Actual start date of recruitment |
11 Jan 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Sweden: 19
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Worldwide total number of subjects |
19
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EEA total number of subjects |
19
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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) |
17
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From 65 to 84 years |
2
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 19 subjects were recruted for this study from two centra in Umeå and in Uppsala. The study population were subjects with secondary or primary progressive MS that had completed the first trial of intrathecal Rituximab with one year of follow-up (ITT-MS; EudraCT number 2008-002626-11) and signed consent to enrol in the extension study. | ||||||||||||||
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Pre-assignment
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Screening details |
Subject were eligible for inclusion in this study if all of the following criteria applied: - Completed the ITT-MS trial (EudraCT number 2008-002626-11) - Other therapy not indicated, contraindicated or failed - Judged as compliant with the protocol - In fertile females, willing to comply with effective contraceptive methods. | ||||||||||||||
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Period 1
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Period 1 title |
Overall trial (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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Active treatment with Rituximab | ||||||||||||||
Arm description |
After signing the informed concent for the extension study patients were treated with Rituximab (Mabthera®) as an intrathecal injection in a Rickham reservoir. A dose of 25 mg were given every 6 month for 2 years with a total of 5 doses. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Rituximab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intrathecal use
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Dosage and administration details |
Rituximab (Mabthera®) was given as an intrathecal injection in a Rickham reservoir. A dose of 25 mg were given every 6 month for 2 years with a total of 5 doses.
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
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End points reporting groups
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Reporting group title |
Active treatment with Rituximab
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Reporting group description |
After signing the informed concent for the extension study patients were treated with Rituximab (Mabthera®) as an intrathecal injection in a Rickham reservoir. A dose of 25 mg were given every 6 month for 2 years with a total of 5 doses. | ||
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End point title |
The time to progression ≥ 1,0 step on the EDSS scale (Expanded Disability Status Scale) [1] | ||||||
End point description |
Assessments were done every 6 months during the study in conjunction with administration of study drug.
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End point type |
Primary
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End point timeframe |
During the Active treatment
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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: Statistical testing will be done as 2-sided on a 5 % level of significance, all confidence intervals (CI) will be 95 % intervals. No specific procedure will be done for treating missing data and testing for multiplicity will not be considered. Data analysis and presentation will be on a descriptive level Each patient is it´s own control. There is no comparison between groups. Test of normality will be performed which will decide as to use parametric or non parametric statistics. |
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| No statistical analyses for this end point | |||||||
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End point title |
Tests of walking ability and hand function (6MWAT or 25 FWT) | |||
End point description |
Assessments were done every 6 months during the study in conjunction with administration of study drug.
6 min walk test or 25 FWT and 9HPT (Ambulation, Arm function) were done at visit 0,6,12,18,24 month
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End point type |
Secondary
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End point timeframe |
During actve treatment
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| No statistical analyses for this end point | ||||
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End point title |
Questionaires regarding MS quality of life, symptom inventory and fatigue (SF12, FSMC) | |||
End point description |
Assessments were done every 6 months during the study in conjunction with administration of study drug.
SF12, SDMT and FSMC (Quality of Life, Cogn function andv Fatigue) were done at visit 0,6,12,18,24 month.
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End point type |
Secondary
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End point timeframe |
During Active treatment
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| No statistical analyses for this end point | ||||
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End point title |
Neurofilament levels in the CSF | |||
End point description |
Assessments were done every 6 months during the study in conjunction with administration of study drug.
LP (Biomarkers) were done at visit 0,12,24 month.
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End point type |
Secondary
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End point timeframe |
During Active treatment
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| No statistical analyses for this end point | ||||
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End point title |
Immunological markers in blood and CSF such as absolute numbers of major lym-phocyte subset as well as regulatory cell subset | |||
End point description |
Assessments were done every 6 months during the study in conjunction with administration of study drug.
LP and Immunology (Biomarkers and Lymphocyte subsets) were done at visit 0,12,24 month.
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End point type |
Secondary
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End point timeframe |
During active treatment
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| No statistical analyses for this end point | ||||
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End point title |
Safety assessment | |||
End point description |
Assessments were done every 6 months during the study in conjunction with administration of study drug.
Blood chemistry, blood pressure and pulse were done at visit 0,6,12,18,24 month.
MRI was done at visit 0,12,24 month
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End point type |
Secondary
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End point timeframe |
During Active treatment
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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 the time a patient consented to participate in the study until he/she completed the study all adverse events (AEs) and serious adverse events (SAEs) were collected, recorded and reported separately.
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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 |
21.0
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Reporting groups
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Reporting group title |
All patients
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Reporting group description |
All patients who consented to participate in the study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
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. | |||
| None reported | |||
