Clinical Trial Results:
Intrathecal therapy with monoclonal antibodies in severe progressive multiple sclerosis
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Summary
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EudraCT number |
2008-002626-11 |
Trial protocol |
SE |
Global end of trial date |
01 Jun 2016
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Results information
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Results version number |
v1 |
This version publication date |
12 Jul 2017
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First version publication date |
12 Jul 2017
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Other versions |
v2 |
Summary report(s) |
Clinical Study Report_Assessment of Safety_ITT-PMS |
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-PMS
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01719159 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Umeå University
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Sponsor organisation address |
Dept of Neurology, Umeå, Sweden, 90185
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Public contact |
Anders Svenningsson, MD, PhD, Dept of Neurology, Umeå University
, anders.svenningsson@umu.se
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Scientific contact |
Anders Svenningsson,MD, PhD, Dept of Neurology, Umeå University
, anders.svenningsson@umu.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 |
22 Jun 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
01 Jun 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
01 Jun 2016
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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 |
Investigate tolerability and efficacy of intrathecally administered Mabthera in severe progressive MS where there is no available effective treatment
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Protection of trial subjects |
1. Development of allergic and anaphylactic reactions
Before each injection, antihistamine and corticosteroids were administered in order to prevent any allergic reaction precipitated by the study drug. There was continuous observation of the patient during the first 4 hours after each injection of study drug and emergency equipment were available for immediate use in case of signs of allergic reactions. Standard treatment with epinephrine, fluids, antihistamine and steroids were available, intensive care specialist were available to be 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 diffuse cerebral symptoms. In case of signs of cytokine release symptom, further treatment with corticosteroids iv and/or was given as well as emergent MRI. Data from treatment of patients with CNS lymphoma indicate a relatively low risk of cytokine release syndrome since only one of the 24 studied cases de-veloped such symptoms which were rapidly reversible.
3. Development of opportunistic CNS infections.
In the period immediately in relation with the it injections, the major risk was contaminating bacterial infections. Precautions were done to make the injections sterile. CSF samples were drawn for bacterial cultures at each time Rituximab is given in the Rickham reservoir. If any sign of infection clinically, infectious disease specialist was consultated. In the longer perspective, special attention will be paid regarding PML. Any type of neurological deterioration that that may raise the suspicion of PML will lead to emergent MRI and CSF examination regarding signs of PML/JC virus infection. Further potential dosing of Rituximab will be halted until PML is safely ruled out.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
16 Sep 2009
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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: 23
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Worldwide total number of subjects |
23
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EEA total number of subjects |
23
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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) |
22
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From 65 to 84 years |
1
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 23 subjects were recruited for the study from two centra in Umeå and Uppsala. Three patients (included in total 23) were initially treated and evaluated regarding side-effects and safety and reported to the Swedish Medical Products Agency as well as the local ethical committee before the remaining patients were recruited. | |||||||||
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Pre-assignment
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Screening details |
Screening details: Subjects which fulfilled the inclusion criteria for the study. Adults, males or non lactating females with progressive MS since at least three years, EDSS 4,0 - 7.0 and where conventional therapy not indicated, contraindicated or failed. | |||||||||
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Period 1
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Period 1 title |
Baseline
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | |||||||||
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Arms
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Arm title
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Baseline | |||||||||
Arm description |
The baseline values of the 23 patients fulfilling the inclusion criteria and enrolled in the study. | |||||||||
Arm type |
Baseline | |||||||||
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 (10 mg/mL; Roche AB, Stockholm, Sweden) was administered as 3 doses of 25 mg at weekly intervals. The first injection was performed approximately 3 weeks after implantation of the Ommaya reservoir in order to allow surgery-related subcutaneous swelling to subside. Patients were premedicated with 1 mg IV clemastine and 4 mg oral betamethasone 1 hour before the IT rituximab injection. In order to assess tolerance, the rituximab dose was titrated for the first 3 patients, with daily doses of 1 mg, 2.5 mg, 5 mg, 10 mg, and finally 25 mg. Daily monitoring of routine blood parameters and lymphocyte subpopulations by flow cytometry was performed to assess the safety and pharmacodynamic profile of IT treatment.
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Period 2
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Period 2 title |
Active treatment period
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Is this the baseline period? |
No | |||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Dose titration treatment with Rituximab | |||||||||
Arm description |
- | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Rituximab dose titration
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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 |
In order to assess tolerance, the rituximab dose was titrated for the first 3 patients, with daily doses of 1 mg, 2.5 mg, 5 mg, 10 mg, and finally 25 mg. Repeated by 25 mg once weekly two times. Daily monitoring of routine blood parameters and lymphocyte subpopulations by flow cytometry was performed to assess the safety and pharmacodynamic profile of IT treatment.
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Arm title
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Active treatment with Rituximab | |||||||||
Arm description |
- | |||||||||
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 |
Before the dose was given 1 ml liquor was drawn and sent for routin culture analysis. Another 4 ml liquor was draw and saved. Rituximab (10 mg/mL; Roche AB, Stockholm, Sweden) was administered as 3 doses of 25 mg at weekly intervals. The first injection was performed approximately 3 weeks after implantation of the Ommaya reservoir in order to allow surgery-related subcutaneous swelling to subside. Patients were premedicated with 1 mg IV clemastine and 4 mg oral betamethasone 1 hour before the IT rituximab injection. 20 patients fulfilled this treatment period.
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Baseline characteristics reporting groups
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Reporting group title |
Baseline
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Reporting group description |
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End points reporting groups
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Reporting group title |
Baseline
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Reporting group description |
The baseline values of the 23 patients fulfilling the inclusion criteria and enrolled in the study. | ||
Reporting group title |
Dose titration treatment with Rituximab
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Reporting group description |
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Reporting group title |
Active treatment with Rituximab
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Reporting group description |
- | ||
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End point title |
Safety parameters during the study | ||||||||||||
End point description |
Baseline assessments will be done twice with 2-4 weeks apart to have a baseline of criti-cal variables. LP and MRI will be performed once during this period. The therapy will be performed inpatient and require approximately 3 weeks hospital stay. Follow-up exami-nations will be performed at month 1, 3, 6, 9 an 12 after the last IT infusion.
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End point type |
Primary
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End point timeframe |
During the active treatment.
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Attachments |
Endpoint AE disposition ITT-PMS |
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Statistical analysis title |
Key Elements of analysis plan | ||||||||||||
Statistical analysis description |
All statistical testing will be done as 2-sided on a 5 % level of significance, and in particu-lar all confidence intervals (CI) will be 95 % intervals. In general, no specific procedure will be done for treating missing data and testing for multiplicity will not be considered. Most data analysis and presentation will be on a descriptive level
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Comparison groups |
Dose titration treatment with Rituximab v Active treatment with Rituximab v Baseline
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Number of subjects included in analysis |
46
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.05 [1] | ||||||||||||
Method |
Wilcoxon signed-rank test | ||||||||||||
Confidence interval |
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| Notes [1] - All statistical testing will be done as 2-sided on a 5 % level of significance, and in particu-lar all confidence intervals (CI) will be 95 % intervals. |
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End point title |
Clinical scoring | ||||||||||||||||
End point description |
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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 |
Questionaires regarding MS quality of life, symptom inventory and fatigue | ||||||||||||||||
End point description |
9HPT
SDMT
FSMC
SF12
25 FWT and 6 MWT if possible
EDSS
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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 |
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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 | ||||||||||||||||
End point description |
Immunologcal markers in blood and CSF such as absolute numbers of major lym-phocyte subset as well as regulatory cell subset.
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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 |
Adverse events are registered from the time point when the study participants sign the informed consent until their last visit.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
CTC AE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
4.0
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Reporting groups
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Reporting group title |
All patients
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Reporting group description |
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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 | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/25745637 |
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