Combination Therapy Using Cellcept and Rebif in RRMS
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT00618527|
Recruitment Status : Completed
First Posted : February 20, 2008
Last Update Posted : November 15, 2012
|First Submitted Date ICMJE||February 6, 2008|
|First Posted Date ICMJE||February 20, 2008|
|Last Update Posted Date||November 15, 2012|
|Study Start Date ICMJE||August 2006|
|Actual Primary Completion Date||May 2012 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||mRNA for MxA gene levels [ Time Frame: Day 0, Week 4, Week 16, Week 28, Week 40, Week 52 ]|
|Original Primary Outcome Measures ICMJE||Same as current|
|Current Secondary Outcome Measures ICMJE||Not Provided|
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Combination Therapy Using Cellcept and Rebif in RRMS|
|Official Title ICMJE||Combination Therapy Using Mycophenolate Mofetil (CellCept) and Human Interferon beta1a (Rebif) in Early Treatment of Multiple Sclerosis|
The purpose of this trial is to examine the benefits of early combination of CellCept® with Rebif® in long-term management of patients with multiple sclerosis. Quantitation of mRNA for MxA gene from ex-vivo lymphocytes obtained from patients receiving both drugs or interferon alone will be used to gauge the usefulness of this combination therapy. In addition we will examine the safety of combination of mycophenolate mofetil and interferon beta 1a in treatment of multiple sclerosis.
This is a pilot study to examine if the combination of CellCept® with Rebif® will prove to be useful in the early treatment of patients with MS. Up-regulation of the MxA gene following the administration of Rebif® will be used as a surrogate marker of interferon bioactivity. This in turn could serve as a surrogate marker of interferon efficacy in these patients.
The null hypothesis is that there will not be any difference in the proportion of patients that produce MxA gene transcripts in the Rebif® group as compared to the group that received Rebif® with CellCept® at the end of this study (1 year).
The alternate hypothesis is that the combination of CellCept® with Rebif® will prove to be useful in prolonging the efficacy of interferon. In other words, the combination will result in a significant proportion of patients in the treatment group continuing to produce MxA as compared to the proportion of patients producing MxA in the Rebif® arm.
A total of 30 patients will be studied, fifteen in each arm. Proportional analysis for sample size estimation could not be done since the proportion of MxA positive patients at 1 year in the Rebif® treatment arm is unknown. Nevertheless, a sample size of 15 patients per arm will allow the detection of a suitable difference between the treatment groups as outlined below:
For purposes of this study an MxA non-producer will be designated as a "treatment failure" irrespective of the clinical status. The definition of an MxA non-producer is a patient who is producing 1 year into treatment; MxA transcripts at a level 2 SD below his/her mean baseline value at entry. Accordingly, patients will be compared to their own initial response to Rebif® at entry into the study. In the following examples the proportion of MxA non-producers in each group will be used for comparisons.
At the end of 1 year, the incidence of neutralizing antibodies in patients receiving Rebif® 44 micrograms SC tiw is approximately 20%. For purposes of calculation of sample size, a proportion of 40% (0.4) was chosen for the MxA non-producers in the Rebif® arm, since the proportion of patients that fail to produce MxA at 1 year is higher than the proportion that show neutralizing antibodies. In other words, mechanisms other than neutralizing antibodies are the basis of interferon unresponsiveness in most patients, an important phenomenon that is lost to detection if the sole focus is restricted to neutralizing antibodies. Assuming that the combination will be effective in maintaining biological activity of interferon at 1 year in most or all of the patients, the following scenarios can be identified.
Patients will be randomly assigned to either receive Rebif with or without CellCept. The randomization process will utilize a computer program designed specifically for randomizing patients. Patients will have an equal chance of being randomized to receive Rebif with or without CellCept therapy.
Each subject must meet the following eligibility criteria (i.e., all of the Inclusion criteria and not of the Exclusion criteria) before enrollment in to the study:
Primary measures of efficacy:
The null hypothesis is that there will not be any difference between the two treatment arms regarding the levels of mRNA for MxA. The alternate hypothesis is that the treatment arm will have a sustained high level of mRNA as compared to the Rebif® alone treatment group.
Secondary measures of efficacy
MxA levels in patients will be determined by measuring relative amounts of MxA mRNA in peripheral blood mononuclear cells (PBMCs) isolated from their blood. Blood will be collected in preservative free heparin tubes and the PBMCs isolated by Ficoll-Histopaque gradient centrifugation. The PBMCs will be harvested, washed, and the total cell counts established. Total RNA will be isolated from these cells. RNA will then be converted to cDNA in a reverse transcription reaction.
Real-time polymerase chain reaction (PCR) will be performed to establish levels of gene activation of MxA. As in standard PCR, oligonucleotide primers and temperature cycling are used to amplify the target sequence from the template DNA. With real-time PCR, an oligonucleotide "probe" is added to the mix. This probe has a high-energy "reporter" dye at the 5' end and a low-energy "quencher" dye at the 3' end. The probe is designed to anneal to a specific portion of the target DNA sequence. When the probe is intact, the proximity of the quencher dye to the reporter dye suppresses its natural fluorescence. As DNA polymerase makes copies of the template DNA molecules in the mix, the attached probe is cleaved, and the distance between the reporter and quencher dyes increases, causing fluorescent emission by the reporter to also increase. Fluorescence is measured throughout the temperature cycles of the PCR reaction. Calculations are made based on the detected fluorescence to determine the amount of initial template DNA that was present in the sample. Because it is impossible to determine the exact number of MxA mRNA molecules that each sample started with, real-time PCR is done to detect levels of GAPDH, a standard housekeeping gene, in each sample so that a comparison between GAPDH and MxA can be made, and relative quantities can be determined between different samples.
Measuring T2 FLAIR Total burden of T2 FLAIR is measured by a semi-automated computer program used within the radiology department. The software will outline all lesions within the scanned area. Once mapped out, the MRIs will be reviewed by Dr. Eric Bourekas for measurement and quantification of total disease burden.
Detailed study procedures
Treatment Schedule Eligible patients will be randomized to receive treatment with or without mycophenolate mofetil 2,000 mg per day for 6 months. After 4 weeks of therapy both groups will receive Rebif® at the standard dose of 44 micrograms SC TIW, after a standard titration dosing regimen. Patients will be evaluated every 3 months for one year. The patient's total time on study will be one year.
Randomization will occur at the Day 0 visit and will utilize a computer program specifically created for this purpose. Patients will have a 50% chance of receiving CellCept.
End of Study
If a patient develops any medical condition that, in the opinion of the investigator, would make it unsafe for them to continue on the study, the patient will be removed from study and followed off study for safety, resolution of any event. Patient removal from study will be evaluated on a case by case basis at the investigators discretion and will be carried out to ensure the patients safety.
If a patient experiences greater than 2 exacerbations requiring corticosteroid therapy (moderate to severe) in any 12 month period, or have confirmed progression in Expanded Disability Status Scale (EDSS) of > 2 points with or without exacerbations they would be considered treatment failures for the appropriate treatment arm and would be removed from the study to pursue other treatment options.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Early Phase 1|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Condition ICMJE||Multiple Sclerosis|
|Study Arms ICMJE||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Actual Study Completion Date ICMJE||May 2012|
|Actual Primary Completion Date||May 2012 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years to 65 Years (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT00618527|
|Other Study ID Numbers ICMJE||2006H0039|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement ICMJE||Not Provided|
|Responsible Party||Aaron Boster, Ohio State University|
|Study Sponsor ICMJE||Aaron Boster|
|PRS Account||Ohio State University|
|Verification Date||November 2012|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP