E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsing-remitting Multiple Sclerosis |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10063399 |
E.1.2 | Term | Relapsing-remitting multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary study objective is to test the superiority of DAC HYP compared to IFN β-1a in preventing MS relapse in subjects with relapsing remitting MS (RRMS). |
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E.2.2 | Secondary objectives of the trial |
The secondary study objectives are to test the superiority of DAC HYP compared to IFN β-1a in slowing functional decline and disability progression and maintaining quality of life in this subject population. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local subject privacy regulations. 2. Must be 18 to 55 years of age, inclusive, at the time of consent. 3. Must have a confirmed diagnosis of RRMS according to McDonald criteria, numbers 1 through 4 (Polman et al, 2005), and a cranial MRI demonstrating lesion(s) consistent with MS (it is not necessary to obtain a current scan if a scan performed previously is available; if a previous scan is not available, then the baseline scan may be used). 4. Must have a baseline EDSS between 0.0 and 5.0, inclusive. 5. Must meet one of the following disease activity-related criteria: a) Two or more clinical relapses within the previous 3 years with at least 1 clinical relapse in the 12 months prior to randomization. OR b) One or more clinical relapses and 1 or more new MRI lesions (Gd+ and/or T2 hyperintense lesion) within the previous 2 years with at least one of these events in the 12 months prior to randomization. The new MRI lesion must be distinct from one associated with the clinical relapse. The baseline MRI may be used to satisfy this criterion. Note: For inclusion purposes, a clinical relapse is defined as neurologic signs and/or symptoms documented in the medical record of at least 24 hours duration that are determined by the Investigator or the Treating Neurologist as consistent with an MS relapse. Time since relapse should be measured from the time of relapse onset. When inclusion is based on a new MRI lesion, activity must be verified by the central MRI reading center. 6. Women of childbearing potential must be willing to practice effective contraception during the study and be willing and able to continue contraception for 4 months after their last dose of study treatment.
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E.4 | Principal exclusion criteria |
1.Diagnosis of primary progressive, secondary progressive,or progressive relapsing MS (as defined by Lublin and Reingold, 1996). 2.Known intolerance, contraindication to, or history of non compliance with Avonex 30 mcg.3.History of malignancy; however, subjects with a history of excised or treated basal cell carcinoma or fewer than 3 squamous cell carcinomas are eligible to participate in this study.4.History of severe allergic or anaphylactic reactions. 5.Known hypersensitivity to study drugs or their excipients. 6.History of abnormal laboratory results that are indicative of any significant cardiac,endocrine, hematological, hepatic, immunologic, metabolic, urologic,pulmonary, gastrointestinal, dermatologic, psychiatric, renal, neurological (other than MS), and/or other major disease that would preclude administration of DAC HYP or Avonex.7.History of human immunodeficiency virus (HIV) or other immunodeficient conditions. 8.History of drug or alcohol abuse within the 2 years prior to randomization.9.History of seizure disorder or unexplained blackouts OR history of a seizure within 6 months prior to Baseline. 10.History of suicidal ideation or an episode of clinically severe depression within 3 months prior to Day 1. Subjects receiving ongoing antidepressant therapy will not be excluded from the study unless the medication has been increased within the 6 months prior to Baseline.11.An MS relapse that has occurred within the 50 days prior to randomization AND/OR the subject has not stabilized from a previous relapse prior to randomization.12.Known history of, or positive screening test result for hepatitis C virus or hepatitis B virus. 13.Varicella or herpes zoster virus infection or any severe viral infection within 6 weeks before screening.14.Exposure to varicella zoster virus within 21 days before screening.15.Any of the following abnormal blood tests at screening: • hemoglobin ≤9.0 g/dL• platelets ≤100 x 10^9/L• lymphocytes ≤1.0 x 10^9/L• neutrophils ≤1.5 x 10^9/L• alanine aminotransferase/serum glutamate pyruvate transaminase (ALT/SGPT), aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT), or gamma glutamyl-transferase ≥2 times the upper limit of normal (ULN)• serum creatinine ≥ULN 16.Any previous treatment with daclizumab or other anti-CD25 monoclonal antibody.17.Any type of live virus vaccine from 4 weeks before randomization.18.Infection requiring hospitalization or intravenous (IV) antibiotics within 8 weeks before randomization. 19.Elective surgery performed from 2 weeks prior to randomization or scheduled through end of the study.20.Treatment with another investigational drug or approved therapy for investigational use within the 6 months prior to randomization. 21.Prior treatment with the any of the following:• total lymphoid irradiation• cladribine• T cell or T cell receptor vaccination• any therapeutic monoclonal antibody, except natalizumab 22.Prior treatment with mitoxantrone, cyclophosphamide, fingolimod, or natalizumab within 1 year prior to randomization.23.Prior treatment with any of the following within the 6 months prior to randomization: • cyclosporine• azathioprine• methotrexate• mycophenolate mofetil•intravenous immunoglobulin • plasmapheresis or cytapheresis.24.Treatment with any of the following medications within the 30 days prior to randomization:• IV corticosteroid treatment• oral corticosteroid treatment• glatiramer acetate 25.Initiation of treatment or dose adjustment of commercially-available Fampridine-SR within the last 90 days.Note: Subject who have been on a stable dose of commercially-available Fampridine-SR for longer than 90 days are not excluded. Use of compounded or other formulations of 4 - aminiopyridine is excluded. 26.For subjects currently taking valproic acid, carbamazepine, lamotrigine, or phenytoin: •Subjects treated with any of these agents for fewer than 6 months prior to randomization are excluded from the study unless they discontinue the agent(s) prior to randomization. •Subjects treated with 2 or more of these agents for more than 6 months prior to randomization are excluded from the study unless they reduce to ≤1 agent prior to randomization. •Subjects who have had dose escalations of one of these agents within the 6 months prior to randomization are excluded from the study unless they revert to a previous dose that had been used for at least 6 months prior to randomization, or unless they discontinue the agent prior to randomization. 27.Subjects who are currently receiving treatment with isoniazid, propylthiouracil, or nimesulide at the time of randomization and are not able to discontinue the agent or change to an alternative medication allowed by the protocol prior to initiation of study treatment. 28/29.Female subjects currently pregnant,breastfeeding or considering becoming pregnant while in the study.30.Previous participation in this study 31.Subjects for whom MRI is contraindicated |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Annualized relapse rate (ARR) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Any relapses and time on study that occur up to Week 144
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E.5.2 | Secondary end point(s) |
a) Number of new or newly-enlarging T2 hyperintense lesions on brain magnetic resonance imaging (MRI) over 96 weeks b) Proportion of subjects with sustained disability progression defined by at least a 1.0-point increase on the Expanded Disability Status Scale (EDSS) from baseline EDSS ≥1.0 that is sustained for 12 weeks or at least a 1.5-point increase on the EDSS from baseline EDSS = 0 that is sustained for 12 weeks c) Proportion of subjects who are relapse-free d) Proportion of subjects with a ≥7.5 point worsening from baseline the MSIS-29 physical score at 96 weeks |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
a) Weeks 0, 24, 96, (and also 144/early termination) b) Screening, weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144/early termination (and also follow up visits 1 and 2, and unscheduled relapse assessment c) up to week 144 (end of study visit) d) 96 weeks |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 117 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Brazil |
Canada |
Czech Republic |
Denmark |
Finland |
France |
Georgia |
Germany |
Greece |
Hungary |
India |
Ireland |
Israel |
Italy |
Mexico |
Moldova, Republic of |
Poland |
Romania |
Russian Federation |
Serbia |
Slovenia |
Spain |
Sweden |
Switzerland |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of study is Last Patient Last Visit (LPLV) for final collection of data for the primary outcome. The End of Study Visit will occur at Week 144 or when the last subject enrolled has completed the Week 96 Visit, whichever is sooner. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |