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 | 14.1 |
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 objective of the study is to assess the
immunogenicity of DAC HYP 150 mg administered every
4 weeks by an SC injection using the pre-filled syringe (PFS) in subjects with RRMS. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are
- to characterize the PK of DAC HYP (using intensive PK data ) following single and multiple doses of DAC HYP administered by the PFS in a subset of subjects with RRMS.
- to evaluate the effect of DAC HYP on the PK of probe drugs for CYP isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A). |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Intensive PK Sub-Study
The following daclizumab PK parameters will be
determined for subjects in the Intensive PK Sub-Study,
following DAC HYP administration at Day 1 (Week 0)
and at Week 20:
o maximum concentration (Cmax)
o time to reach maximum concentration (Tmax)
o area-under-the-curve from start to end of the
dosing interval (AUCτ)
o trough concentrations (Ctrough)
o apparent volume of distribution (V/F)
o elimination half-life (t½)
o apparent clearance (CL/F)
Additional PK parameters may be calculated as
appropriate during data analysis
TP-DI Sub-Study
• The following PK parameters for individual probe drugs will be determined for subjects in the TP-DI Sub Study:
Primary:
o area-under-the-curve from zero to infinity (AUC0–∞). If the extrapolated AUC >20%, AUC0-t where t is the time of last point with quantifiable data (tlast) may be considered if appropriate.
o dextromethorphan to dextrorphan urine concentration ratio
Secondary:
o Cmax
o CL/F
o omeprazole/hydroxyomeprazole concentration ratio at 2 hours postomeprazole dosing.
Additional PK parameters may be calculated as appropriate during data analysis.
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E.3 | Principal inclusion criteria |
Main 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. Aged 18 to 65 years old, inclusive, at the time of informed consent.
3. Must have a confirmed diagnosis of RRMS according to McDonald criteria, and a previous cranial MRI demonstrating lesion(s) consistent with MS.
4. Must have a baseline EDSS between 0.0 and 5.0.
5. Must have had 1 or more clinical relapses within the previous 2 years.
Inclusion Criteria for 3-Year Treatment Extension
1. Must have been compliant with the 205MS302 protocol during the initial 24-week treatment period and the 20-week washout period.
2. Must resume DAC HYP treatment ≤12 weeks after completion of the washout period
Inclusion Criteria for the TP-DI Sub-Study
1. Compliance with the 205MS302 protocol during the initial 24-week treatment period and through Week 40 of the 20-week washout period.
2. Must agree to resume DAC HYP treatment ≤12 weeks after completion of the washout period
3. Must have normal LFT results (total bilirubin ≤1.5 × ULN, ALT/AST ≤ 2 × ULN, and prothrombin time/partial thromboplastin time ≤1.2 × ULN).
4. Must have estimated creatinine clearance >60 mL/min. |
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E.4 | Principal exclusion criteria |
Exclusion Criteria
1. Diagnosis of primary progressive, secondary progressive, or
progressive relapsing MS
2. History of malignancy.
3. History of severe allergic or anaphylactic reactions.
4. History of abnormal laboratory results that is indicative of any significant major disease that would preclude administration of DAC HYP.
5. History of human immunodeficiency virus or other immunodeficient conditions.
6. MS relapse that has occurred within the 30 days prior to Day 1 AND/OR the subject has not stabilized from a previous relapse prior to Day 1.
7. History of, or positive screening test for hepatitis C or hepatitis B infection.
8. Varicella or herpes zoster virus infection within 6 weeks before screening.
9. Exposure to varicella zoster virus within 21 days before screening.
10. Any of the following abnormal blood tests at screening:
• hemoglobin ≤9.0 g/dL, platelets ≤100 x 109/L ,lymphocytes ≤1.0 x109/L, neutrophils ≤1.5 x 109/L
• (ALT)/(ALT/SGPT), (AST)/ (AST/SGOT), or (GGT) ≥2 ×ULN)
• serum creatinine ≥ULN
Treatment History
Any previous treatment with daclizumab or other anti-CD25 monoclonal antibody, total lymphoid irradiation, cladribine, T-cell or T-cell receptor vaccination or any therapeutic monoclonal antibody, except natalizumab.
Any live virus vaccine within the 4 weeks prior to Day 1.
12. Infections requiring hospitalization or IV antibiotics within the 8 weeks prior to Day 1.
13. Elective surgery performed within the 2 weeks prior to Day 1 or scheduled through the end of the study.
14. Treatment with another investigational drug or approved therapy for investigational use within the 6 months prior to Day 1.
15. Treatment with mitoxantrone, cyclophosphamide, fingolimod, or natalizumab within 1 year prior to Day 1.
16. Treatment with any of the following medications or procedures within the 6 months prior to Day 1:
• cyclosporine
• azathioprine
• methotrexate
• mycophenolate mofetil
• IV immunoglobulin (IVIg)
• Plasmapheresis/ cytapheresis
17. Treatment with any of the following medications within the 30 days prior to Day 1:
• IV or oral corticosteroid treatment
• glatiramer acetate
18. For subjects currently taking valproic acid, carbamazepine, lamotrigine, or phenytoin:
• Treatment with any of these agents ≤ 6 months prior to study entry
• Treatment with 2 or more of these agents for more than 6 months prior to study entry are excluded unless they reduce to ≤1 agent prior to study entry.
• Dose escalations of one of these agents within the 6 months prior to study entry are excluded
Current treatment with isoniazid, propylthiouracil, or nimesulide at the time of study entry .
Exclusion Criteria for 3-Year Treatment Extension
1. Subjects who permanently discontinued DAC HYP treatment in Study 205MS302 for any reason prior to the 20 week washout period.
2. ALT/SGPT, (AST/SGOT), or GGT ≥2xULN within 7 days prior to reinitiation of DAC HYP.
Additional Exclusion Criteria for Specific TP-DI Sub-Study
Subject permanently discontinued DAC HYP treatment in Study 205MS302 for any reason prior to Week 40.
Subject is positive for NAbs at Week 36.
Subject is on a regimen of therapeutic anticoagulation.
Subject has narrow angle glaucoma.
Use of any drug or supplement that inhibits or induces CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A activity within 14 days or 5 halflives (whichever is longer) before the first dose of probe-drug cocktail.
Consumption of grapefruit or grapefruit-containing products within 3 days before the first dose of probe-drug cocktail. History of gastrointestinal malabsorption conditions or bleeding. History of hypersensitivity to midazolam, caffeine, warfarin, vitamin K, dextromethorphan, or omeprazole. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Incidence of anti-DAC HYP binding antibodies
(ADAbs) through week 44
• Incidence of anti-DAC HYP neutralizing antibodies
(NAbs) through week 44 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At every study visit as indicated in the Study Events section of the protocol |
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E.5.2 | Secondary end point(s) |
• Daclizumab population PK parameters including apparent clearance
(CL/F) and apparent volume of distribution (V/F)
• PK parameters for subjects in the intensive PK Sub-Study:
• maximum concentration (Cmax)
• time to reach maximum concentration (Tmax)
• area-under-the-curve from start to end of the dosing interval (AUC)
• trough concentrations (Ctrough)
• apparent volume of distribution (V/F)
• elimination half-life (t½)
• apparent clearance (CL/F)
• The following PK parameters for individual probe drugs will be determined for subjects in the TP-DI Sub Study:
Primary:
o area-under-the-curve from zero to infinity (AUC0–∞). If the extrapolated AUC >20%, AUC0-t where t is the time of last point with quantifiable data (tlast) may be considered if appropriate.
o dextromethorphan to dextrorphan urine concentration ratio
Secondary:
o Cmax
o CL/F
o omeprazole/hydroxyomeprazole concentration ratio at 2 hours post-omeprazole dosing |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Daclizumab PK parameters: Weeks 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36,
44, 48, 52, 56, 68, 80, 92, 104, 116, 128, 140, 152, 164, 176, 188
Sub-study parameters: Weeks 0 and 20
TP-DI Sub-Study paramaters: Weeks 43, 48, 52, and 53 |
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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 | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
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 | Yes |
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 | Yes |
E.7.1.3.1 | Other trial type description |
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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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 19 |
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 |
Hungary |
Poland |
Russian Federation |
Czech Republic |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
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 | 5 |
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 |