E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsing-Remitting Multiple Sclerosis (RRMS) |
Relapsno-remitirajuća multipla skleroza |
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E.1.1.1 | Medical condition in easily understood language |
Relapsing-Remitting Multiple Sclerosis (RRMS) |
Relapsno-remitirajuća multipla skleroza |
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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 | 18.1 |
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 this study is to compare patient medication satisfaction as measured by the Medication Satisfaction Questionnaire (MSQ) scores between the Copaxone 40 mg/mL three times a week (TIW) group and the Copaxone 20 mg/mL once daily (QD) group over 6 months of treatment. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are as follows:
- To compare the convenience perception as measured by the convenience scale within the Treatment Satisfaction Questionnaire for Medication (TSQM-9) in patients treated with subcutaneous (SC) injection of Copaxone 40 mg/mL TIW vs. Copaxone 20 mg/mL QD over 6 months of treatment
- To compare symptomatic changes as determined by the Multiple Sclerosis Quality of Life Inventory (MSQLI) subscales Modified Fatigue Impact Scale (MFIS) and Mental Health Inventory (MHI) in patients treated with SC injection of Copaxone 40 mg/mL TIW vs. Copaxone 20 mg/mL QD over 6 months of treatment
- To compare patient’s depressive symptoms as measured by Beck Depression Inventory II (BDI-II) scale in patients treated with SC injection of Copaxone 40 mg/mL TIW vs. Copaxone 20 mg/mL QD over 6 months of treatment
The exploratory and other objectives of the study are detailed in the study protocol. |
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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 |
Neuroimmunological Ancillary Study: The neuroimmunological ancillary study has the following objectives:
- To compare throughout the study, the cytokine profile induced in the Copaxone 40 mg/mL TIW group as compared to baseline.
- To compare throughout the study, the distribution of T and B cells subpopulations as measured by flow cytometry in the Copaxone 40 mg/mL TIW group as compared to baseline.
- To compare throughout the study, the levels of neurotrophic and gliotrophic factors (platelet-derived growth factor [PDGF], nerve growth factor [NGF], brain-derived neurotrophic factor [BDNF], and epidermal growth factor core domain peptide of neuregulin-1 [eNRG1]) in the Copaxone 40 mg/mL TIW group as compared to baseline. |
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E.3 | Principal inclusion criteria |
Patients may be included in the study only if they meet all of the following criteria:
a. Men or women at least 18 years of age or older
b. Patients must have a confirmed and documented RRMS diagnosis, as defined by the Revised
McDonald criteria (Polman et al 2011).
c. Patients must be ambulatory with a Kurtzke Expanded Disability Status Scale (EDSS) score of 0 to 5.5 at Screening visit.
d. Patients must be in a stable neurological condition, relapse-free and free of any corticosteroid treatment (intravenous [IV], intramuscular [IM] and/or per os [PO]) or adrenocorticotrophic hormone (ACTH), 30 days prior to randomization.
e. Women of child-bearing potential must have a negative serum pregnancy test at screening visit and must practice a highly effective method of birth control. Highly effective methods of birth control are defined as those, alone or in combination, that result in a low failure rate (ie, less than 1% per year) when used consistently and correctly. Highly effective methods of birth control in this study include: combined (estrogen and progestogen containing) or progestogen‑only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone‑releasing system, bilateral tubal occlusion, vasectomized partner, and sexual abstinence.
f. Patients must be able to sign and date a written informed consent prior to entering the study.
g. Patients must be willing and able to comply with the protocol requirements for the duration of the study. |
Kriteriji za uključivanje
Ispitanici se mogu uključiti u ispitivanje samo ako ispunjavaju sve sljedeće kriterije:
a. muškarci ili žene ne mlađi od 18 godina;
b. ispitanici moraju imati potvrđenu i dokumentiranu dijagnozu relapsno-remitentne multiple skleroze definiranu prema revidiranim McDonaldovim kriterijima (Polman et al 2011.);
c. ispitanici moraju biti izvanbolnički pacijenti s rezultatom Kurtzkeove proširene ljestvice stanja nesposobnosti (EDSS) između 0 i 5,5 na posjetu za probir;
d. ispitanici moraju biti u stabilnom neurološkom stanju, bez relapsa, i ne smiju primati liječenje kortikosteroidima (intravenskim, intramuskularnim ili oralnim) ili adrenokortikotrofnim hormonima u 30 dana prije randomizacije;
e. žene koje mogu zatrudnjeti moraju imati negativan mokraćni test na trudnoću na posjetu za probir te moraju koristiti prihvatljivu metodu kontracepcije (prihvatljive metode kontracepcije u ovom ispitivanju uključuju kiruršku sterilizaciju, unutarmaternične usatke, oralnu kontracepciju, kontracepcijske flastere, dugodjelujuću injektivnu kontracepciju, vazektomiju partnera ili dvostruku barijernu metodu [kondom ili dijafragma sa spermicidnim sredstvom]);
f. prije uključivanja u ispitivanje ispitanici moraju biti sposobni potpisati i datirati informirani pristanak;
g. ispitanici moraju biti voljni i sposobni pridržavati se zahtjeva plana ispitivanja tijekom ispitivanja.
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E.4 | Principal exclusion criteria |
Patients will be excluded from participating in this study if they meet any of the following
criteria:
a. Patient had any contraindication to Copaxone therapy.
b. Previous use of Copaxone 40 mg/mL TIW.
c. Patients with progressive forms of MS.
d. Patients with neuromyelitis optica.
e. Use of experimental or investigational drugs, and/or participation in drug clinical studies within the 6 months prior to screening.
f. Patients who have been treated with:
- immunosuppressive medications such as azathioprine or methotrexate within 6 months prior
to the first visit
- immunoglobulins and/or monoclonal antibodies (including natalizumab) within at least
3 months prior to inclusion
- alemtuzumab, cladribine, cyclophosphamide or mitoxantrone at any time
g. Chronic (more than 30 consecutive days) systemic (IV, PO or IM) corticosteroid treatment within 6 months prior to screening visit.
h. Pregnancy or breastfeeding.
i. Clinically significant or unstable medical or surgical condition that would preclude safe and complete study participation
j. Employees of the clinical study site or any other individuals involved with the conduct of the study, or immediate family members of such individuals |
Kriteriji za neuključivanje
Ispitanici se neće uključiti u ispitivanje ako ispunjavaju bilo koji od sljedećih kriterija:
a. imaju bilo koju kontraindikaciju na lijek Copaxone;
b. prethodno su uzimali lijek Copaxone u dozi od 40 mg/ml triput na tjedan;
c. imaju progresivan oblik multiple skleroze;
d. oboljeli su od optičkog neuromijelitisa;
e. uzimali su eksperimentalni ili ispitivani lijek i/ili su sudjelovali u kliničkim ispitivanjima lijeka u 6 mjeseci prije probira;
f. liječeni su:
o imunosupresivima poput azatioprina ili metotreksata u 6 mjeseci prije prvog posjeta;
o imunoglobulinima i/ili monoklonskim antitijelima (uključujući natalizumab) u najmanje 3 mjeseca prije uključivanja;
o alemtuzumabom, kladribinom, ciklofosfamidom ili mitoksantronom u bilo kojem trenutku.
g. kronično (dulje od 30 uzastopnih dana) sistemsko (intravensko, oralno ili intramuskularno) liječenje kortikosteroidima u 6 mjeseci prije posjeta za probir;
h. trudnoća ili dojenje;
i. klinički značajno ili nestabilno zdravstveno ili kirurško stanje koje bi spriječilo sigurno i cjelovito sudjelovanje u ispitivanju;
j. zaposlenici ispitivačkog centra ili bilo koje druge osobe uključene u provođenje ispitivanja ili bliski članovi obitelji ili slične osobe.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint(s):
- MSQ scores over 6 months of treatment. |
Primarne krajnje točke učinkovitosti su:
• rezultati Upitnika o zadovoljstvu lijekom (MSQ) nakon 6 mjeseci liječenja.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Efficacy Measure and Time Point: Medication satisfaction will be assessed with the MSQ at months 0 (baseline, except for treatment naïve patients), 1, 3, 6 (end of core phase), 9, and 12 (end of extension phase), and the ETD visit (if applicable). In addition MSQ will be SRFH on days 1 to 7. |
Zadovoljstvo lijekom procijenit će se Upitnikom o zadovoljstvu lijekom (MSQ) u 0. (utvrđivanje početnih vrijednosti, osim za ispitanike koji nisu primali liječenje), 1., 3., 6. (kraj glavne faze), 9. i 12. mjesecu (kraj produljene faze) te na posjetu za raniji prekid ispitivanja (ako ga je bilo). Dodatno će se Upitnik o zadovoljstvu lijekom (MSQ) ispunjavati kao vlastiti izvještaj od kuće od 1. do 7. dana. |
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E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
- Convenience perception as measured by the convenience scale within TSQM-9 over 6 months of treatment
- Symptomatic changes as determined by the MSQLI subscales MFIS and MHI over 6 months of
treatment
- Depressive symptoms as measured by BDI-II scale over 6 months of treatment
Exploratory Endpoints:
- Gene expression profiles of patients over 6 and 12 months of treatment (patients previously naïve to Copaxone only)
- Associations between genetics and selected clinical and exploratory endpoints over 6 and 12 months of treatment
- Retention rate at 6, 9, and 12 months.
- Adherence to treatment as measured by the MS-TAQ scale over 6 months of treatment
- For patients who use the CSYNC device, device satisfaction after 1, 6, and 12 months of treatment
- Evaluation of key variables at 9 and 12 months
Endpoints - Neuroimmunological Ancillary Study
- Cytokine profiles throughout the study.
- Distribution of T and B cells subpopulations as measured by flow cytometry, throughout the study.
- Levels of neurotrophic and gliotrophic factors (PDGF, NGF, BDNF, and eNRG1).
Safety Endpoints: Safety variables and endpoints will include the following:
- occurrence of adverse events throughout the study
- vital signs measurements at each visit
- clinical laboratory test results at screening, and months 1, 3, and 6
Assessment of Tolerability: Tolerability variables and endpoints are as follows:
-Proportion of patients (%) who prematurely discontinued from the study due to adverse events and the time to withdrawal. |
Sekundarne krajnje točke učinkovitosti su:
• percepcija praktičnosti mjerena ljestvicom praktičnosti Upitnika o zadovoljstvu terapijom za lijek (TSQM-9) nakon 6 mjeseci liječenja;
• simptomatske promjene utvrđene putem Modificirane ljestvice utjecaja umora (MFIS) i Upitnika o mentalnom zdravlju (MHI), kao podljestvicama Upitnika o kvaliteti života za multiplu sklerozu (MSQLI) nakon 6 mjeseci liječenja;
• simptomi depresije mjereni ljestvicom Beckova upitnika o depresiji II (BDI-II) nakon 6 mjeseci liječenja.
Istraživačke krajnje točke su:
• profili ekspresije gena ispitanika nakon 6 i 12 mjeseci liječenja (samo za ispitanike koji prethodno nisu primali lijek Copaxone);
• povezanost genetike i izabranih kliničkih i istraživačkih krajnjih točaka nakon 6 i 12 mjeseci liječenja;
• stopa retencije nakon 6, 9 i 12 mjeseci;
• ustrajavanje na liječenju mjereno ljestvicom Upitnika o ustrajavanju na liječenju multiple skleroze (MS-TAQ) nakon 6 mjeseci liječenja;
• zadovoljstvo uređajem nakon 1, 6 i 12 mjeseci liječenja za ispitanike koji koriste uređaj CSYNC;
• procjena ključnih varijabli nakon 9 i 12 mjeseci.
Krajnje točke pomoćnog neuroimunološkog ispitivanja su:
• profili citokina tijekom ispitivanja;
• distribucija subpopulacija stanica T i B tijekom ispitivanja mjerena protočnom citometrijom;
• razine neurotrofnih i gliotrofnih čimbenika (PDGF, NGF, BDNF, eNRG1).
Sigurnosne krajnje točke
Sigurnosne varijable i krajnje točke uključivat će:
• pojavu štetnih događaja tijekom ispitivanja;
• mjerenje vitalnih znakova na svakom posjetu;
• rezultate kliničkih laboratorijskih testova na probiru i nakon 1, 3 i 6 mjeseci.
Procjene podnošljivosti
Varijable i krajnje točke podnošljivosti su:
• udio ispitanika (u postocima) koji se prerano povuku iz ispitivanja zbog štetnih događaja i vrijeme do povlačenja.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Efficacy Measures:
- Convenience : months 0, 1, 3, 6, 9, and 12, ETD visit
- Symptomatic changes: months 0, 1, 3, 6, 9, and 12, ETD visit
- Depression: months 0, 1, 3, 6, 9, and 12, ETD visit
Safety Measures:
- inquiries about adverse events at every visit
- CBC at screening, and months 1, 3, and 6
- serum chemistry at screening, months 1, 3, and 6
- β-hCG in women of child-bearing potential at screening.
- urine pregnancy test at months 0, 1, 3, 6, 9, and 12, ETD visit
- vital signs at every visit
- physical examinations at screening, month 6, 12 and ETD visit
- inquiries about concomitant medication usage at every visit
Exploratory and Ancillary Study Measures and Time Points are detailed in the study protocol.
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•praktičnost, koja će se mjeriti sa TSQM-9 u 0, 1, 3, 6, 9 i 12.mjesecu te na posjetu za raniji prekid
•simptomatske promjene, procjenom putem MFIS i MHI, u sklop MSQLI u 0,1, 3, 6, 9. i 12.mj. te na posjetu za raniji prekid;
• depresija, mjeri se sa BDI-II u 0, 9. i 12.mj. te na posjetu za raniji prekid
Mjere sigurnosti:
•upiti o štetnim događajima na svakom posjetu;
• KKS i DKS na probiru i u 1, 3, 6. 9. i 12.mj. te na posjetu za raniji prekid ispitivanja;
•elektroliti na probiru i u 1.3,6.mj.
• β-hCG za žene koje mogu zatrudnjeti;
•mokraćni test na trudnoću u 0, 1,3,6,9. i 12.mj. te na posjetu za raniji prekid
•vitalni znakovi na svakom posjetu
•fizikalni pregledi na probiru, u 6. i 12.mj. te na posjetu za raniji prekid
•upiti o popratnim lijekovima na svakom posjetu.
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Patient medication satisfaction |
Zadovoljstvo ispitanika lijekom |
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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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | 91 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 68 |
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 |
Austria |
Belgium |
Croatia |
Germany |
Ireland |
Israel |
Italy |
Mexico |
Russian Federation |
Turkey |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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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LVLS |
Zadnji posjet zadnjeg ispitanika |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |