E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
relapse-remitting multiple sclerosis |
schubförmige Multiple Sklerose |
|
E.1.1.1 | Medical condition in easily understood language |
Multiple Sclerosis |
Multiple Sklerose |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
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 |
To evaluate the concept of natalizumab de-escalation to
interferon-beta-1b e.o.d in relapsing-remitting multiple sclerosis
patients, who consider stopping natalizumab due to a benefit-risk
assessment. In particular, to evaluate if interferon beta-1b
treatment may be able to overcome the recurrence of significant
clinical and radiological disease activity after natalizumab
cessation and keep disease activity better under control as
compared to the time prior to natalizumab. |
|
E.2.2 | Secondary objectives of the trial |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
· Female or male patients with relapsing-remitting forms of multiple
sclerosis (according to McDonald's criteria);
· Age between 18 and 70 years;
· Natalizumab-treatment for at least 12 months following the current Swiss guidelines for treatment initiation;
· Treated with a disease-modifying therapy other than interferon beta-1b for at least 12 months before natalizumab was initiated;
· Never treated with interferon beta-1b;
· Eligible patients are clinically stable (free from relapses and 6-month confirmed disability progression for at least 6 months) while on natalizumab-treatment and do not show any Gd-enhancement on their last MRI performed while on Tysabri;
· In eligible patients MRI were performed in the past as following
a) 6-18 months prior to natalizumab-treatment
b) at natalizumab start
c) 12 months after natalizumab initiation;
· Good records with regard to clinical disease activity (relapse rate,
EDSS progression) in the year prior to natalizumab and during
natalizumab;
· Patients who decide to stop natalizumab treatment after a careful
benefit/risk assessment. Risk for PML increases with duration of
natalizumab exposure, pretreatment with an immunosuppressant
agent or serological status of anti-JC-virus positivity;
· Patients, who in context with cessation of natalizumab have decided, after a careful benefit/risk assessment, to continue treatment of their MS with Interferon beta-1b;
· Women of potential childbearing with active contraceptive methods;
· Patients who are willing to undergo study procedures;
· Patients who are willing to undergo MRI;
· Patients who are willing and able to sign informed consent. |
• Männer und Frauen mit der Diagnose einer schubförmigremittierenden
Multiplen Sklerose;
• Alter zwischen 18 und 70 Jahren;
• Behandlung mit Natalizumab während mindestens 12 Monaten
gemäss den schweizerischen und österreichischen Leitlinien betreffend
den Beginn einer solchen Therapie;
• Behandlung mit einer anderen Therapie erster Linie als Interferon
Beta-1b während mindestens 12 Monaten vor dem Beginn der
Behandlung mit Natalizumab;
• keine vorhergehende Therapie mit Interferon Beta-1b;
• klinische Stabilität (keine Schübe und/oder
Behinderungsprogression bestätigt während mindestens 6 Monaten
während der Behandlung mit Natalizumab, keine neuen
Gadoliniumanreichernden Lesionen in der letzten Magnetresonanz,
welche während der Behandlung mit Natalizumab durchgeführt
wurde);
• Verfügbarkeit vertrauenswürdiger und vollständiger betreffend
vorausgehender Krankheitsaktivität (Rückfallquote,
Behinderungsprogression bestimmt mit EDSS) im Jahr vor und
während der Natalizumabtherapie;
• Entscheid zur Beendigung der Natalizumabtherapie nach einer
angemessenen Nutzen-/Risikobestimmung (Patienten mit langer
Therapiedauer, vorhergehender immunsuprimierender Therapie,
positiven AK-anti-JC-Virus haben ein höheres Risiko der progressiven
multifokalen Leukenzephalopathie);
• Patienten, die im Rahmen der Unterbrechung der Behandlung mit
Natalizumab nach einer angemessenen Nutzen-/Risikobestimmung
entschieden haben, ihre MS mit Interferon Beta 1-b weiter zu
behandeln;
• Frauen in gebärfähigem alter mit aktiver kontrazeptiver Methode;
• Patienten, welche mit dem Studienablauf einschliesslich der
Magnetresonanz einverstanden sind;
• Patienten, welche einverstanden sind teilzunehmen und die
Fähigkeit haben, die Einverständniserklärung zu verstehen und zu
unterschreiben. |
|
E.4 | Principal exclusion criteria |
· Patients who have previously entered this study;
· Natalizumab-treatment for less than 12 months following the current Swiss guidelines for treatment initiation;
· Prior treatment with interferon beta-1b (ever interferon beta-1b);
· Sign of clinical disease activity within the 6 months;
· One or more relapses and/or 6-month confirmed disability
progression during the 6 months prior to the study;
· Secondary progressive MS;
· Primary progressive MS;
· Pregnancy - Serum pregnancy test at screening visit positive- or
breast feeding;
· Uncontrolled, clinically significant heart diseases, such as
arrhythmias, angina, or uncompensated congestive heart failure;
· History of severe depression or attempted suicide or current suicidal
ideation;
· Medical or psychiatric conditions that compromise the ability to give informed consent, to comply with the protocol, or to complete the study;
· Uncontrolled seizure disorder;
· Myopathy or clinically significant liver disease;
· Inability, in the opinion of the principal investigator or staff, to comply with protocol requirements for the duration of the study;
· Known hypersensitivity to interferon-beta or other human proteins including albumin;
· Any contraindication for MRI or contrast administration;
· A history of drug abuse in the 6 months prior to screening;
· Treatment with any of the following in the 30 days before day 1:
systemic corticosteroids, ACTH, or other investigational drugs;
· Participation in any other study involving investigational or marketed products, concomitantly or within 30 days prior to entry in the study;
· Current participation on other clinical trials;
· Treatment with drugs which might interfere with the evaluation of
study drugs during the study protocol such as immunomodulants,
immunosuppressives other than interferon beta-1b;
· Likelihood of requiring treatment during the study period with drugs not permitted by the study protocol such as immunomodulants, immunosuppressives other than interferon beta-1b. |
• Patienten, welche bereits in diese Studie eingeschlossen sind;
• Behandlungsdauer mit Natalizumab weniger als 12 Monate;
• Vorhergehende Behandlung mit Interferon Beta-1b;
• klinische Zeichen der Krankheitsaktivität während der letzten 6
Monate (eine oder mehrere Schübe und/oder Behinderungsprogression bestätigt nach 6 Monaten);
• Patienten mit primär oder sekundär progressiver Multipler Sklerose;
• bestehende Schwangerschaft (Schwangerschaftstest anlässlich des Screenings) oder stillende Mütter;
• klinisch signifikante kardiovaskuläre Krankheiten, welche nicht
kontrolliert sind, mit Arrhythmien, Angina pectoris oder
dekompensierter, kongestiver Herzinsuffizienz;
• vorhergehende oder bestehende schwere Depression oder
Suizidversuch oder bestehende suizidale Ideen;
• allgemeinmedizinische oder psychiatrische Einschränkungen, welche das Erbringen der Einverständniserklärung, das Folgen des
Studienprotokolls oder die Beendigung der Studie verhindern können;
• nicht kontrollierte Epilepsie;
• klinisch signifikante Myopathie oder Hepatopathie;
• Unfähigkeit, sich während der Studiendauer an das Studienprotokoll zu halten, sei es aufgrund personeller oder nach Einschätzung des untersuchenden Arztes;
• bekannte Unverträglichkeit von Interferon Beta-1b oder
menschlicher Proteine einschliesslich Albumin;
• jegliche Kontraindikation zur Durchführung von Magnetresonanzen oder der Verabreichung von Kontrastmitteln zur Durchführung der Magnetresonanz;
• Bekannter Substanzabusus in den 6 Monaten vor dem
Studienscreening;
• Therapie mit einem der folgenden Medikamente 30 Tage vor
Studienbeginn: systemische Kortikosteroide, ACTH, andere
Medikamente welche sich noch in klinischen Studien befinden;
• Teilnahme an anderen klinischen Studien, aktuell und in den 30
Tagen vor Studienbeginn;
• Einnahme anderer Therapien, welche das Studienmedikament
beeinflussen könnten;
• hohe Wahrscheinlichkeit des Bedarfs eines während der Studie
verbotenen Medikaments. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint:
Annualized relapse rate on study after treatment with interferon beta 1b compared to annualized relapse rate in the year prior to
natalizumab initiation on first line disease modifying treatment. |
Primärer Endpunkt:
Inzidenz der jährlichen Schubrate während der Studie im Vergleich mit derjenigen im während dem Jahr vor Beginn der Natalizumabtherapie |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary endpoint:
Annualized relapse rate on study after 12 months of treatment with interferon beta 1b (Assessments: Day 1, month 3, 6, 9, 12)
compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12). |
|
E.5.2 | Secondary end point(s) |
Secondary endpoints:
1) Change of clinical parameters (severity of relapses by functional
system score, proportion of relapse-free patients), 3-month confirmed EDSS progression (of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5), MSFC compared to baseline.
2) Change of EDSS, MSFC scores from baseline to 12 months
compared to the changes in the year prior to natalizumab treatment.
3) MRI parameters (number of new T2-hyperintense lesions, number of Gd-enhancing lesions on T1-weighted images) with subtraction MRI.
4) Patient reported outcome: Quality of life using EQ-5D, Functional assessment of multiple sclerosis (FAMS). |
Sekundäre Endpunkte:
1) Klinische Parameter: Schweregrad der Schübe, Anzahl der Patienten ohne Schübe, Behinderungsprogression (EDSS) bestätigt nach 3
Monaten (Erhöhung des EDSS um mindestens 1.0 Punkte ausgehend von einem EDSS < 5.5, um mindestens 0.5 Punkte bei EDSS ≥5.5).
2) Beurteilung des Behinderungsgrades alle 3 Monate mittels MSFC.
3) Parameter der alle 6 Monate durchgeführten Magnetresonanz:
Anzahl neuer hyperintenser Läsionen in den T2-Sequenzen, ermittelt mittels der Bildsubstraktionsmethode, Anzahl
Gadoliniumanreichernder Läsionen in den T1-Sequenzen.
4) Patientenfragebogen: Lebensqualität EQ-5D, FAMS |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints:
Change of clinical parameters (severity of relapses by functional
system score, proportion of relapse-free patients), 3-month
confirmed EDSS progression (of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5), MSFC at months 3, 6, 9, 12, 15, 18, 21, 24 compared to baseline (Day 1).
Change of EDSS, MSFC scores from baseline to 12 months
compared to the changes in the year prior to natalizumab treatment (month -24 to -12).
MRI parameters (number of new T2-hyperintense lesions, number of Gd-enhancing lesions on T1-weighted images) with subtraction MRI at months 6,12, 24.
Patient reported outcome
Quality of life using EQ-5D, Functional assessment |
|
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 | No |
E.6.12 | Pharmacoeconomic | No |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
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 | 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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | No |
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 |
|
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |