Natalizumab De-escalation to Interferon-beta-1b in Patients With Relapsing-remitting Multiple Sclerosis

• Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12) [ Time Frame: 3 months ] [ Designated as safety issue: No ]
• Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12) [ Time Frame: 9 months ] [ Designated as safety issue: No ]
• Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12) [ Time Frame: 15 months ] [ Designated as safety issue: No ]
• Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
• Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12) [ Time Frame: 21 months ] [ Designated as safety issue: No ]
• Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12) [ Time Frame: 24 months ] [ Designated as safety issue: No ]

• Severity of relapses [ Time Frame: 3 months ] [ Designated as safety issue: No ]
• Severity of relapses [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Severity of relapses [ Time Frame: 9 months ] [ Designated as safety issue: No ]
• Severity of relapses [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Severity of relapses [ Time Frame: 15 months ] [ Designated as safety issue: No ]
• Severity of relapses [ Time Frame: 18 months ] [ Designated as safety issue: No ]
• Severity of relapses [ Time Frame: 21 months ] [ Designated as safety issue: No ]
• Severity of relapses [ Time Frame: 24 months ] [ Designated as safety issue: No ]
• Proportion of relapse free patients [ Time Frame: 3 months ] [ Designated as safety issue: No ]
• Proportion of relapse free patients [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Proportion of relapse free patients [ Time Frame: 9 months ] [ Designated as safety issue: No ]
• Proportion of relapse free patients [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Proportion of relapse free patients [ Time Frame: 15 months ] [ Designated as safety issue: No ]
• Proportion of relapse free patients [ Time Frame: 18 months ] [ Designated as safety issue: No ]
• Proportion of relapse free patients [ Time Frame: 21 months ] [ Designated as safety issue: No ]
• Proportion of relapse free patients [ Time Frame: 24 months ] [ Designated as safety issue: No ]
• 3-month confirmed EDSS progression [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5
• 3-month confirmed EDSS progression [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5
• 3-month confirmed EDSS progression [ Time Frame: 9 months ] [ Designated as safety issue: No ]
  of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5
• 3-month confirmed EDSS progression [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5
• 3-month confirmed EDSS progression [ Time Frame: 15 months ] [ Designated as safety issue: No ]
  of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5
• 3-month confirmed EDSS progression [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5
• 3-month confirmed EDSS progression [ Time Frame: 21 months ] [ Designated as safety issue: No ]
  of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5
• 3-month confirmed EDSS progression [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5
• MSFC [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).
• MSFC [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).
• MSFC [ Time Frame: 9 months ] [ Designated as safety issue: No ]
  Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).
• MSFC [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).
• MSFC [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).
• MSFC [ Time Frame: 21 months ] [ Designated as safety issue: No ]
  Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).
• MSFC [ Time Frame: 24 ] [ Designated as safety issue: No ]
  Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).
• Change of EDSS score compared to change in the year prior to natalizumab treatment (month -24 to-12 [ Time Frame: 3 months ] [ Designated as safety issue: No ]
• Change of EDSS score compared to change in the year prior to natalizumab treatment (month -24 to-12 [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Change of EDSS score compared to change in the year prior to natalizumab treatment (month -24 to-12 [ Time Frame: 9 months ] [ Designated as safety issue: No ]
• Change of EDSS score compared to change in the year prior to natalizumab treatment (month -24 to-12 [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Change of MSFC score compared to change in the year prior to natalizumab treatment (month -24 to-12 [ Time Frame: 3 months ] [ Designated as safety issue: No ]
• Change of MSFC score compared to change in the year prior to natalizumab treatment (month -24 to-12 [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Change of MSFC score compared to change in the year prior to natalizumab treatment (month -24 to-12 [ Time Frame: 9 months ] [ Designated as safety issue: No ]
• Change of MSFC score compared to change in the year prior to natalizumab treatment (month -24 to-12 [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Number of new/enlarging T2-hyperintense lesions [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  MRI
• Number of new/enlarging T2-hyperintense lesions [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  MRI
• Number of new/enlarging T2-hyperintense lesions [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  MRI
• Number of Gd-enhancing lesions [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  MRI
• Number of Gd-enhancing lesions [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  MRI
• Number of Gd-enhancing lesions [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  MRI
• EQ-5D [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  Quality of life questionnaire
• EQ-5D [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  Quality of life questionnaire
• EQ-5D [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  Quality of life questionnaire
• FAMS [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  Quality of life questionnaire
• FAMS [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  Quality of life questionnaire
• MSFC [ Time Frame: 15 months ] [ Designated as safety issue: No ]
  Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).
• EQ-5D [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  Quality of life questionnaire
• FAMS [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  Quality of life questionnaire
• FAMS [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  Quality of life questionnaire

Multiple Sclerosis (MS) is the most common neurological disorder causing disability in young adults affecting approximately 1 in 1.000 people in western countries. The clinical manifestations usually begin at the age of 20 to 40 years with a median age of 28 years at onset with acute episodes of neurological dysfunction, followed by periods of partial or complete remission and clinical stability in between relapses. This relapsing-remitting phase (RR-MS) of the disease is usually followed by progressive clinical disability (secondary progressive phase, SP-MS).

At present, there is no cure for MS. Based on the pathological concept that neuroinflammation is the common element leading or contributing to neurodegenerative changes, immune interventions have been introduced into clinical practice such as Natalizumab (Tysabri), a humanized monoclonal antibody. Natalizumab (Tysabri) is indicated as a disease-modifying monotherapy of highly active relapsing MS. The associated risks, especially progressive multifocal leukoencephalopathy, necessitate active monitoring of patients and a continuous discussion of optimum use of this drug. In clinical practice, the question how to manage patients on natalizumab at a higher risk for progressive multifocal leukoencephalopathy remains unresolved.

This prospective, controlled (comparison to the period prior to natalizumab treatment), single-arm, open-label, multi-centre, phase IV study aims to evaluating 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 evaluating if interferon beta-1b treatment may be able to overcome the recurrence of significant clinical and radiological disease activity after natalizumab cessation and may keep disease activity better under control as compared to the time prior to natalizumab.

The study population includes patients with relapsing-remitting multiple sclerosis (RR-MS) being treated at least for 12 months with natalizumab and having decided to stop natalizumab treatment and to de-escalate their therapy to a first line treatment with interferon beta-1b. They will be treated during 12 months with interferon-beta 1b 250 mcg given subcutaneously every other day. A 12-month follow-up period with the same treatment is planned.

• Multiple Sclerosis Therapy Consensus Group (MSTCG); Wiendl H, Toyka KV, Rieckmann P, Gold R, Hartung HP, Hohlfeld R. Basic and escalating immunomodulatory treatments in multiple sclerosis: current therapeutic recommendations. J Neurol. 2008 Oct;255(10):1449-63. Epub 2008 Oct 29.
• Kappos L, Bates D, Edan G, Eraksoy M, Garcia-Merino A, Grigoriadis N, Hartung HP, Havrdová E, Hillert J, Hohlfeld R, Kremenchutzky M, Lyon-Caen O, Miller A, Pozzilli C, Ravnborg M, Saida T, Sindic C, Vass K, Clifford DB, Hauser S, Major EO, O'Connor PW, Weiner HL, Clanet M, Gold R, Hirsch HH, Radü EW, Sørensen PS, King J. Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring. Lancet Neurol. 2011 Aug;10(8):745-58. Review.
• Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, Montalbán X, Barkhof F, Radü EW, Metzig C, Bauer L, Lanius V, Sandbrink R, Pohl C; BENEFIT Study Group. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol. 2009 Nov;8(11):987-97. Epub 2009 Sep 10.
• Putzki N, Yaldizli O, Bühler R, Schwegler G, Curtius D, Tettenborn B. Natalizumab reduces clinical and MRI activity in multiple sclerosis patients with high disease activity: results from a multicenter study in Switzerland. Eur Neurol. 2010;63(2):101-6. Epub 2010 Jan 16.

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

  • 6-18 months prior to natalizumab-treatment
  • at natalizumab start
  • 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, pre-treatment 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.

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.