Natalizumab De-escalation With Interferon Beta-1b

• Sponsor: Claudio Gobbi (Other)
• Overall Status: Completed
• CT.gov ID: NCT01144052
• Collaborator: Ospedale Civico, Lugano (Other)
• Enrollment: 19
• Location: 1
• Arms: 2
• Duration (Months): 17
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

Multiple Sclerosis (MS) is the most common neurological disorder causing disability in young adults. The management of MS-patients requires treatment with disease-modifying agents, monoclonal antibodies such as natalizumab or immunosuppressants. Natalizumab showed good efficacy and is approved for treatment of relapsing MS with a number of restrictions due to safety issues. Cognitive data related to natalizumab treatment are still scarce. Interferon-beta-1b is approved for high-frequency, subcutaneous (sc) administration in the treatment of multiple sclerosis. It reduces the relapse rate, severity, hospitalisation and the disease activity as seen on MRI.

This is a pilot study to explore the concept of de-escalating natalizumab treatment to interferon-beta-1b e.o.d compared to continuous treatment with natalizumab in patients with relapsing-remitting multiple sclerosis previously treated with natalizumab for 12 months. The study is designed as prospective, controlled, randomized, rater-blinded, parallel-group, two arm, mono-centric including patients of the Ticino Cohort. One arm will be treated with Interferon-beta 1b 250mcg given subcutaneously every other day, the other with Natalizumab 300 mg given intravenously (i.v.), every four weeks. The treatment duration is 12 months, the follow-up period 12 months. The time to first on-study relapse will be compared between the to treatment arms (primary outcome). Other efficacy parameter include clinical and radiological parameters, patient reported outcome on quality of life and fatigue. Safety is assessed by reports of adverse events.

Condition or Disease	Intervention/Treatment	Phase
Relapsing-remitting Multiple Sclerosis	Drug: interferon beta-1b; Drug: Natalizumab	Phase 4

Detailed Description

At present, there is no cure for multiple sclerosis and the management of MS-patients requires treatment with disease-modifying agents such as interferon-beta or glatiramer acetate, monoclonal antibodies such as natalizumab or immunsuppressants such as mitoxantrone, azathioprine or methotrexate. Acute relapses are usually treated with corticosteroids. Natalizumab is a humanized monoclonal antibody directed against α4-integrin, a component of VLA-4 (very late antigen-4) present on leukocytes. Following submission of additional safety data, the agencies such as Swissmedic or EMEA have issued approval of natalizumab for treatment of relapsing MS with a number of restrictions. The preparation has been available in Switzerland since 2006. According to the current scientific information, natalizumab (Tysabri®) is indicated as a "disease-modifying monotherapy of highly active relapsing MS" for the following patient groups: 1) patients showing high levels of disease activity despite treatment with an IFN-β preparation, or 2) untreated/treatment-naive patients with rapidly progressing relapsing-remitting MS (at least two serious relapses per year).

The primary objective of this pilot study is to generate first data and hypotheses on the concept of de-escalating natalizumab-treated relapsing-remitting multiple sclerosis patients to interferon-beta-1b e.o.d compared to continuous treatment on natalizumab for planning of further clinical studies regarding safety and efficacy.

As secondary objectives, clinical, neuropsychological parameters, MRI and laboratory parameter and safety aspects will be assessed in accordance to the protocol available for the management of patient on natalizumab at our service.

This is a prospective, controlled, randomized, rater-blinded, parallel-group, monocentric, two arm, phase IV pilot study. Patients with relapsing-remitting forms of MS, respecting all inclusion/exclusion criteria, will be randomized into two equal-size parallel arms for de-escalation to interferon beta-1b (after a month wash-out) or for continued treatment on natalizumab.

it is planned to enrol 20 patients (1/2 in the natalizumab group, 1/2 in the interferon beta-1b group. Patients providing written informed consent will be treated for 12 months; pre-planned follow-up of further 12 month

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: De-escalation After Natalizumab Treatment With Interferon-beta-1b in Patients With Relapsing-remitting Multiple Sclerosis
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Nov 1, 2011
• Actual Study Completion Date: Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Natalizumab Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 months at study entry. Natalizumab continues to be administered every four weeks by intravenous infusion from the beginning of the study as indicated by the manufacturers' instructions.	Drug: Natalizumab; Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 months at study entry. Natalizumab continues to be administered every four weeks by intravenous infusion from the beginning of the study as indicated by the manufacturers' instructions.; Other Names: Tysabri
Experimental: Interferon-beta-1b 250 mcg (8 MIU) subcutaneous injections every other day	Drug: interferon beta-1b; Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 month at study entry. After a wash-out period of one month, interferon-beta-1b will be administered subcutaneously every other day as indicated by the manufacturers' instructions including the stepwise up-titration scheme as recommended for treatment start. The final dose of interferon beta-1b is 250 mcg (8 million International Units [MIU]); Other Names: Betaferon®

Outcome Measures

Primary Outcome Measures

1. Number of Days Until First On-study Relapse [12 months]

   Patients were followed-up during 12 months and time to first on-study relapse from randomization was recorded.

Secondary Outcome Measures

1. Number of Participants With Relapses [12 months]

2. Number of Relapses [12 months]

3. Proportion of Relapse Free Patients [12 months]

4. Severity of Relapses [12 months vs baseline]

   Change of Expanded Disability Status Scale (EDSS 1-10). Higher values represent a worser outcome.

5. MRI Parameters [12 months]

   Number of new T2-hyperintense lesions, Number of Gd-enhancing lesions on T1-weighted images. Assessments at month 3, 6, 9, 12, 18, 24.

6. Number of Patients With Adverse Events [12 months]

   Recording and reporting according to regulations. Monthly assessments or if necessary.

7. Number of Infections [12 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Female or male patients with relapsing-remitting forms of multiple sclerosis (according to McDonald's criteria)

• Age between 18 and 60 years

• Natalizumab-treatment for at least 12 month following the current Swiss guidelines for treatment initiation

• Eligible patients are clinically stable (free from relapses and 6-month confirmed disability progression for at least 6 months) while on natalizumab-treatment

• Women of potential childbearing with active contraceptive methods

• Patients who are willing to undergo study procedures

• 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 month following the current Swiss guidelines for treatment initiation

• Sign of clinical disease activity within the 6 month

• One or more relapses and/or 6-month confirmed disability progression during the 6 months prior to the study

• Any disease other than multiple sclerosis that would better explain the patient's signs and symptoms

• Secondary progressive MS

• Primary progressive MS

• Pregnancy - Urine pregnancy test at baseline visit - 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

• Likelihood of requiring treatment during the study period with drugs not permitted by the study protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Neurocenter of Southern Switzerland, Ospedale Civico Lugano	Lugano	Ticino	Switzerland	6900

Sponsors and Collaborators

• Claudio Gobbi
• Ospedale Civico, Lugano

Investigators

• Principal Investigator: Claudio Gobbi, Dr med., Neurocenter of Southern Switzerland, Ospedale Civico Lugano

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Homepage of the hospital organisation in Ticino
• Homepage of the Swiss Society of Multiple Sclerosis

Publications

• IFNB Multiple Sclerosis Study Group. Interferon beta-lb is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. 1993 [classical article]. Neurology. 2001 Dec;57(12 Suppl 5):S3-9.
• 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. doi: 10.1007/s00415-008-0061-1. Epub 2008 Oct 29.
• Paty DW, Li DK; UBC MS/MRI Study Group and IFNB Multiple Sclerosis Study Group. Interferon beta-lb is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. 1993 [classical article]. Neurology. 2001 Dec;57(12 Suppl 5):S10-5.
• Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW; AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006 Mar 2;354(9):899-910.
• Putzki N, Yaldizli O, Tettenborn B, Diener HC. Multiple sclerosis associated fatigue during natalizumab treatment. J Neurol Sci. 2009 Oct 15;285(1-2):109-13. doi: 10.1016/j.jns.2009.06.004. Epub 2009 Jun 26.
• Ransohoff RM. Natalizumab and PML. Nat Neurosci. 2005 Oct;8(10):1275.
• Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, Lublin FD, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA, Sandrock AW; SENTINEL Investigators. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006 Mar 2;354(9):911-23.
• Sadovnick AD, Ebers GC. Epidemiology of multiple sclerosis: a critical overview. Can J Neurol Sci. 1993 Feb;20(1):17-29. Review.

• Responsible Party: Claudio Gobbi, Dr. med., Ospedale Civico, Lugano
• ClinicalTrials.gov Identifier: NCT01144052
• Other Study ID Numbers: EOC.NC.09.01
• First Posted: Jun 15, 2010
• Last Update Posted: Apr 17, 2014
• Last Verified: Mar 1, 2014

• Keywords provided by Claudio Gobbi, Dr. med., Ospedale Civico, Lugano: Natalizumab; Interferon-beta 1b; De-escalation; Ticino
• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Interferons; Interferon-beta; Natalizumab; Interferon beta-1b

Study Results

Participant Flow

Recruitment Details	Recruitment period: 2010 to 2011 Out-patients of Neurology ambulatory

Arm/Group Title	Natalizumab	Interferon-beta-1b
Arm/Group Description	Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 months at study entry. Natalizumab continues to be administered every four weeks by intravenous infusion from the beginning of the study as indicated by the manufacturers' instructions.	250 mcg (8 MIU) subcutaneous injections every other day
Period Title: Overall Study
STARTED	10	9
COMPLETED	9	8
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Natalizumab	Interferon-beta-1b	Total
Arm/Group Description	Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 months at study entry. Natalizumab continues to be administered every four weeks by intravenous infusion from the beginning of the study as indicated by the manufacturers' instructions.	250 mcg (8 MIU) subcutaneous injections every other day	Total of all reporting groups
Overall Participants	10	9	19
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	10 100%	9 100%	19 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43 (10.83)	39 (13.26)	41 (12.05)
Sex: Female, Male (Count of Participants)
Female	6 60%	3 33.3%	9 47.4%
Male	4 40%	6 66.7%	10 52.6%
Region of Enrollment (participants) [Number]
Switzerland	10 100%	9 100%	19 100%

Outcome Measures

1. Primary Outcome

Title	Number of Days Until First On-study Relapse
Description	Patients were followed-up during 12 months and time to first on-study relapse from randomization was recorded.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

All enrolled and randomized patients fulfilled the criteria for analysis.

Arm/Group Title	Natalizumab	Interferon-beta-1b
Arm/Group Description	Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 months at study entry. Natalizumab continues to be administered every four weeks by intravenous infusion from the beginning of the study as indicated by the manufacturers' instructions.	250 mcg (8 MIU) subcutaneous injections every other day
Measure Participants	10	9
Median (Full Range) [days]	NA	103

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Natalizumab, Interferon-beta-1b
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No statistical hypothesis tests for efficacy were performed as this was a pilot study serving to generate first data and hypotheses.
Statistical Test of Hypothesis	p-Value	0.125
	Comments
	Method	Log Rank
	Comments

2. Secondary Outcome

Title	Number of Participants With Relapses
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

All enrolled and randomized patients were analyzed.

Arm/Group Title	Natalizumab	Interferon-beta-1b
Arm/Group Description	Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 months at study entry. Natalizumab continues to be administered every four weeks by intravenous infusion from the beginning of the study as indicated by the manufacturers' instructions.	250 mcg (8 MIU) subcutaneous injections every other day
Measure Participants	10	9
Number [participants]	0 0%	2 22.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Natalizumab, Interferon-beta-1b
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.447
	Comments
	Method	non-parametric
	Comments

3. Secondary Outcome

Title	Number of Relapses
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Natalizumab	Interferon-beta-1b
Arm/Group Description	Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 months at study entry. Natalizumab continues to be administered every four weeks by intravenous infusion from the beginning of the study as indicated by the manufacturers' instructions.	250 mcg (8 MIU) subcutaneous injections every other day
Measure Participants	10	9
Number [number of events]	0	3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Natalizumab, Interferon-beta-1b
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.447
	Comments
	Method	non-parametric
	Comments

4. Secondary Outcome

Title	Proportion of Relapse Free Patients
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Natalizumab	Interferon-beta-1b
Arm/Group Description	Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 months at study entry. Natalizumab continues to be administered every four weeks by intravenous infusion from the beginning of the study as indicated by the manufacturers' instructions. Natalizumab: Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 months at study entry. Natalizumab continues to be administered every four weeks by intravenous infusion from the beginning of the study as indicated by the manufacturers' instructions.	250 mcg (8 MIU) subcutaneous injections every other day interferon beta-1b: Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 month at study entry. After a wash-out period of one month, interferon-beta-1b will be administered subcutaneously every other day as indicated by the manufacturers' instructions including the stepwise up-titration scheme as recommended for treatment start. The final dose of interferon beta-1b is 250 mcg (8 million International Units [MIU])
Measure Participants	10	9
Number [participants]	10 100%	7 77.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Natalizumab, Interferon-beta-1b
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.206
	Comments
	Method	t-test, 2 sided
	Comments

5. Secondary Outcome

Title	Severity of Relapses
Description	Change of Expanded Disability Status Scale (EDSS 1-10). Higher values represent a worser outcome.
Time Frame	12 months vs baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Natalizumab	Interferon-beta-1b
Arm/Group Description	Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 months at study entry. Natalizumab continues to be administered every four weeks by intravenous infusion from the beginning of the study as indicated by the manufacturers' instructions. Natalizumab: Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 months at study entry. Natalizumab continues to be administered every four weeks by intravenous infusion from the beginning of the study as indicated by the manufacturers' instructions.	250 mcg (8 MIU) subcutaneous injections every other day interferon beta-1b: Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 month at study entry. After a wash-out period of one month, interferon-beta-1b will be administered subcutaneously every other day as indicated by the manufacturers' instructions including the stepwise up-titration scheme as recommended for treatment start. The final dose of interferon beta-1b is 250 mcg (8 million International Units [MIU])
Measure Participants	10	9
Median (Full Range) [units on a scale]	0	0.5

6. Secondary Outcome

Title	MRI Parameters
Description	Number of new T2-hyperintense lesions, Number of Gd-enhancing lesions on T1-weighted images. Assessments at month 3, 6, 9, 12, 18, 24.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

All enrolled and randomized patients were analyzed.

Arm/Group Title	Natalizumab	Interferon-beta-1b
Arm/Group Description	Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 months at study entry. Natalizumab continues to be administered every four weeks by intravenous infusion from the beginning of the study as indicated by the manufacturers' instructions.	250 mcg (8 MIU) subcutaneous injections every other day
Measure Participants	10	9
nT2L month 3	0	0.5
nT2L month 6	0	1.5
nT2L month 9	0	0.5
nT2L month 12	0	0
GD+L month 3	0	0
GD+L month 6	0	0
GD+L month 9	0	0
GD+L month 12	0	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Natalizumab, Interferon-beta-1b
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No statistical hypothesis tests for efficacy were performed, as this was pilot study serving to generate first data and hypotheses.
Statistical Test of Hypothesis	p-Value	0.234
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	p-value refers to nT2L at month 12

7. Secondary Outcome

Title	Number of Patients With Adverse Events
Description	Recording and reporting according to regulations. Monthly assessments or if necessary.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

All patients enrolled and randomized were analyzed.

Arm/Group Title	Natalizumab	Interferon-beta-1b
Arm/Group Description	Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 months at study entry. Natalizumab continues to be administered every four weeks by intravenous infusion from the beginning of the study as indicated by the manufacturers' instructions.	250 mcg (8 MIU) subcutaneous injections every other day
Measure Participants	10	9
Number of patients with infections	7 70%	4 44.4%
Number of patients with injections site reactions	0 0%	4 44.4%

8. Secondary Outcome

Title	Number of Infections
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Natalizumab	Interferon-beta-1b
Arm/Group Description	Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 months at study entry. Natalizumab continues to be administered every four weeks by intravenous infusion from the beginning of the study as indicated by the manufacturers' instructions.	250 mcg (8 MIU) subcutaneous injections every other day
Measure Participants	10	9
Number [events]	25	8

Adverse Events

Time Frame	Adverse events were collected during the 12 months of the trial
Arm/Group Title	Natalizumab		Interferon-beta-1b
Arm/Group Description	Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 months at study entry. Natalizumab continues to be administered every four weeks by intravenous infusion from the beginning of the study as indicated by the manufacturers' instructions.		250 mcg (8 MIU) subcutaneous injections every other day
All Cause Mortality
	Natalizumab		Interferon-beta-1b
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Natalizumab		Interferon-beta-1b
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/10 (10%)		0/9 (0%)
Gastrointestinal disorders
gastroenteritis	1/10 (10%)	1	0/9 (0%)	0
Other (Not Including Serious) Adverse Events
	Natalizumab		Interferon-beta-1b
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/10 (70%)		7/9 (77.8%)
Infections and infestations
Infection	7/10 (70%)	7	3/9 (33.3%)	3
Investigations
Injection site reaction	0/10 (0%)	0	4/9 (44.4%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.