Extension Study to Evaluate Safety and Efficacy of Natalizumab in Japanese Participants With Relapsing-Remitting Multiple Sclerosis

• Sponsor: Biogen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01416155
• Collaborator: (none)
• Enrollment: 97
• Locations: 22
• Arm: 1
• Duration (Months): 50
• Patients Per Site: 4.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective of the study is to further evaluate the long-term safety and tolerability profiles of BG00002 (natalizumab) in Japanese participants with relapsing-remitting multiple sclerosis (RRMS). The secondary objective of this study is to further evaluate the long-term efficacy profile of BG00002 in Japanese participants with RRMS.

Condition or Disease	Intervention/Treatment	Phase
Relapsing-Remitting Multiple Sclerosis; Multiple Sclerosis	Drug: natalizumab	Phase 2

Detailed Description

This is a multicenter, long-term, open-label, extension study in participants who have successfully completed Study 101MS203 (NCT01440101).

Study Design

• Study Type: Interventional
• Actual Enrollment: 97 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Long-Term, Open-Label, Multicenter, Extension Study to Evaluate Safety and Efficacy of BG00002 in Japanese Subjects With Relapsing-Remitting Multiple Sclerosis
• Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: natalizumab 300 mg intravenous (IV) infusions of natalizumab every 4 weeks until product is approved in Japan or development is discontinued in Japan, whichever comes first.	Drug: natalizumab; Other Names: Tysabri BG00002

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs [Day 1 through First Follow-Up (12 Weeks After Last Infusion) +/- 7 days. Approximately 62 months]

   An AE was any untoward medical occurrence that did not necessarily have a causal relationship with this treatment. An SAE was any untoward medical occurrence that at any dose: resulted in death; in the view of the Investigators, placed the subject at immediate risk of death (a life-threatening event); however, this did not include an event that, had it occurred in a more severe form, might have caused death; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in a congenital anomaly/birth defect; any other medically important event that, in the opinion of the Investigators, could have jeopardized the subject or may have required intervention to prevent one of the other outcomes listed in the definition above.

2. Number of Participants With Serum Antibodies to Natalizumab [Day 1 up to approximately 50 months]

   Negative is defined as negative for antibodies at all post-baseline results. Transient positivity is defined as only 1 positive result. Persistent positivity is defined as 2 positive results separated by at least 6 to 12 weeks.

Secondary Outcome Measures

1. Adjusted Annualized Relapse Rate [Day 1 up to approximately 50 months]

   Clinical relapses are defined as new or recurrent neurologic symptoms, not associated with fever or infection, lasting for at least 24 hours, and accompanied by new objective neurological findings upon examination by the neurologist. The annualized relapse rate is calculated overall as the total number of relapses experienced in the study divided by the number of days followed in the study, and the ratio multiplied by 365. Obtained from a Poisson regression model, adjusted for the baseline relapse rate from study 101MS203 (NCT01440101).

2. Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192 [Day 1 up to Week 192]

   The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. Scoring is based on measures of impairment in eight functional systems on examination by a neurologist.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Ability to understand the purpose and risks of the study and provide signed and dated informed consent and any authorizations required by local law.

• Subjects who participated in and completed all protocol-related evaluations through Week 24 of Study 101MS203 (NCT01440101).

• Subjects participating in study 101MS204 (NCT01416155) participated either in the open label pharmacokinetics-pharmacodynamics study or placebo-controlled study of natalizumab 300 mg q4wks (parts A and B of study 101MS203, respectively).

• Subjects of childbearing potential must practice effective contraception during the study and be willing and able to continue contraception for 12 weeks after their last dose of study treatment.

• Must be willing to remain free from concomitant immunosuppressive or immunomodulatory treatment (including interferon beta [IFNβ] and long-term systemic corticosteroids) for the duration of the study.

Key Exclusion Criteria Medical History

• Any significant change in medical history since Study 101MS203 (NCT01440101), including laboratory tests, or current clinically important condition that in the opinion of the Investigator would have excluded the subject's participation in the previous study. The Investigator must re-review the subject's medical fitness for participation and consider diseases that would preclude treatment.

• Subjects from Study 101MS203 (NCT01440101) who discontinued study treatment due to an adverse event.

• Subjects who are determined to be persistently positive for anti-BG0002 antibodies based on prior testing.

Treatment History

• Treatment with any of the following medications between last dose of study treatment in Study 101MS203 (NCT01440101) and the start of this study: intravenous immunoglobulin (IVIg), plasmapheresis, cytapheresis, immunosuppressant medications (e.g., mitoxantrone, azathioprine, cyclophosphamide, methotrexate, cyclosporine, FTY720), immunomodulatory medications (including IFNβ and glatiramer acetate [GA]) total lymphoid irradiation, cladribine, T-cell or T-cell receptor vaccination, any murine protein, any other therapeutic monoclonal antibody, or any 4-aminopyridine or related products.

Miscellaneous

• For female subjects, unless postmenopausal for at least 1 year or surgically sterile (does not include tubal ligation), unwillingness to practice effective contraception, as defined by the Investigator, during the study. Women considering becoming pregnant while on study are to be excluded.

• Female subjects who are currently pregnant or breast feeding, including subjects whose pregnancy test is positive at Week 0.

• Unwillingness or inability to comply with the requirements of this protocol, including the presence of any condition (physical, mental, or social) that is likely to affect the subject's ability to comply with the study protocol.

• Subjects with any other condition, clinical finding, or reason that in the opinion of the Investigator and/or the Sponsor makes the subject unsuitable for enrollment into the study.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Sapporo	Hokkaido	Japan	060-8648
2	Research Site	Sapporo	Hokkaido	Japan	063-0005
3	Research Site	Tsukuba	Ibaraki	Japan	305-8576
4	Research Site	Morioka	Iwate	Japan	020-8505
5	Research Site	Yokohama	Kanagawa	Japan	232-0024
6	Research Site	Sendai	Miyagi	Japan	980-8574
7	Research Site	Suita	Osaka	Japan	565-0871
8	Research Site	Kawagoe	Saitama	Japan	350-8550
9	Research Site	Tokorozawa	Saitama	Japan	359-8513
10	Research Site	Bunkyo-ku	Tokyo	Japan	113-8431
11	Research Site	Bunkyo-ku	Tokyo	Japan	113-8519
12	Research Site	Kodaira	Tokyo	Japan	187-8551
13	Research Site	Ota-ku	Tokyo	Japan	145-0065
14	Research Site	Ube	Yamaguchi	Japan	755-8505
15	Research Site	Chiba		Japan	260-8677
16	Research Site	Fukuoka		Japan	812-8582
17	Research Site	Hiroshima		Japan	734-8551
18	Research Site	Kyoto		Japan	604-8453
19	Research Site	Kyoto		Japan	606-8507
20	Research Site	Kyoto		Japan	616-8255
21	Research Site	Niigata		Japan	951-8520
22	Research Site	Osaka		Japan	556-0016

Sponsors and Collaborators

• Biogen

Investigators

• Study Director: Medical Director, Biogen

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Biogen
• ClinicalTrials.gov Identifier: NCT01416155
• Other Study ID Numbers: 101MS204
• First Posted: Aug 12, 2011
• Last Update Posted: Jan 14, 2016
• Last Verified: Dec 1, 2015

• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Natalizumab

Study Results

Participant Flow

Recruitment Details	Subjects who participated in and completed all protocol-related evaluations through Week 24 in Study 101MS203 (NCT01440101) were eligible for this study.

Arm/Group Title	Natalizumab
Arm/Group Description	300 mg intravenous (IV) infusions of natalizumab open label every 4 weeks
Period Title: Overall Study
STARTED	97
COMPLETED	39
NOT COMPLETED	58

Baseline Characteristics

Arm/Group Title	Natalizumab
Arm/Group Description	300 mg IV infusions of natalizumab open label every 4 weeks
Overall Participants	97
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.2 (8.67)
Age, Customized (participants) [Number]
18 to 19 years	1 1%
20 to 29 years	16 16.5%
30 to 39 years	44 45.4%
40 to 49 years	28 28.9%
50 to 59 years	7 7.2%
>= 60 years	1 1%
Sex: Female, Male (Count of Participants)
Female	66 68%
Male	31 32%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs
Description	An AE was any untoward medical occurrence that did not necessarily have a causal relationship with this treatment. An SAE was any untoward medical occurrence that at any dose: resulted in death; in the view of the Investigators, placed the subject at immediate risk of death (a life-threatening event); however, this did not include an event that, had it occurred in a more severe form, might have caused death; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in a congenital anomaly/birth defect; any other medically important event that, in the opinion of the Investigators, could have jeopardized the subject or may have required intervention to prevent one of the other outcomes listed in the definition above.
Time Frame	Day 1 through First Follow-Up (12 Weeks After Last Infusion) +/- 7 days. Approximately 62 months

Outcome Measure Data

Analysis Population Description

Safety population: all participants who received at least 1 dose of study treatment.

Arm/Group Title	Natalizumab
Arm/Group Description	300 mg IV infusions of natalizumab open label every 4 weeks
Measure Participants	97
Participants with an event	92 94.8%
Participants with a moderate or severe event	52 53.6%
Participants with a severe event	10 10.3%
Participants with an event related to study drug	33 34%
Participants with an SAE	29 29.9%
Participants with an SAE related to study drug	7 7.2%
Participants discontinuing treatment due to event	10 10.3%
Participants withdrawing from study due to event	10 10.3%

2. Primary Outcome

Title	Number of Participants With Serum Antibodies to Natalizumab
Description	Negative is defined as negative for antibodies at all post-baseline results. Transient positivity is defined as only 1 positive result. Persistent positivity is defined as 2 positive results separated by at least 6 to 12 weeks.
Time Frame	Day 1 up to approximately 50 months

Outcome Measure Data

Analysis Population Description

Immunogenicity population: all participants who had received at least 1 infusion of BG00002, were negative for BG00002 antibodies at baseline and had at least 1 nonmissing post-baseline assessment of antibody status.

Arm/Group Title	Natalizumab
Arm/Group Description	300 mg IV infusions of natalizumab open label every 4 weeks
Measure Participants	96
Participants negative	91 93.8%
Participants positive at any time	5 5.2%
Participants transiently positive	3 3.1%
Participants positive at final evaluation only	2 2.1%
Participants persistently positive	2 2.1%

3. Secondary Outcome

Title	Adjusted Annualized Relapse Rate
Description	Clinical relapses are defined as new or recurrent neurologic symptoms, not associated with fever or infection, lasting for at least 24 hours, and accompanied by new objective neurological findings upon examination by the neurologist. The annualized relapse rate is calculated overall as the total number of relapses experienced in the study divided by the number of days followed in the study, and the ratio multiplied by 365. Obtained from a Poisson regression model, adjusted for the baseline relapse rate from study 101MS203 (NCT01440101).
Time Frame	Day 1 up to approximately 50 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Natalizumab
Arm/Group Description	300 mg IV infusions of natalizumab open label every 4 weeks
Measure Participants	97
Measure Participants with a relapse	26
Number (95% Confidence Interval) [relapses per subject-years]	0.243

4. Secondary Outcome

Title	Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192
Description	The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. Scoring is based on measures of impairment in eight functional systems on examination by a neurologist.
Time Frame	Day 1 up to Week 192

Outcome Measure Data

Analysis Population Description

n=number of participants with an assessment at given timepoint.

Arm/Group Title	Natalizumab
Arm/Group Description	300 mg IV infusions of natalizumab open label every 4 weeks
Measure Participants	97
Change from Baseline to Week 12; n=92	-0.05 (0.486)
Change from Baseline to Week 24; n=86	-0.15 (0.490)
Change from Baseline to Week 36; n=84	-0.08 (0.647)
Change from Baseline to Week 48; n=78	-0.09 (0.585)
Change from Baseline to Week 60; n=76	-0.09 (0.534)
Change from Baseline to Week 72; n=72	-0.04 (0.804)
Change from Baseline to Week 84; n=60	-0.08 (0.764)
Change from Baseline to Week 96; n=53	-0.10 (0.743)
Change from Baseline to Week 108; n=46	-0.18 (0.791)
Change from Baseline to Week 120; n=38	-0.12 (0.842)
Change from Baseline to Week 132; n=31	-0.11 (0.854)
Change from Baseline to Week 144; n=22	-0.07 (0.877)
Change from Baseline to Week 156; n=11	0.14 (0.778)
Change from Baseline to Week 168; n=8	0.31 (0.961)
Change from Baseline to Week 180; n=8	0.25 (0.926)
Change from Baseline to Week 192; n=2	0.50 (0.00)
Change from Baseline to Final Treatment Visit;n=36	-0.17 (0.862)

Adverse Events

Time Frame	Day 1 through First Follow-Up (12 Weeks After Last Infusion) +/- 7 days. Approximately 62 months.
Arm/Group Title	Natalizumab
Arm/Group Description	300 mg IV infusions of natalizumab open label every 4 weeks
All Cause Mortality
	Natalizumab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Natalizumab
	Affected / at Risk (%)	# Events
Total	29/97 (29.9%)
Blood and lymphatic system disorders
Eosinophilia	1/97 (1%)
Endocrine disorders
Hypothyroidism	1/97 (1%)
Gastrointestinal disorders
Enteritis	1/97 (1%)
Haemorrhoids	1/97 (1%)
Inguinal hernia	1/97 (1%)
Oesophageal ulcer	1/97 (1%)
Infections and infestations
Bronchitis	1/97 (1%)
Meningitis	2/97 (2.1%)
Mycoplasma infection	1/97 (1%)
Metabolism and nutrition disorders
Decreased appetite	1/97 (1%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/97 (1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine cancer	1/97 (1%)
Nervous system disorders
Central nervous system lesion	1/97 (1%)
Multiple sclerosis relapse	17/97 (17.5%)
Trigeminal neuralgia	1/97 (1%)
Pregnancy, puerperium and perinatal conditions
Ectopic pregnancy	1/97 (1%)
Psychiatric disorders
Asperger's disorder	1/97 (1%)
Schizophrenia	1/97 (1%)
Reproductive system and breast disorders
Uterine prolapse	1/97 (1%)
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease	1/97 (1%)
Skin and subcutaneous tissue disorders
Rash	1/97 (1%)
Other (Not Including Serious) Adverse Events
	Natalizumab
	Affected / at Risk (%)	# Events
Total	78/97 (80.4%)
Gastrointestinal disorders
Constipation	7/97 (7.2%)
Dental caries	6/97 (6.2%)
Diarrhoea	8/97 (8.2%)
Gastritis	5/97 (5.2%)
Stomatitis	5/97 (5.2%)
General disorders
Pyrexia	6/97 (6.2%)
Immune system disorders
Seasonal allergy	6/97 (6.2%)
Infections and infestations
Cystitis	5/97 (5.2%)
Gastroenteritis	5/97 (5.2%)
Influenza	12/97 (12.4%)
Nasopharyngitis	49/97 (50.5%)
Pharyngitis	8/97 (8.2%)
Injury, poisoning and procedural complications
Fall	5/97 (5.2%)
Nervous system disorders
Dizziness	5/97 (5.2%)
Headache	6/97 (6.2%)
Multiple sclerosis relapse	21/97 (21.6%)
Psychiatric disorders
Depression	5/97 (5.2%)
Insomnia	10/97 (10.3%)
Skin and subcutaneous tissue disorders
Eczema	8/97 (8.2%)
Rash	8/97 (8.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.