Multiple Sclerosis, Relapsing-Remitting
Conditions
Keywords
Multiple Sclerosis, MS
Brief summary
The primary objectives of this study are to further evaluate the safety of natalizumab (Tysabri®) monotherapy by evaluating the risk of hypersensitivity and immunogenicity following re-exposure to natalizumab, and to confirm the safety of switching to natalizumab from interferon beta (IFN-β), glatiramer acetate (GA), or other multiple sclerosis (MS) therapies.
Detailed description
Study 101-MS-322 (NCT00306592) is conducted to evaluate the safety of natalizumab monotherapy following re-exposure to natalizumab of former clinical trial participants in Studies C-1801 (NCT00027300), C-1802 (NCT00030966), and C-1803 (NCT00097760). This study includes participants in North America. In parallel with the conduct of this study, a similar study, 101-MS-321 (NCT00297232) is initiated for participants in Europe and the rest of the world. The primary purpose and primary outcome for both studies are identical, therefore, the combined Week 48 data from both studies are presented. In addition, after 48 weeks, participants from 101-MS-322 (NCT00306592) can enter study 101-MS-321 (NCT 00297232), which is considered the Long-Term Treatment Period of 101-MS-322 (NCT00306592).
Interventions
BIOLOGICALBG00002 (natalizumab)
Sponsors
Elan Pharmaceuticals
Biogen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* MS subjects who completed Study C-1801 (NCT00027300), C-1802 (NCT00030966), or C-1803 (NCT00097760) and completed a Dosing Suspension Safety Evaluation (neurological examination and magnetic resonance imaging \[MRI\] scan) * Considered by the investigator to be free of signs and symptoms suggestive of progressive multifocal leukoencephalopathy (PML) based on medical history, physical examination, or laboratory testing (results from the Dosing Suspension Safety Evaluation from Study C-1808 \[NCT000276172\] may be used) * Other protocol-defined inclusion criteria may apply
Exclusion criteria
* Considered by the investigator to be immunocompromised, based on medical history, physical examination, or laboratory testing (results from the Dosing Suspension Safety Evaluation from Study C-1808 may be used), or due to prior immunosuppressive treatment * History of persistent anti-natalizumab antibodies, based upon testing from prior natalizumab studies * Other protocol-defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious AEs (SAEs) | Baseline through Week 48 | AEs: any sign, symptom, or diagnosis/disease that is unfavorable or unintended, that is new, or if pre-existing, worsens in participants administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. SAEs: an event that results in death; an event that, in the view of the investigator, places the participant at immediate risk of death (a life-threatening event); an outcome that results in a congenital anomaly/birth defect diagnosed in a child of a participant; an event that requires or prolongs inpatient hospitalization; an event that results in persistent or significant disability/incapacity. Any other medically important event that, in the opinion of the investigator, may jeopardize the participant or may require intervention to prevent one of the other outcomes listed in the definition above. Treatment-emergent AEs: events in participants who had received at least 1 dose of study drug, regardless of relationship to study drug. |
| Number of Participants With Hypersensitivity-related Adverse Events | Baseline through Week 48 | For purposes of this analysis, the terms 'hypersensitivity' and 'drug hypersensitivity' were categorized by their temporal relationship to study drug infusion (within 2 hours of the start of the infusion), and were considered equivalent. Hypersensitivity reactions are defined as infusion reactions with the following preferred terms: hypersensitivity not otherwise specified (NOS), anaphylactic reaction, anaphylactoid reaction, dermatitis allergic, drug hypersensitivity, urticaria NOS, vasoconstriction, urticaria generalised, hypersensitivity, urticaria. |
| Number of Participants With Antibodies to Natalizumab | Baseline (Week 0), Week 4, Week 24 (test was repeated after 8 weeks if positive, to confirm persistence) | 'Positive with unknown persistence' is defined as a positive result (≥0.5 micrograms/mL) at one timepoint only with no confirmatory re-test available at least 42 days later. 'Transient positive' is defined as a positive at one timepoint but negative upon re-test at least 42 days later. 'Persistent positive' is defined as positive at 2 or more timepoints separated by at least 42 days. The threshold for classifying a sample as 'antibody positive' was set at the lowest level of reactivity that had a measurable impact on drug serum concentrations. |
Countries
Canada, United States
Participant flow
Pre-assignment details
Participants from studies 101-MS-321 (NCT00297232) and 101-MS-322 (NCT00306592) are included in this presentation of combined Week 48 data.
Participants by arm
| Arm | Count |
|---|---|
| 300 mg Natalizumab IV Monthly All study participants in 101-MS-322 (NCT00306592) and 101-MS-321 (NCT00297232) received open label 300 mg intravenous (IV) natalizumab 60-minute infusion once every 4 weeks (28 days ±7 days) for up to 48 weeks. After 48 weeks, participants from 101-MS-322 (NCT00306592) entering study 101-MS-321 (NCT 00297232; considered the Long-Term Treatment Period of 101-MS-322) were continued on treatment from Week 52 through Week 480. | 1,094 |
| Total | 1,094 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | 48-week Treatment Period Ongoing | 0 | 20 |
| Overall Study | Adverse Event | 8 | 15 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Noncompliance | 0 | 2 |
| Overall Study | Other | 5 | 10 |
| Overall Study | Persistent Antibodies | 6 | 3 |
| Overall Study | Voluntary | 10 | 6 |
Baseline characteristics
| Characteristic | 300 mg Natalizumab IV Monthly |
|---|---|
| Age, Continuous | 41.4 years STANDARD_DEVIATION 8.12 |
| Age, Customized ≥ 18 to < 20 years | 0 participants |
| Age, Customized ≥ 20 to < 30 years | 98 participants |
| Age, Customized ≥ 30 to < 40 years | 347 participants |
| Age, Customized ≥ 40 to < 50 years | 454 participants |
| Age, Customized ≥ 50 to < 59 years | 195 participants |
| Age, Customized >/= 60 years | 0 participants |
| Sex: Female, Male Female | 755 Participants |
| Sex: Female, Male Male | 339 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 492 / 1,094 |
| serious Total, serious adverse events | 61 / 1,094 |
Outcome results
Primary
Number of Participants With Antibodies to Natalizumab
'Positive with unknown persistence' is defined as a positive result (≥0.5 micrograms/mL) at one timepoint only with no confirmatory re-test available at least 42 days later. 'Transient positive' is defined as a positive at one timepoint but negative upon re-test at least 42 days later. 'Persistent positive' is defined as positive at 2 or more timepoints separated by at least 42 days. The threshold for classifying a sample as 'antibody positive' was set at the lowest level of reactivity that had a measurable impact on drug serum concentrations.
Time frame: Baseline (Week 0), Week 4, Week 24 (test was repeated after 8 weeks if positive, to confirm persistence)
Population: All participants who received at least 1 dose of natalizumab, had a negative baseline antibody result, and had at least 1 antibody result after the first dose.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 300 mg Natalizumab IV Monthly | Number of Participants With Antibodies to Natalizumab | Antibody negative | 1004 participants |
| 300 mg Natalizumab IV Monthly | Number of Participants With Antibodies to Natalizumab | Antibody positive with unknown persistence | 15 participants |
| 300 mg Natalizumab IV Monthly | Number of Participants With Antibodies to Natalizumab | Antibody transient positive | 8 participants |
| 300 mg Natalizumab IV Monthly | Number of Participants With Antibodies to Natalizumab | Antibody persistent positive | 16 participants |
Primary
Number of Participants With Hypersensitivity-related Adverse Events
For purposes of this analysis, the terms 'hypersensitivity' and 'drug hypersensitivity' were categorized by their temporal relationship to study drug infusion (within 2 hours of the start of the infusion), and were considered equivalent. Hypersensitivity reactions are defined as infusion reactions with the following preferred terms: hypersensitivity not otherwise specified (NOS), anaphylactic reaction, anaphylactoid reaction, dermatitis allergic, drug hypersensitivity, urticaria NOS, vasoconstriction, urticaria generalised, hypersensitivity, urticaria.
Time frame: Baseline through Week 48
Population: Participants receiving at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 300 mg Natalizumab IV Monthly | Number of Participants With Hypersensitivity-related Adverse Events | 8 participants |
Primary
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious AEs (SAEs)
AEs: any sign, symptom, or diagnosis/disease that is unfavorable or unintended, that is new, or if pre-existing, worsens in participants administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. SAEs: an event that results in death; an event that, in the view of the investigator, places the participant at immediate risk of death (a life-threatening event); an outcome that results in a congenital anomaly/birth defect diagnosed in a child of a participant; an event that requires or prolongs inpatient hospitalization; an event that results in persistent or significant disability/incapacity. Any other medically important event that, in the opinion of the investigator, may jeopardize the participant or may require intervention to prevent one of the other outcomes listed in the definition above. Treatment-emergent AEs: events in participants who had received at least 1 dose of study drug, regardless of relationship to study drug.
Time frame: Baseline through Week 48
Population: Participants receiving at least 1 dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 300 mg Natalizumab IV Monthly | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious AEs (SAEs) | Severe AE | 66 participants |
| 300 mg Natalizumab IV Monthly | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious AEs (SAEs) | Discontinuation of study drug due to AE | 24 participants |
| 300 mg Natalizumab IV Monthly | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious AEs (SAEs) | AE | 826 participants |
| 300 mg Natalizumab IV Monthly | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious AEs (SAEs) | Moderate or severe AE | 487 participants |
| 300 mg Natalizumab IV Monthly | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious AEs (SAEs) | AE related to study drug | 161 participants |
| 300 mg Natalizumab IV Monthly | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious AEs (SAEs) | SAE | 61 participants |
| 300 mg Natalizumab IV Monthly | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious AEs (SAEs) | SAE related to study drug | 5 participants |
| 300 mg Natalizumab IV Monthly | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious AEs (SAEs) | Withdrawal from study due to AE | 24 participants |