Multiple Sclerosis, Relapsing-Remitting
Conditions
Keywords
Relapsing multiple sclerosis, interferon beta 1b, Betaferon, Betaseron
Brief summary
The BEYOND Follow-Up study will give patients who participated in the preceding BEYOND study the opportunity to continue treatment with the 500µg dose of interferon beta (IFNB) 1b and will further investigate the safety and tolerability profile of interferon beta 1b 500µg during longer-term treatment.
Detailed description
Phase A (3 arm parallel group): All patients randomized during the BEYOND study (Bayer 306440) to either IFNB 1b group (250µg or 500µg) will continue their previously assigned study medication, applying the same level of blinding as during the BEYOND study, All patients randomized during the BEYOND study to Copaxone and all patients with premature discontinuation of study medication during the BEYOND study will receive open-label IFNB 1b 250µg. Phase B (single arm): All patients will receive open-label IFNB 1b 500µg) Randomization: No randomization in this trial, patient's allocation in this follow-up study depends only on prior trial groups. The preceding study was randomized. The trial is sponsored by Bayer Schering Pharma AG, Germany, Bayer HealthCare and Bayer HealthCare Pharmaceuticals Inc. Secondary outcome measure Assessment of patient-reported outcomes (FAMS and EQ 5D: The variables FAMS and EQ-5D were not analyzed due to the termination of the study before start of Phase B.
Interventions
Phase A: 250ug administrated s.c. every other day (double blind). For patients previously randomized in Bayer study 91162 to the same treatment. Phase B: All patients will receive 500µg s.c.every other day (open-label).
Sponsors
Bayer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Completion of the BEYOND study 306440 as scheduled * Relapsing multiple sclerosis * Medical assessment by the investigator that there is no objection to the patient's participation in this trial considering the medical experience from study 306440. Special attention should be given to laboratory abnormalities and clinically relevant liver, renal and bone-marrow dysfunction. * Females of child-bearing potential: * Agreement to practice adequate contraception methods and * Negative pregnancy test and * No lactation * Written informed consent
Exclusion criteria
* Serious or acute heart diseases * History of severe depression or suicide attempt * Epilepsy not adequately controlled by treatment * Known allergy to IFNs, to human albumin or to mannitol * Medical, psychiatric or other conditions that compromise the patient's ability to understand the patient information, to give informed consent, to comply with the trial protocol, or to complete the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Flu-like-syndrome | 309 days | The variable Flu-like-syndrome will consist of a combination of MedDRA terms (Preferred Terms and Lower Level Terms) indicative for this condition. |
| Injection-site Reactions | 309 days | The variable Injection-site reactions will consist of a combination of MedDRA terms (Preferred Terms only) indicative for this condition. |
| Liver Enzyme Elevations | 309 days | The variable Liver enzyme elevations will consist of a combination of MedDRA terms (Preferred Terms only) indicative for this condition. |
| Hematological Abnormalities | 309 days | The variable Hematological abnormalities will consist of a combination of MedDRA terms (Preferred Terms only) indicative for this condition. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Neutralizing Antibody Titer to IFNB-1b of Different Cut-off Values | 309 days | Serum samples of about 8 mL for analysis of neutralizing antibodies (NAbs) to interferon (IFN) beta-1b were drawn at Baseline, Week 26 and the EOS visit. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Latvia, Netherlands, Norway, Poland, Russia, Slovenia, Spain, Sweden, Switzerland, Ukraine, United States
Participant flow
Recruitment details
Eligible patients for this study included only those who completed the preceding BEYOND study. Patients were enrolled at the conclusion of the preceding study from 03 May 2007 until 14 March 2008. Patients who interrupted study medication in accordance with the investigator were eligible, provided it did not result in premature End of Study.
Pre-assignment details
All enrolled patients who had been randomized during the predecessor study to IFNB 1b (Interferon 1b) continued on previously double-blinded medication in the BEYOND-FU study; all patients who had been previously randomized to Copaxone and all patients with premature end of study medication received open-label IFNB 1b 250 µg (IFNB 1b 250 µg\*).
Participants by arm
| Arm | Count |
|---|---|
| IFNB-1b 500 mcg Interferon beta 1b (\[IFNB 1b\] Betaseron) 500 mcg administered s.c. every other day (double blind) | 586 |
| IFNB-1b 250 mcg Interferon beta 1b (\[IFNB 1b\] Betaseron) 250 mcg administered s.c. every other day (double blind) | 645 |
| IFNB-1b 250 mcg* Interferon beta 1b (\[IFNB 1b\] Betaseron) 250 mcg administered s.c. every other day
\*(Subjects who were administered Copaxone and subjects who had prematurely discontinued medication during BEYOND study.) | 180 |
| Total | 1,411 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 9 | 12 | 8 |
| Overall Study | Lost to Follow-up | 5 | 9 | 3 |
| Overall Study | No treatment administered | 6 | 3 | 1 |
| Overall Study | Other disease modifying treatment | 1 | 2 | 1 |
| Overall Study | Other reason (incl. 2 missing subjects) | 12 | 15 | 1 |
| Overall Study | Pregnancy | 1 | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 5 | 5 |
Baseline characteristics
| Characteristic | IFNB-1b 500 mcg | IFNB-1b 250 mcg | IFNB-1b 250 mcg* | Total |
|---|---|---|---|---|
| Age, Continuous Mean±Standard Deviation | 36.2 years STANDARD_DEVIATION 9.36 | 35.8 years STANDARD_DEVIATION 9.17 | 34.9 years STANDARD_DEVIATION 9.5 | 35.9 years STANDARD_DEVIATION 9.29 |
| Age, Customized >18 and <55 years | 580 participants | 640 participants | 178 participants | 1398 participants |
| Age, Customized <=18 years | 6 participants | 5 participants | 2 participants | 13 participants |
| Age, Customized >=55 years | 0 participants | 0 participants | 0 participants | 0 participants |
| Sex: Female, Male Female | 414 Participants | 445 Participants | 113 Participants | 972 Participants |
| Sex: Female, Male Male | 172 Participants | 200 Participants | 67 Participants | 439 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 455 / 586 | 467 / 645 | 136 / 180 |
| serious Total, serious adverse events | 11 / 586 | 16 / 645 | 6 / 180 |
Outcome results
Primary
Flu-like-syndrome
The variable Flu-like-syndrome will consist of a combination of MedDRA terms (Preferred Terms and Lower Level Terms) indicative for this condition.
Time frame: 309 days
Population: The analysis set used for safety analysis (SAF) comprised 1411 patients. AEs were defined as events with an onset date after the first application of study drug. The incidence rate of Flu-Like-Syndrome with 95% confidence intervals were provided.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IFNB-1b 500 mcg | Flu-like-syndrome | 17.4 Percentage of participants |
| IFNB-1b 250 mcg | Flu-like-syndrome | 15.8 Percentage of participants |
| IFNB-1b 250 mcg* | Flu-like-syndrome | 31.1 Percentage of participants |
Comparison: The 95% Confidence Interval was calculated for number of patients w/ Flu-Like-Syndrome95% CI: [14.4, 20.7]
Comparison: The 95% Confidence Interval was calculated for number of patients w/ Flu-Like-Syndrome95% CI: [13.1, 18.9]
Comparison: The 95% Confidence Interval was calculated for number of patients w/ Flu-Like-Syndrome95% CI: [24.4, 38.4]
Primary
Hematological Abnormalities
The variable Hematological abnormalities will consist of a combination of MedDRA terms (Preferred Terms only) indicative for this condition.
Time frame: 309 days
Population: The analysis set used for safety analysis (SAF) comprised 1411 patients. AEs were defined as events with an onset date after the first application of study drug. The incidence rate of hematological abnormalities were provided.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IFNB-1b 500 mcg | Hematological Abnormalities | White blood cells decreased | 0.5 Percentage of participants |
| IFNB-1b 500 mcg | Hematological Abnormalities | Platelet count decreased | 0.7 Percentage of participants |
| IFNB-1b 500 mcg | Hematological Abnormalities | Lymphocyte count decreased | 1.5 Percentage of participants |
| IFNB-1b 500 mcg | Hematological Abnormalities | Hemoglobin decreased | 1.2 Percentage of participants |
| IFNB-1b 500 mcg | Hematological Abnormalities | Neutrophil count decreased | 0.5 Percentage of participants |
| IFNB-1b 250 mcg | Hematological Abnormalities | Hemoglobin decreased | 1.1 Percentage of participants |
| IFNB-1b 250 mcg | Hematological Abnormalities | White blood cells decreased | 1.9 Percentage of participants |
| IFNB-1b 250 mcg | Hematological Abnormalities | Neutrophil count decreased | 1.2 Percentage of participants |
| IFNB-1b 250 mcg | Hematological Abnormalities | Lymphocyte count decreased | 0.6 Percentage of participants |
| IFNB-1b 250 mcg | Hematological Abnormalities | Platelet count decreased | 0.2 Percentage of participants |
| IFNB-1b 250 mcg* | Hematological Abnormalities | Neutrophil count decreased | 2.2 Percentage of participants |
| IFNB-1b 250 mcg* | Hematological Abnormalities | Hemoglobin decreased | 0 Percentage of participants |
| IFNB-1b 250 mcg* | Hematological Abnormalities | Platelet count decreased | 0.6 Percentage of participants |
| IFNB-1b 250 mcg* | Hematological Abnormalities | White blood cells decreased | 1.7 Percentage of participants |
| IFNB-1b 250 mcg* | Hematological Abnormalities | Lymphocyte count decreased | 0 Percentage of participants |
Primary
Injection-site Reactions
The variable Injection-site reactions will consist of a combination of MedDRA terms (Preferred Terms only) indicative for this condition.
Time frame: 309 days
Population: The analysis set used for safety analysis (SAF) comprised 1411 patients. AEs were defined as events with an onset date after the first application of study drug. The incidence rate of Injection-site reactions with 95% confidence intervals were provided.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IFNB-1b 500 mcg | Injection-site Reactions | 31.7 Percentage of participants |
| IFNB-1b 250 mcg | Injection-site Reactions | 26.2 Percentage of participants |
| IFNB-1b 250 mcg* | Injection-site Reactions | 31.7 Percentage of participants |
Comparison: The 95% Confidence Interval was calculated for number of patients w/ Injection-site (IS) reactions.95% CI: [28, 35.7]
Comparison: The 95% Confidence Interval was calculated for number of patients w/ Injection-site (IS) reactions.95% CI: [22.8, 29.8]
Comparison: The 95% Confidence Interval was calculated for number of patients w/ Injection-site (IS) reactions.95% CI: [24.9, 39]
Primary
Liver Enzyme Elevations
The variable Liver enzyme elevations will consist of a combination of MedDRA terms (Preferred Terms only) indicative for this condition.
Time frame: 309 days
Population: The analysis set used for safety analysis (SAF) comprised 1411 patients. AEs were defined as events with an onset date after the first application of study drug. The incidence rate of liver enzyme elevations were provided.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IFNB-1b 500 mcg | Liver Enzyme Elevations | GGT increased | 2.7 Percentage of participants |
| IFNB-1b 500 mcg | Liver Enzyme Elevations | ALT increased | 2.6 Percentage of participants |
| IFNB-1b 500 mcg | Liver Enzyme Elevations | AST increased | 2.0 Percentage of participants |
| IFNB-1b 250 mcg | Liver Enzyme Elevations | GGT increased | 1.2 Percentage of participants |
| IFNB-1b 250 mcg | Liver Enzyme Elevations | ALT increased | 1.7 Percentage of participants |
| IFNB-1b 250 mcg | Liver Enzyme Elevations | AST increased | 1.4 Percentage of participants |
| IFNB-1b 250 mcg* | Liver Enzyme Elevations | ALT increased | 4.4 Percentage of participants |
| IFNB-1b 250 mcg* | Liver Enzyme Elevations | AST increased | 3.9 Percentage of participants |
| IFNB-1b 250 mcg* | Liver Enzyme Elevations | GGT increased | 3.9 Percentage of participants |
Secondary
Percentage of Patients With Neutralizing Antibody Titer to IFNB-1b of Different Cut-off Values
Serum samples of about 8 mL for analysis of neutralizing antibodies (NAbs) to interferon (IFN) beta-1b were drawn at Baseline, Week 26 and the EOS visit.
Time frame: 309 days
Population: For the NAb analyses data were provided for 572 patients at Baseline, 238 at Week 26 and 1261 at EOS. The patients missing to the total number of 1411 patients had no data at the respective visits (table shows number of patients with positive titer in the extension treatment cohorts; the analyses provide frequencies of positive titers).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IFNB-1b 500 mcg | Percentage of Patients With Neutralizing Antibody Titer to IFNB-1b of Different Cut-off Values | NAbs titer, cut-off value 100 NU/ml | 16.5 Percentage of participants |
| IFNB-1b 500 mcg | Percentage of Patients With Neutralizing Antibody Titer to IFNB-1b of Different Cut-off Values | NAbs titer, cut-off value 20 NU/ml | 26.6 Percentage of participants |
| IFNB-1b 500 mcg | Percentage of Patients With Neutralizing Antibody Titer to IFNB-1b of Different Cut-off Values | NAbs titer, cut-off value 400 NU/ml | 10.8 Percentage of participants |
| IFNB-1b 250 mcg | Percentage of Patients With Neutralizing Antibody Titer to IFNB-1b of Different Cut-off Values | NAbs titer, cut-off value 100 NU/ml | 12.4 Percentage of participants |
| IFNB-1b 250 mcg | Percentage of Patients With Neutralizing Antibody Titer to IFNB-1b of Different Cut-off Values | NAbs titer, cut-off value 20 NU/ml | 21.7 Percentage of participants |
| IFNB-1b 250 mcg | Percentage of Patients With Neutralizing Antibody Titer to IFNB-1b of Different Cut-off Values | NAbs titer, cut-off value 400 NU/ml | 6.1 Percentage of participants |
| IFNB-1b 250 mcg* | Percentage of Patients With Neutralizing Antibody Titer to IFNB-1b of Different Cut-off Values | NAbs titer, cut-off value 20 NU/ml | 16.6 Percentage of participants |
| IFNB-1b 250 mcg* | Percentage of Patients With Neutralizing Antibody Titer to IFNB-1b of Different Cut-off Values | NAbs titer, cut-off value 400 NU/ml | 0 Percentage of participants |
| IFNB-1b 250 mcg* | Percentage of Patients With Neutralizing Antibody Titer to IFNB-1b of Different Cut-off Values | NAbs titer, cut-off value 100 NU/ml | 2.5 Percentage of participants |