A Phase 3 interventional study of ALKS 8700 in Multiple Sclerosis, sponsored by Biogen. Completed at 115 sites in 10 countries. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2022-07-26.
Sponsored by Biogen · Phase 3, Interventional, and Treatment
The primary objective of this study is to evaluate the long-term safety and tolerability of ALKS 8700 for the treatment of Relapsing Remitting Multiple Sclerosis (RRMS). The secondary objective of this study is to evaluate treatment effect over time in adult participants with RRMS treated with ALKS 8700.
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Key Inclusion Criteria:
Exclusion Criteria:
NOTE: Other protocol defined Includison/Exclusion criteria may apply.
Oral capsules taken twice daily.
Drug: ALKS 8700
Administered as specified in the treatment arm.
Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. TEAE is any AE that start or worsen on or after the date of first dose of study treatment. An SAE is any untoward medical occurrence that at any dose, results in death; in the view of the investigator places the participant at immediate risk of death; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital anomaly/birth defect; is a medically important event.
Time frame: From first dose to two weeks after last dose of study drug (Up to 98 weeks)
Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities
Vital sign measurements included heart rate (low: \<=50 beats per minute \[bpm\] and decrease \>=15 bpm; High: \>=120 bpm and increase \>=15 bpm), systolic blood pressure (BP) (low: \<=90 millimeters of mercury \[mmHg\] and decrease \>=20 mmHg; High: \>=180 mmHg and increase \>=20 mmHg) and diastolic BP (low: \<=50 mmHg and decrease \>=15 mmHg; High: \>=105 mmHg and increase \>=15 mmHg).
Time frame: From first dose to two weeks after last dose of study drug (Up to 98 weeks)
Number of Participants With Potentially Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities
Potentially clinically significant QTcF values (\>450 to \<=480 millisecond \[msec\], \>480 to \<=500 msec) at any post-baseline visit during treatment period were reported.
Time frame: From first dose to two weeks after last dose of study drug (Up to 98 weeks)
Number of Participants With Columbia Suicide Severity Rating Scale (C-SSRS) Score at Any Post-Baseline Visit
The C-SSRS is a clinician-administered instrument that systematically assess suicidal ideation and behavior rating scale. It rates an individual's degree of suicidal ideation (SI) on a scale, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent." The scale identifies SI severity and intensity, which may be indicative of an individual's intent to commit suicide. C-SSRS SI severity subscale ranges from 0 (no SI) to 5 (active SI with plan and intent). The scale identifies specific behaviors ranging from "preparatory acts or behavior" to "suicide" which may be indicative of an individual's intent to complete suicide.
Time frame: Up to 98 weeks
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities
Laboratory assessments included hematology, biochemistry, and urinalysis. Abnormality criteria: \>=3xupper limit of normal (ULN) in alanine aminotransferase, aspartate aminotransferase; In millimoles per liter (mmol/L) \[bicarbonate\<15/\>31, chloride\<=90, potassium\<3/\>5.5, sodium\<130/\>150\]; In mg per decilitre(mg/dL) {total bilirubin\>=2.0, calcium\<8.2/\>12, total cholesterol\>300, creatinine\>=2.0, glucose\<50/\>200, cholesterol: High density lipoprotein (HDL)\<=30, low density lipoprotein (LDL)\>=160, triglycerides\>=120 \[female(F)\]/\>=160 \[male(M)\], urate\>9/\>8(F), blood urea nitrogen\>30}; \>3xULN in creatine kinase, lactate dehydrogenase; Hematocrit \<=32(F)/\<=37(M) percentage(%),3 point decrease from baseline; Hemoglobin\<=9.5(F)/\<=11.5(M)g/dL; Lymphocytes\<0.5x10\^9/L; In 10\^3/microliter(uL) \[Eosinophils\>1; Absolute neutrophils\<1.5; Platelets\<75.1/\>=700; Leukocytes\<=2.8/\>=16\]; Albumin/creatinine\>200g/kilograms(kg); Beta-2 microglobulin \>0.3milligrams/liter(mg/L); Glucose/protein at least 2+.
Time frame: From first dose to two weeks after last dose of study drug (Up to 98 weeks)
Annualized Relapse Rate (ARR)
Relapse was defined as new or recurrent neurologic symptoms, not associated with fever or infection, lasting for at least 24 hours, accompanied by one or more of the following: New objective neurological findings upon examination by the treating neurologist that are functionally consistent with findings on the Expanded Disability Status Scale \[EDSS\] (performed within 7 days of onset of symptoms) with an increase over the prior visit of ≥ 0.5 for the total score, an increase of ≥ 2 in 1 functional system (FS), except bladder/cognitive changes, and/or, an increase of ≥ 1 in 2 FS, except bladder/cognitive changes. The relapse rate for an individual participant was calculated as the number of relapses for that participant divided by the number of participant-years followed. The ARR for each enrollment group was calculated as the total number of relapses experienced in the group divided by the total number of participant-years on study.
Time frame: Up to 96 weeks
Percentage of Participants With Multiple Sclerosis (MS) Relapse
Relapse was defined as new or recurrent neurologic symptoms, not associated with fever or infection, lasting for at least 24 hours, accompanied by one or more of the following: New objective neurological findings upon examination by the treating neurologist that are functionally consistent with findings on the EDSS (performed within 7 days of onset of symptoms) with an increase over the prior visit of ≥ 0.5 for the total score, an increase of ≥ 2 in 1 FS, except bladder/cognitive changes, and/or, an increase of ≥ 1 in 2 FS, except bladder/cognitive changes.
Time frame: Up to 96 weeks
Change From Baseline in Expanded Disability Status Scale (EDSS) Score
The EDSS is used to measure and evaluate MS participants' level of functioning. The EDSS provides a total score on a scale that ranges from 0 to 10. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability. The range of main categories include (0) = normal neurologic examination; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS. Higher scores indicate more disability. Positive change from baseline indicates more disability.
Time frame: Baseline up to Week 96
Change From Baseline in Timed 25-Foot Walk Test (T25-FW) Score
The T25-FW is a reliable quantitative mobility and leg function performance test based on a timed 25-foot walk. The participant was directed to one end of a clearly marked 25-foot course and was instructed to walk 25 feet as quickly as possible, but safely. Participants were allowed to use assistive devices (canes, crutches, walkers) as needed. The time was calculated from when the lead foot crosses the start point to when the participant had reached the 25-foot mark. The task was immediately administered again by having the participant walk back the same distance. The score for the T25-FW was calculated as the average of the 2 completed trials. A negative change from Baseline indicates improvement.
Time frame: Baseline up to Week 96
Change From Baseline in the EuroQol 5-Dimension 5-Level Visual Analog Scale (EQ-5D-5L VAS) Score
The EQ-5D-5L is an instrument designed to assess decrements in health. The EQ-5D-5L includes a VAS and a descriptive system that defines health in terms of 5 dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each dimension has 5 response categories corresponding to the level of severity (i.e., no problems, slight problems, moderate problems, severe problems, and unable to/extreme problems). The EQ-5D-5L VAS records the participant's self-rated health on a vertical visual analogue scale numbered from 100 (best health imagined) to 0 (worst health imagined). Higher scores indicate good health. Positive change from baseline indicates improved health.
Time frame: Baseline up to Week 96
Change From Baseline in the EQ-5D-5L Index Score
The EQ-5D-5L is an instrument designed to assess decrements in health. The EQ-5D-5L includes a VAS and a descriptive system that defines health in terms of 5 dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each dimension has 5 response categories corresponding to the level of severity (i.e., no problems, slight problems, moderate problems, severe problems, and unable to/extreme problems). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). Higher scores indicate good health. Positive change from baseline indicates improved health.
Time frame: Baseline up to Week 96
Change From Baseline in the 12-item Short Form Health Survey (SF-12) Score
The SF-12 uses 12 questions to measure functional health and well-being from the study participant's perspective across eight domains: physical functioning, role, bodily pain, general health perceptions, vitality, social functioning, emotional role, and mental health. Mental and physical composite scores (MCS \& PCS) are computed using the scores of twelve questions and range from 0 to 100, where a higher score indicates better health. Positive change from baseline indicates improved health.
Time frame: Baseline up to Week 96
Time to Onset of 12-week Confirmed Disability Progression
The time to onset of 12-week confirmed disability progression is defined as the time from baseline to the first disability progression that is confirmed at the next regularly scheduled visit ≥ 12 weeks after the initial disability progression. Disability progression is defined by one of the following: an EDSS increase of at least 1.5 points from baseline EDSS = 0, an EDSS increase of at least a 1.0 point from baseline EDSS between 1.0 and 5.5 (inclusive), or an EDSS increase of at least 0.5 points from baseline EDSS = 6.0.
Time frame: Up to Week 96
Percentage of Participants With No Evidence of Disease Activity (NEDA) at Week 96
The definition of NEDA-3 encompasses a combination of the following 3 related measures of disease activity: No relapses, no confirmed disability progression sustained for 12 weeks as measured on EDSS, and no magnetic resonance imaging (MRI) disease activity, defined as no gadolinium-enhancing (GdE) lesions and no new or enlarging T2 lesions. The definition of NEDA-4 was the above definition of NEDA-3 with the addition of a mean annualized rate of brain volume loss of less than 0.4% where annualized rate of brain volume loss was derived from percentage brain volume change (PBVC) from baseline and was calculated as (\[PBVC/100+1\]\^\[365.25/days\]-1) × 100.
Time frame: Week 96
Participants were enrolled at investigational sites in North America and Europe from 10 December 2015 to 11 November 2021.
| Milestone | De Novo | Rollover: ALKS 8700 | Rollover: DMF |
|---|---|---|---|
| Started | 593 | 239 | 225 |
| Safety population | 593 | 239 | 225 |
| Full analysis set (fas) population | 582 | 235 | 224 |
| Completed | 468 | 168 | 164 |
| Not completed | 125 | 71 | 61 |
| Withdrew: Adverse event | 50 | 24 | 14 |
| Withdrew: Lost to follow-up | 21 | 5 | 6 |
| Withdrew: Pregnancy | 5 | 1 | 3 |
| Withdrew: Withdrawal by subject | 38 | 24 | 18 |
| Withdrew: Non-compliance with study drug | 0 | 2 | 2 |
| Withdrew: Lack of efficacy | 1 | 5 | 3 |
| Withdrew: Physician decision | 7 | 5 | 5 |
| Withdrew: Reason not specified | 3 | 5 | 10 |
An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. TEAE is any AE that start or worsen on or after the date of first dose of study treatment. An SAE is any untoward medical occurrence that at any dose, results in death; in the view of the investigator places the participant at immediate risk of death; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital anomaly/birth defect; is a medically important event.
| Participants | De Novo | Rollover: ALKS 8700 | Rollover: DMF |
|---|---|---|---|
| TEAEs | 519 | 212 | 207 |
| SAEs | 69 | 29 | 25 |
Vital sign measurements included heart rate (low: \<=50 beats per minute \[bpm\] and decrease \>=15 bpm; High: \>=120 bpm and increase \>=15 bpm), systolic blood pressure (BP) (low: \<=90 millimeters of mercury \[mmHg\] and decrease \>=20 mmHg; High: \>=180 mmHg and increase \>=20 mmHg) and diastolic BP (low: \<=50 mmHg and decrease \>=15 mmHg; High: \>=105 mmHg and increase \>=15 mmHg).
| Participants | De Novo | Rollover: ALKS 8700 | Rollover: DMF |
|---|---|---|---|
| Systolic BP (Low: <=90 mmHg and decrease >=20 mmHg) | 15 | 4 | 2 |
| Systolic BP (High: >=180 mmHg and increase >=20 mmHg) | 3 | 2 | 1 |
| Diastolic BP (Low: <=50 mmHg and decrease >=15 mmHg) | 10 | 2 | 4 |
| Diastolic BP (High: >=105 mmHg and increase >=15 mmHg) | 6 | 2 | 2 |
| Heart Rate (Low: <=50 bpm and decrease >=15 bpm) | 5 | 1 | 2 |
| Heart Rate (High: >=120 bpm and increase >=15 bpm) | 1 | 1 | 2 |
Potentially clinically significant QTcF values (\>450 to \<=480 millisecond \[msec\], \>480 to \<=500 msec) at any post-baseline visit during treatment period were reported.
| Participants | De Novo | Rollover: ALKS 8700 | Rollover: DMF |
|---|---|---|---|
| >450 - <=480 msec | 15 | 5 | 6 |
| >480 - <=500 msec | 0 | 0 | 1 |
The C-SSRS is a clinician-administered instrument that systematically assess suicidal ideation and behavior rating scale. It rates an individual's degree of suicidal ideation (SI) on a scale, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent." The scale identifies SI severity and intensity, which may be indicative of an individual's intent to commit suicide. C-SSRS SI severity subscale ranges from 0 (no SI) to 5 (active SI with plan and intent). The scale identifies specific behaviors ranging from "preparatory acts or behavior" to "suicide" which may be indicative of an individual's intent to complete suicide.
| Participants | De Novo | Rollover: ALKS 8700 | Rollover: DMF |
|---|---|---|---|
| Suicidal Behavior: Preparatory acts or behavior | 0 | 0 | 0 |
| Suicidal Behavior: Aborted attempt | 0 | 0 | 0 |
| Suicidal Behavior: Interrupted attempt | 0 | 0 | 0 |
| Suicidal Behavior: Actual attempt | 1 | 0 | 0 |
| Suicidal Behavior: Completed suicide | 0 | 0 | 0 |
| Suicidal Ideation: Wish to be dead | 12 | 2 | 4 |
| Suicidal Ideation: Non-specific active suicidal thoughts | 8 | 2 | 2 |
| Suicidal Ideation: Active ideation without intention to act | 2 | 0 | 1 |
| Suicidal Ideation: Active ideation with some intent to act without a plan | 1 | 0 | 0 |
| Suicidal Ideation: Active ideation with a specific plan and intent | 1 | 0 | 0 |
| Non-Suicidal Self-Injurious Behavior | 0 | 0 | 0 |
Laboratory assessments included hematology, biochemistry, and urinalysis. Abnormality criteria: \>=3xupper limit of normal (ULN) in alanine aminotransferase, aspartate aminotransferase; In millimoles per liter (mmol/L) \[bicarbonate\<15/\>31, chloride\<=90, potassium\<3/\>5.5, sodium\<130/\>150\]; In mg per decilitre(mg/dL) {total bilirubin\>=2.0, calcium\<8.2/\>12, total cholesterol\>300, creatinine\>=2.0, glucose\<50/\>200, cholesterol: High density lipoprotein (HDL)\<=30, low density lipoprotein (LDL)\>=160, triglycerides\>=120 \[female(F)\]/\>=160 \[male(M)\], urate\>9/\>8(F), blood urea nitrogen\>30}; \>3xULN in creatine kinase, lactate dehydrogenase; Hematocrit \<=32(F)/\<=37(M) percentage(%),3 point decrease from baseline; Hemoglobin\<=9.5(F)/\<=11.5(M)g/dL; Lymphocytes\<0.5x10\^9/L; In 10\^3/microliter(uL) \[Eosinophils\>1; Absolute neutrophils\<1.5; Platelets\<75.1/\>=700; Leukocytes\<=2.8/\>=16\]; Albumin/creatinine\>200g/kilograms(kg); Beta-2 microglobulin \>0.3milligrams/liter(mg/L); Glucose/protein at least 2+.
| Participants | De Novo | Rollover: ALKS 8700 | Rollover: DMF |
|---|---|---|---|
| Alanine Aminotransferase (U/L) >=3 x ULN | 13 | 6 | 1 |
| Aspartate Aminotransferase (U/L) >=3 x ULN | 8 | 3 | 1 |
| Bicarbonate <15 mmol/L | 3 | 0 | 0 |
| Bicarbonate >31 mmol/L | 13 | 1 | 3 |
| Bilirubin, Total >=2.0 mg/dL | 2 | 1 | 0 |
| Calcium <8.2 mg/dL | 2 | 0 | 0 |
| Calcium >12 mg/dL | 0 | 1 | 0 |
| Cholesterol, Total >300 mg/dL | 23 | 8 | 8 |
| Creatine Kinase (U/L) >3 x ULN | 26 | 11 | 8 |
| Chloride <=90 mmol/L | 1 | 0 | 0 |
| Creatinine >=2.0 mg/dL | 1 | 0 | 2 |
| Glucose <50 mg/dL | 4 | 6 | 4 |
| Glucose >200 mg/dL | 6 | 5 | 4 |
| HDL Cholesterol <=30 mg/dL | 13 | 6 | 3 |
| Potassium <3 mmol/L | 1 | 0 | 0 |
| Potassium >5.5 mmol/L | 39 | 8 | 16 |
| Lactate Dehydrogenase (U/L) >3 x ULN | 1 | 0 | 0 |
| LDL Cholesterol >=160 mg/dL | 69 | 27 | 29 |
| Sodium <130 mmol/L | 1 | 0 | 0 |
| Sodium >150 mmol/L | 3 | 0 | 0 |
| Triglycerides >=120 mg/dL (Female) | 123 | 45 | 61 |
| Triglycerides >=160 mg/dL (Male) | 54 | 32 | 24 |
| Urate >9 mg/dL | 10 | 5 | 2 |
| Urate >8 mg/dL (Female) | 8 | 3 | 4 |
| Blood Urea Nitrogen >30 mg/dL | 5 | 3 | 2 |
| Eosinophils >1x10^3/uL | 8 | 3 | 1 |
| Hematocrit <=32% and 3 point decrease from baseline (Female) | 18 | 5 | 8 |
| Hematocrit <=37% and 3 point decrease from baseline (Male) | 6 | 4 | 3 |
| Hemoglobin <=9.5 g/dL (Female) | 5 | 1 | 3 |
| Hemoglobin <=11.5 g/dL (Male) | 2 | 1 | 0 |
| Lymphocytes <0.5x10^9/L | 47 | 25 | 24 |
| Neutrophils, Absolute <1.5x10^3/uL | 39 | 10 | 13 |
| Platelets <75.1x10^3/uL | 2 | 0 | 1 |
| Platelets >=700x10^3/uL | 0 | 0 | 0 |
| Leukocytes <=2.8x10^3/uL | 45 | 17 | 15 |
| Leukocytes >=16x10^3/uL | 4 | 5 | 5 |
| Albumin/Creatinine >200 g/kg | 15 | 8 | 5 |
| Beta-2 Microglobulin >0.300 mg/L | 95 | 32 | 31 |
| Glucose at least 2+ | 10 | 4 | 3 |
| Protein at least 2+ | 15 | 4 | 9 |
Relapse was defined as new or recurrent neurologic symptoms, not associated with fever or infection, lasting for at least 24 hours, accompanied by one or more of the following: New objective neurological findings upon examination by the treating neurologist that are functionally consistent with findings on the Expanded Disability Status Scale \[EDSS\] (performed within 7 days of onset of symptoms) with an increase over the prior visit of ≥ 0.5 for the total score, an increase of ≥ 2 in 1 functional system (FS), except bladder/cognitive changes, and/or, an increase of ≥ 1 in 2 FS, except bladder/cognitive changes. The relapse rate for an individual participant was calculated as the number of relapses for that participant divided by the number of participant-years followed. The ARR for each enrollment group was calculated as the total number of relapses experienced in the group divided by the total number of participant-years on study.
| relapses per participant year | De Novo | Rollover: ALKS 8700 | Rollover: DMF |
|---|---|---|---|
| Annualized Relapse Rate (ARR) | 0.14 | 0.11 | 0.13 |
Relapse was defined as new or recurrent neurologic symptoms, not associated with fever or infection, lasting for at least 24 hours, accompanied by one or more of the following: New objective neurological findings upon examination by the treating neurologist that are functionally consistent with findings on the EDSS (performed within 7 days of onset of symptoms) with an increase over the prior visit of ≥ 0.5 for the total score, an increase of ≥ 2 in 1 FS, except bladder/cognitive changes, and/or, an increase of ≥ 1 in 2 FS, except bladder/cognitive changes.
| percentage of participants | De Novo | Rollover: ALKS 8700 | Rollover: DMF |
|---|---|---|---|
| Percentage of Participants With Multiple Sclerosis (MS) Relapse | 17.66 | 16.66 | 18.30 |
The EDSS is used to measure and evaluate MS participants' level of functioning. The EDSS provides a total score on a scale that ranges from 0 to 10. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability. The range of main categories include (0) = normal neurologic examination; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS. Higher scores indicate more disability. Positive change from baseline indicates more disability.
| score on a scale | De Novo | Rollover: ALKS 8700 | Rollover: DMF |
|---|---|---|---|
| Baseline | 2.71 ± 1.457 | 2.64 ± 1.481 | 2.71 ± 1.445 |
| Change From Baseline at Week 12 | -0.01 ± 0.490 | -0.03 ± 0.548 | 0.05 ± 0.557 |
| Change From Baseline at Week 24 | 0.00 ± 0.518 | -0.02 ± 0.603 | -0.01 ± 0.696 |
| Change From Baseline at Week 36 | 0.01 ± 0.558 | -0.01 ± 0.597 | -0.03 ± 0.733 |
| Change From Baseline at Week 48 | 0.03 ± 0.614 | -0.01 ± 0.579 | 0.00 ± 0.702 |
| Change From Baseline at Week 60 | 0.04 ± 0.617 | -0.02 ± 0.643 | -0.02 ± 0.633 |
| Change From Baseline at Week 72 | 0.05 ± 0.617 | -0.04 ± 0.639 | 0.08 ± 0.713 |
| Change From Baseline at Week 84 | 0.07 ± 0.641 | -0.03 ± 0.616 | -0.02 ± 0.759 |
| Change From Baseline at Week 96 | 0.07 ± 0.631 | -0.01 ± 0.775 | 0.03 ± 0.735 |
The T25-FW is a reliable quantitative mobility and leg function performance test based on a timed 25-foot walk. The participant was directed to one end of a clearly marked 25-foot course and was instructed to walk 25 feet as quickly as possible, but safely. Participants were allowed to use assistive devices (canes, crutches, walkers) as needed. The time was calculated from when the lead foot crosses the start point to when the participant had reached the 25-foot mark. The task was immediately administered again by having the participant walk back the same distance. The score for the T25-FW was calculated as the average of the 2 completed trials. A negative change from Baseline indicates improvement.
| seconds | De Novo | Rollover: ALKS 8700 | Rollover: DMF |
|---|---|---|---|
| Baseline | 5.875 (4.900 to 7.500) | 5.350 (4.500 to 6.850) | 5.635 (4.575 to 7.020) |
| Change From Baseline at Week 12 | -0.050 (-0.450 to 0.250) | 0.000 (-0.250 to 0.350) | 0.000 (-0.425 to 0.375) |
| Change From Baseline at Week 24 | 0.000 (-0.450 to 0.300) | -0.050 (-0.350 to 0.400) | 0.000 (-0.450 to 0.400) |
| Change From Baseline at Week 36 | -0.050 (-0.500 to 0.300) | -0.100 (-0.450 to 0.350) | 0.000 (-0.500 to 0.500) |
| Change From Baseline at Week 48 | 0.000 (-0.450 to 0.400) | 0.000 (-0.450 to 0.350) | -0.050 (-0.450 to 0.550) |
| Change From Baseline at Week 60 | -0.050 (-0.600 to 0.400) | -0.090 (-0.550 to 0.300) | 0.000 (-0.550 to 0.550) |
| Change From Baseline at Week 72 | 0.000 (-0.550 to 0.500) | -0.050 (-0.600 to 0.350) | 0.000 (-0.550 to 0.600) |
| Change From Baseline at Week 84 | -0.050 (-0.600 to 0.450) | -0.075 (-0.500 to 0.300) | 0.000 (-0.500 to 0.700) |
| Change From Baseline at Week 96 | -0.050 (-0.550 to 0.400) | -0.050 (-0.500 to 0.400) | 0.000 (-0.450 to 0.650) |
The EQ-5D-5L is an instrument designed to assess decrements in health. The EQ-5D-5L includes a VAS and a descriptive system that defines health in terms of 5 dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each dimension has 5 response categories corresponding to the level of severity (i.e., no problems, slight problems, moderate problems, severe problems, and unable to/extreme problems). The EQ-5D-5L VAS records the participant's self-rated health on a vertical visual analogue scale numbered from 100 (best health imagined) to 0 (worst health imagined). Higher scores indicate good health. Positive change from baseline indicates improved health.
| score on a scale | De Novo | Rollover: ALKS 8700 | Rollover: DMF |
|---|---|---|---|
| Baseline | 73.7 ± 17.48 | 80.3 ± 14.65 | 80.0 ± 16.26 |
| Change From Baseline at Week 24 | 1.0 ± 15.30 | -1.6 ± 12.24 | -1.6 ± 12.31 |
| Change From Baseline at Week 48 | 0.3 ± 15.27 | -2.8 ± 10.68 | -1.9 ± 12.48 |
| Change From Baseline at Week 72 | 1.3 ± 14.85 | -2.8 ± 11.97 | -2.1 ± 12.50 |
| Change From Baseline at Week 96 | 0.6 ± 14.59 | -4.2 ± 12.35 | -3.7 ± 14.71 |
The EQ-5D-5L is an instrument designed to assess decrements in health. The EQ-5D-5L includes a VAS and a descriptive system that defines health in terms of 5 dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each dimension has 5 response categories corresponding to the level of severity (i.e., no problems, slight problems, moderate problems, severe problems, and unable to/extreme problems). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). Higher scores indicate good health. Positive change from baseline indicates improved health.
| score on a scale | De Novo | Rollover: ALKS 8700 | Rollover: DMF |
|---|---|---|---|
| Baseline | 0.793 ± 0.137 | 0.841 ± 0.128 | 0.837 ± 0.128 |
| Change From Baseline at Week 24 | -0.002 ± 0.110 | -0.018 ± 0.085 | -0.035 ± 0.096 |
| Change From Baseline at Week 48 | -0.006 ± 0.108 | -0.026 ± 0.086 | -0.037 ± 0.101 |
| Change From Baseline at Week 72 | -0.010 ± 0.109 | -0.030 ± 0.108 | -0.036 ± 0.110 |
| Change From Baseline at Week 96 | -0.009 ± 0.114 | -0.042 ± 0.109 | -0.057 ± 0.117 |
The SF-12 uses 12 questions to measure functional health and well-being from the study participant's perspective across eight domains: physical functioning, role, bodily pain, general health perceptions, vitality, social functioning, emotional role, and mental health. Mental and physical composite scores (MCS \& PCS) are computed using the scores of twelve questions and range from 0 to 100, where a higher score indicates better health. Positive change from baseline indicates improved health.
| score on a scale | De Novo | Rollover: ALKS 8700 | Rollover: DMF |
|---|---|---|---|
| PCS: Baseline | 42.90 ± 10.662 | 44.68 ± 10.629 | 45.03 ± 10.720 |
| PCS: Change From Baseline at Week 24 | 0.35 ± 7.329 | -0.28 ± 6.893 | -1.00 ± 6.248 |
| PCS: Change From Baseline at Week 48 | 0.22 ± 6.804 | -0.04 ± 7.428 | -1.62 ± 6.546 |
| PCS: Change From Baseline at Week 72 | 0.04 ± 7.341 | -0.27 ± 7.902 | -1.25 ± 6.849 |
| PCS: Change From Baseline at Week 96 | 0.48 ± 7.154 | -0.28 ± 7.095 | -1.44 ± 7.191 |
| MCS: Baseline | 47.75 ± 10.345 | 50.90 ± 8.926 | 51.14 ± 9.299 |
| MCS: Change From Baseline at Week 24 | 0.29 ± 8.745 | -2.12 ± 7.962 | -1.69 ± 8.415 |
| MCS: Change From Baseline at Week 48 | -0.62 ± 9.412 | -2.57 ± 8.059 | -2.20 ± 9.386 |
| MCS: Change From Baseline at Week 72 | -0.34 ± 9.866 | -2.63 ± 7.786 | -3.50 ± 9.663 |
| MCS: Change From Baseline at Week 96 | -0.35 ± 9.517 | -2.93 ± 8.681 | -3.57 ± 10.582 |
The time to onset of 12-week confirmed disability progression is defined as the time from baseline to the first disability progression that is confirmed at the next regularly scheduled visit ≥ 12 weeks after the initial disability progression. Disability progression is defined by one of the following: an EDSS increase of at least 1.5 points from baseline EDSS = 0, an EDSS increase of at least a 1.0 point from baseline EDSS between 1.0 and 5.5 (inclusive), or an EDSS increase of at least 0.5 points from baseline EDSS = 6.0.
| days | De Novo | Rollover: ALKS 8700 | Rollover: DMF |
|---|---|---|---|
| Time to Onset of 12-week Confirmed Disability Progression | 250.0 (91.0 to 420.0) | 254.5 (89.0 to 419.0) | 176.0 (89.0 to 333.0) |
The definition of NEDA-3 encompasses a combination of the following 3 related measures of disease activity: No relapses, no confirmed disability progression sustained for 12 weeks as measured on EDSS, and no magnetic resonance imaging (MRI) disease activity, defined as no gadolinium-enhancing (GdE) lesions and no new or enlarging T2 lesions. The definition of NEDA-4 was the above definition of NEDA-3 with the addition of a mean annualized rate of brain volume loss of less than 0.4% where annualized rate of brain volume loss was derived from percentage brain volume change (PBVC) from baseline and was calculated as (\[PBVC/100+1\]\^\[365.25/days\]-1) × 100.
| percentage of participants | De Novo | Rollover: ALKS 8700 | Rollover: DMF |
|---|---|---|---|
| NEDA-3 | 24.8 | 34.6 | 28.6 |
| NEDA-4 | 14.3 | 15.2 | 11.9 |
Collected over From first dose to two weeks after last dose of study drug (Up to 98 weeks). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| De Novo | 3/593 (0.5%) | 69/593 (11.6%) | 461/593 (77.7%) |
| Rollover: ALKS 8700 | 1/239 (0.4%) | 29/239 (12.1%) | 186/239 (77.8%) |
| Rollover: DMF | 0/225 (0%) | 25/225 (11.1%) | 189/225 (84%) |
| Event | De Novo | Rollover: ALKS 8700 | Rollover: DMF |
|---|---|---|---|
| Multiple sclerosis relapseNervous system disorders | 32/593 | 19/239 | 10/225 |
| Abdominal painGastrointestinal disorders | 1/593 | 0/239 | 2/225 |
| Myocardial infarctionCardiac disorders | 0/593 | 0/239 | 1/225 |
| ChorioretinopathyEye disorders | 0/593 | 0/239 | 1/225 |
| GastritisGastrointestinal disorders | 0/593 | 1/239 | 1/225 |
| VomitingGastrointestinal disorders | 0/593 | 0/239 | 1/225 |
| CholecystitisHepatobiliary disorders | 0/593 | 1/239 | 1/225 |
| Cholestatic liver injuryHepatobiliary disorders | 0/593 | 0/239 | 1/225 |
| CellulitisInfections and infestations | 0/593 | 0/239 | 1/225 |
| Pharyngeal abscessInfections and infestations | 0/593 | 0/239 | 1/225 |
| Event | De Novo | Rollover: ALKS 8700 | Rollover: DMF |
|---|---|---|---|
| FlushingVascular disorders | 226/593 | 33/239 | 29/225 |
| Multiple sclerosis relapseNervous system disorders | 93/593 | 47/239 | 44/225 |
| Upper respiratory tract infectionInfections and infestations | 76/593 | 42/239 | 35/225 |
| LymphopeniaBlood and lymphatic system disorders | 51/593 | 35/239 | 38/225 |
| NasopharyngitisInfections and infestations | 86/593 | 24/239 | 27/225 |
| DiarrhoeaGastrointestinal disorders | 66/593 | 18/239 | 25/225 |
| FatigueGeneral disorders | 39/593 | 26/239 | 22/225 |
| Urinary tract infectionInfections and infestations | 55/593 | 25/239 | 24/225 |
| HeadacheNervous system disorders | 49/593 | 23/239 | 24/225 |
| ArthralgiaMusculoskeletal and connective tissue disorders | 32/593 | 18/239 | 20/225 |
Safety Analysis Set included all enrolled participants who received at least one dose of ALKS 8700.
| Age, Continuous(years) | De Novo | Rollover: ALKS 8700 | Rollover: DMF | Total |
|---|---|---|---|---|
| Mean | 41.5 ± 10.96 | 44.0 ± 11.00 | 43.7 ± 9.77 | 42.5 ± 10.78 |
| Sex: Female, Male(Participants) | De Novo | Rollover: ALKS 8700 | Rollover: DMF | Total |
|---|---|---|---|---|
| Female | 427 | 165 | 170 | 762 |
| Male | 166 | 74 | 55 | 295 |
| Ethnicity (NIH/OMB)(Participants) | De Novo | Rollover: ALKS 8700 | Rollover: DMF | Total |
|---|---|---|---|---|
| Hispanic or Latino | 25 | 5 | 10 | 40 |
| Not Hispanic or Latino | 568 | 234 | 215 | 1017 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
| Race/Ethnicity, Customized(Participants) | De Novo | Rollover: ALKS 8700 | Rollover: DMF | Total |
|---|---|---|---|---|
| Race — White | 547 | 220 | 205 | 972 |
| Race — Black or African American | 37 | 19 | 16 | 72 |
| Race — Asian | 4 | 0 | 1 | 5 |
| Race — Native Hawaiian or Other Pacific Islander | 0 | 0 | 1 | 1 |
| Race — Other | 5 | 0 | 2 | 7 |
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