A Study of ALKS 8700 in Adults With Relapsing Remitting Multiple Sclerosis (MS) EVOLVE-MS-1

• ClinicalTrials.gov Identifier: NCT02634307
• Recruitment Status: Completed
• First Posted: December 18, 2015
• Results First Posted: June 24, 2022
• Last Update Posted: July 26, 2022
• Sponsor: Biogen
• Collaborator: Alkermes, Inc.
• Information provided by (Responsible Party): Biogen

Tracking Information

• First Submitted Date: December 16, 2015
• First Posted Date: December 18, 2015
• Results First Submitted Date: May 30, 2022
• Results First Posted Date: June 24, 2022
• Last Update Posted Date: July 26, 2022
• Actual Study Start Date: December 10, 2015
• Actual Primary Completion Date: June 1, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 30, 2022)

• Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: From first dose to two weeks after last dose of study drug (Up to 98 weeks) ]
  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.
• Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities [ Time Frame: From first dose to two weeks after last dose of study drug (Up to 98 weeks) ]
  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).
• Number of Participants With Potentially Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities [ Time Frame: From first dose to two weeks after last dose of study drug (Up to 98 weeks) ]
  Potentially clinically significant QTcF values (>450 to <=480 millisecond [msec], >480 to <=500 msec) at any post-baseline visit during treatment period were reported.
• Number of Participants With Columbia Suicide Severity Rating Scale (C-SSRS) Score at Any Post-Baseline Visit [ Time Frame: Up to 98 weeks ]
  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.
• Number of Participants With Potentially Clinically Significant Laboratory Abnormalities [ Time Frame: From first dose to two weeks after last dose of study drug (Up to 98 weeks) ]
  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+.

Original Primary Outcome Measures (submitted: December 16, 2015)

Safety will be demonstrated by incidence of Adverse Events [ Time Frame: Up to 96 weeks ]

All enrolled subjects who receive at least one dose of ALKS 8700 will be used in the safety and tolerability analysis

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided

Current Other Pre-specified Outcome Measures (submitted: May 30, 2022)

• Annualized Relapse Rate (ARR) [ Time Frame: Up to 96 weeks ]
  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.
• Percentage of Participants With Multiple Sclerosis (MS) Relapse [ Time Frame: Up to 96 weeks ]
  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.
• Change From Baseline in Expanded Disability Status Scale (EDSS) Score [ Time Frame: Baseline up to Week 96 ]
  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.
• Change From Baseline in Timed 25-Foot Walk Test (T25-FW) Score [ Time Frame: Baseline up to Week 96 ]
  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.
• Change From Baseline in the EuroQol 5-Dimension 5-Level Visual Analog Scale (EQ-5D-5L VAS) Score [ Time Frame: Baseline up to Week 96 ]
  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.
• Change From Baseline in the EQ-5D-5L Index Score [ Time Frame: Baseline up to Week 96 ]
  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.
• Change From Baseline in the 12-item Short Form Health Survey (SF-12) Score [ Time Frame: Baseline up to Week 96 ]
  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 to Onset of 12-week Confirmed Disability Progression [ Time Frame: Up to Week 96 ]
  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.
• Percentage of Participants With No Evidence of Disease Activity (NEDA) at Week 96 [ Time Frame: 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.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of ALKS 8700 in Adults With Relapsing Remitting Multiple Sclerosis (MS) EVOLVE-MS-1
• Official Title: A Phase 3 Open Label Study to Evaluate the Long-term Safety and Tolerability of ALKS 8700 in Adults With Relapsing Remitting Multiple Sclerosis
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Multiple Sclerosis

Intervention

Drug: ALKS 8700

Administered as specified in the treatment arm.

Study Arms

Experimental: ALKS 8700

Oral capsules taken twice daily.

Intervention: Drug: ALKS 8700

Publications *

• Wray S, Then Bergh F, Wundes A, Arnold DL, Drulovic J, Jasinska E, Bowen JD, Negroski D, Naismith RT, Hunter SF, Gudesblatt M, Chen H, Lyons J, Shankar SL, Kapadia S, Mendoza JP, Singer BA. Efficacy and Safety Outcomes with Diroximel Fumarate After Switching from Prior Therapies or Continuing on DRF: Results from the Phase 3 EVOLVE-MS-1 Study. Adv Ther. 2022 Apr;39(4):1810-1831. doi: 10.1007/s12325-022-02068-7. Epub 2022 Feb 24.
• Naismith RT, Wolinsky JS, Wundes A, LaGanke C, Arnold DL, Obradovic D, Freedman MS, Gudesblatt M, Ziemssen T, Kandinov B, Bidollari I, Lopez-Bresnahan M, Nangia N, Rezendes D, Yang L, Chen H, Liu S, Hanna J, Miller C, Leigh-Pemberton R. Diroximel fumarate (DRF) in patients with relapsing-remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study. Mult Scler. 2020 Nov;26(13):1729-1739. doi: 10.1177/1352458519881761. Epub 2019 Nov 4.
• Palte MJ, Wehr A, Tawa M, Perkin K, Leigh-Pemberton R, Hanna J, Miller C, Penner N. Improving the Gastrointestinal Tolerability of Fumaric Acid Esters: Early Findings on Gastrointestinal Events with Diroximel Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis from the Phase 3, Open-Label EVOLVE-MS-1 Study. Adv Ther. 2019 Nov;36(11):3154-3165. doi: 10.1007/s12325-019-01085-3. Epub 2019 Sep 19.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 26, 2019): 1057
• Original Estimated Enrollment (submitted: December 16, 2015): 600
• Actual Study Completion Date: November 11, 2021
• Actual Primary Completion Date: June 1, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

• Has a confirmed diagnosis of RRMS
• Neurologically stable with no evidence of relapse within 30 days prior to Visit 2

Exclusion Criteria:

• Subject is pregnant or breastfeeding or plans to become pregnant or begin breastfeeding at any point during the study and for 30 days after any study drug administration
• Diagnosis of primary progressive, secondary progressive, or progressive relapsing MS
• History of clinically significant cardiovascular, pulmonary, gastrointestinal, dermatologic, psychiatric, neurologic (other than MS), and/or other major disease that would preclude participation in a clinical trial
• History of a myocardial infarction, including a silent myocardial infarction identified on ECG, or unstable angina

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Bulgaria, Canada, Germany, Poland, Russian Federation, Serbia, Spain, Ukraine, United States

Administrative Information

• NCT Number: NCT02634307
• Other Study ID Numbers: ALK8700-A301; 2015-005160-41 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Biogen
• Original Responsible Party: Alkermes, Inc.
• Current Study Sponsor: Biogen
• Original Study Sponsor: Alkermes, Inc.
• Collaborators: Alkermes, Inc.

Investigators

• Study Director: Medical Director; Biogen

• PRS Account: Biogen
• Verification Date: July 2022