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

A Phase 3 Open Label Study to Evaluate the Long-term Safety and Tolerability of ALKS 8700 in Adults With Relapsing Remitting Multiple Sclerosis

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.

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Drug: ALKS 8700

• Study Type: Interventional
• Enrollment (Actual): 1057
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brugge, Belgium, 8000
    • Alkermes Investigational Site
  • Fraiture, Belgium, 4557
    • Alkermes Investigational Site
  • La Louviere, Belgium, 7100
    • Alkermes Investigational Site
• Bulgaria
  • Blagoevgrad, Bulgaria, 2700
    • Alkermes Investigational Site
  • Pleven, Bulgaria, 5800
    • Alkermes Investigational Site
  • Sofia, Bulgaria, 1606
    • Alkermes Investigational Site
  • Sofia, Bulgaria, 1309
    • Alkermes Investigational Site
  • Sofia, Bulgaria, 1797
    • Alkermes Investigational Site
• Canada
  • Quebec
    • Gatineau, Quebec, Canada, J8Y 1W2
      • Alkermes Investigational Site
• Germany
  • Berlin, Germany, 10713
    • Alkermes Investigational Site
  • Berlin, Germany, 12099
    • Alkermes Investigational Site
  • Dresden, Germany, 01307
    • Alkermes Investigational Site
  • Leipzig, Germany, 4103
    • Alkermes Investigational Site
  • Ulm, Germany, 89073
    • Alkermes Investigational Site
  • Ulm, Germany, 89081
    • Alkermes Investigational Site
  • Westerstede, Germany, 26655
    • Alkermes Investigational Site
• Poland
  • Gdansk, Poland, 80-803
    • Alkermes Investigational Site
  • Katowice, Poland, 40-123
    • Alkermes Investigational Site
  • Katowice, Poland, 40-648
    • Alkermes Investigational Site
  • Kielce, Poland, 25-726
    • Alkermes Investigational Site
  • Krakow, Poland, 31-505
    • Alkermes Investigational Site
  • Lodz, Poland, 90-324
    • Alkermes Investigational Site
  • Lublin, Poland, 20-718
    • Alkermes Investigational Site
  • Plewiska, Poland, 62-064
    • Alkermes Investigational Site
  • Szczecin, Poland, 70-111
    • Alkermes Investigational Site
• Russian Federation
  • Krasnoyarsk, Russian Federation, 66037
    • Alkermes Investigational Site
  • Nizhniy Novgorod, Russian Federation, 603155
    • Alkermes Investigational Site
• Serbia
  • Belgrade, Serbia, 11000
    • Alkermes Investigational Site
  • Kragujevac, Serbia, 34000
    • Alkermes Investigational Site
  • Nis, Serbia, 18000
    • Alkermes Investigational Site
• Spain
  • Barcelona, Spain, 08916
    • Alkermes Investigational Site
  • Madrid, Spain, 28905
    • Alkermes Investigational Site
  • Santa Cruz de Tenerife, Spain, 38010
    • Alkermes Investigational Site
• Ukraine
  • Dnipro, Ukraine, 49005
    • Alkermes Investigational Site
  • Ivano-Frankivsk, Ukraine, 76008
    • Alkermes Investigational Site
  • Kharkiv, Ukraine, 61068
    • Alkermes Investigational Site
  • Kharkiv, Ukraine, 61103
    • Alkermes Investigational Site
  • Lviv, Ukraine, 79000
    • Alkermes Investigational Site
  • Odessa, Ukraine, 65025
    • Alkermes Investigational Site
  • Zaporizhzhya, Ukraine, 69035
    • Alkermes Investigational Site
  • Zaporizhzhya, Ukraine, 69600
    • Alkermes Investigational Site
• United States
  • Alabama
    • Cullman, Alabama, United States, 35058
      • Alkermes Investigational Site
  • Arizona
    • Phoenix, Arizona, United States, 85004
      • Alkermes Investigational Site
    • Phoenix, Arizona, United States, 85018
      • Alkermes Investigational Site
    • Phoenix, Arizona, United States, 85032
      • Alkermes Investigational Site
    • Tucson, Arizona, United States, 85704
      • Alkermes Investigational Site
  • California
    • Berkeley, California, United States, 94705
      • Alkermes Investigational Site
    • Loma Linda, California, United States, 92354
      • Alkermes Investigational Site
    • Long Beach, California, United States, 90806
      • Alkermes Investigational Site
    • San Diego, California, United States, 92103
      • Alkermes Investigational Site
  • Colorado
    • Basalt, Colorado, United States, 81621
      • Alkermes Investigational Site
    • Centennial, Colorado, United States, 80111
      • Alkermes Investigational Site
    • Denver, Colorado, United States, 80209
      • Alkermes Investigational Site
  • Connecticut
    • Middlebury, Connecticut, United States, 06762
      • Alkermes Investigational Site
    • Stamford, Connecticut, United States, 06905
      • Alkermes Investigational Site
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Alkermes Investigational Site
  • Florida
    • Atlantis, Florida, United States, 33462
      • Alkermes Investigational Site
    • Bradenton, Florida, United States, 34209
      • Alkermes Investigational Site
    • Jacksonville, Florida, United States, 32209
      • Alkermes Investigational Site
    • Maitland, Florida, United States, 32751
      • Alkermes Investigational Site
    • Naples, Florida, United States, 34102
      • Alkermes Investigational Site
    • Ormond Beach, Florida, United States, 32174
      • Alkermes Investigational Site
    • Sarasota, Florida, United States, 34239
      • Alkermes Investigational Site
    • Tampa, Florida, United States, 33634
      • Alkermes Investigational Site
    • Vero Beach, Florida, United States, 32960
      • Alkermes Investigational Site
  • Georgia
    • Atlanta, Georgia, United States, 30327
      • Alkermes Investigational Site
    • Atlanta, Georgia, United States, 30342
      • Alkermes Investigational Site
    • Atlanta, Georgia, United States, 30312-4201
      • Alkermes Investigational Site
    • Columbus, Georgia, United States, 31904
      • Alkermes Investigational Site
  • Illinois
    • Evanston, Illinois, United States, 60201
      • Alkermes Investigational Site
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Alkermes Investigational Site
    • Indianapolis, Indiana, United States, 46260
      • Alkermes Investigational Site
  • Iowa
    • Des Moines, Iowa, United States, 50314
      • Alkermes Investigational Site
  • Kansas
    • Overland Park, Kansas, United States, 66213
      • Alkermes Investigational Site
  • Kentucky
    • Lexington, Kentucky, United States, 40513
      • Alkermes Investigational Site
  • Louisiana
    • Alexandria, Louisiana, United States, 71301
      • Alkermes Investigational Site
    • Baton Rouge, Louisiana, United States, 70810
      • Alkermes Investigational Site
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Alkermes Investigational Site
    • Traverse City, Michigan, United States, 49684
      • Alkermes Investigational Site
  • Minnesota
    • Golden Valley, Minnesota, United States, 55422
      • Alkermes Investigational Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Alkermes Investigational Site
    • Saint Louis, Missouri, United States, 63104
      • Alkermes Investigational Site
    • Saint Louis, Missouri, United States, 63131
      • Alkermes Investigational Site
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • Alkermes Investigational Site
  • New York
    • Patchogue, New York, United States, 11772
      • Alkermes Investigational Site
    • Plainview, New York, United States, 11803
      • Alkermes Investigational Site
    • Stony Brook, New York, United States, 11794
      • Alkermes Investigational Site
    • Syracuse, New York, United States, 13210
      • Alkermes Investigational Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Alkermes Investigational Site
    • Greensboro, North Carolina, United States, 27405
      • Alkermes Investigational Site
    • Raleigh, North Carolina, United States, 27607
      • Alkermes Investigational Site
    • Winston-Salem, North Carolina, United States, 27103
      • Alkermes Investigational Site
  • Ohio
    • Canton, Ohio, United States, 44718
      • Alkermes Investigational Site
    • Columbus, Ohio, United States, 43210
      • Alkermes Investigational Site
    • Dayton, Ohio, United States, 45417
      • Alkermes Investigational Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Alkermes Investigational Site
  • Oregon
    • Medford, Oregon, United States, 97504
      • Alkermes Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Alkermes Investigational Site
  • South Carolina
    • Charleston, South Carolina, United States, 29406
      • Alkermes Investigational Site
    • Greer, South Carolina, United States, 29650
      • Alkermes Investigational Site
    • Rock Hill, South Carolina, United States, 29732
      • Alkermes Investigational Site
    • Spartanburg, South Carolina, United States, 29307
      • Alkermes Investigational Site
  • Tennessee
    • Cordova, Tennessee, United States, 38018
      • Alkermes Investigational Site
    • Franklin, Tennessee, United States, 37064
      • Alkermes Investigational Site
    • Knoxville, Tennessee, United States, 37922
      • Alkermes Investigational Site
  • Texas
    • Dallas, Texas, United States, 75231
      • Alkermes Investigational Site
    • Houston, Texas, United States, 77030
      • Alkermes Investigational Site
    • Houston, Texas, United States, 77074
      • Alkermes Investigational Site
    • Lubbock, Texas, United States, 79410
      • Alkermes Investigational Site
  • Utah
    • Salt Lake City, Utah, United States, 84103
      • Alkermes Investigational Site
  • Virginia
    • Newport News, Virginia, United States, 23601
      • Alkermes Investigational Site
    • Richmond, Virginia, United States, 23228
      • Alkermes Investigational Site
  • Washington
    • Seattle, Washington, United States, 98101
      • Alkermes Investigational Site
    • Seattle, Washington, United States, 98122
      • Alkermes Investigational Site
    • Seattle, Washington, United States, 98133
      • Alkermes Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ALKS 8700; Oral capsules taken twice daily.	Drug: ALKS 8700; Administered as specified in the treatment arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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).	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.	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.	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+.	From first dose to two weeks after last dose of study drug (Up to 98 weeks)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	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.	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.	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.	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.	Week 96

Collaborators and Investigators

• Sponsor: Biogen
• Collaborators: Alkermes, Inc.

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2015
• Primary Completion (Actual): June 1, 2021
• Study Completion (Actual): November 11, 2021

Study Registration Dates

• First Submitted: December 16, 2015
• First Submitted That Met QC Criteria: December 16, 2015
• First Posted (Estimate): December 18, 2015

Study Record Updates

• Last Update Posted (Actual): July 26, 2022
• Last Update Submitted That Met QC Criteria: July 18, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: RRMS; MS; Relapsing Remitting Multiple Sclerosis; dimethyl fumarate; DMF
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting
• Other Study ID Numbers: ALK8700-A301; 2015-005160-41 (EudraCT Number)