A Tolerability Study of ALKS 8700 in Subjects With Relapsing Remitting Multiple Sclerosis (RRMS) EVOLVE-MS-2

• ClinicalTrials.gov Identifier: NCT03093324
• Recruitment Status: Completed
• First Posted: March 28, 2017
• Results First Posted: July 14, 2020
• Last Update Posted: July 14, 2020
• Sponsor: Biogen
• Collaborator: Alkermes, Inc.
• Information provided by (Responsible Party): Biogen

Study Description

Brief Summary:

The objectives of this study are to evaluate the utility of two gastrointestinal (GI) symptom scales (Individual GI Symptom and Impact Scale {IGISIS} and Global GI Symptom and Impact Scale {GGISIS}) in assessing GI tolerability in adult subjects with RRMS after administration of ALKS 8700 or Dimethyl Fumarate (DMF) in Part A, to compare the GI tolerability of ALKS 8700 and DMF in adult subjects with RRMS using IGISIS and GGISIS in Part B, and to Evaluate the safety and tolerability of ALKS 8700 in adult subjects with RRMS in Parts A and B.

Condition or disease	Intervention/treatment	Phase
Relapsing Remitting Multiple Sclerosis	Drug: ALKS 8700; Drug: Dimethyl Fumarate	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 506 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Study in Subjects With Relapsing Remitting Multiple Sclerosis to Evaluate the Tolerability of ALKS 8700 and Dimethyl Fumarate
• Actual Study Start Date: March 15, 2017
• Actual Primary Completion Date: June 27, 2019
• Actual Study Completion Date: June 27, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: ALKS 8700; Oral capsules, administered orally twice daily.	Drug: ALKS 8700; Administered as specified in the treatment arm.
Active Comparator: Dimethyl Fumarate; Oral capsules, administered orally twice daily.	Drug: Dimethyl Fumarate; Administered as specified in the treatment arm.; Other Name: Tecfidera

Outcome Measures

Primary Outcome Measures :

1. Number of Days With Any Individual Gastrointestinal Symptom and Impact Scale (IGISIS) Individual Symptom Intensity Score ≥2 Relative to Exposure Days in Parts A and B [ Time Frame: End of treatment (up to Week 6) for both Parts A and B ]
   IGISIS assessed the intensity of five individual GI symptoms: nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea. Participants rated the intensity of each individual symptom via an 11-point numeric rating scale ranging from 0 (did not have) to 10 (extreme). IGISIS was completed by the participants using e-diaries.

Secondary Outcome Measures :

1. Number of Days With Any IGISIS Individual Symptom Intensity Score ≥2 Relative to Exposure Days in Part B [ Time Frame: End of treatment (up to Week 6) for Part B ]
   IGISIS assessed the intensity of five individual GI symptoms: nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea. Participants rated the intensity of each individual symptom via an 11-point numeric rating scale ranging from 0 (did not have) to 10 (extreme). IGISIS was completed by the participants using e-diaries.
2. Number of Days With Any IGISIS Individual Symptom Intensity Score ≥1 Relative to Exposure Days in Parts A and B [ Time Frame: End of treatment (up to Week 6) for both Parts A and B ]
   IGISIS assessed the intensity of five individual GI symptoms: nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea. Participants rated the intensity of each individual symptom via an 11-point numeric rating scale ranging from 0 (did not have) to 10 (extreme). IGISIS was completed by the participants using e-diaries.
3. Number of Days With Any IGISIS Individual Symptom Intensity Score ≥3 Relative to Exposure Days in Parts A and B [ Time Frame: End of treatment (up to Week 6) for both Parts A and B ]
   IGISIS assessed the intensity of five individual GI symptoms: nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea. Participants rated the intensity of each individual symptom via an 11-point numeric rating scale ranging from 0 (did not have) to 10 (extreme). IGISIS was completed by the participants using e-diaries.
4. Number of Days With a Global GI Symptom and Impact Scale (GGISIS) Symptom Intensity Score ≥1 Relative to Exposure Days in Parts A and B [ Time Frame: End of treatment (up to Week 6) for both Parts A and B ]
   GGISIS is a global scale to assess the overall intensity of GI symptoms (nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea). Participants rated the intensity of GI symptoms via an 11-point numeric rating scale ranging from 0 (did not have) to 10 (extreme). GGISIS was completed by the participants using e-diaries.
5. Number of Days With a GGISIS Symptom Intensity Score ≥2 Relative to Exposure Days in Parts A and B [ Time Frame: End of treatment (up to Week 6) for both Parts A and B ]
   GGISIS is a global scale to assess the overall intensity of GI symptoms (nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea). Participants rated the intensity of GI symptoms via an 11-point numeric rating scale ranging from 0 (did not have) to 10 (extreme). GGISIS was completed by the participants using e-diaries.
6. Number of Days With a GGISIS Symptom Intensity Score ≥3 Relative to Exposure Days in Parts A and B [ Time Frame: End of treatment (up to Week 6) for both Parts A and B ]
   GGISIS is a global scale to assess the overall intensity of GI symptoms (nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea). Participants rated the intensity of GI symptoms via an 11-point numeric rating scale ranging from 0 (did not have) to 10 (extreme). GGISIS was completed by the participants using e-diaries.
7. Worst IGISIS Individual Symptom Intensity Score During the 5-Week Treatment Period in Parts A and B [ Time Frame: End of treatment (up to Week 6) for both Parts A and B ]
   IGISIS assessed the intensity of five individual GI symptoms: nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea. Participants rated the intensity of each individual symptom via an 11-point numeric rating scale ranging from 0 (did not have) to 10 (extreme). IGISIS was completed by the participants using e-diaries. Scores were averaged for 5-week treatment period.
8. Number of Participants With Adverse Events (AEs) [ Time Frame: End of study (up to Week 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 laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

Eligibility Criteria

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

Criteria

Key Inclusion Criteria:

• Capable of understanding and complying with the protocol
• Has a confirmed diagnosis of RRMS
• Neurologically stable with no evidence of relapse within 30 days prior to randomization
• Agrees to use an acceptable method of contraception for the duration of the study and for 30 days after any study drug administration, or is surgically sterile or post-menopausal

Key Exclusion Criteria:

• Have any finding(s) that would compromise the safety of the subject, affect the subject's ability to adhere to the protocol visit schedule or to fulfill visit requirements, or would make the subject unsuitable for participation in the study
• Diagnosis of primary progressive, secondary progressive, or progressive relapsing MS
• History of clinically significant cardiovascular, pulmonary, GI, dermatologic, psychiatric, neurologic (other than MS), endocrine, renal, and/or other major disease that would preclude participation in a clinical trial
• History of GI surgery (except appendectomy that occurred more than 6 months prior to screening
• History of clinically significant recurring or active gastrointestinal symptoms (eg, nausea, diarrhea, dyspepsia, constipation) within 3 months of screening
• Chronic use (7 days) of medical therapy to treat any GI symptoms within 1 month of screening Has a clinically significant medical condition or observed abnormality at screening
• History of a myocardial infarction, including a silent myocardial infarction or unstable angina
• History of clinically significant drug or alcohol abuse within the past year prior to screening
• Clinically significant history of suicidal ideation or suicidal behavior in the last 12 months
• 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
• Prior use of Dimethyl Fumarate (DMF)

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

Contacts and Locations

Locations

United States, Alabama

Alkermes Investigational Site

Cullman, Alabama, United States, 35058

United States, Arizona

Alkermes Investigational Site

Phoenix, Arizona, United States, 85004

Alkermes Investigational Site

Tucson, Arizona, United States, 85704

United States, California

Alkermes Investigational Site

Long Beach, California, United States, 90806

Alkermes Investigational Site

San Diego, California, United States, 92103

United States, Colorado

Alkermes Investigational Site

Basalt, Colorado, United States, 81621

Alkermes Investigational Site

Centennial, Colorado, United States, 80112

Alkermes Investigational Site

Denver, Colorado, United States, 80209

United States, Connecticut

Alkermes Investigational Site

Middlebury, Connecticut, United States, 06762

Alkermes Investigational Site

Stamford, Connecticut, United States, 06905

United States, District of Columbia

Alkermes Investigational Site

Washington, District of Columbia, United States, 20007

United States, Florida

Alkermes Investigational Site

Atlantis, Florida, United States, 33462

Alkermes Investigational Site

Bradenton, Florida, United States, 34209

Alkermes Investigational Site

Maitland, Florida, United States, 32751

Alkermes Investigational Site

Naples, Florida, United States, 34105

Alkermes Investigational Site

Ormond Beach, Florida, United States, 32174

Alkermes Investigational Site

Sarasota, Florida, United States, 34233

Alkermes Investigational Site

Tampa, Florida, United States, 33634

Alkermes Investigational Site

Vero Beach, Florida, United States, 32960

United States, Georgia

Alkermes Investigational Site

Atlanta, Georgia, United States, 30312

Alkermes Investigational Site

Atlanta, Georgia, United States, 30327

Alkermes Investigational Site

Atlanta, Georgia, United States, 30342

Alkermes Investigational Site

Columbus, Georgia, United States, 31904

United States, Illinois

Alkermes Investigational Site

Evanston, Illinois, United States, 60201

United States, Iowa

Alkermes Investigational Site

Des Moines, Iowa, United States, 50314

United States, Kansas

Alkermes Investigational Site

Lenexa, Kansas, United States, 66214

United States, Louisiana

Alkermes Investigational Site

Alexandria, Louisiana, United States, 71301

United States, Michigan

Alkermes Investigational Site

Detroit, Michigan, United States, 48202

United States, Minnesota

Alkermes Investigational Site

Golden Valley, Minnesota, United States, 55422

United States, Missouri

Alkermes Investigational Site

Saint Louis, Missouri, United States, 63104

Alkermes Investigational Site

Saint Louis, Missouri, United States, 63110

Alkermes Investigational Site

Saint Louis, Missouri, United States, 63131

United States, New Mexico

Alkermes Investigational Site

Albuquerque, New Mexico, United States, 87106

United States, New York

Alkermes Investigational Site

Patchogue, New York, United States, 11772

Alkermes Investigational Site

Stony Brook, New York, United States, 11794

Alkermes Investigational Site

Syracuse, New York, United States, 13210

United States, North Carolina

Alkermes Investigational Site

Charlotte, North Carolina, United States, 28203

Alkermes Investigational Site

Greensboro, North Carolina, United States, 27405

Alkermes Investigational Site

Winston-Salem, North Carolina, United States, 27103

United States, Ohio

Alkermes Investigational Site

Canton, Ohio, United States, 44718

Alkermes Investigational Site

Columbus, Ohio, United States, 43221

Alkermes Investigational Site

Dayton, Ohio, United States, 45417

United States, Oklahoma

Alkermes Investigational Site

Oklahoma City, Oklahoma, United States, 73104

United States, South Carolina

Alkermes Investigational Site

Charleston, South Carolina, United States, 29406

Alkermes Investigational Site

Greer, South Carolina, United States, 29650

Alkermes Investigational Site

Indian Land, South Carolina, United States, 29707

Alkermes Investigational Site

Spartanburg, South Carolina, United States, 29307

United States, Tennessee

Alkermes Investigational Site

Franklin, Tennessee, United States, 37064

Alkermes Investigational Site

Knoxville, Tennessee, United States, 37922

United States, Texas

Alkermes Investigational Site

Dallas, Texas, United States, 75231

Alkermes Investigational Site

Houston, Texas, United States, 77030

Alkermes Investigational Site

Houston, Texas, United States, 77074

United States, Virginia

Alkermes Investigational Site

Newport News, Virginia, United States, 23601

Alkermes Investigational Site

Richmond, Virginia, United States, 23226

United States, Washington

Alkermes Investigational Site

Seattle, Washington, United States, 98101

Alkermes Investigational Site

Seattle, Washington, United States, 98122

Alkermes Investigational Site

Seattle, Washington, United States, 98133

Germany

Alkermes Investigational Site

Dresden, Germany

Alkermes Investigational Site

Leipzig, Germany

Alkermes Investigational Site

Ulm, Germany

Alkermes Investigational Site

Westerstede, Germany

Poland

Alkermes Investigational Site

Gdańsk, Poland, 80-803

Alkermes Investigational Site

Katowice, Poland, 40-123

Alkermes Investigational Site

Kielce, Poland, 25-726

Alkermes Investigational Site

Lodz, Poland, 90-324

Alkermes Investigational Site

Plewiska, Poland, 62-064

Alkermes Investigational Site

Szczecin, Poland, 70-111

Sponsors and Collaborators

Biogen

Alkermes, Inc.

Investigators

• Study Director: Medical Director; Biogen

  Study Documents (Full-Text)

Documents provided by Biogen:

Study Protocol  [PDF] December 15, 2016

Statistical Analysis Plan  [PDF] February 20, 2019

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Wundes A, Wray S, Gold R, Singer BA, Jasinska E, Ziemssen T, de Seze J, Repovic P, Chen H, Hanna J, Messer J, Miller C, Naismith RT. Improved gastrointestinal profile with diroximel fumarate is associated with a positive impact on quality of life compared with dimethyl fumarate: results from the randomized, double-blind, phase III EVOLVE-MS-2 study. Ther Adv Neurol Disord. 2021 Mar 19;14:1756286421993999. doi: 10.1177/1756286421993999. eCollection 2021.

Naismith RT, Wundes A, Ziemssen T, Jasinska E, Freedman MS, Lembo AJ, Selmaj K, Bidollari I, Chen H, Hanna J, Leigh-Pemberton R, Lopez-Bresnahan M, Lyons J, Miller C, Rezendes D, Wolinsky JS; EVOLVE-MS-2 Study Group. Diroximel Fumarate Demonstrates an Improved Gastrointestinal Tolerability Profile Compared with Dimethyl Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis: Results from the Randomized, Double-Blind, Phase III EVOLVE-MS-2 Study. CNS Drugs. 2020 Feb;34(2):185-196. doi: 10.1007/s40263-020-00700-0.

• Responsible Party: Biogen
• ClinicalTrials.gov Identifier: NCT03093324
• Other Study ID Numbers: ALK8700-A302; 2017-001294-16 ( EudraCT Number )
• First Posted: March 28, 2017
• Results First Posted: July 14, 2020
• Last Update Posted: July 14, 2020
• Last Verified: July 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Biogen:

RRMS; Multiple Sclerosis; MS; Alkermes; ALKS 8700; Dimethyl Fumarate; DMF; Tecfidera

Additional relevant MeSH terms:

Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Dimethyl Fumarate; Dermatologic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs