SUSTAIN: Efficacy and Safety of Daclizumab in Participants With RRMS Switching From Natalizumab

• Sponsor: Biogen (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02881567
• Collaborator: AbbVie (Industry)
• Enrollment: 41
• Locations: 11
• Arm: 1
• Actual Duration (Months): 16.8
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The primary objective of the study is to evaluate the effects of treatment with daclizumab on the proportion of participants relapse-free at 6 months in Relapsing-Remitting Multiple Sclerosis (RRMS) participants, who switched from treatment with natalizumab to daclizumab due to safety concerns. The secondary objectives of this study in this study population are to evaluate the effects of daclizumab on the following: 1) Multiple Sclerosis (MS) relapse activity including the annualized relapse rate (ARR) and the proportion of participants experiencing relapses requiring hospitalization and/or steroid treatment; 2) MS-related outcomes measured using magnetic resonance imaging (MRI); 3) Safety and tolerability in participants previously treated with natalizumab.

Condition or Disease	Intervention/Treatment	Phase
Relapsing-Remitting Multiple Sclerosis (RRMS)	Drug: Daclizumab	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3b, 12-month, Open-label, Multicenter Study to Evaluate the Efficacy and Safety of BIIB019, Daclizumab, in Subjects With Relapsing-Remitting Multiple Sclerosis (RRMS) Switching From Natalizumab (SUSTAIN)
• Actual Study Start Date: Apr 18, 2017
• Actual Primary Completion Date: Sep 12, 2018
• Actual Study Completion Date: Sep 12, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Daclizumab	Drug: Daclizumab; High yield formulation; Other Names: BIIB019 Zinbryta

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Relapse-free at Month 6 [Month 6]

   Relapses were defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Examining Neurologist. The Kaplan-Meier estimate of the percentage of participants relapse-free at Month 6 is reported.

Secondary Outcome Measures

1. Percentage of Participants Relapse-free at Month 12 [Month 12]

   Relapses were defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Examining Neurologist.

2. Percentage of Participants Experiencing Relapse Requiring Hospitalization and/or Steroid Treatment at Month 12 [Month 12]

   Relapses were defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Examining Neurologist.

3. Annualized Relapse Rate (ARR) at Month 12 [Month 12]

   Relapses were defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Examining Neurologist. The ARR was calculated by tabulating the total number of relapses experienced in the group divided by the number of days up to the end of Month 12, and the ratio then multiplied by 365.

4. Number of Participants With New Gadolinium-Enhanced (Gd+) and T1 Hypointense Lesions at Months 6 and 12 [Months 6 and 12]

   New Gadolinium-Enhanced (Gd+) and T1 Hypointense Lesions were assessed using magnetic resonance imaging (MRI).

5. Number of Participants With New and Newly Enlarged T2 Hypointense Lesions at Months 6 and 12 [Months 6 and 12]

   New and newly enlarged T2 Hypointense Lesions were measured by MRI.

6. Permanent Discontinuation Rate of Daclizumab at Month 12 [Month 12]

   Permanent Discontinuation Rate was calculated as the ratio of number of participants who had permanently discontinued daclizumab prior to Month 12 over the total number of participants who received at least 1 dose of daclizumab in the study.

7. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [First dose of study drug to within 30 days of last dose (up to 11 months)]

   An AE can 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. An SAE is any untoward medical occurrence that at any dose results in death or in the view of the Investigator, places the participant at immediate risk of death or requires inpatient hospitalization or prolongation of existing hospitalization or results in persistent or significant disability or results in a birth defect.

8. Number of Participants With Clinically Relevant Shifts in Laboratory Assessments [First dose of study drug to within 30 days of last dose (up to 11 months)]

   Clinical Laboratory assessments were tests of Chemistry and Hematology. The investigator determined if any of the laboratory results were clinically relevant shifts from Baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria

• Must have documented diagnosis of RRMS (McDonald 2010 Criteria) at screening [Polman 2011].

• Must have been treated with natalizumab for at least the 12 months prior to screening and have not missed 2 or more consecutive scheduled doses.

• Must be naïve to daclizumab and other forms of daclizumab such as Zenapax® prior to enrollment.

• Must have a confirmed Expanded Disability Status Scale (EDSS) score of 0 to 5.5, inclusive, at screening.

• Female participants of childbearing potential must practice effective contraception from Day -1 and be willing and able to continue contraception for duration of the study.

Key Exclusion Criteria

• Current participation in another investigational study.

• Diagnosis of primary progressive, secondary progressive, or progressive relapsing MS (as defined by Lublin and Reingold) [Lublin 2014].

• Females breastfeeding, pregnant, or planning to become pregnant; or women who have a positive pregnancy test result during screening.

• History of drug or alcohol abuse (as defined by the Investigator) within 1 year prior to screening.

• History of severe hypersensitivity (e.g., anaphylaxis or anaphylactoid reactions) to the active ingredient or any of the excipients.

• History of severe opportunistic infections (including progressive multifocal leukoencephalopathy (PML)) or any clinically significant, cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic (other than MS), dermatologic, psychiatric, and renal, or other major disease, as determined by the Investigator.

• Discontinued natalizumab due to suspicion of PML.

• Known active malignancies (participants with cutaneous basal cell carcinoma that has been completely excised prior to study entry remain eligible).

• The participant is using another MS therapy concomitantly.

• Known history of human immunodeficiency virus (HIV).

• Positive test result for Hepatitis C virus (test for hepatitis C virus antibody [HCV Ab]) or hepatitis B virus (test for hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibody [HBcAb]).

• The participant has been treated with immunosuppressive or immunomodulating treatments including mitoxantrone, azathioprine, methotrexate, cyclophosphamide, or mycophenolate mofetil.

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Tampa	Florida	United States	33612
2	Research Site	Des Moines	Iowa	United States	50314
3	Research Site	Milwaukee	Wisconsin	United States	53501
4	Research Site	Edmonton	Alberta	Canada	T6G 2G3
5	Research Site	Muenchen	Bayern	Germany	81675
6	Research Site	Potsdam	Brandenburg	Germany	14471
7	Research Site	Dresden	Sachsen	Germany	01307
8	Research Site	Hamburg		Germany	20249
9	Research Site	Pozzilli	Isernia	Italy	86077
10	Research Site	Napoli		Italy	80131
11	Research Site	Guaynabo		Puerto Rico	00968

Sponsors and Collaborators

• Biogen
• AbbVie

Investigators

• Study Director: Medical Director, Biogen

Study Documents (Full-Text)

• Statistical Analysis Plan - Jun 14, 2018
• Study Protocol - Jul 6, 2016

More Information

Publications

None provided.

• Responsible Party: Biogen
• ClinicalTrials.gov Identifier: NCT02881567
• Other Study ID Numbers: 205MS305; 2016-002820-10
• First Posted: Aug 29, 2016
• Last Update Posted: Sep 27, 2019
• Last Verified: Sep 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Biogen: Multiple Sclerosis; Daclizumab; Tysabri-Switch
• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Daclizumab

Study Results

Participant Flow

Recruitment Details	Participants enrolled in the study at 11 investigative sites in Canada, Germany, Italy, and the United States from 05 April 2017 to 12 September 2018.
Pre-assignment Detail	Participants who discontinued treatment with natalizumab due to safety concerns were enrolled to receive daclizumab 150 milligrams (mg) per 1.0 milliliter (mL).

Arm/Group Title	Daclizumab
Arm/Group Description	Participants previously treated with natalizumab for at least 12 months and who discontinued treatment, received daclizumab 150 mg per 1.0 mL administered subcutaneously once a month for up to 11 months.
Period Title: Overall Study
STARTED	41
COMPLETED	23
NOT COMPLETED	18

Baseline Characteristics

Arm/Group Title	Daclizumab
Arm/Group Description	Participants previously treated with natalizumab for at least 12 months and who discontinued treatment, received daclizumab 150 mg per 1.0 mL administered subcutaneously once a month for up to 11 months.
Overall Participants	41
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.9 (9.71)
Sex: Female, Male (Count of Participants)
Female	28 68.3%
Male	13 31.7%
Race/Ethnicity, Customized (Count of Participants)
White	9 22%
Black or African American	4 9.8%
Not Reported Due to Confidentiality Regulation	27 65.9%
Other (Aboriginal)	1 2.4%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Relapse-free at Month 6
Description	Relapses were defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Examining Neurologist. The Kaplan-Meier estimate of the percentage of participants relapse-free at Month 6 is reported.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

FAS included all participants enrolled in the study.

Arm/Group Title	Daclizumab
Arm/Group Description	Participants previously treated with natalizumab for at least 12 months and who discontinued treatment, received daclizumab 150 mg per 1.0 mL administered subcutaneously once a month for up to 11 months.
Measure Participants	41
Number [percentage of participants]	66.615 162.5%

2. Secondary Outcome

Title	Percentage of Participants Relapse-free at Month 12
Description	Relapses were defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Examining Neurologist.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

The study was terminated. No participants reached the 12-month time point.

Arm/Group Title	Daclizumab
Arm/Group Description	Participants previously treated with natalizumab for at least 12 months and who discontinued treatment, received daclizumab 150 mg per 1.0 mL administered subcutaneously once a month for up to 11 months.
Measure Participants	0

3. Secondary Outcome

Title	Percentage of Participants Experiencing Relapse Requiring Hospitalization and/or Steroid Treatment at Month 12
Description	Relapses were defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Examining Neurologist.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

The study was terminated. No participants reached the 12-month time point.

Arm/Group Title	Daclizumab
Arm/Group Description	Participants previously treated with natalizumab for at least 12 months and who discontinued treatment, received daclizumab 150 mg per 1.0 mL administered subcutaneously once a month for up to 11 months.
Measure Participants	0

4. Secondary Outcome

Title	Annualized Relapse Rate (ARR) at Month 12
Description	Relapses were defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Examining Neurologist. The ARR was calculated by tabulating the total number of relapses experienced in the group divided by the number of days up to the end of Month 12, and the ratio then multiplied by 365.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

The study was terminated. No participants reached the 12-month time point.

Arm/Group Title	Daclizumab
Arm/Group Description	Participants previously treated with natalizumab for at least 12 months and who discontinued treatment, received daclizumab 150 mg per 1.0 mL administered subcutaneously once a month for up to 11 months.
Measure Participants	0

5. Secondary Outcome

Title	Number of Participants With New Gadolinium-Enhanced (Gd+) and T1 Hypointense Lesions at Months 6 and 12
Description	New Gadolinium-Enhanced (Gd+) and T1 Hypointense Lesions were assessed using magnetic resonance imaging (MRI).
Time Frame	Months 6 and 12

Outcome Measure Data

Analysis Population Description

FAS included all participants enrolled in the study. Number Analyzed is the number of participants with available assessment. No data was collected for T1 Hypointense Lesions at Month 6. No participants reached the 12-month time point since the study was terminated.

Arm/Group Title	Daclizumab
Arm/Group Description	Participants previously treated with natalizumab for at least 12 months and who discontinued treatment, received daclizumab 150 mg per 1.0 mL administered subcutaneously once a month for up to 11 months.
Measure Participants	41
Month 6, Gd+ Lesions	3 7.3%

6. Secondary Outcome

Title	Number of Participants With New and Newly Enlarged T2 Hypointense Lesions at Months 6 and 12
Description	New and newly enlarged T2 Hypointense Lesions were measured by MRI.
Time Frame	Months 6 and 12

Outcome Measure Data

Analysis Population Description

FAS included all participants enrolled in the study. Number Analyzed is the number of participants with available assessment. No participants reached the 12-month time point since the study was terminated.

Arm/Group Title	Daclizumab
Arm/Group Description	Participants previously treated with natalizumab for at least 12 months and who discontinued treatment, received daclizumab 150 mg per 1.0 mL administered subcutaneously once a month for up to 11 months.
Measure Participants	41
Month 6	3 7.3%

7. Secondary Outcome

Title	Permanent Discontinuation Rate of Daclizumab at Month 12
Description	Permanent Discontinuation Rate was calculated as the ratio of number of participants who had permanently discontinued daclizumab prior to Month 12 over the total number of participants who received at least 1 dose of daclizumab in the study.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

The study was terminated. No participants reached the 12-month time point.

Arm/Group Title	Daclizumab
Arm/Group Description	Participants previously treated with natalizumab for at least 12 months and who discontinued treatment, received daclizumab 150 mg per 1.0 mL administered subcutaneously once a month for up to 11 months.
Measure Participants	0

8. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An AE can 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. An SAE is any untoward medical occurrence that at any dose results in death or in the view of the Investigator, places the participant at immediate risk of death or requires inpatient hospitalization or prolongation of existing hospitalization or results in persistent or significant disability or results in a birth defect.
Time Frame	First dose of study drug to within 30 days of last dose (up to 11 months)

Outcome Measure Data

Analysis Population Description

Safety Population included all enrolled participants who received at least 1 dose of study drug.

Arm/Group Title	Daclizumab
Arm/Group Description	Participants previously treated with natalizumab for at least 12 months and who discontinued treatment, received daclizumab 150 mg per 1.0 mL administered subcutaneously once a month for up to 11 months.
Measure Participants	41
Participants with AEs	27 65.9%
Participants with SAEs	9 22%

9. Secondary Outcome

Title	Number of Participants With Clinically Relevant Shifts in Laboratory Assessments
Description	Clinical Laboratory assessments were tests of Chemistry and Hematology. The investigator determined if any of the laboratory results were clinically relevant shifts from Baseline.
Time Frame	First dose of study drug to within 30 days of last dose (up to 11 months)

Outcome Measure Data

Analysis Population Description

Safety Population included all enrolled participants who received at least 1 dose of study drug.

Arm/Group Title	Daclizumab
Arm/Group Description	Participants previously treated with natalizumab for at least 12 months and who discontinued treatment, received daclizumab 150 mg per 1.0 mL administered subcutaneously once a month for up to 11 months.
Measure Participants	41
Count of Participants [Participants]	0 0%

Adverse Events

Time Frame	First dose of study drug to within 30 days of last dose (up to 11 months)
Arm/Group Title	Daclizumab
Arm/Group Description	Participants previously treated with natalizumab for at least 12 months and who discontinued treatment, received daclizumab 150 mg per 1.0 mL administered subcutaneously once a month for up to 11 months.
All Cause Mortality
	Daclizumab
	Affected / at Risk (%)	# Events
Total	0/41 (0%)
Serious Adverse Events
	Daclizumab
	Affected / at Risk (%)	# Events
Total	9/41 (22%)
Blood and lymphatic system disorders
Lymphadenopathy	1/41 (2.4%)
Gastrointestinal disorders
Gastrointestinal ulcer	1/41 (2.4%)
Hepatobiliary disorders
Cholelithiasis	1/41 (2.4%)
Infections and infestations
Encephalitis	1/41 (2.4%)
Influenza	1/41 (2.4%)
Oesophageal candidiasis	1/41 (2.4%)
Subcutaneous abscess	1/41 (2.4%)
Musculoskeletal and connective tissue disorders
Rhabdomyolysis	1/41 (2.4%)
Nervous system disorders
Multiple sclerosis relapse	2/41 (4.9%)
Skin and subcutaneous tissue disorders
Drug reaction with eosinophilia and systemic symptoms	1/41 (2.4%)
Other (Not Including Serious) Adverse Events
	Daclizumab
	Affected / at Risk (%)	# Events
Total	23/41 (56.1%)
Blood and lymphatic system disorders
Lymphadenopathy	3/41 (7.3%)
Gastrointestinal disorders
Nausea	5/41 (12.2%)
Vomiting	3/41 (7.3%)
General disorders
Injection site pain	7/41 (17.1%)
Infections and infestations
Influenza	9/41 (22%)
Nasopharyngitis	4/41 (9.8%)
Nervous system disorders
Migraine	3/41 (7.3%)
Multiple sclerosis relapse	7/41 (17.1%)
Psychiatric disorders
Depression	4/41 (9.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.