ESCALATE: Natalizumab as an Efficacy Switch in Participants With Relapsing Multiple Sclerosis After Failure on Other Therapies

• Sponsor: Biogen (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02241785
• Collaborator: (none)
• Enrollment: 47
• Locations: 11
• Arm: 1
• Actual Duration (Months): 19.1
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The primary objective of the study is to determine the efficacy of natalizumab (Tysabri, BG00002) in participants with relapsing forms of multiple sclerosis (MS) who have failed Gilenya or BRACET (Betaseron, Rebif, Avonex, Copaxone, Extavia, Tecfidera) as measured by the proportion of participants with no evidence of disease activity (NEDA) at Year 1. The secondary objectives in this study population are: change in total T1 hypointense and total T2 hyperintense lesion volume; proportion of participants with NEDA at Year 2; evaluation of the impact of natalizumab on annualized relapse rate (ARR); and change in Multiple Sclerosis Impact Scale-29 (MSIS-29) physical impact score.

Condition or Disease	Intervention/Treatment	Phase
Relapsing Multiple Sclerosis	Drug: natalizumab	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 47 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 4 Multicenter, Open-Label, Single Arm Study to Evaluate Switching From BRACET/Gilenya® to Natalizumab in Subjects With Relapsing Forms of Multiple Sclerosis (MS)
• Actual Study Start Date: Sep 30, 2014
• Actual Primary Completion Date: May 2, 2016
• Actual Study Completion Date: May 2, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: natalizumab natalizumab 300 mg intravenously (IV) every 4 weeks	Drug: natalizumab; Administered as specified in the treatment arm; Other Names: BG00002 Tysabri

Outcome Measures

Primary Outcome Measures

1. Proportion of Participants With No Evidence of Disease Activity (NEDA) From Reset Baseline (Week 8) to Week 56 [Reset Baseline (Week 8) to Week 56]

   The proportion of participants with NEDA, defined as follows: no Expanded Disability Status Scale (EDSS) progression (12-week sustained); no relapses; no gadolinium enhancing (Gd+) lesions; no new or enlarging T2 hyperintense lesions over 48 weeks after resetting the Baseline at Week 8 to remove contribution of combined unique active (CUA) lesions that occurred prior to Week 8, when natalizumab was not yet active. The EDSS quantifies disability in 8 functional systems. The final EDSS score is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments.

Secondary Outcome Measures

1. Change in T1 Unenhancing Lesion Volume and T2 Lesion Volume From Baseline (Day -1) to Reset Baseline (Week 8) [Baseline (Day -1) to Reset Baseline (Week 8)]

   As measured by magnetic resonance imaging.

2. Proportion of Participants With NEDA From Week 8 (Reset Baseline) to Week 104 [from Week 8 (Reset Baseline) to Week 104]

   Proportion of participants with NEDA from Week 8 (Reset Baseline) to Week 104 (with no 12-week confirmed EDSS progression determined at Week 116). NEDA was defined as follows: no EDSS progression (12-week sustained); no relapses; no Gd+ lesions; no new or enlarging T2 hyperintense lesions over 48 weeks after resetting the Baseline at Week 8 to remove contribution of CUA lesions that occurred prior to Week 8, when natalizumab was not yet active. The EDSS quantifies disability in 8 functional systems. The final EDSS score is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments.

3. Pre- and Post-Natalizumab Infusion Annualized Relapse Rate (ARR) Comparison at Month 12 [From 12 months prior to natalizumab infusion and 12 months post-natalizumab infusion]

   An MS relapse was defined as the onset of new or recurrent neurological symptoms lasting at least 24 hours, accompanied by new objective abnormalities on a neurological examination, and not explained solely by non-MS processes such as fever, infection, severe stress, or drug toxicity. 95% confidence interval is based on a Poisson regression model.

4. Change in MSIS-29 Physical Impact Scores From Baseline (Day -1) to Reset Baseline (Week 8) [Baseline (Day -1) to Reset Baseline (Week 8)]

   The MSIS-29 is a brief self-administered MS-specific instrument measuring physical (20 items) and mental/psychological (9 items) impact of MS. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 to 100, where high scores indicate worse health.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

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

• Must have documented diagnosis of relapsing MS (McDonald 2010 Criteria [Polman 2011]) at Screening.

• Must have been treated with Gilenya or Betaseron, Rebif, Avonex, Copaxone, Extavia, Tecfidera (BRACET) for at least the 12 months prior to Screening with no interruption of treatment greater than 1 month. Prior treatment with natalizumab is allowed; however, there must be a minimum 1 year since last natalizumab infusion and the Screening visit of this study, and if discontinuation of natalizumab in the past was not due to intolerance, anti-natalizumab antibodies, or efficacy loss.

• Must have had disease activity in the 6 months prior to Screening while on Gilenya or BRACET (as defined by at least 1 gadolinium enhancing lesion OR at least 2 new T2 lesions compared with magnetic resonance imaging done within 12 months of screening OR clinical relapse, or Expanded Disability Status Scale [EDSS] progression of 1 point)

• Must have an EDSS score from 0 to 5.5 inclusive at Screening.

• Must have lymphocyte count that is documented as at or above the lower limit of normal (LLN) by the day before the first Tysabri infusion. If lymphocytes have not returned to LLN or above the day before the first Tysabri infusion (day 0), the subject has screen failed. The subject who screen fails is eligible to undergo Rescreening once; if additional Rescreening is considered, please contact the study medical monitor.

Key Exclusion Criteria:

• History or positive test result at Screening for human immunodeficiency virus.

• History or positive test result at Screening for hepatitis C virus antibody or current hepatitis B infection (defined as positive for hepatitis B surface antigen and/or hepatitis core antibody).

• Prior treatment with natalizumab (either commercially or through a clinical study) within 1 year of Day -1.

• Contraindications to treatment with natalizumab as described in the Prescribing Information for each of the participating countries.

• Known allergy to natalizumab or any of its ingredients, or known to be anti-natalizumab antibody positive.

• Diagnosis of primary progressive MS, secondary progressive MS, and/or progressive-relapsing MS.

• An MS relapse that has occurred within the 30 days prior to Day -1 and/or the subject has not stabilized from a previous relapse prior to Day -1.

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

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

• Clinically severe active infection within 1 month prior to Screening.

• Females breastfeeding, pregnant, or planning to become pregnant; women who are not post-menopausal or surgically sterile who are unwilling to practice contraception; women who have a positive pregnancy test result at Day -1.

• Prior history of immunosuppressant use (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate, cladribine, rituximab) in the last 12 months prior to Screening. Prior history of alemtuzumab use at any point in the past.

NOTE: Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Fullerton	California	United States	92835
2	Research Site	Aurora	Colorado	United States	80045
3	Research Site	Des Moines	Iowa	United States	50314
4	Research Site	Saint Louis	Missouri	United States	63110
5	Research Site	Plainview	New York	United States	11803
6	Research Site	Raleigh	North Carolina	United States	27607-6010
7	Research Site	Akron	Ohio	United States	44320
8	Research Site	Cleveland	Ohio	United States	44195
9	Research Site	Knoxville	Tennessee	United States	37922
10	Research Site	Round Rock	Texas	United States	78681
11	Research Site	Tacoma	Washington	United States	98405

Sponsors and Collaborators

• Biogen

Investigators

• Study Director: Medical Director, Biogen

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Biogen
• ClinicalTrials.gov Identifier: NCT02241785
• Other Study ID Numbers: 101MS409; 2013-005586-39
• First Posted: Sep 16, 2014
• Last Update Posted: Jun 5, 2017
• Last Verified: Apr 1, 2017

• Additional relevant MeSH terms: Multiple Sclerosis; Sclerosis; Natalizumab

Study Results

Participant Flow

Arm/Group Title	Natalizumab
Arm/Group Description	natalizumab 300 mg intravenously (IV) every 4 weeks
Period Title: Overall Study
STARTED	47
COMPLETED	0
NOT COMPLETED	47

Baseline Characteristics

Arm/Group Title	Natalizumab
Arm/Group Description	natalizumab 300 mg IV every 4 weeks
Overall Participants	47
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.9 (10.43)
Sex: Female, Male (Count of Participants)
Female	34 72.3%
Male	13 27.7%

Outcome Measures

1. Primary Outcome

Title	Proportion of Participants With No Evidence of Disease Activity (NEDA) From Reset Baseline (Week 8) to Week 56
Description	The proportion of participants with NEDA, defined as follows: no Expanded Disability Status Scale (EDSS) progression (12-week sustained); no relapses; no gadolinium enhancing (Gd+) lesions; no new or enlarging T2 hyperintense lesions over 48 weeks after resetting the Baseline at Week 8 to remove contribution of combined unique active (CUA) lesions that occurred prior to Week 8, when natalizumab was not yet active. The EDSS quantifies disability in 8 functional systems. The final EDSS score is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments.
Time Frame	Reset Baseline (Week 8) to Week 56

Outcome Measure Data

Analysis Population Description

The limited number of participants enrolled and the early termination of the study resulted in efficacy data not collected, and efficacy outcomes not analyzed, as per the pre-specified plan of analysis.

Arm/Group Title	Natalizumab
Arm/Group Description	natalizumab 300 mg IV every 4 weeks
Measure Participants	0

2. Secondary Outcome

Title	Change in T1 Unenhancing Lesion Volume and T2 Lesion Volume From Baseline (Day -1) to Reset Baseline (Week 8)
Description	As measured by magnetic resonance imaging.
Time Frame	Baseline (Day -1) to Reset Baseline (Week 8)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: participants who received at least 1 infusion of study treatment and had an assessment.

Arm/Group Title	Natalizumab
Arm/Group Description	natalizumab 300 mg IV every 4 weeks
Measure Participants	43
Change in T1 Unenhancing Lesion Volume	0.11 (0.65)
Change in T2 Lesion Volume	0.01 (1.76)

3. Secondary Outcome

Title	Proportion of Participants With NEDA From Week 8 (Reset Baseline) to Week 104
Description	Proportion of participants with NEDA from Week 8 (Reset Baseline) to Week 104 (with no 12-week confirmed EDSS progression determined at Week 116). NEDA was defined as follows: no EDSS progression (12-week sustained); no relapses; no Gd+ lesions; no new or enlarging T2 hyperintense lesions over 48 weeks after resetting the Baseline at Week 8 to remove contribution of CUA lesions that occurred prior to Week 8, when natalizumab was not yet active. The EDSS quantifies disability in 8 functional systems. The final EDSS score is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments.
Time Frame	from Week 8 (Reset Baseline) to Week 104

Outcome Measure Data

Analysis Population Description

The limited number of participants enrolled and the early termination of the study resulted in efficacy data not collected, and efficacy outcomes not analyzed, as per the pre-specified plan of analysis.

Arm/Group Title	Natalizumab
Arm/Group Description	natalizumab 300 mg IV every 4 weeks
Measure Participants	0

4. Secondary Outcome

Title	Pre- and Post-Natalizumab Infusion Annualized Relapse Rate (ARR) Comparison at Month 12
Description	An MS relapse was defined as the onset of new or recurrent neurological symptoms lasting at least 24 hours, accompanied by new objective abnormalities on a neurological examination, and not explained solely by non-MS processes such as fever, infection, severe stress, or drug toxicity. 95% confidence interval is based on a Poisson regression model.
Time Frame	From 12 months prior to natalizumab infusion and 12 months post-natalizumab infusion

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: participants who received at least 1 infusion of study treatment and had an assessment.

Arm/Group Title	Natalizumab
Arm/Group Description	natalizumab 300 mg IV every 4 weeks
Measure Participants	47
12 months pre-natalizumab infusion	1.553
12 months post-natalizumab infusion	0.159

5. Secondary Outcome

Title	Change in MSIS-29 Physical Impact Scores From Baseline (Day -1) to Reset Baseline (Week 8)
Description	The MSIS-29 is a brief self-administered MS-specific instrument measuring physical (20 items) and mental/psychological (9 items) impact of MS. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 to 100, where high scores indicate worse health.
Time Frame	Baseline (Day -1) to Reset Baseline (Week 8)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: participants who received at least 1 infusion of study treatment and had an assessment.

Arm/Group Title	Natalizumab
Arm/Group Description	natalizumab 300 mg IV every 4 weeks
Measure Participants	45
Mean (Standard Deviation) [units on a scale]	-2.53 (12.42)

Adverse Events

Time Frame	From Screening through end of study. Duration of study treatment was up to 13 months.
Adverse Event Reporting Description	SAEs only were collected per protocol. Events were not coded by MedDRA.
Arm/Group Title	Natalizumab
Arm/Group Description	natalizumab 300 mg IV every 4 weeks
All Cause Mortality
	Natalizumab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Natalizumab
	Affected / at Risk (%)	# Events
Total	2/47 (4.3%)
General disorders
Non-cardiac chest pain	1/47 (2.1%)	1
Nervous system disorders
Syncope	1/47 (2.1%)	1
Other (Not Including Serious) Adverse Events
	Natalizumab
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)

Limitations/Caveats

As a result of early study termination and limited available data, no meaningful conclusions can be drawn.

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.