Efficacy and Safety of BIIB033 (Opicinumab) as an Add-on Therapy to Disease-Modifying Therapies (DMTs) in Relapsing Multiple Sclerosis (MS)

Multiple Sclerosis Clinical Trial

— AFFINITY  

Official title:

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study With Optional Open-Label Extension in Subjects With Relapsing Multiple Sclerosis to Evaluate the Efficacy and Safety of BIIB033 as an Add-On Therapy to Anti-Inflammatory Disease-Modifying Therapies

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03222973
• Other study ID #: 215MS202
• Secondary ID: 2017-001224-22
• Status: Terminated
• Phase: Phase 2
• Start date: November 15, 2017
• Est. completion date: February 12, 2021

Study information

• Verified date: March 2022
• Source: Biogen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of Part 1 of this study is to evaluate the effects of BIIB033 versus placebo on disability improvement over 72 weeks. The primary objective of Part 2 of this study is to evaluate the long-term safety profile of BIIB033 as an add-on therapy in participants with MS.

The secondary objective of Part 1 is to evaluate the effects of BIIB033 versus placebo on additional measures of disability improvement. The secondary objective of Part 2 is to investigate long-term efficacy (disability improvement) and additional safety measures of BIIB033 as an add-on therapy in participants with MS.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 263
• Est. completion date: February 12, 2021
• Est. primary completion date: February 12, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 58 Years

Eligibility

Key Inclusion Criteria: Part 1

• Baseline Expanded Disability Status Scale (EDSS) of 2.0 to 6.0, have a diagnosis of relapsing-remitting multiple sclerosis (RRMS) per the 2010 McDonald's criteria or onset of secondary progressive multiple sclerosis (SPMS) per the Lublin and Reingold criteria, and should have experienced their first MS symptom(s) within the previous 20 years.

• Subjects must have experienced at least 1 of the following within 24 months prior to Day 1/Baseline: a clinical relapse (but not within 24 weeks prior to Day 1/Baseline), gadolinium-enhancing lesions on brain or spinal cord magnetic resonance imaging (MRI), or new T2 lesion(s) on brain or spinal cord MRI.

• Subjects must be on a stable dose of a protocol-specified anti-inflammatory disease-modifying therapy (DMT) (IFNß [Avonex, Plegridy, Betaferon/Betaseron, or Rebif], dimethyl fumarate (DMF) [Tecfidera], or natalizumab [Tysabri]) for at least 24 weeks prior to enrollment.

• In addition, subjects must have met protocol-defined MRI characteristics using magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) sequences at Screening/Baseline.

Key Inclusion Criteria: Part 2

-Subjects who complete study treatment (BIIB033 or placebo) at Part 1/Week 72 Visit.

Key Exclusion Criteria: Part 1

• Primary progressive MS

• An MS relapse that has occurred within 24 weeks prior to Day 1/Baseline or the subject has not stabilized from a previous relapse at the time of Screening.

• Treatment with any chemotherapeutic agents (e.g., mitoxantrone, cyclophosphamide, cladribine), cell-depleting monoclonal antibodies (mAbs) (e.g., rituximab, ocrelizumab, alemtuzumab), total lymphoid irradiation, T-cell or T-cell receptor vaccination, or teriflunomide within 1 year prior to Day 1/Baseline.

• Treatment with other anti-inflammatory DMTs (e.g., GA, fingolimod, daclizumab) or plasmapheresis within 24 weeks prior to Day1/Baseline.

• Treatment with Botox for limb spasticity within 24 weeks before Day 1/Baseline.

• Contraindications to MRI, for example, presence of pacemakers or other implanted metal devices (excluding dental braces), an allergy to gadolinium renal impairment, or claustrophobia that cannot be medically managed.

• History of human immunodeficiency virus or other immunodeficient conditions.

• History of malignancy; however, subjects with a history of excised or treated basal cell carcinoma or fewer than 3 squamous cell carcinomas are eligible to participate in this study.

Key Exclusion Criteria: Part 2

• Subjects who did not complete study treatment in Part 1/Week 72 Visit

• Subjects who have a duration >12 weeks between their Part 1/Week 72 Visit and Part 2/Day 1.

• Contraindications to MRI, for example, presence of pacemakers or other implanted metal devices (excluding dental braces), an allergy to Gd, renal impairment, or claustrophobia that cannot be medically managed.

• History of human immunodeficiency virus or other immunodeficient conditions not related to DMT treatment.

• History of malignancy unless enrollment is approved by the Sponsor; subjects with a history of excised or treated basal cell carcinoma or fewer than 3 squamous cell carcinomas are eligible to participate in this study.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply

Related Conditions & MeSH terms

• Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• BIIB033 (opicinumab)
Administered as specified in the treatment arm
• Placebo
Administered as specified in the treatment arm

Locations

Country	Name	City	State
Australia	Research Site	Box Hill	Victoria
Australia	Research Site	Clayton	Victoria
Australia	Research Site	Heidelberg	Victoria
Australia	Research Site	Melbourne	Victoria
Australia	Research Site	New Lambton Heights
Australia	Research Site	Parkville	Victoria
Australia	Research Site	Westmead
Belgium	Research Site	Brugge
Belgium	Research Site	Bruxelles
Belgium	Research Site	Bruxelles
Belgium	Research Site	Gent
Belgium	Research Site	La Louvière
Belgium	Research Site	Leuven
Belgium	Research Site	Roeselare
Canada	Research Site	Edmonton	Alberta
Canada	Research Site	Gatineau	Quebec
Canada	Research Site	Longueuil	Quebec
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Ottawa	Ontario
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Vancouver	British Columbia
Canada	Research Site	Victoria	British Columbia
Czechia	Research Site	Brno
Czechia	Research Site	Brno
Czechia	Research Site	Hradec Kralove
Czechia	Research Site	Jihlava
Czechia	Research Site	Pardubice
Czechia	Research Site	Praha 2
France	Research Site	Amiens Cedex 1	Somme
France	Research Site	Bordeaux	Gironde
France	Research Site	Bron Cedex	Rhone
France	Research Site	Clermont-Ferrand	Puy De Dome
France	Research Site	Lille	Nord
France	Research Site	Montpellier	Herault
France	Research Site	Nantes Cedex 1	Loire Atlantique
France	Research Site	Nimes	Gard
France	Research Site	Paris
France	Research Site	Strasbourg Cedex	Bas Rhin
France	Research Site	Toulouse	Haute Garonne
Germany	Research Site	Berlin
Germany	Research Site	Bochum	North Rhine-Westphalia
Germany	Research Site	Dresden	Saxony
Germany	Research Site	Duesseldorf	North Rhine-Westphalia
Germany	Research Site	Freiburg	Baden Wuerttemberg
Germany	Research Site	Muenchen	Bavaria
Germany	Research Site	Muenster
Germany	Research Site	Trier	Rhineland-Palatinate
Germany	Research Site	Tuebingen	Baden Wuerttemberg
Germany	Research Site	Ulm	Baden Wuerttemberg
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Esztergom
Hungary	Research Site	Kistarcsa
Hungary	Research Site	Pecs
Israel	Research Site	Ramat Gan
Italy	Research Site	Cefalù	Palermo
Italy	Research Site	Genova
Italy	Research Site	Messina
Italy	Research Site	Milano
Italy	Research Site	Milano
Italy	Research Site	Montichiari	Brescia
Italy	Research Site	Napoli
Italy	Research Site	Napoli
Italy	Research Site	Napoli
Italy	Research Site	Pisa
Italy	Research Site	Pozzilli	Isernia
Italy	Research Site	Roma
Italy	Research Site	Verona
Netherlands	Research Site	Geleen
Poland	Research Site	Bydgoszcz
Poland	Research Site	Gdansk
Poland	Research Site	Katowice
Poland	Research Site	Katowice
Poland	Research Site	Krakow
Poland	Research Site	Lodz
Poland	Research Site	Lublin
Poland	Research Site	Szczecin
Poland	Research Site	Warszawa
Poland	Research Site	Zabrze
Spain	Research Site	Barakaldo	Vizcaya
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	Cordoba
Spain	Research Site	Madrid
Spain	Research Site	Majadahonda	Madrid
Spain	Research Site	Salt	Girona
Spain	Research Site	Sevilla
Switzerland	Research Site	Aarau
Switzerland	Research Site	Basel
Switzerland	Research Site	Bern
Switzerland	Research Site	Lugano
Switzerland	Research Site	Zurich
United Kingdom	Research Site	Brighton
United Kingdom	Research Site	Exeter	Devon
United Kingdom	Research Site	Glasgow	Strathclyde
United Kingdom	Research Site	Leeds	West Yorkshire
United Kingdom	Research Site	Liverpool	Merseyside
United Kingdom	Research Site	London	Greater London
United Kingdom	Research Site	London	Greater London
United Kingdom	Research Site	Newcastle Upon Tyne	Tyne & Wear
United Kingdom	Research Site	Nottingham	Nottinghamshire
United Kingdom	Research Site	Oxford	Oxfordshire
United Kingdom	Research Site	Plymouth	Devon
United Kingdom	Research Site	Salford	Greater Manchester
United Kingdom	Research Site	Sheffield
United Kingdom	Research Site	Swansea
United States	Research Site	Atlanta	Georgia
United States	Research Site	Baltimore	Maryland
United States	Research Site	Berkeley	California
United States	Research Site	Boston	Massachusetts
United States	Research Site	Boston	Massachusetts
United States	Research Site	Centennial	Colorado
United States	Research Site	Chicago	Illinois
United States	Research Site	Chicago	Illinois
United States	Research Site	Columbus	Ohio
United States	Research Site	Cullman	Alabama
United States	Research Site	Dallas	Texas
United States	Research Site	Dayton	Ohio
United States	Research Site	Durham	North Carolina
United States	Research Site	Farmington Hills	Michigan
United States	Research Site	Fort Collins	Colorado
United States	Research Site	Freehold	New Jersey
United States	Research Site	Gilbert	Arizona
United States	Research Site	Houston	Texas
United States	Research Site	Knoxville	Tennessee
United States	Research Site	Las Vegas	Nevada
United States	Research Site	Latham	New York
United States	Research Site	Lexington	Kentucky
United States	Research Site	Lexington	Massachusetts
United States	Research Site	Long Beach	California
United States	Research Site	Memphis	Tennessee
United States	Research Site	Minneapolis	Minnesota
United States	Research Site	New York	New York
United States	Research Site	Newport Beach	California
United States	Research Site	Oklahoma City	Oklahoma
United States	Research Site	Orange	California
United States	Research Site	Orem	Utah
United States	Research Site	Overland Park	Kansas
United States	Research Site	Patchogue	New York
United States	Research Site	Pittsburgh	Pennsylvania
United States	Research Site	Portland	Oregon
United States	Research Site	Raleigh	North Carolina
United States	Research Site	Rochester	New York
United States	Research Site	Round Rock	Texas
United States	Research Site	Saint Louis	Missouri
United States	Research Site	Saint Louis	Missouri
United States	Research Site	Salt Lake City	Utah
United States	Research Site	Seattle	Washington
United States	Research Site	Seattle	Washington
United States	Research Site	Stamford	Connecticut
United States	Research Site	Stony Brook	New York
United States	Research Site	Sunrise	Florida
United States	Research Site	Tampa	Florida
United States	Research Site	Teaneck	New Jersey
United States	Research Site	Washington	District of Columbia
United States	Research Site	Wellesley	Massachusetts
United States	Research Site	Willow Grove	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Biogen

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Czechia,  France,  Germany,  Hungary,  Israel,  Italy,  Netherlands,  Poland,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1: Overall Response Score	Overall Response Score is a multicomponent score based on 4 components: Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test in the dominant hand (9HPT-D), and 9HPT in the nondominant hand (9HPT-ND). Overall Score was sum of 4 components at each visit and ranges from +4 (improvement) to -4 (worsening). At each visit, each component is given a score relative to baseline (BL): -1 if threshold is met for worsening, 0 if no changes meet threshold criteria, or +1 if threshold is met for improvement. For T25FW and 9HPT improvement is =15% decrease in time from BL and worsening is =15% increase in time from BL. For EDSS, improvement is: =1.0-point decrease in EDSS from a BL score of =6.0, and worsening is defined as a =1-point increase from a BL score of =5.5 or a =0.5-point increase from a BL score equal to 6.0. Positive Overall Response Score indicated that there was improvement in more components than there was worsening.	Part 1: Baseline to Week 72
Primary	Part 2: Number of Participants Experiencing Adverse Events (AEs) 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 laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly.	Part 2: Baseline to Week 169
Secondary	Part 1: Percentage of Participants With 12-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND	EDSS measures disability status over time in MS on a scale ranging from 0 to 10, with higher scores indicating more disability. For EDSS, improvement is defined as a =1.0-point decrease in EDSS from a BL score of =6.0. T25FW is a quantitative mobility and leg function performance test based on a timed walk over 25 feet that is averaged between two completed trials. Longer time indicates slower walking. The 9HPT is a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs. Longer time indicates poorer upper limb function. For T25FW and 9HPT =15% decrease in time from BL indicates improvement.	Part 1: Baseline to Week 72
Secondary	Part 1: Percentage of Participants With 12-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, or 3-Second Paced Auditory Serial Addition Test (PASAT-3)	EDSS measures disability status over time in MS (scale range: 0-10), higher scores=more disability and improvement defined as =1.0-point decrease in EDSS from BL score =6.0. T25FW is quantitative mobility and leg function performance test, where timed walk over 25 feet that is averaged between two completed trials. Longer time=slower walking. 9HPT is quantitative test of upper extremity function, measures time to place 9 pegs into 9 holes and then remove pegs. Longer time=poorer upper limb function. PASAT assesses auditory information processing speed. In 3-second PASAT, numbers are presented at a rate of 1 every 3 seconds with scores (range 0-120), higher scores=better working memory. For T25FW and 9HPT =15% decrease in time from BL is improvement. For PASAT =15% increase from BL is improvement.	Part 1: Baseline to Week 72
Secondary	Part 1: Percentage of Participants With 12-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND, and Without Confirmed Worsening in Any of the 4 Assessments During the 72 Weeks of the Study	EDSS measures disability status over time in MS on a scale ranging from 0 to 10, with higher scores indicating more disability. For EDSS, improvement is defined as a =1.0-point decrease in EDSS from a BL score of =6.0, and worsening is defined as a =1-point increase from a BL score of =5.5 or a =0.5-point increase from a BL score equal to 6.0. T25FW is a quantitative mobility and leg function performance test based on a timed walk over 25 feet that is averaged between two completed trials. Longer time indicates slower walking. The 9HPT is a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs. Longer time indicates poorer upper limb function. For T25FW and 9HPT =15% decrease in time from BL indicates improvement and =15% increase in time from BL indicates worsening.	Part 1: Baseline to Week 72
Secondary	Part 1: Percentage of Participants With 12-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, and Symbol Digit Modalities Test (SDMT)	EDSS measures disability status over time in MS on a scale (range 0-10), higher scores=more disability. For EDSS, improvement is: a =1.0-point decrease in EDSS from a BL score of =6.0. T25FW is a quantitative mobility and leg function performance test based on a timed walk over 25 feet that is averaged between two completed trials. Longer time=slower walking. 9HPT is quantitative test of upper extremity function that measures time it takes to place 9 pegs into 9 holes and then remove pegs. Longer time=poorer upper limb function. For T25FW and 9HPT =15% decrease in time from BL indicates improvement. The SDMT measures time to pair abstract geometric symbols with specific numbers. The score is the number of correctly coded items (range 0-110) in 90 seconds, higher scores=better outcome. Improvement is: =4-point increase from BL.	Part 1: Baseline to Week 72
Secondary	Part 1: Percentage of Participants With 12-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND (20% Thresholds for T25FW and 9HPT)	EDSS measures disability status over time in MS on a scale ranging from 0 to 10, with higher scores indicating more disability. For EDSS, improvement is defined as a =1.0-point decrease in EDSS from a BL score of =6.0. T25FW is a quantitative mobility and leg function performance test based on a timed walk over 25 feet that is averaged between two completed trials. Longer time indicates slower walking. The 9HPT is a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs. Longer time indicates poorer upper limb function. For T25FW and 9HPT =15% decrease in time from BL indicates improvement.	Part 1: Baseline to Week 72
Secondary	Part 2: Overall Response Score		Part 2: Baseline to Week 96
Secondary	Part 2: Percentage of Participants With 24-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND		Part 2: Baseline to Week 108
Secondary	Part 2: Percentage of Participants With 24-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, or PASAT-3		Part 2: Baseline to Week 108
Secondary	Part 2: Percentage of Participants With 24-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND, and Without Confirmed Worsening in Any of the 4 Assessments During the 96 Weeks of the Study		Part 2: Baseline to Week 96
Secondary	Part 2: Percentage of Participants With 24-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, and SDMT		Part 2: Baseline to Week 108
Secondary	Part 2: Percentage of Participants With 24-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND (20% Thresholds for T25FW and 9HPT)		Part 2: Baseline to Week 108
Secondary	Part 2: Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values	Laboratory assessments including hematology and blood chemistry were evaluated for safety. Criteria for abnormality: In 10^9/liter (L) [white blood cells <3.0/>16, neutrophils <1.5/ >13.5, lymphocytes <0.8/ >12, monocytes >2.5, eosinophils >1.6, basophils >1.6, platelets <=75/ >=700], hemoglobin <=95 [female (F)] or <=115 [male (M)] or >=175 (F) or >=190 (M) gram per liter (g/L), hematocrit <=32 (F) or <=37 (M) or >=54 (F) or >=60 (M) percentage (%), red blood cells <=3.5/ >=6.4 10^12/L, in millimoles per liter (mmol/L) [sodium <=126/ >=156, potassium <=3/ >=6, chloride <=90/ >=118, bicarbonate <=16/ >=35, calcium <=2/ >=3, phosphorous <=0.5491/ >=1.7119, glucose (non-fasting) <=2.2/>=13.75], AST/SGOT >=3x upper limit of normal (ULN), ALT/SGPT >=3xULN, alkaline phosphatase >=3xULN, creatinine >=1.5xULN, total bilirubin >=1.5xULN, total protein <=45/ >=100 g/L, albumin <=25 g/L, uric acid >=501.5 (F)/>=619.5 (M) micromole (umol)/L	Part 2: Baseline to Week 96
Secondary	Part 2: Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Values	The ECG result was classified as "normal", "abnormal", "abnormal, not adverse event", or "abnormal, adverse event". Shift to 'abnormal, not adverse event' included shift from normal or unknown to 'abnormal, not adverse event'. Shift to 'abnormal, adverse event' included shift from normal or unknown to 'abnormal, adverse event'.	Part 2: Baseline to Week 96
Secondary	Part 2: Percentage of Participants With Potentially Clinically Significant Abnormal Vital Signs Values	Vital sign measurements including temperature, pulse rate (supine), systolic blood pressure (BP) and diastolic (supine) BP were evaluated for safety. Criteria for abnormalities: Temperature: >38 degree celsius (?C) or >=1 ?C increase from baseline (BL); Pulse: [>100 beats per minute (bpm) or increase from BL of >30 bpm] or (<40 bpm or decrease from BL of >20 bpm); Systolic BP: [>160 millimeters of mercury (mmHg)/increase from BL of >40 mmHg] or (<90 mmHg/decrease from BL of >30 mmHg); Diastolic BP: (>100 mmHg/increase from BL of >30 mmHg) or (<45 mmHg/decrease from BL of >20 mmHg).	Part 2: Baseline to Week 96
Secondary	Part 2: Percentage of Participants With Potentially Clinically Significant Abnormal Weight Values	Criteria for abnormality was defined as a >7% increase or decrease in weight at the specified time point.	Part 2: Baseline, Week 12, 24, 36, 48, 72 and 96
Secondary	Part 2: Number of Participants With Columbia Suicide Severity Rating Scale (C-SSRS) Score at Any Post-Baseline Visit	C-SSRS systematically assess suicidal ideation and behavior rating scale. It rates an individual's degree of suicidal ideation on a scale, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent and behaviors". 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.	Part 2: Baseline to Week 96