Efficacy and Safety Study of Peginterferon Beta-1a in Participants With Relapsing Multiple Sclerosis (ADVANCE)

A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study to Evaluate the Efficacy and Safety of PEGylated Interferon Beta-1a (BIIB017) in Subjects With Relapsing Multiple Sclerosis

The primary objective of this study is to determine the efficacy of peginterferon beta-1a in reducing the annualized relapse rate (ARR) in participants with relapsing multiple sclerosis (RMS) at 1 year. The secondary objectives of this study are to determine whether peginterferon beta-1a, at 1 year when compared with placebo, is effective in reducing the total number of new or newly enlarging T2 hyperintense lesions on brain magnetic resonance imaging (MRI) scans, reducing the proportion of participants who relapse, and slowing the progression of disability.

Study Overview

• Status: Completed
• Conditions: Relapsing Multiple Sclerosis
• Intervention / Treatment: Drug: BIIB017 (peginterferon beta-1a); Drug: Placebo

Detailed Description

This is a global multicenter, randomized, double-blind, parallel-group, placebo-controlled study. The treatment period is 96 weeks (2 years) in duration. Treatment Year 1 (Week 0 to Week 48) is referred to as the placebo-controlled treatment period of the study. At the beginning of Treatment Year 1, participants were randomized to receive placebo, peginterferon beta-1a 125 μg every 2 weeks, or peginterferon beta-1a 125 μg every 4 weeks. At the end of Treatment Year 1, participants in the placebo group were re-randomized to receive peginterferon beta-1a treatment so that during treatment Year 2 (Weeks 48 to Week 96) all participants received peginterferon beta-1a 125 μg every 2 or every 4 weeks. Per protocol, all primary and secondary endpoints pertain to Year 1 data.

• Study Type: Interventional
• Enrollment (Actual): 1516
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • 'Sint-Truiden, Belgium, 3800
    • Research Site
  • Bruxelles, Belgium, 1200
    • Research Site
• Bulgaria
  • Plovdiv, Bulgaria, 4002
    • Research Site
  • Sofia, Bulgaria, 1431
    • Research Site
  • Sofia, Bulgaria, 1407
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  • Sofia, Bulgaria, 1527
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  • Sofia, Bulgaria, 1309
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  • Sofia, Bulgaria, 1606
    • Research Site
  • Sofia, Bulgaria, 1113
    • Research Site
• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • Research Site
  • Quebec
    • Montreal, Quebec, Canada, H2L4M1
      • Research Site
• Chile
  • Santiago, Chile, 8207257
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• Colombia
  • Bogota, Colombia
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  • Atlantico
    • Barranquilla, Atlantico, Colombia
      • Research Site
  • Cundinamarca
    • Bogota, Cundinamarca, Colombia
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• Croatia
  • Osijek, Croatia, 31000
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  • Zagreb, Croatia, 10000
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• Czech Republic
  • Brno, Czech Republic, 62500
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  • Olomouc, Czech Republic, 77520
    • Research Site
  • Ostrava, Czech Republic, 70852
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  • Ostrava - Vitkovice, Czech Republic, 70200
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  • Ostrava-Poruba, Czech Republic, 70300
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  • Praha 2, Czech Republic, 12808
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  • Praha 5, Czech Republic, 15006
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  • Teplice, Czech Republic, 41529
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• Estonia
  • Parnu, Estonia, EE 80010
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  • Tallinn, Estonia, EE 10617
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  • Tartu, Estonia, EE 51014
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• France
  • Amiens, France, 80054
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  • Clermont-Ferrand, France, 63003
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  • Lyon, France, 69394
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  • Marseille, France, 13385
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  • Nice, France, 6002
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• Georgia
  • Tbilisi, Georgia, 112
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  • Tbilisi, Georgia, 179
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  • Tbilisi, Georgia, 186
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  • Tbilisi, Georgia, 141
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• Germany
  • Bayreuth, Germany, 95445
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  • Berlin, Germany, 10713
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  • Berlin, Germany, 14163
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  • Bochum, Germany, 44791
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  • Erbach, Germany, 64711
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  • Erlangen, Germany, 91054
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  • Hamburg, Germany, 20099
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  • Hannover, Germany, 30559
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  • Koln, Germany, 50935
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  • Leipzig, Germany, 04103
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  • Marburg, Germany, 35043
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  • Munchen, Germany, 80331
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  • Munster, Germany, 48149
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  • Prien, Germany, 83209
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  • Ulm, Germany, 89079
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  • Westerstede, Germany, 26655
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• Greece
  • Athens, Greece, 11521
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  • Athens, Greece, 11525
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  • Thessaloniki, Greece, 57010
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• India
  • Bangalore, India, 560017
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  • Mangalore, India, 575018
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  • Navi Mumbai, India, 400703
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  • Nehru Nagar, India, 110065
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  • Delhi
    • New Delhi, Delhi, India, 110029
      • Research Site
    • New Delhi, Delhi, India, 110060
      • Research Site
    • Saket, Delhi, India, 110017
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  • Gujarat
    • Ahmedabad, Gujarat, India, 380006
      • Research Site
    • Rajkot, Gujarat, India, 360001
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  • Karnataka
    • Bangalore, Karnataka, India, 560043
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  • Madhyr Pradesh
    • Indore, Madhyr Pradesh, India, 452018
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  • Maharashtra
    • Mumbai, Maharashtra, India, 400026
      • Research Site
    • Nagpur, Maharashtra, India, 440010
      • Research Site
    • Nasik, Maharashtra, India, 422004
      • Research Site
    • Pune, Maharashtra, India, 411004
      • Research Site
    • Pune, Maharashtra, India, 411030
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  • Punjab
    • Amritsar, Punjab, India, 143001
      • Research Site
  • Rajasthan
    • Jaipur, Rajasthan, India, 302004
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  • Tamil Nadu
    • Chennai, Tamil Nadu, India, 600017
      • Research Site
    • Coimbatore, Tamil Nadu, India, 641014
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  • West Bengal
    • Kolkata, West Bengal, India, 700068
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• Latvia
  • Riga, Latvia, LV 1005
    • Research Site
• Mexico
  • Aquas Calientes, Mexico, 20127
    • Research Site
  • Chihuahua, Mexico, 31203
    • Research Site
  • Mexico City, Mexico, 10700
    • Research Site
  • Mexico DF, Mexico, 03310
    • Research Site
  • Monterrey, Nuevo Leon, Mexico, 64710
    • Research Site
  • Tijuana, Baja California, Mexico, 22320
    • Research Site
• Netherlands
  • Breda, Netherlands, 4818CK
    • Research Site
  • Nieuwegein, Netherlands, 3435CM
    • Research Site
• New Zealand
  • Auckland, New Zealand, 1023
    • Research Site
  • Christchurch, New Zealand
    • Research Site
  • Dunedin, New Zealand
    • Research Site
• Peru
  • Lima, Peru, LIMA 01
    • Research Site
  • Lima, Peru, LIMA 1
    • Research Site
  • Lima, Peru, LIMA 21
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  • San Isidro, Peru, Lima 27
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• Poland
  • Bialystok, Poland, 15276
    • Research Site
  • Bialystok, Poland, 15402
    • Research Site
  • Bydgoszcz, Poland, 85681
    • Research Site
  • Gdansk, Poland, 80299
    • Research Site
  • Gdansk, Poland, 80803
    • Research Site
  • Gdansk, Poland, 80952
    • Research Site
  • Katowice, Poland, 40662
    • Research Site
  • Katowice, Poland, 40650
    • Research Site
  • Katowice, Poland, 40684
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  • Konskie, Poland, 26200
    • Research Site
  • Krakow, Poland, 31505
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  • Krakow, Poland, 31637
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  • Krakow, Poland, 31826
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  • Lodz, Poland, 90153
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  • Lublin, Poland, 20954
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  • Lublin, Poland, 20718
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  • Olsztyn, Poland, 10082
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  • Plewiska, Poland, 62064
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  • Poznan, Poland, 60355
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  • Poznan, Poland, 61853
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  • Szczecin, Poland, 71252
    • Research Site
  • Szczecin, Poland, 70215
    • Research Site
  • Warsawa, Poland, 00851
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  • Warsawa, Poland, 02957
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  • Warsawa, Poland, 04141
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  • Warsawa, Poland, 04749
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  • Wroclaw, Poland, 50556
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  • Zabrze, Poland, 41800
    • Research Site
• Romania
  • Brasov, Romania, 500123
    • Research Site
  • Bucharest, Romania, 50098
    • Research Site
  • Campulung, Romania, 115100
    • Research Site
  • Iasi, Romania, 700656
    • Research Site
  • Sibiu, Romania, 550166
    • Research Site
  • Targu Mures, Romania, 540136
    • Research Site
• Russian Federation
  • Chelyabinsk, Russian Federation, 454136
    • Research Site
  • Kaluga, Russian Federation, 248007
    • Research Site
  • Kazan, Russian Federation, 420021
    • Research Site
  • Krasnodar, Russian Federation, 350012
    • Research Site
  • Kursk, Russian Federation, 305007
    • Research Site
  • Moscow, Russian Federation, 125367
    • Research Site
  • Moscow, Russian Federation, 107150
    • Research Site
  • Moscow, Russian Federation, 127018
    • Research Site
  • Moscow, Russian Federation, 119021
    • Research Site
  • Novosibirsk, Russian Federation, 630007
    • Research Site
  • Perm, Russian Federation, 614990
    • Research Site
  • Rostov-on-Don, Russian Federation, 344015
    • Research Site
  • Smolensk, Russian Federation, 214018
    • Research Site
  • Tomsk, Russian Federation, 634050
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  • Ufa, Russian Federation, 450005
    • Research Site
• Serbia
  • Belgrade, Serbia, 11000
    • Research Site
  • Kragujevac, Serbia, 34000
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  • Nis, Serbia, 18000
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• Spain
  • Cordoba, Spain, 14008
    • Research Site
  • Madrid, Spain, 28046
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  • Madrid, Spain, 28041
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  • Malaga, Spain, 29010
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  • Sevilla, Spain, 41071
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• Ukraine
  • Chernivtsi, Ukraine, 58018
    • Research Site
  • Dnipropetrovsk, Ukraine, 49027
    • Research Site
  • Donetsk, Ukraine, 83099
    • Research Site
  • Kharkiv, Ukraine, 61103
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  • Kharkiv, Ukraine, 61068
    • Research Site
  • Kyiv, Ukraine, 3110
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  • Kyiv, Ukraine, 4107
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  • Odesa, Ukraine, 65025
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  • Poltava, Ukraine, 26011
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  • Simferopol, Ukraine, 95017
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  • Ternopil, Ukraine, 46027
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  • Vinnytsya, Ukraine, 21005
    • Research Site
• United Kingdom
  • London, United Kingdom, E1 1BB
    • Research Site
  • Nottingham, United Kingdom, NG7 2UH
    • Research Site
  • Salford, United Kingdom, M6 8HD
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  • Sheffield, United Kingdom, S10 2JF
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• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Research Site
  • Florida
    • Ponte Vedra Beach, Florida, United States, 32082 4040
      • Research Site
  • Georgia
    • Atlanta, Georgia, United States, 30327
      • Research Site
  • Iowa
    • Des Moines, Iowa, United States, 50314
      • Research Site
  • Kentucky
    • Lexington, Kentucky, United States, 40513
      • Research Site
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Research Site
  • New Jersey
    • Teaneck, New Jersey, United States, 07666
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  • North Carolina
    • Raleigh, North Carolina, United States, 27607 6520
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  • Ohio
    • Akron, Ohio, United States, 44320
      • Research Site
    • Cleveland, Ohio, United States, 44195
      • Research Site
  • Tennessee
    • Franklin, Tennessee, United States, 37064
      • Research Site
  • Texas
    • Round Rock, Texas, United States, 78681
      • Research 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:

• Must have a confirmed diagnosis of relapsing multiple sclerosis (RMS), as defined by McDonald criteria 1 through 4 (Polman, 2005)
• Must have an EDSS score between 0.0 and 5.0.
• Must have experienced at least 2 relapses that have been medically documented within the last 3 years with at least one occurring in the last 12 months

Key Exclusion Criteria:

• Other chronic disease of immune system, malignancies, urologic, pulmonary, gastrointestinal disease
• Pregnant or nursing women
• Prior treatment with interferon could not exceed 4 weeks and subjects must have discontinued interferon treatment 6 months prior to Baseline

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo every 2 weeks for 48 weeks followed by 125 µg peginterferon beta-1a subcutaneously every 2 or 4 weeks for 48 weeks.	Drug: BIIB017 (peginterferon beta-1a); Supplied as a liquid in pre-filled syringes to deliver 0.5 mL of 0.25 mg/mL (125 µg dose), self-administered by subcutaneous injection.; Other Names: Plegridy; PEGylated interferon beta-1a; PEG IFN ß-1a; Drug: Placebo; Matched placebo provided in pre-filled syringes, to deliver 0.5 mL self-administered by subcutaneous injection.
Experimental: Peginterferon Beta-1a Q2W; 125 µg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 96 weeks.	Drug: BIIB017 (peginterferon beta-1a); Supplied as a liquid in pre-filled syringes to deliver 0.5 mL of 0.25 mg/mL (125 µg dose), self-administered by subcutaneous injection.; Other Names: Plegridy; PEGylated interferon beta-1a; PEG IFN ß-1a
Experimental: Peginterferon Beta-1a Q4W; 125 µg peginterferon beta-1a subcutaneously every 4 weeks (Q4W) for 96 weeks. Participants received a placebo injection 2 weeks after each active injection (in order to maintain the blind with Q2W arm).	Drug: BIIB017 (peginterferon beta-1a); Supplied as a liquid in pre-filled syringes to deliver 0.5 mL of 0.25 mg/mL (125 µg dose), self-administered by subcutaneous injection.; Other Names: Plegridy; PEGylated interferon beta-1a; PEG IFN ß-1a; Drug: Placebo; Matched placebo provided in pre-filled syringes, to deliver 0.5 mL self-administered by subcutaneous injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized Relapse Rate (ARR) at 1 Year	A relapse is defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting for at least 24 hours, and accompanied by new objective neurologic findings. Only relapses confirmed by an independent neurology evaluation committee (INEC) are included in the analysis. Data after participants switched to alternative multiple sclerosis (MS) medications are excluded. Data were analyzed using negative binomial regression, adjusted for baseline Expanded Disability Status Scale (EDSS) score (< 4 versus ≥ 4), baseline age (< 40 versus ≥ 40 years), and baseline relapse rate (number of relapses in 3 years prior to study entry divided by 3).	1 Year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of New Or Newly Enlarging T2 Hyperintense Lesions at 1 Year	Number of new or newly enlarging T2 hyperintense lesions on brain magnetic resonance imaging (MRI) scans. Data observed after participants switched to alternative MS medications are excluded. Adjusted mean is based on negative binomial regression, adjusted for baseline number of T2 lesions.	1 Year
Proportion of Participants Relapsed at 1 Year	A relapse is defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting for at least 24 hours, and accompanied by new objective neurologic findings. Only relapses confirmed by INEC were included in the analysis. Estimated proportion of participants relapsed is based on the Kaplan-Meier product limit method.	Year 1
Estimated Proportion of Participants With Sustained Disability Progression at 1 Year	Sustained disability progression is defined as: at least a 1.0 point increase on the EDSS from baseline EDSS ≥ 1.0 that is sustained for 12 weeks, or at least a 1.5 point increase on the EDSS from baseline EDSS = 0 that is sustained for 12 weeks. The EDSS measures the disability status of people with MS on a scale that ranges from 0 to 10. 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). Estimated proportion of participants with progression based on the Kaplan-Meier product limit method.	1 Year

Collaborators and Investigators

• Sponsor: Biogen

Publications and helpful links

General Publications

• Calabresi PA, Kieseier BC, Arnold DL, Balcer LJ, Boyko A, Pelletier J, Liu S, Zhu Y, Seddighzadeh A, Hung S, Deykin A; ADVANCE Study Investigators. Pegylated interferon beta-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol. 2014 Jul;13(7):657-65. doi: 10.1016/S1474-4422(14)70068-7. Epub 2014 Apr 30.
• Calabresi PA, Arnold DL, Sangurdekar D, Singh CM, Altincatal A, de Moor C, Engle B, Goyal J, Deykin A, Szak S, Kieseier BC, Rudick RA, Plavina T. Temporal profile of serum neurofilament light in multiple sclerosis: Implications for patient monitoring. Mult Scler. 2021 Sep;27(10):1497-1505. doi: 10.1177/1352458520972573. Epub 2020 Dec 14.
• Cleanthous S, Cano S, Kinter E, Marquis P, Petrillo J, You X, Wakeford C, Sabatella G. Measuring the impact of multiple sclerosis: Enhancing the measurement performance of the Multiple Sclerosis Impact Scale (MSIS-29) using Rasch Measurement Theory (RMT). Mult Scler J Exp Transl Clin. 2017 Aug 15;3(3):2055217317725917. doi: 10.1177/2055217317725917. eCollection 2017 Jul-Sep.
• Scott TF, Kieseier BC, Newsome SD, Arnold DL, You X, Hung S, Sperling B. Improvement in relapse recovery with peginterferon beta-1a in patients with multiple sclerosis. Mult Scler J Exp Transl Clin. 2016 Nov 15;2:2055217316676644. doi: 10.1177/2055217316676644. eCollection 2016 Jan-Dec.
• Newsome SD, Kieseier BC, Liu S, You X, Kinter E, Hung S, Sperling B. Peginterferon beta-1a reduces disability worsening in relapsing-remitting multiple sclerosis: 2-year results from ADVANCE. Ther Adv Neurol Disord. 2017 Jan;10(1):41-50. doi: 10.1177/1756285616676065. Epub 2016 Nov 16.
• Arnold DL, Calabresi PA, Kieseier BC, Liu S, You X, Fiore D, Hung S. Peginterferon beta-1a improves MRI measures and increases the proportion of patients with no evidence of disease activity in relapsing-remitting multiple sclerosis: 2-year results from the ADVANCE randomized controlled trial. BMC Neurol. 2017 Feb 10;17(1):29. doi: 10.1186/s12883-017-0799-0.
• Newsome SD, Guo S, Altincatal A, Proskorovsky I, Kinter E, Phillips G, You X, Sabatella G. Impact of peginterferon beta-1a and disease factors on quality of life in multiple sclerosis. Mult Scler Relat Disord. 2015 Jul;4(4):350-7. doi: 10.1016/j.msard.2015.06.004. Epub 2015 Jun 14.
• Arnold DL, Calabresi PA, Kieseier BC, Sheikh SI, Deykin A, Zhu Y, Liu S, You X, Sperling B, Hung S. Effect of peginterferon beta-1a on MRI measures and achieving no evidence of disease activity: results from a randomized controlled trial in relapsing-remitting multiple sclerosis. BMC Neurol. 2014 Dec 31;14:240. doi: 10.1186/s12883-014-0240-x.
• Kieseier BC, Arnold DL, Balcer LJ, Boyko AA, Pelletier J, Liu S, Zhu Y, Seddighzadeh A, Hung S, Deykin A, Sheikh SI, Calabresi PA. Peginterferon beta-1a in multiple sclerosis: 2-year results from ADVANCE. Mult Scler. 2015 Jul;21(8):1025-35. doi: 10.1177/1352458514557986. Epub 2014 Nov 28.
• Hu X, Cui Y, White J, Zhu Y, Deykin A, Nestorov I, Hung S. Pharmacokinetics and pharmacodynamics of peginterferon beta-1a in patients with relapsing-remitting multiple sclerosis in the randomized ADVANCE study. Br J Clin Pharmacol. 2015 Mar;79(3):514-22. doi: 10.1111/bcp.12521.

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: May 20, 2009
• First Submitted That Met QC Criteria: May 20, 2009
• First Posted (Estimate): May 21, 2009

Study Record Updates

• Last Update Posted (Estimate): September 19, 2014
• Last Update Submitted That Met QC Criteria: September 15, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: interferon; MS; subcutaneous; multiple sclerosis; relapsing; injectable; SC; PEGylated; PEG; Interferon beta-1a
• 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; Physiological Effects of Drugs; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Immunologic Factors; Adjuvants, Immunologic; Interferons; Interferon beta-1a; Interferon-beta
• Other Study ID Numbers: 105MS301; 2008-006333-27 (EudraCT Number)