Clinical trial NCT01067521: A Study in Subjects With Relapsing-Remitting Multiple Sclerosis (RRMS) to Assess the Efficacy, Safety and Tolerability of Glatiramer Acetate (GA) Injection 40 mg Administered Three Times a Week Compared to Placebo
Official title: A Multinational, Multicenter, Randomized, Parallel-group Study Performed in Subjects With Relapsing-Remitting Multiple Sclerosis (RRMS) to Assess the Efficacy, Safety and Tolerability of Glatiramer Acetate (GA) Injection 40 mg Administered Three Times a Week Compared to Placebo in a Double-blind Design
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Relapsing Remitting Multiple Sclerosis
Keywords: Relapsing Remitting Multiple Sclerosis
Glatiramer Acetate
Lead sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Sponsor class: INDUSTRY
First posted: 2010-02-11
Enrollment: 1404
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The study is designed to assess the efficacy of Glatiramer Acetate (GA) injection 40 mg administered three times a week compared to placebo in subjects with RRMS, as measured by the number of confirmed relapses during the 12 month placebo controlled period. The study has two periods:

* Placebo Controlled Period: 12 months of 40 mg administered three times a week by subcutaneous injection or matching placebo.
* Open Label Extension Period: All subjects will continue treatment with GA 40 mg administered three times a week, until this dose strength is commercially available for the treatment of relapsing remitting multiple sclerosis (RRMS) patients or until the development of this GA dose regimen is stopped by the Sponsor

Detailed description: Participants who were randomized to the GA 40 mg treatment arm in the Double-Blind Period, continue that treatment in the Open-Label Extension Period and are referred to as "Early Start" participants. Participants randomized to the Placebo arm in the Double-Blind Period and switched to GA 40 mg subcutaneous injections three times a week in the Open-Label Extension are referred to as "Delayed Start" participants.

Eligibility criteria: Inclusion Criteria:

1. Subjects must have a confirmed and documented MS diagnosis as defined by the Revised McDonald criteria with a relapsing-remitting disease course.
2. Subjects must be ambulatory with an EDSS score of 0-5.5 in both screening and baseline visits.
3. Subjects must be in a relapse-free, stable neurological condition and free of corticosteroid treatment \[intravenous (IV), intramuscular (IM) and/or per os (PO)\] or ACTH 30 days prior to screening (month -1) and between screening and baseline (month 0) visits.
4. Subjects must have experienced one of the following:

   At least one documented relapse in the 12 months prior to screening, or At least two documented relapses in the 24 months prior to screening, or One documented relapse between 12 and 24 months prior to screening with at least one documented T1-Gd enhancing lesion in an MRI performed within 12 months prior to screening.
5. Subjects must be between 18 and 55 years of age, inclusive.
6. Women of child-bearing potential must practice an acceptable method of birth control.
7. Subjects must be able to sign and date a written informed consent prior to entering the study.
8. Subjects must be willing and able to comply with the protocol requirements for the duration of the study

Exclusion Criteria:

1. Subjects with progressive forms of MS.
2. Use of experimental or investigational drugs, and/or participation in drug clinical studies within the 6 months prior to screening.
3. Use of immunosuppressive (including Mitoxantrone and Fingolimod) or cytotoxic agents within 6 months prior to the screening visit.
4. Use of natalizumab (Tysabri®) or any other monoclonal antibodies within 2 years prior to screening.
5. Use of cladribine within 2 years prior to screening.
6. Previous treatment with immunomodulators (including IFNβ 1a and 1b, and IV Immunoglobulin (IVIg) within 2 months prior to screening.
7. Previous use of GA or any other glatiramoid.
8. Chronic (more than 30 consecutive days) systemic (IV, PO or IM) corticosteroid treatment within 6 months prior to screening visit.
9. Previous total body irradiation or total lymphoid irradiation.
10. Previous stem-cell treatment, autologous bone marrow transplantation or allogenic bone marrow transplantation.
11. Pregnancy or breastfeeding.
12. Subjects with a clinically significant or unstable medical or surgical condition that would preclude safe and complete study participation, as determined by medical history, physical exams, ECG, abnormal laboratory tests and chest X-ray. Such conditions may include hepatic, renal or metabolic diseases, systemic disease, acute infection, current malignancy or recent history (5 years) of malignancy, major psychiatric disorder, history of drug and/or alcohol abuse and allergies that could be detrimental according to the investigator's judgment.
13. A known history of sensitivity to Gadolinium.
14. Inability to successfully undergo MRI scanning.
15. A known drug hypersensitivity to Mannitol.

Primary outcomes:
measure: Total Number of Confirmed Relapses During the Placebo Controlled (PC) Treatment Period Estimated by Negative Binomial Regression
timeFrame: Day 1 to 12 months
measure: Annualized Rate of Confirmed Relapses Comparing Early Starters to Delayed Starters Estimated by Negative Binomial Regression
timeFrame: Day 1 up to 6.5 years
Secondary outcomes:
measure: The Cumulative Number of New/Enlarging T2 Lesions Taken at Month 6 and Month 12 During the Placebo Controlled (PC) Treatment Period Estimated by Negative Binomial Regression
timeFrame: Baseline (Day -7), Month 6, Month 12
measure: The Cumulative Number of Gadolinium (Gd)-Enhanced Lesions on T1-Weighted Images At Month 6 and Month 12 of the Placebo-Controlled (PC) Treatment Period Estimated by Negative Binomial Regression
timeFrame: Baseline (Day -7), Month 6, Month 12
measure: Brain Atrophy As Defined by the Percent of Change in Normalized Brain Volume From Baseline to Month 12 During the Placebo Controlled (PC) Treatment Period
timeFrame: Baseline (Day -7), Month 12
measure: The Number of New/Enlarging T2 Lesions at Months 6, 12 and 36 Estimated by Negative Binomial Regression
timeFrame: Baseline (Day -7), Month 6, Month 12, Month 36
measure: The Cumulative Number of Gadolinium (Gd)-Enhanced Lesions on T1-Weighted Images At Months 6, 12 and 36 Estimated by Negative Binomial Regression
timeFrame: Baseline (Day -7), Month 6, Month 12, Month 36
measure: Brain Atrophy As Defined by the Percent of Change in Brain Volume From Baseline to Months 6, 12 and 36 Estimated by a Mixed Model for Repeated Measures
timeFrame: Baseline (Day -7), Month 6, Month 12, Month 36
measure: Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Early Start: Day 1 up to 6.5 years Delayed Start - Placebo: Day 1 up to Month 12 Delayed Start - GA: Month 13 up to 6.5 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Teva Investigational Site 1332
state: Alabama
city: Gilbert
country: United States
facility: Teva Investigational Site 1327
state: Arizona
city: Phoenix
country: United States
facility: Teva Investigational Site 1311
state: Arizona
city: Fullerton
country: United States
facility: Teva Investigational Site 1326
state: California
city: La Jolla
country: United States
facility: Teva Investigational Site 1335
state: California
city: Aurora
country: United States
facility: Teva Investigational Site 1297
state: Colorado
city: Boulder
country: United States
facility: Teva Investigational Site 1344
state: Colorado
city: Centennial
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facility: Teva Investigational Site 1315
state: Colorado
city: Fort Collins
country: United States
facility: Teva Investigational Site 1350
state: Colorado
city: Miami
country: United States
facility: Teva Investigational Site 1345
state: Florida
city: Naples
country: United States
facility: Teva Investigational Site 1336
state: Florida
city: Pompano Beach
country: United States
facility: Teva Investigational Site 1347
state: Florida
city: Ponte Vedra
country: United States
facility: Teva Investigational Site 1319
state: Florida
city: Sarasota
country: United States
facility: Teva Investigational Site 1298
state: Florida
city: Sarasota
country: United States
facility: Teva Investigational Site 1316
state: Florida
city: Tampa
country: United States
facility: Teva Investigational Site 1340
state: Florida
city: Vero Beach
country: United States
facility: Teva Investigational Site 1317
state: Florida
city: Northbrook
country: United States
facility: Teva Investigational Site 1303
state: Illinois
city: Lenexa
country: United States
facility: Teva Investigational Site 1334
state: Kansas
city: Lexington
country: United States
facility: Teva Investigational Site 1302
state: Kentucky
city: Shreveport
country: United States
facility: Teva Investigational Site 1322
state: Louisiana
city: Detroit
country: United States
facility: Teva Investigational Site 1306
state: Michigan
city: Akron
country: United States
facility: Teva Investigational Site 1329
state: Ohio
city: Columbus
country: United States
facility: Teva Investigational Site 1349
state: Ohio
city: Dayton
country: United States
facility: Teva Investigational Site 1313
state: Ohio
city: Uniontown
country: United States
facility: Teva Investigational Site 1318
state: Ohio
city: Oklahoma City
country: United States
facility: Teva Investigational Site 1341
state: Oklahoma
city: Nashville
country: United States
facility: Teva Investigational Site 1310
state: Tennessee
city: Lubbock
country: United States
facility: Teva Investigational Site 1321
state: Texas
city: Round Rock
country: United States
facility: Teva Investigational Site 1337
state: Texas
city: San Antonio
country: United States
facility: Teva Investigational Site 1301
state: Texas
city: San Antonio
country: United States
facility: Teva Investigational Site 1346
state: Texas
city: Salt Lake City
country: United States
facility: Teva Investigational Site 1343
state: Utah
city: Richmond
country: United States
facility: Teva Investigational Site 1338
state: Virginia
city: Roanoke
country: United States
facility: Teva Investigational Site 1339
state: Virginia
city: Vienna
country: United States
facility: Teva Investigational Site 1300
state: Virginia
city: Kirkland
country: United States
facility: Teva Investigational Site 1323
state: Washington
city: Blagoevgrad
country: Bulgaria
facility: Teva Investigational Site 5940
city: Pleven
country: Bulgaria
facility: Teva Investigational Site 5931
city: Pleven
country: Bulgaria
facility: Teva Investigational Site 5932
city: Plovdiv
country: Bulgaria
facility: Teva Investigational Site 5933
city: Ruse
country: Bulgaria
facility: Teva Investigational Site 5936
city: Shumen
country: Bulgaria
facility: Teva Investigational Site 5935
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5939
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5921
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5922
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5926
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5938
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5924
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5927
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5923
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5925
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5928
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5929
city: Stara Zagora
country: Bulgaria
facility: Teva Investigational Site 5934
city: Varna
country: Bulgaria
facility: Teva Investigational Site 5930
city: Veliko Tarnovo
country: Bulgaria
facility: Teva Investigational Site 5937
city: Osijek
country: Croatia
facility: Teva Investigational Site 6011
city: Zagreb
country: Croatia
facility: Teva Investigational Site 6009
city: Zagreb
country: Croatia
facility: Teva Investigational Site 6010
city: Zagreb
country: Croatia
facility: Teva Investigational Site 6012
city: Zagreb
country: Croatia
facility: Teva Investigational Site 6013
city: Olomouc
country: Czechia
facility: Teva Investigational Site 5433
city: Ostrava - poruba
country: Czechia
facility: Teva Investigational Site 5434
city: Prague 10
country: Czechia
facility: Teva Investigational Site 5432
city: Teplice
country: Czechia
facility: Teva Investigational Site 5435
city: Kohtla-Jarve
country: Estonia
facility: Teva Investigational Site 5513
city: Tallinn
country: Estonia
facility: Teva Investigational Site 5510
city: Tartu
country: Estonia
facility: Teva Investigational Site 5512
city: Tbilisi
country: Georgia
facility: Teva Investigational Site 8110
city: Tbilisi
country: Georgia
facility: Teva Investigational Site 8111
city: Bad Wildbad
country: Germany
facility: Teva Investigational Site 3268
city: Bayreuth
country: Germany
facility: Teva Investigational Site 3272
city: Berlin
country: Germany
facility: Teva Investigational Site 3262
city: Berlin
country: Germany
facility: Teva Investigational Site 3276
city: Bonn
country: Germany
facility: Teva Investigational Site 3271
city: Dresden
country: Germany
facility: Teva Investigational Site 3265
city: Duesseldorf
country: Germany
facility: Teva Investigational Site 3267
city: Erbach
country: Germany
facility: Teva Investigational Site 3263
city: Hamburg
country: Germany
facility: Teva Investigational Site 3269
city: Hannover
country: Germany
facility: Teva Investigational Site 3266
city: Herborn
country: Germany
facility: Teva Investigational Site 3270
city: Kaltenkirchen
country: Germany
facility: Teva Investigational Site 3273
city: Marburg
country: Germany
facility: Teva Investigational Site 3275
city: Munster
country: Germany
facility: Teva Investigational Site 3261
city: Ulm
country: Germany
facility: Teva Investigational Site 3264
city: Budapest
country: Hungary
facility: Teva Investigational Site 5127
city: Debrecen
country: Hungary
facility: Teva Investigational Site 5129
city: Eger
country: Hungary
facility: Teva Investigational Site 5130
city: Esztergom
country: Hungary
facility: Teva Investigational Site 5132
city: Gyor
country: Hungary
facility: Teva Investigational Site 5131
city: Kaposvar
country: Hungary
facility: Teva Investigational Site 5128
city: Veszprem
country: Hungary
facility: Teva Investigational Site 5133
city: Ramat Gan
country: Israel
facility: Teva Investigational Site 8052
city: Bologna
country: Italy
facility: Teva Investigational Site 3089
city: Cefalu
country: Italy
facility: Teva Investigational Site 3084
city: Cosenza
country: Italy
facility: Teva Investigational Site 3092
city: Milano
country: Italy
facility: Teva Investigational Site 3080
city: Rome
country: Italy
facility: Teva Investigational Site 3086
city: Kaunas
country: Lithuania
facility: Teva Investigational Site 5710
city: Siauliai
country: Lithuania
facility: Teva Investigational Site 5712
city: Vilnius
country: Lithuania
facility: Teva Investigational Site 5711
city: Czestochowa
country: Poland
facility: Teva Investigational Site 5374
city: Elblag
country: Poland
facility: Teva Investigational Site 5377
city: Gdansk
country: Poland
facility: Teva Investigational Site 5381
city: Gdansk
country: Poland
facility: Teva Investigational Site 5380
city: Gorzow Wielkopolski
country: Poland
facility: Teva Investigational Site 5376
city: Grodzisk Mazowiecki
country: Poland
facility: Teva Investigational Site 5372
city: Katowice
country: Poland
facility: Teva Investigational Site 5375
city: Katowice
country: Poland
facility: Teva Investigational Site 5368
city: Kielce
country: Poland
facility: Teva Investigational Site 5379
city: Konskie
country: Poland
facility: Teva Investigational Site 5382
city: Koscierzyna
country: Poland
facility: Teva Investigational Site 5369
city: Krakow
country: Poland
facility: Teva Investigational Site 5378
city: Lodz
country: Poland
facility: Teva Investigational Site 5366
city: Olsztyn
country: Poland
facility: Teva Investigational Site 5373
city: Poznan
country: Poland
facility: Teva Investigational Site 5384
city: Szczecin
country: Poland
facility: Teva Investigational Site 5371
city: Warszawa
country: Poland
facility: Teva Investigational Site 5367
city: Wroclaw
country: Poland
facility: Teva Investigational Site 5370
city: Balotesti
country: Romania
facility: Teva Investigational Site 5233
city: Bucharest
country: Romania
facility: Teva Investigational Site 5222
city: Bucuresti
country: Romania
facility: Teva Investigational Site 5221
city: Bucuresti
country: Romania
facility: Teva Investigational Site 5220
city: Cluj-Napoca
country: Romania
facility: Teva Investigational Site 5227
city: Cluj-Napoca
country: Romania
facility: Teva Investigational Site 5230
city: Constanta
country: Romania
facility: Teva Investigational Site 5225
city: Constanta
country: Romania
facility: Teva Investigational Site 5226
city: Craiova
country: Romania
facility: Teva Investigational Site 5232
city: Iasi
country: Romania
facility: Teva Investigational Site 5231
city: Piatra-Neamt
country: Romania
facility: Teva Investigational Site 5223
city: Sibiu
country: Romania
facility: Teva Investigational Site 5228
city: Targu-Mures
country: Romania
facility: Teva Investigational Site 5229
city: Timisoara
country: Romania
facility: Teva Investigational Site 5224
city: Barnaul
country: Russian Federation
facility: Teva Investigational Site 5063
city: Ekaterinburg
country: Russian Federation
facility: Teva Investigational Site 5059
city: Irkutsk
country: Russian Federation
facility: Teva Investigational Site 5068
city: Krasnoyarsk
country: Russian Federation
facility: Teva Investigational Site 5067
city: Moscow
country: Russian Federation
facility: Teva Investigational Site 5052
city: Nizhny Novgorod
country: Russian Federation
facility: Teva Investigational Site 5057
city: Novosibirsk
country: Russian Federation
facility: Teva Investigational Site 5062
city: Perm
country: Russian Federation
facility: Teva Investigational Site 5060
city: Saint Petersburg
country: Russian Federation
facility: Teva Investigational Site 5053
city: Samara
country: Russian Federation
facility: Teva Investigational Site 5058
city: Smolensk
country: Russian Federation
facility: Teva Investigational Site 5064
city: St. Petersburg
country: Russian Federation
facility: Teva Investigational Site 5056
city: St. Petersburg
country: Russian Federation
facility: Teva Investigational Site 5055
city: St. Petersburg
country: Russian Federation
facility: Teva Investigational Site 5054
city: Tomsk
country: Russian Federation
facility: Teva Investigational Site 5066
city: Ufa
country: Russian Federation
facility: Teva Investigational Site 5061
city: Yaroslavl
country: Russian Federation
facility: Teva Investigational Site 5065
city: Johannesburg
country: South Africa
facility: Teva Investigational Site 9020
city: Johannesburg
country: South Africa
facility: Teva Investigational Site 9019
city: Pietermaritzburg
country: South Africa
facility: Teva Investigational Site 9022
city: Pretoria
country: South Africa
facility: Teva Investigational Site 9025
city: Pretoria
country: South Africa
facility: Teva Investigational Site 9018
city: Rosebank
country: South Africa
facility: Teva Investigational Site 9021
city: Umhlanga
country: South Africa
facility: Teva Investigational Site 9024
city: Chernihiv
country: Ukraine
facility: Teva Investigational Site 5835
city: Chernivtsi
country: Ukraine
facility: Teva Investigational Site 5834
city: Dnipropetrovsk
country: Ukraine
facility: Teva Investigational Site 5827
city: Donetsk
country: Ukraine
facility: Teva Investigational Site 5828
city: Ivano-Frankivsk
country: Ukraine
facility: Teva Investigational Site 5829
city: Kharkiv
country: Ukraine
facility: Teva Investigational Site 5830
city: Kyiv
country: Ukraine
facility: Teva Investigational Site 5833
city: Kyiv
country: Ukraine
facility: Teva Investigational Site 5836
city: Lviv
country: Ukraine
facility: Teva Investigational Site 5825
city: Odesa
country: Ukraine
facility: Teva Investigational Site 5839
city: Poltava
country: Ukraine
facility: Teva Investigational Site 5832
city: Simferopol
country: Ukraine
facility: Teva Investigational Site 5838
city: Uzhgorod
country: Ukraine
facility: Teva Investigational Site 5837
city: Vinnytsya
country: Ukraine
facility: Teva Investigational Site 5826
city: Zaporizhzhya
country: Ukraine
facility: Teva Investigational Site 5831
city: Nottingham
country: United Kingdom
facility: Teva Investigational Site 3439
city: Salford
country: United Kingdom
facility: Teva Investigational Site 3438
city: Sheffield
country: United Kingdom
facility: Teva Investigational Site 3440
Study officials:
References:
citation: Khan O, Rieckmann P, Boyko A, Selmaj K, Ashtamker N, Davis MD, Kolodny S, Zivadinov R. Efficacy and safety of a three-times-weekly dosing regimen of glatiramer acetate in relapsing-remitting multiple sclerosis patients: 3-year results of the Glatiramer Acetate Low-Frequency Administration open-label extension study. Mult Scler. 2017 May;23(6):818-829. doi: 10.1177/1352458516664033. Epub 2016 Aug 8.