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

Relapsing Remitting Multiple Sclerosis Clinical Trial

— GALA  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01067521
• Other study ID #: MS-GA-301
• Secondary ID: 2009-018084-27
• Status: Completed
• Phase: Phase 3
• Start date: June 22, 2010
• Est. completion date: May 12, 2017

Study information

• Verified date: December 2021
• Source: Teva Branded Pharmaceutical Products R&D, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1404
• Est. completion date: May 12, 2017
• Est. primary completion date: May 8, 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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 IFNß 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.

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Relapsing Remitting Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• Glatiramer acetate (GA)
GA 40 mg/mL administered 3 times a week by subcutaneous injection for a period of 12 months for participants assigned to GA treatment in the Double-Blind Period, and GA 40 mg/mL administered 3 times a week by subcutaneous injection for all participants in the Open-Label Extension Period.
• Placebo
Placebo comparator administered by subcutaneous injection three times each week for 12 months during the Double-Blind Period.

Locations

Country	Name	City	State
Bulgaria	Teva Investigational Site 5940	Blagoevgrad
Bulgaria	Teva Investigational Site 5931	Pleven
Bulgaria	Teva Investigational Site 5932	Pleven
Bulgaria	Teva Investigational Site 5933	Plovdiv
Bulgaria	Teva Investigational Site 5936	Ruse
Bulgaria	Teva Investigational Site 5935	Shumen
Bulgaria	Teva Investigational Site 5921	Sofia
Bulgaria	Teva Investigational Site 5922	Sofia
Bulgaria	Teva Investigational Site 5923	Sofia
Bulgaria	Teva Investigational Site 5924	Sofia
Bulgaria	Teva Investigational Site 5925	Sofia
Bulgaria	Teva Investigational Site 5926	Sofia
Bulgaria	Teva Investigational Site 5927	Sofia
Bulgaria	Teva Investigational Site 5928	Sofia
Bulgaria	Teva Investigational Site 5929	Sofia
Bulgaria	Teva Investigational Site 5938	Sofia
Bulgaria	Teva Investigational Site 5939	Sofia
Bulgaria	Teva Investigational Site 5934	Stara Zagora
Bulgaria	Teva Investigational Site 5930	Varna
Bulgaria	Teva Investigational Site 5937	Veliko Tarnovo
Croatia	Teva Investigational Site 6011	Osijek
Croatia	Teva Investigational Site 6009	Zagreb
Croatia	Teva Investigational Site 6010	Zagreb
Croatia	Teva Investigational Site 6012	Zagreb
Croatia	Teva Investigational Site 6013	Zagreb
Czechia	Teva Investigational Site 5433	Olomouc
Czechia	Teva Investigational Site 5434	Ostrava - poruba
Czechia	Teva Investigational Site 5432	Prague 10
Czechia	Teva Investigational Site 5435	Teplice
Estonia	Teva Investigational Site 5513	Kohtla-Jarve
Estonia	Teva Investigational Site 5510	Tallinn
Estonia	Teva Investigational Site 5512	Tartu
Georgia	Teva Investigational Site 8110	Tbilisi
Georgia	Teva Investigational Site 8111	Tbilisi
Germany	Teva Investigational Site 3268	Bad Wildbad
Germany	Teva Investigational Site 3272	Bayreuth
Germany	Teva Investigational Site 3262	Berlin
Germany	Teva Investigational Site 3276	Berlin
Germany	Teva Investigational Site 3271	Bonn
Germany	Teva Investigational Site 3265	Dresden
Germany	Teva Investigational Site 3267	Duesseldorf
Germany	Teva Investigational Site 3263	Erbach
Germany	Teva Investigational Site 3269	Hamburg
Germany	Teva Investigational Site 3266	Hannover
Germany	Teva Investigational Site 3270	Herborn
Germany	Teva Investigational Site 3273	Kaltenkirchen
Germany	Teva Investigational Site 3275	Marburg
Germany	Teva Investigational Site 3261	Munster
Germany	Teva Investigational Site 3264	Ulm
Hungary	Teva Investigational Site 5127	Budapest
Hungary	Teva Investigational Site 5129	Debrecen
Hungary	Teva Investigational Site 5130	Eger
Hungary	Teva Investigational Site 5132	Esztergom
Hungary	Teva Investigational Site 5131	Gyor
Hungary	Teva Investigational Site 5128	Kaposvar
Hungary	Teva Investigational Site 5133	Veszprem
Israel	Teva Investigational Site 8052	Ramat Gan
Italy	Teva Investigational Site 3089	Bologna
Italy	Teva Investigational Site 3084	Cefalu
Italy	Teva Investigational Site 3092	Cosenza
Italy	Teva Investigational Site 3080	Milano
Italy	Teva Investigational Site 3086	Rome
Lithuania	Teva Investigational Site 5710	Kaunas
Lithuania	Teva Investigational Site 5712	Siauliai
Lithuania	Teva Investigational Site 5711	Vilnius
Poland	Teva Investigational Site 5374	Czestochowa
Poland	Teva Investigational Site 5377	Elblag
Poland	Teva Investigational Site 5380	Gdansk
Poland	Teva Investigational Site 5381	Gdansk
Poland	Teva Investigational Site 5376	Gorzow Wielkopolski
Poland	Teva Investigational Site 5372	Grodzisk Mazowiecki
Poland	Teva Investigational Site 5368	Katowice
Poland	Teva Investigational Site 5375	Katowice
Poland	Teva Investigational Site 5379	Kielce
Poland	Teva Investigational Site 5382	Konskie
Poland	Teva Investigational Site 5369	Koscierzyna
Poland	Teva Investigational Site 5378	Krakow
Poland	Teva Investigational Site 5366	Lodz
Poland	Teva Investigational Site 5373	Olsztyn
Poland	Teva Investigational Site 5384	Poznan
Poland	Teva Investigational Site 5371	Szczecin
Poland	Teva Investigational Site 5367	Warszawa
Poland	Teva Investigational Site 5370	Wroclaw
Romania	Teva Investigational Site 5233	Balotesti
Romania	Teva Investigational Site 5222	Bucharest
Romania	Teva Investigational Site 5220	Bucuresti
Romania	Teva Investigational Site 5221	Bucuresti
Romania	Teva Investigational Site 5227	Cluj-Napoca
Romania	Teva Investigational Site 5230	Cluj-Napoca
Romania	Teva Investigational Site 5225	Constanta
Romania	Teva Investigational Site 5226	Constanta
Romania	Teva Investigational Site 5232	Craiova
Romania	Teva Investigational Site 5231	Iasi
Romania	Teva Investigational Site 5223	Piatra-Neamt
Romania	Teva Investigational Site 5228	Sibiu
Romania	Teva Investigational Site 5229	Targu-Mures
Romania	Teva Investigational Site 5224	Timisoara
Russian Federation	Teva Investigational Site 5063	Barnaul
Russian Federation	Teva Investigational Site 5059	Ekaterinburg
Russian Federation	Teva Investigational Site 5068	Irkutsk
Russian Federation	Teva Investigational Site 5067	Krasnoyarsk
Russian Federation	Teva Investigational Site 5052	Moscow
Russian Federation	Teva Investigational Site 5057	Nizhny Novgorod
Russian Federation	Teva Investigational Site 5062	Novosibirsk
Russian Federation	Teva Investigational Site 5060	Perm
Russian Federation	Teva Investigational Site 5053	Saint Petersburg
Russian Federation	Teva Investigational Site 5058	Samara
Russian Federation	Teva Investigational Site 5064	Smolensk
Russian Federation	Teva Investigational Site 5054	St. Petersburg
Russian Federation	Teva Investigational Site 5055	St. Petersburg
Russian Federation	Teva Investigational Site 5056	St. Petersburg
Russian Federation	Teva Investigational Site 5066	Tomsk
Russian Federation	Teva Investigational Site 5061	Ufa
Russian Federation	Teva Investigational Site 5065	Yaroslavl
South Africa	Teva Investigational Site 9019	Johannesburg
South Africa	Teva Investigational Site 9020	Johannesburg
South Africa	Teva Investigational Site 9022	Pietermaritzburg
South Africa	Teva Investigational Site 9018	Pretoria
South Africa	Teva Investigational Site 9025	Pretoria
South Africa	Teva Investigational Site 9021	Rosebank
South Africa	Teva Investigational Site 9024	Umhlanga
Ukraine	Teva Investigational Site 5835	Chernihiv
Ukraine	Teva Investigational Site 5834	Chernivtsi
Ukraine	Teva Investigational Site 5827	Dnipropetrovsk
Ukraine	Teva Investigational Site 5828	Donetsk
Ukraine	Teva Investigational Site 5829	Ivano-Frankivsk
Ukraine	Teva Investigational Site 5830	Kharkiv
Ukraine	Teva Investigational Site 5833	Kyiv
Ukraine	Teva Investigational Site 5836	Kyiv
Ukraine	Teva Investigational Site 5825	Lviv
Ukraine	Teva Investigational Site 5839	Odesa
Ukraine	Teva Investigational Site 5832	Poltava
Ukraine	Teva Investigational Site 5838	Simferopol
Ukraine	Teva Investigational Site 5837	Uzhgorod
Ukraine	Teva Investigational Site 5826	Vinnytsya
Ukraine	Teva Investigational Site 5831	Zaporizhzhya
United Kingdom	Teva Investigational Site 3439	Nottingham
United Kingdom	Teva Investigational Site 3438	Salford
United Kingdom	Teva Investigational Site 3440	Sheffield
United States	Teva Investigational Site 1329	Akron	Ohio
United States	Teva Investigational Site 1297	Aurora	Colorado
United States	Teva Investigational Site 1332	Birmingham	Alabama
United States	Teva Investigational Site 1344	Boulder	Colorado
United States	Teva Investigational Site 1315	Centennial	Colorado
United States	Teva Investigational Site 1349	Columbus	Ohio
United States	Teva Investigational Site 1313	Dayton	Ohio
United States	Teva Investigational Site 1306	Detroit	Michigan
United States	Teva Investigational Site 1350	Fort Collins	Colorado
United States	Teva Investigational Site 1326	Fullerton	California
United States	Teva Investigational Site 1327	Gilbert	Arizona
United States	Teva Investigational Site 1323	Kirkland	Washington
United States	Teva Investigational Site 1335	La Jolla	California
United States	Teva Investigational Site 1334	Lenexa	Kansas
United States	Teva Investigational Site 1302	Lexington	Kentucky
United States	Teva Investigational Site 1321	Lubbock	Texas
United States	Teva Investigational Site 1345	Miami	Florida
United States	Teva Investigational Site 1336	Naples	Florida
United States	Teva Investigational Site 1310	Nashville	Tennessee
United States	Teva Investigational Site 1303	Northbrook	Illinois
United States	Teva Investigational Site 1341	Oklahoma City	Oklahoma
United States	Teva Investigational Site 1311	Phoenix	Arizona
United States	Teva Investigational Site 1347	Pompano Beach	Florida
United States	Teva Investigational Site 1319	Ponte Vedra	Florida
United States	Teva Investigational Site 1338	Richmond	Virginia
United States	Teva Investigational Site 1339	Roanoke	Virginia
United States	Teva Investigational Site 1337	Round Rock	Texas
United States	Teva Investigational Site 1343	Salt Lake City	Utah
United States	Teva Investigational Site 1301	San Antonio	Texas
United States	Teva Investigational Site 1346	San Antonio	Texas
United States	Teva Investigational Site 1298	Sarasota	Florida
United States	Teva Investigational Site 1316	Sarasota	Florida
United States	Teva Investigational Site 1322	Shreveport	Louisiana
United States	Teva Investigational Site 1340	Tampa	Florida
United States	Teva Investigational Site 1318	Uniontown	Ohio
United States	Teva Investigational Site 1317	Vero Beach	Florida
United States	Teva Investigational Site 1300	Vienna	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
Teva Branded Pharmaceutical Products R&D, Inc.

Countries where clinical trial is conducted

United States,  Bulgaria,  Croatia,  Czechia,  Estonia,  Georgia,  Germany,  Hungary,  Israel,  Italy,  Lithuania,  Poland,  Romania,  Russian Federation,  South Africa,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Total Number of Confirmed Relapses During the Placebo Controlled (PC) Treatment Period Estimated by Negative Binomial Regression	Relapses were monitored throughout the study. During the PC Period, two neurologists/physicians assessed subjects' general medical and neurological evaluations separately. A relapse was defined as the appearance of 1+ new neurological abnormalities or the reappearance of 1+ previously observed neurological abnormalities lasting >= 48 hours and immediately preceded by an improving neurological state of at >=30 days from onset of previous relapse. An event was counted as a relapse only when the subject's symptoms were accompanied by observed objective neurological changes, consistent with >= one of the following: - An increase of >= 0.5 in the Expanded Disability Status Scale (EDSS) score as compared to previous evaluation. - An increase of one grade in the actual score of >=2 of the 7 functional systems (FS), as compared to previous evaluation. - An increase of 2 grades in the actual score of one FS as compared to the previous evaluation. Adjusted mean values are displayed.	Day 1 to 12 months
Primary	Annualized Rate of Confirmed Relapses Comparing Early Starters to Delayed Starters Estimated by Negative Binomial Regression	The annualized relapse rate (ARR) was calculated for the study by dividing the cumulative number of confirmed relapses by the number of person-years of exposure to treatment. The analysis of the annualized relapse rate is based on estimating a contrast (early start vs delayed start) derived from a baseline-adjusted, Negative Binomial Regression model to the number of confirmed relapses observed during study (post randomization) with an "offset" based on the log of exposure to treatment.	Day 1 up to 6.5 years
Secondary	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	T2 lesions are hyperintense brain lesions that show on magnetic resonance imaging (MRI) and are associated with multiple sclerosis. The cumulative number of T2 lesions at Months 6 and 12 that are new or enlarged as compared to the baseline MRI are offered. Note that the two timeframes (Months 6 and 12) are combined. Adjusted mean is based on negative binomial regression, adjusted for baseline number of T2 lesions and country or geographical region as covariates.	Baseline (Day -7), Month 6, Month 12
Secondary	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	The cumulative number of gadolinium (Gd)-enhanced lesions on T1-weighted images at Months 6 and 12 as compared to the baseline MRI are offered. Note that the two timeframes (Months 6 and 12) are combined. Adjusted mean is based on negative binomial regression with an "offset" employing the log of the proportion of the number of the available post-baseline scans to adjust for missing MRI scans (if any), adjusted for baseline number of enhancing lesions on T1-weighted images and country or geographical region as covariates.	Baseline (Day -7), Month 6, Month 12
Secondary	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	The analysis of brain atrophy as defined by the percentage change in normalized brain volume from baseline to Month 12 was based on the outcome of a contrast (GA 40 mg TIW vs. placebo) derived from a baseline-adjusted ANCOVA. In addition to the treatment group, the model included the following covariates: - SIENAX normalized brain volume at baseline. - The number of enhancing lesions on T1-weighted images at baseline. - country or geographical region.; Sienax estimates total brain tissue volume, from a single image, normalised for skull size.	Baseline (Day -7), Month 12
Secondary	The Number of New/Enlarging T2 Lesions at Months 6, 12 and 36 Estimated by Negative Binomial Regression	All data accumulated from screening, the PC Treatment period up to the end of the Open Label (OL) period are combined and referred to as the Long Term Period. T2 lesions are hyperintense brain lesions that show on magnetic resonance imaging (MRI) and are associated with multiple sclerosis. The number of T2 lesions at Months 6, 12 and 36 that are new or enlarged as compared to the baseline MRI are offered. Adjusted mean is based on negative binomial regression, adjusted for baseline number of T2 lesions and country or geographical region as covariates. An "offset" employing the log of the proportion of the number of the available post-placebo-controlled baseline (PCBL) scans was used to adjust for missing MRI scans.	Baseline (Day -7), Month 6, Month 12, Month 36
Secondary	The Cumulative Number of Gadolinium (Gd)-Enhanced Lesions on T1-Weighted Images At Months 6, 12 and 36 Estimated by Negative Binomial Regression	All data accumulated from screening, the PC Treatment period up to the end of the Open Label (OL) period are combined and referred to as the Long Term Period. The cumulative number of gadolinium (Gd)-enhanced lesions on T1-weighted images at Months 6, 12 and 36 as compared to the baseline MRI are offered. Adjusted mean is based on negative binomial regression The model was fit using an autoregressive covariance structure. Covariates used: number of enhancing lesions on T1-weighted images at placebo-controlled baseline and country or geographical region. The cumulative number is derived from all the data points before it. For example, if the participant skipped one time point in between the baseline and 36 months, then it cannot be calculated.	Baseline (Day -7), Month 6, Month 12, Month 36
Secondary	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	The analysis of brain atrophy as defined by the percentage change in brain volume from baseline to Months 6, 12 and 36 was performed using mixed model for repeated measures (MMRM) with SIENAX normalized brain volume at baseline, number of Gd-enhancing lesions at baseline, and country or geographical region as fixed effects.; Sienax estimates total brain tissue volume, from a single image, normalised for skull size.	Baseline (Day -7), Month 6, Month 12, Month 36
Secondary	Participants With Treatment-Emergent Adverse Events (TEAEs)	Adverse events (AEs) summarized in this table are those that began or worsened after treatment with study drug (treatment-emergent AEs). An adverse event was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.	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