ARPEGGIO: A Phase 2 Clinical Study in Subjects With Primary Progressive Multiple Sclerosis to Assess the Efficacy, Safety and Tolerability of Two Oral Doses of Laquinimod Either of 0.6 mg/Day or 1.5mg/Day (Experimental Drug) as Compared to Placebo

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02284568
• Collaborator: (none)
• Enrollment: 374
• Locations: 99
• Arms: 3
• Actual Duration (Months): 32.6
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This Phase 2 study is intended to serve as a proof of concept for potential treatment with laquinimod in patients with PPMS. The study is also aimed at evaluating 2 doses of laquinimod in this population.

Condition or Disease	Intervention/Treatment	Phase
Primary Progressive Multiple Sclerosis	Drug: Placebo; Drug: Laquinimod; Drug: Placebo	Phase 2

Detailed Description

Due to serious cardiovascular adverse events, Data Monitoring Committee (DMC) made a recommendation to stop all laquinimod treatment arms above 0.6 mg in the multiple sclerosis (MS) trials; therefore the 1.5 mg treatment arm in the ARPEGGIO study was discontinued as of 01 January 2016.

The DMC did not identify any definite cardiovascular risk in the 0.6 mg treatment arm, but felt that long term monitoring for emergence of any potential signal was necessary. Therefore, the 0.6 mg treatment arm was continued while the sponsor closely monitored cardiovascular events in all laquinimod studies. Prior to 01 January 2016, eligible patients were randomized in a 1:1:1 ratio into 1 of the following treatment arms (a total of 286 patients were randomized 1:1:1 prior to

01 January 2016):

• Laquinimod 0.6 mg daily

• Laquinimod 1.5 mg daily

• Daily placebo

As of 01 January 2016, following the decision to discontinue the laquinimod 1.5 mg dose arm, additional eligible patients (87 patients) who were enrolled were randomized in a 1:1 ratio into one of the following treatment arms:

• Laquinimod 0.6 mg daily

• Daily placebo

Study Design

• Study Type: Interventional
• Actual Enrollment: 374 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multinational, Multicenter, Randomized, Double Blind, Parallel Group, Placebo Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Once Daily Oral Administration of Laquinimod (0.6 or 1.5 mg) in Patients With Primary Progressive Multiple Sclerosis (PPMS)
• Actual Study Start Date: Jan 12, 2015
• Actual Primary Completion Date: May 4, 2017
• Actual Study Completion Date: Oct 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo once daily oral dose	Drug: Placebo; Placebo
Experimental: Laquinimod 0.6 mg 1 capsule containing 0.6 mg laquinimod and 2 capsules containing placebo were administered orally once daily for at least 48 weeks.	Drug: Laquinimod; Laquinimod capsules in 0.5 mg and 0.6 mg strengths; Other Names: TV-5600 ; Drug: Placebo; Placebo capsules
Experimental: Laquinimod 1.5 mg 3 capsules containing 0.5 mg laquinimod were administered orally once daily for at least 48 weeks. However this arm was discontinued as of 01 January 2016 and no participants reached the 48 week timeframe.	Drug: Laquinimod; Laquinimod capsules in 0.5 mg and 0.6 mg strengths; Other Names: TV-5600

Outcome Measures

Primary Outcome Measures

1. Percent Brain Volume Change (PBVC) From Baseline to Week 48 Using a Repeated Measures ANCOVA Model [Baseline (at least 14 days but not more than 6 weeks prior to Day 1), Weeks 24, 48 and including early termination visits]

   Brain atrophy (BA) was measured using magnetic resonance imaging (MRI) scans of the brain. BA was analyzed using baseline-adjusted repeated measures analysis of covariance (ANCOVA- SAS® PROC MIXED) in which 1 contrast was constructed in order to compare between laquinimod 0.6 mg and placebo. The statistical model was a repeated measures analysis of covariance with treatment group, week, treatment group by week interaction, normalized brain volume at baseline, natural logarithm of T2 lesion volume at baseline, and country as fixed effects. Only on-treatment observations (include all the assessments done up to one month after the last dose of the study drug) were included. Values are adjusted means. The cancelled laquinimod 1.5 mg treatment arm was not included in the repeated measures ANCOVA model analysis. However PBVC by visit data are offered in outcome #2.

2. Percent Brain Volume Change (PBVC) From Baseline to Weeks 24 and 48 [Baseline (at least 14 days but not more than 6 weeks prior to Day 1), Weeks 24, 48]

   Brain atrophy (BA) was measured using magnetic resonance imaging (MRI) scans of the brain. Early termination scans of participants who discontinued the study after week 36 are considered scans at week 48.

Secondary Outcome Measures

1. Percentage of Participants With 12-Week Confirmed Disability Progression (CDP) As Measured by Expanded Disability Status Scale (EDSS) up to Week 48 [Baseline (Week 0), Weeks 12, 24, 36, 48 (end if treatment if < 48 weeks)]

   CDP was defined as increase in EDSS of >=1 point from baseline EDSS, if EDSS at entry is ≤5.0 or increase of >=0.5 point, if EDSS at entry is >=5.5. This increase should be confirmed after at least 12 weeks. Progression cannot be confirmed during a protocol defined relapse. EDSS is a method of quantifying disability in multiple sclerosis and monitoring changes in the level of disability over time. The EDSS scale ranges from 0 to 10 in 0.5 unit increments with 0=no disability and 10=death due to MS. Only an Examining Neurologist administered the EDSS. The Examining Neurologist did not have access to the patient's medical records or source documents, including previous EDSS forms or adverse events. If a patient died due to MS disease progression, the patient was analyzed as having CDP with the time to CDP as the onset date of progression. If a patient died due to MS before having progression, then the time to disability progression was censored using the date of death.

2. Percentage of Participants With 12-Week Confirmed Disability Progression (CDP) As Measured by Expanded Disability Status Scale (EDSS) or the Timed 25-foot Walk (T25FW) Test up to Week 48 [Baseline (Week 0), Weeks 12, 24, 36, 48 (end if treatment if < 48 weeks)]

   CDP was defined as increase in EDSS of >=1 point from baseline EDSS, if EDSS at entry is ≤5.0 or increase of >=0.5 point, if EDSS at entry is >=5.5 confirmed after at least 12 weeks, OR increase of >= 20% from baseline in the T25FW test, confirmed after at least 12 weeks. EDSS quantifies disability in MS and monitors changes in the level of disability over time. The EDSS scale is 0-10 in 0.5 unit increments with 0=no disability and 10=death due to MS. The T25-FW is a quantitative mobility and leg function performance test based on the average time of two trials in which participants walk 25 feet as quickly as possible. Increasing time scores indicate increasing impairment. If a patient died due to MS disease progression, the patient was analyzed as having CDP with the time to CDP as the onset date of progression. If a patient died due to MS before having progression, then the time to disability progression was censored using the date of death.

3. Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48 [Baseline (Week 0), Weeks 12, 24, 36, 48]

   The T25FW is a quantitative mobility and leg function performance test based on the average time of two trials in which participants walk 25 feet as quickly as possible. In cases when a patient could not complete a T25FW trial due to the physical limitations, a value of 180 seconds was assigned for that trial (this is the maximal possible value for the T25FW test). Increasing time scores indicate increasing impairment. Baseline values are summaries of observed values. Week values are change from baseline values.

4. Number of New T2 Brain Lesions at Week 48 [Baseline (Week 0), 48 weeks]

   Inflammatory disease activity was assessed by magnetic resonance imaging (MRI) measurement of the number of new T2 lesions at week 48 as compared to baseline. Scans of patients who discontinued the study after week 36 are considered scans at week 48, and are included in week 48.

5. Participants With Treatment-Emergent Adverse Events (TEAEs) [Day 1 up to Week 130 (longest duration of treatment)]

   An adverse event (AE) was defined 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 usual activities. Relationship 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 25 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients must have a confirmed and documented PPMS diagnosis as defined by the 2010 Revised McDonald criteria

2. Baseline magnetic resonance imaging (MRI) showing lesions consistent with PPMS in either or both brain and spinal cord

3. Patients must have an Expanded Disability Status Scale (EDSS) score of 3 to 6.5, inclusive, at both screening and baseline visits

4. Documented evidence of clinical disability progression in the 2 years prior to screening.

5. Functional System Score (FSS) of > or equal 2 for the pyramidal system or gait impairment due to lower extremity dysfunction

6. Patients must be between 25 to 55 years of age, inclusive

7. Women of child-bearing potential must practice an acceptable method of birth control for 30 days before taking the study drug, and 2 acceptable methods of birth control during all study duration and until 30 days after the last dose of treatment is administered.

8. Patients must sign and date a written informed consent prior to entering the study.

9. Patients must be willing and able to comply with the protocol requirements for the duration of the study.

Exclusion Criteria:

1. Patients with history of any multiple sclerosis (MS) exacerbations or relapses, including any episodes of optic neuritis.

2. Progressive neurological disorder other than PPMS.

3. Any MRI record showing presence of cervical cord compression.

4. Baseline MRI showing other findings (including lesions that are atypical for PPMS) that may explain the clinical signs and symptoms.

5. Relevant history of vitamin B12 deficiency.

6. Positive human T-lymphotropic virus Type I and II (HTLV-I/II) serology.

7. Use of experimental or investigational drugs in a clinical study within 24 weeks prior to baseline. Use of a currently marketed drug in a clinical study within 24 weeks prior to baseline would not be exclusionary, provided no other exclusion criteria are met.

8. Use of immunosuppressive agents, or cytotoxic agents, including cyclophosphamide and azathioprine within 48 weeks prior to baseline.

9. Previous treatment with fingolimod (GILENYA®, Novartis), dimethyl fumarate (TECFIDERA®, Biogen Idec Inc), glatiramer acetate (COPAXONE®, Teva), interferon-β (either 1a or 1b), intravenous immunoglobulin, or plasmapheresis within 8 weeks prior to baseline.

10. Use of teriflunomide (AUBAGIO®, Sanofi) within 2 years prior to baseline, except if active washout (with either cholestyramine or activated charcoal) was done 2 months or more prior to baseline.

11. Prior use of monoclonal antibodies ever, except for:

12. natalizumab (TYSABRI®, Biogen Idec Inc), if given more than 24 weeks prior to baseline AND the patient is John Cunningham (JC) virus antibody test negative (as per medical history)

13. rituximab, ocrelizumab, or ofatumumab, if B cell count (CD19, as per medical history) is higher than 80 cells/μL

14. Use of mitoxantrone (NOVANTRONE®, Immunex) within 5 years prior to screening. Use of mitoxantrone >5 years before screening is allowed in patients with normal ejection fraction and who did not exceed the total lifetime maximal dose.

15. Previous use of laquinimod.

16. Chronic (eg, more than 30 consecutive days or monthly dosing, with the intent of MS disease modification) systemic (intravenous, intramuscular or oral) corticosteroid treatment within 8 weeks prior to baseline.

17. Previous use of cladribine or alemtuzumab (LEMTRADA®, Sanofi).

18. Previous total body irradiation or total lymphoid irradiation.

19. Previous stem cell treatment, cell-based treatment, or bone marrow transplantation of any kind.

20. Patients who underwent endovascular treatment for chronic cerebrospinal venous insufficiency (CCSVI) within 12 weeks prior to baseline.

21. Use of moderate/strong inhibitors of cytochrome P450 (CYP) 3A4 within 2 weeks prior to baseline.

22. Use of inducers of CYP3A4 within 2 weeks prior to baseline.

23. Pregnancy or breastfeeding.

24. Serum levels ≥3× upper limit of the normal range (ULN) of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at screening.

25. Serum direct bilirubin which is ≥2×ULN at screening.

26. Patients with a clinically significant or unstable medical or surgical condition that (in the opinion of the Investigator) would preclude safe and complete study participation, as determined by medical history, physical examinations, electrocardiogram (ECG), laboratory tests or chest X-ray.

27. A known history of hypersensitivity to gadolinium (Gd).

28. Glomerular filtration rate (GFR) < or equal 60 mL/min at screening visit.

29. Inability to successfully undergo MRI scanning, including claustrophobia.

30. Known drug hypersensitivity that would preclude administration of laquinimod, such as hypersensitivity to mannitol, meglumine or sodium stearyl fumarate.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Investigational Site 12966	Phoenix	Arizona	United States	85018
2	Teva Investigational Site 12967	Newport Beach	California	United States	92663
3	Teva Investigational Site 12962	San Francisco	California	United States	94158
4	Teva Investigational Site 12964	Aurora	Colorado	United States	80045
5	Teva Investigational Site 12973	Northbrook	Illinois	United States	60062
6	Teva Investigational Site 12975	Kansas City	Kansas	United States	66160-7314
7	Teva Investigational Site 12969	Lenexa	Kansas	United States	66214
8	Teva Investigational Site 12977	Golden Valley	Minnesota	United States	55422
9	Teva Investigational Site 13010	Golden Valley	Minnesota	United States	55422
10	Teva Investigational Site 12965	Chesterfield	Missouri	United States	63017
11	Teva Investigational Site 12968	Saint Louis	Missouri	United States	63110
12	Teva Investigational Site 12963	New York	New York	United States	10016
13	Teva Investigational Site 12971	Charlotte	North Carolina	United States	28207
14	Teva Investigational Site 12976	Columbus	Ohio	United States	43221
15	Teva Investigational Site 12970	Uniontown	Ohio	United States	44685
16	Teva Investigational Site 11089	Calgary	AL	Canada	T2N 4Z1
17	Teva Investigational Site 11084	Halifax	Nova Scotia	Canada	B3H 4K4
18	Teva Investigational Site 11081	Ottawa	Ontario	Canada	K1H 8L6
19	Teva Investigational Site 11087	Toronto	Ontario	Canada	M5B-1W8
20	Teva Investigational Site 11082	Montreal	Quebec	Canada	H3A 2B4
21	Teva Investigational Site 11088	Quebec		Canada	G1J 1Z4
22	Teva Investigational Site 32505	Bad Mergentheim		Germany	97980
23	Teva Investigational Site 32512	Bamberg		Germany	96049
24	Teva Investigational Site 32510	Berlin		Germany	10117
25	Teva Investigational Site 32522	Bochum		Germany	44791
26	Teva Investigational Site 32509	Dresden		Germany	01307
27	Teva Investigational Site 32517	Dusseldorf		Germany	40225
28	Teva Investigational Site 32543	Goettigen		Germany	37075
29	Teva Investigational Site 32514	Hamburg		Germany	20099
30	Teva Investigational Site 32507	Hannover		Germany	30625
31	Teva Investigational Site 32513	Munchen		Germany	81675
32	Teva Investigational Site 32504	Munchen		Germany	D-81377
33	Teva Investigational Site 32516	Rostock		Germany	18057
34	Teva Investigational Site 32523	Trier		Germany	54292
35	Teva Investigational Site 32503	Ulm		Germany	89081
36	Teva Investigational Site 32511	Wurzburg		Germany	97080
37	Teva Investigational Site 30106	Cefalu		Italy	90015
38	Teva Investigational Site 30110	Firenze		Italy	50134
39	Teva Investigational Site 30105	Gallarate		Italy	21013
40	Teva Investigational Site 30108	Genova		Italy	16132
41	Teva Investigational Site 30102	Milano		Italy	20127
42	Teva Investigational Site 30107	Orbassano		Italy	10043
43	Teva Investigational Site 30103	Padova		Italy	35128
44	Teva Investigational Site 30101	Rome		Italy	00133
45	Teva Investigational Site 30104	Rome		Italy	?00152
46	Teva Investigational Site 38068	Amsterdam		Netherlands	1081 HV
47	Teva Investigational Site 38067	Nijmegen		Netherlands	6532 SZ
48	Teva Investigational Site 38069	Sittard		Netherlands	6162 BG
49	Teva Investigational Site 53262	Bialystok		Poland	15-402
50	Teva Investigational Site 53250	Bydgoszcz		Poland	85-795
51	Teva Investigational Site 53253	Gdansk		Poland	80-803
52	Teva Investigational Site 53257	Katowice		Poland	40-635
53	Teva Investigational Site 53258	Katowice		Poland	40-684
54	Teva Investigational Site 53256	Katowice		Poland	40-749
55	Teva Investigational Site 53255	Kielce		Poland	25-726
56	Teva Investigational Site 53260	Lublin		Poland	20-954
57	Teva Investigational Site 53261	Olsztyn		Poland	10-560
58	Teva Investigational Site 53252	Warsaw		Poland	02-957
59	Teva Investigational Site 50285	Kaluga		Russian Federation	248007
60	Teva Investigational Site 50288	Kazan		Russian Federation	420021
61	Teva Investigational Site 50290	Kazan		Russian Federation	420103
62	Teva Investigational Site 50294	Kirov		Russian Federation	610006
63	Teva Investigational Site 50292	Krasnoyarsk		Russian Federation	660022
64	Teva Investigational Site 50287	Moscow		Russian Federation	127018
65	Teva Investigational Site 50291	Nizhny Novgorod		Russian Federation	603126
66	Teva Investigational Site 50286	Novosibirsk		Russian Federation	630007
67	Teva Investigational Site 50295	Perm		Russian Federation	614990
68	Teva Investigational Site 50293	Saint Petersburg		Russian Federation	197022
69	Teva Investigational Site 50289	St. Petersburg		Russian Federation	194044
70	Teva Investigational Site 31108	Barcelona		Spain	08036
71	Teva Investigational Site 31106	Barcelona		Spain	8035
72	Teva Investigational Site 31105	El Palmar		Spain	30120
73	Teva Investigational Site 31111	Lleida		Spain	25198
74	Teva Investigational Site 31112	Madrid		Spain	28040
75	Teva Investigational Site 31192	Madrid		Spain	28223
76	Teva Investigational Site 31101	Malaga		Spain	29010
77	Teva Investigational Site 31104	San Sebastian		Spain	20014
78	Teva Investigational Site 31102	Sevilla		Spain	41009
79	Teva Investigational Site 31100	Valencia		Spain	46026
80	Teva Investigational Site 58158	Dnipropetrovsk		Ukraine	49005
81	Teva Investigational Site 58159	Ivano-Frankivsk		Ukraine	76014
82	Teva Investigational Site 58157	Kharkiv		Ukraine	61068
83	Teva Investigational Site 58160	Kyiv		Ukraine	?03110
84	Teva Investigational Site 58152	Lutsk		Ukraine	43005
85	Teva Investigational Site 58154	Lviv		Ukraine	79010
86	Teva Investigational Site 58153	Lviv		Ukraine	79044
87	Teva Investigational Site 58156	Zaporizhzhia		Ukraine	69068
88	Teva Investigational Site 58150	Zaporizhzhya		Ukraine	69035
89	Teva Investigational Site 58151	Zaporizhzhya		Ukraine	69600
90	Teva Investigational Site 34190	Bristol		United Kingdom	BS10 5NB
91	Teva Investigational Site 34188	Edinburgh		United Kingdom	EH4 2XU
92	Teva Investigational Site 34189	Exeter		United Kingdom	EX2 5DW
93	Teva Investigational Site 34182	Liverpool		United Kingdom	L9 7LJ
94	Teva Investigational Site 34181	London		United Kingdom	E1 2AT
95	Teva Investigational Site 34183	Nottingham		United Kingdom	NG7 2UH
96	Teva Investigational Site 34184	Oxford		United Kingdom	OX3 9DU
97	Teva Investigational Site 34186	Plymouth		United Kingdom	PL6 8DH
98	Teva Investigational Site 34185	Stoke-on-Trent		United Kingdom	ST4 6GQ
99	Teva Investigational Site 34187	Swansea		United Kingdom	SA6 6NL

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

• Study Director: Teva Medical Expert, MD, Teva Branded Pharmaceutical Products R&D, Inc.

Study Documents (Full-Text)

• Study Protocol - Feb 1, 2016
• Statistical Analysis Plan - Jun 1, 2017

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT02284568
• Other Study ID Numbers: TV5600-CNS-20006; 2014-001579-30
• First Posted: Nov 6, 2014
• Last Update Posted: Mar 10, 2022
• Last Verified: Mar 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Teva Branded Pharmaceutical Products R&D, Inc.: multiple sclerosis; primary progressive multiple sclerosis; oral immunomodulator
• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis

Study Results

Participant Flow

Pre-assignment Detail	A total of 447 patients were screened for enrollment into this study. Of the patients screened, 374 patients met entry criteria and were enrolled into the study. One participant withdrew before taking any study drug.

Arm/Group Title	Placebo	Laquinimod 0.6 mg	Laquinimod 1.5 mg
Arm/Group Description	3 capsules containing placebo were administered orally once daily for at least 48 weeks.	1 capsule containing 0.6 mg laquinimod and 2 capsules containing placebo were administered orally once daily for at least 48 weeks.	3 capsules containing 0.5 mg laquinimod were administered orally once daily for at least 48 weeks. However this arm was discontinued as of 01 January 2016 and no participants reached the 48 week timeframe.
Period Title: Overall Study
STARTED	140	139	95
Safety Population	140	138	95
Completed Week 48 MRI - on Treatment	113	107	0
COMPLETED	109	93	0
NOT COMPLETED	31	46	95

Baseline Characteristics

Arm/Group Title	Placebo	Laquinimod 0.6 mg	Laquinimod 1.5 mg	Total
Arm/Group Description	3 capsules containing placebo were administered orally once daily for at least 48 weeks.	1 capsule containing 0.6 mg laquinimod and 2 capsules containing placebo were administered orally once daily for at least 48 weeks.	3 capsules containing 0.5 mg laquinimod were administered orally once daily for at least 48 weeks. However this arm was discontinued as of 01 January 2016 and no participants reached the 48 week timeframe.	Total of all reporting groups
Overall Participants	140	139	95	374
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.6 (7.18)	46.1 (6.68)	46.1 (7.21)	46.3 (6.99)
Sex: Female, Male (Count of Participants)
Female	67 47.9%	57 41%	45 47.4%	169 45.2%
Male	73 52.1%	82 59%	50 52.6%	205 54.8%
Race/Ethnicity, Customized (Count of Participants)
White	138 98.6%	132 95%	92 96.8%	362 96.8%
Black	0 0%	2 1.4%	2 2.1%	4 1.1%
Asian	0 0%	2 1.4%	0 0%	2 0.5%
Other	2 1.4%	3 2.2%	1 1.1%	6 1.6%
Race/Ethnicity, Customized (Count of Participants)
Not HIspanic or Latino	135 96.4%	134 96.4%	91 95.8%	360 96.3%
Hispanic or Latino	4 2.9%	5 3.6%	1 1.1%	10 2.7%
Unknown	1 0.7%	0 0%	3 3.2%	4 1.1%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	73.97 (16.809)	75.91 (16.668)	73.47 (14.831)	74.57 (16.275)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	171.25 (9.818)	172.61 (9.246)	171.03 (9.677)	171.70 (9.573)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	25.136 (5.0283)	25.373 (4.5539)	25.026 (4.1002)	25.196 (4.6208)
Time Since First MS Symptom (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	7.4 (5.22)	8.3 (6.33)	8.5 (5.61)	8.0 (5.76)
Time Since First PPMS Diagnosis (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	3.1 (2.98)	4.0 (4.05)	4.1 (4.04)	3.7 (3.70)
Normalized Brain Volume (mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mL]	1457.9 (109.78)	1461.3 (96.63)	1455.2 (101.44)	1458.5 (102.69)
Expanded Disability Status Scale (EDSS) (Count of Participants)
EDSS score 3	10 7.1%	12 8.6%	10 10.5%	32 8.6%
EDSS score 3.5	27 19.3%	25 18%	20 21.1%	72 19.3%
EDSS score 4	24 17.1%	30 21.6%	18 18.9%	72 19.3%
EDSS score 4.5	26 18.6%	19 13.7%	17 17.9%	62 16.6%
EDSS score 5	17 12.1%	15 10.8%	6 6.3%	38 10.2%
EDSS score 5.5	24 17.1%	23 16.5%	16 16.8%	63 16.8%
EDSS score 6	9 6.4%	12 8.6%	4 4.2%	25 6.7%
EDSS score 6.5	3 2.1%	3 2.2%	4 4.2%	10 2.7%

Outcome Measures

1. Primary Outcome

Title	Percent Brain Volume Change (PBVC) From Baseline to Week 48 Using a Repeated Measures ANCOVA Model
Description	Brain atrophy (BA) was measured using magnetic resonance imaging (MRI) scans of the brain. BA was analyzed using baseline-adjusted repeated measures analysis of covariance (ANCOVA- SAS® PROC MIXED) in which 1 contrast was constructed in order to compare between laquinimod 0.6 mg and placebo. The statistical model was a repeated measures analysis of covariance with treatment group, week, treatment group by week interaction, normalized brain volume at baseline, natural logarithm of T2 lesion volume at baseline, and country as fixed effects. Only on-treatment observations (include all the assessments done up to one month after the last dose of the study drug) were included. Values are adjusted means. The cancelled laquinimod 1.5 mg treatment arm was not included in the repeated measures ANCOVA model analysis. However PBVC by visit data are offered in outcome #2.
Time Frame	Baseline (at least 14 days but not more than 6 weeks prior to Day 1), Weeks 24, 48 and including early termination visits

Outcome Measure Data

Analysis Population Description

Modified Intent to Treat 1 (mITT1) population with at least 1 post-baseline PBVC value and will include assessments taken up to/including early termination/study completion visit.

Arm/Group Title	Placebo	Laquinimod 0.6 mg	Laquinimod 1.5 mg
Arm/Group Description	3 capsules containing placebo were administered orally once daily for at least 48 weeks.	1 capsule containing 0.6 mg laquinimod and 2 capsules containing placebo were administered orally once daily for at least 48 weeks.	3 capsules containing 0.5 mg laquinimod were administered orally once daily for at least 48 weeks. However this arm was discontinued as of 01 January 2016 and no participants reached the 48 week timeframe.
Measure Participants	128	124	0
Mean (Standard Error) [percentage change from baseline]	-0.454 (0.0897)	-0.438 (0.0945)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Laquinimod 0.6 mg
	Comments	The statistical model was a repeated measures analysis of covariance with treatment group, week, treatment group by week interaction, normalized brain volume at baseline, natural logarithm of T2 lesion volume at baseline, and country as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.903
	Comments	significance at 0.05.
	Method	Repeated Measures ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.016
	Confidence Interval	(2-Sided) 95%; -0.2390 to 0.2705
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1293
	Estimation Comments

2. Primary Outcome

Title	Percent Brain Volume Change (PBVC) From Baseline to Weeks 24 and 48
Description	Brain atrophy (BA) was measured using magnetic resonance imaging (MRI) scans of the brain. Early termination scans of participants who discontinued the study after week 36 are considered scans at week 48.
Time Frame	Baseline (at least 14 days but not more than 6 weeks prior to Day 1), Weeks 24, 48

Outcome Measure Data

Analysis Population Description

Modified Intent to Treat 1 (mITT1) population with at least 1 post-baseline PBVC value.

Arm/Group Title	Placebo	Laquinimod 0.6 mg	Laquinimod 1.5 mg
Arm/Group Description	3 capsules containing placebo were administered orally once daily for at least 48 weeks.	1 capsule containing 0.6 mg laquinimod and 2 capsules containing placebo were administered orally once daily for at least 48 weeks.	3 capsules containing 0.5 mg laquinimod were administered orally once daily for at least 48 weeks. However this arm was discontinued as of 01 January 2016 and no participants reached the 48 week timeframe.
Measure Participants	131	128	47
Week 24	-0.241 (0.8978)	-0.042 (0.7537)	-0.820 (1.2693)
Week 48	-0.455 (0.9770)	-0.418 (0.9806)	0.550

3. Secondary Outcome

Title	Percentage of Participants With 12-Week Confirmed Disability Progression (CDP) As Measured by Expanded Disability Status Scale (EDSS) up to Week 48
Description	CDP was defined as increase in EDSS of >=1 point from baseline EDSS, if EDSS at entry is ≤5.0 or increase of >=0.5 point, if EDSS at entry is >=5.5. This increase should be confirmed after at least 12 weeks. Progression cannot be confirmed during a protocol defined relapse. EDSS is a method of quantifying disability in multiple sclerosis and monitoring changes in the level of disability over time. The EDSS scale ranges from 0 to 10 in 0.5 unit increments with 0=no disability and 10=death due to MS. Only an Examining Neurologist administered the EDSS. The Examining Neurologist did not have access to the patient's medical records or source documents, including previous EDSS forms or adverse events. If a patient died due to MS disease progression, the patient was analyzed as having CDP with the time to CDP as the onset date of progression. If a patient died due to MS before having progression, then the time to disability progression was censored using the date of death.
Time Frame	Baseline (Week 0), Weeks 12, 24, 36, 48 (end if treatment if < 48 weeks)

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Placebo	Laquinimod 0.6 mg	Laquinimod 1.5 mg
Arm/Group Description	3 capsules containing placebo were administered orally once daily for at least 48 weeks.	1 capsule containing 0.6 mg laquinimod and 2 capsules containing placebo were administered orally once daily for at least 48 weeks.	3 capsules containing 0.5 mg laquinimod were administered orally once daily for at least 48 weeks. However this arm was discontinued as of 01 January 2016 and no participants reached the 48 week timeframe.
Measure Participants	140	139	95
Number [percentage of participants]	23 16.4%	17 12.2%	1 1.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Laquinimod 0.6 mg
	Comments	The statistical model was a Cox proportional hazards regression model with treatment group, categorical EDSS at baseline (≤4.5 or >4.5), age at baseline, natural logarithm of T2 lesion volume at baseline, and country as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.426
	Comments	significance at 0.05. p-value was from a log-rank test, and estimate and confidence limits were from a Cox model with treatment group as fixed effect, due to the violation of the proportionality assumption.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; 0.48 to 1.37
	Parameter Dispersion	Type: Value:
	Estimation Comments	Laquinimod 0.6 mg vs placebo

4. Secondary Outcome

Title	Percentage of Participants With 12-Week Confirmed Disability Progression (CDP) As Measured by Expanded Disability Status Scale (EDSS) or the Timed 25-foot Walk (T25FW) Test up to Week 48
Description	CDP was defined as increase in EDSS of >=1 point from baseline EDSS, if EDSS at entry is ≤5.0 or increase of >=0.5 point, if EDSS at entry is >=5.5 confirmed after at least 12 weeks, OR increase of >= 20% from baseline in the T25FW test, confirmed after at least 12 weeks. EDSS quantifies disability in MS and monitors changes in the level of disability over time. The EDSS scale is 0-10 in 0.5 unit increments with 0=no disability and 10=death due to MS. The T25-FW is a quantitative mobility and leg function performance test based on the average time of two trials in which participants walk 25 feet as quickly as possible. Increasing time scores indicate increasing impairment. If a patient died due to MS disease progression, the patient was analyzed as having CDP with the time to CDP as the onset date of progression. If a patient died due to MS before having progression, then the time to disability progression was censored using the date of death.
Time Frame	Baseline (Week 0), Weeks 12, 24, 36, 48 (end if treatment if < 48 weeks)

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Placebo	Laquinimod 0.6 mg	Laquinimod 1.5 mg
Arm/Group Description	3 capsules containing placebo were administered orally once daily for at least 48 weeks.	1 capsule containing 0.6 mg laquinimod and 2 capsules containing placebo were administered orally once daily for at least 48 weeks.	3 capsules containing 0.5 mg laquinimod were administered orally once daily for at least 48 weeks. However this arm was discontinued as of 01 January 2016 and no participants reached the 48 week timeframe.
Measure Participants	140	139	95
Number [percentage of participants]	34 24.3%	32 23%	2 2.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Laquinimod 0.6 mg
	Comments	The statistical model was a Cox proportional hazards regression model with treatment group, categorical EDSS at baseline (≤4.5 or >4.5), age at baseline, natural logarithm of T2 lesion volume at baseline, and country as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.867
	Comments	significance at 0.05.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; 0.68 to 1.59
	Parameter Dispersion	Type: Value:
	Estimation Comments	Laquinimod 0.6 mg vs placebo

5. Secondary Outcome

Title	Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48
Description	The T25FW is a quantitative mobility and leg function performance test based on the average time of two trials in which participants walk 25 feet as quickly as possible. In cases when a patient could not complete a T25FW trial due to the physical limitations, a value of 180 seconds was assigned for that trial (this is the maximal possible value for the T25FW test). Increasing time scores indicate increasing impairment. Baseline values are summaries of observed values. Week values are change from baseline values.
Time Frame	Baseline (Week 0), Weeks 12, 24, 36, 48

Outcome Measure Data

Analysis Population Description

Modified Intent to Treat #2 (mITT2) population is a subset of the ITT population. It includes all participants in the ITT population with at least 1 post baseline efficacy assessment other than PBVC.

Arm/Group Title	Placebo	Laquinimod 0.6 mg	Laquinimod 1.5 mg
Arm/Group Description	3 capsules containing placebo were administered orally once daily for at least 48 weeks.	1 capsule containing 0.6 mg laquinimod and 2 capsules containing placebo were administered orally once daily for at least 48 weeks.	3 capsules containing 0.5 mg laquinimod were administered orally once daily for at least 48 weeks. However this arm was discontinued as of 01 January 2016 and no participants reached the 48 week timeframe.
Measure Participants	139	137	89
Baseline	7.750	7.600	6.850
Week 12	0.100	0.050	0.100
Week 24	0.100	0.350	0.150
Week 36	0.200	0.450	12.550
Week 48	0.300	0.050

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Laquinimod 0.6 mg
	Comments	placebo n=121 Laquinimod 0.6 mg n=108 The estimate of parameter, standard error, and 95% confidence intervals for change from baseline was from a Mann-Whitney-Wilcoxon Test using Hodges-Lehmann estimates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.248
	Comments	significance at 0.05. The p-value for ranked change from baseline values was from a repeated measures analysis of covariance with trt group, week, treatment group by week interaction, rank of T25FW score at baseline, and country as fixed effects.
	Method	Repeated Measures ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.325
	Confidence Interval	(2-Sided) 95%; -0.8500 to 0.2000
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.2679
	Estimation Comments	Laquinimod 0.6 mg vs. placebo treatment effect

6. Secondary Outcome

Title	Number of New T2 Brain Lesions at Week 48
Description	Inflammatory disease activity was assessed by magnetic resonance imaging (MRI) measurement of the number of new T2 lesions at week 48 as compared to baseline. Scans of patients who discontinued the study after week 36 are considered scans at week 48, and are included in week 48.
Time Frame	Baseline (Week 0), 48 weeks

Outcome Measure Data

Analysis Population Description

Modified intent to treat 1 (mITT1) population includes participants with at least 1 post-baseline PBVC value. Participants from the mITT1 with MRI data at week 48 are reported .

Arm/Group Title	Placebo	Laquinimod 0.6 mg	Laquinimod 1.5 mg
Arm/Group Description	3 capsules containing placebo were administered orally once daily for at least 48 weeks.	1 capsule containing 0.6 mg laquinimod and 2 capsules containing placebo were administered orally once daily for at least 48 weeks.	3 capsules containing 0.5 mg laquinimod were administered orally once daily for at least 48 weeks. However this arm was discontinued as of 01 January 2016 and no participants reached the 48 week timeframe.
Measure Participants	119	112	1
Mean (Standard Deviation) [lesions]	3.5 (10.82)	1.3 (3.01)	1.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Laquinimod 0.6 mg
	Comments	This analysis was performed using baseline adjusted negative binomial regression model (SAS® PROC GENMOD) in which 1 contrast for comparing laquinimod 0.6 mg to placebo was constructed. In addition to the treatment group, the natural logarithm of T2 lesion volume at baseline, age at baseline and country/geographical region (CGR) were used as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	significance at 0.05
	Method	negative binomial regression model
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95%; 0.26 to 0.69
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments	Laquinimod 0.6 mg vs. placebo risk ratio

7. Secondary Outcome

Title	Participants With Treatment-Emergent Adverse Events (TEAEs)
Description	An adverse event (AE) was defined 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 usual activities. Relationship 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.
Time Frame	Day 1 up to Week 130 (longest duration of treatment)

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Placebo	Laquinimod 0.6 mg	Laquinimod 1.5 mg
Arm/Group Description	3 capsules containing placebo were administered orally once daily for at least 48 weeks.	1 capsule containing 0.6 mg laquinimod and 2 capsules containing placebo were administered orally once daily for at least 48 weeks.	3 capsules containing 0.5 mg laquinimod were administered orally once daily for at least 48 weeks. However this arm was discontinued as of 01 January 2016 and no participants reached the 48 week timeframe.
Measure Participants	140	138	95
Any TEAE	109 77.9%	115 82.7%	63 66.3%
Severe TEAE	6 4.3%	6 4.3%	3 3.2%
Treatment-related TEAE	27 19.3%	41 29.5%	29 30.5%
Deaths	0 0%	0 0%	1 1.1%
Serious TEAE	6 4.3%	10 7.2%	3 3.2%
Withdrawn from treatment due to TEAE	2 1.4%	8 5.8%	4 4.2%

Adverse Events

Time Frame	Day 1 up to Week 130 (longest duration of treatment)
Arm/Group Title	Placebo		Laquinimod 0.6 mg		Laquinimod 1.5 mg
Arm/Group Description	3 capsules containing placebo were administered orally once daily for at least 48 weeks.		1 capsule containing 0.6 mg laquinimod and 2 capsules containing placebo were administered orally once daily for at least 48 weeks.		3 capsules containing 0.5 mg laquinimod were administered orally once daily for at least 48 weeks. However this arm was discontinued as of 01 January 2016 and no participants reached the 48 week timeframe.
All Cause Mortality
	Placebo		Laquinimod 0.6 mg		Laquinimod 1.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/140 (0%)		0/138 (0%)		1/95 (1.1%)
Serious Adverse Events
	Placebo		Laquinimod 0.6 mg		Laquinimod 1.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/140 (4.3%)		10/138 (7.2%)		3/95 (3.2%)
Cardiac disorders
Acute myocardial infarction	1/140 (0.7%)	1	0/138 (0%)	0	0/95 (0%)	0
Angina unstable	0/140 (0%)	0	0/138 (0%)	0	1/95 (1.1%)	1
General disorders
Influenza like illness	1/140 (0.7%)	1	0/138 (0%)	0	0/95 (0%)	0
Oedema peripheral	0/140 (0%)	0	1/138 (0.7%)	1	0/95 (0%)	0
Infections and infestations
Bacterial pyelonephritis	0/140 (0%)	0	1/138 (0.7%)	1	0/95 (0%)	0
Pneumonia	0/140 (0%)	0	1/138 (0.7%)	1	0/95 (0%)	0
Testicular abscess	0/140 (0%)	0	0/138 (0%)	0	1/95 (1.1%)	1
Urinary tract infection	2/140 (1.4%)	2	1/138 (0.7%)	1	0/95 (0%)	0
Urosepsis	0/140 (0%)	0	1/138 (0.7%)	1	0/95 (0%)	0
Injury, poisoning and procedural complications
Radius fracture	0/140 (0%)	0	1/138 (0.7%)	1	0/95 (0%)	0
Subdural haematoma	1/140 (0.7%)	1	0/138 (0%)	0	0/95 (0%)	0
Investigations
HIV test positive	0/140 (0%)	0	1/138 (0.7%)	1	0/95 (0%)	0
Metabolism and nutrition disorders
Hypokalaemia	1/140 (0.7%)	1	0/138 (0%)	0	0/95 (0%)	0
Musculoskeletal and connective tissue disorders
Intervertebral disc disorder	1/140 (0.7%)	1	0/138 (0%)	0	0/95 (0%)	0
Muscle spasms	0/140 (0%)	0	1/138 (0.7%)	1	0/95 (0%)	0
Nervous system disorders
Dizziness	0/140 (0%)	0	1/138 (0.7%)	1	0/95 (0%)	0
Facial paralysis	0/140 (0%)	0	1/138 (0.7%)	1	0/95 (0%)	0
Lumbosacral plexopathy	0/140 (0%)	0	0/138 (0%)	0	1/95 (1.1%)	1
Multiple sclerosis relapse	1/140 (0.7%)	1	1/138 (0.7%)	1	0/95 (0%)	0
Neuromyelitis optica spectrum disorder	0/140 (0%)	0	0/138 (0%)	0	1/95 (1.1%)	1
Renal and urinary disorders
Acute kidney injury	1/140 (0.7%)	1	0/138 (0%)	0	0/95 (0%)	0
Urinary retention	0/140 (0%)	0	1/138 (0.7%)	1	0/95 (0%)	0
Reproductive system and breast disorders
Uterine haemorrhage	0/140 (0%)	0	1/138 (0.7%)	1	0/95 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Laquinimod 0.6 mg		Laquinimod 1.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	77/140 (55%)		74/138 (53.6%)		40/95 (42.1%)
Gastrointestinal disorders
Abdominal pain upper	3/140 (2.1%)	4	5/138 (3.6%)	5	5/95 (5.3%)	5
Constipation	6/140 (4.3%)	8	7/138 (5.1%)	7	3/95 (3.2%)	3
Diarrhoea	6/140 (4.3%)	7	9/138 (6.5%)	12	1/95 (1.1%)	1
Nausea	3/140 (2.1%)	3	4/138 (2.9%)	4	6/95 (6.3%)	6
General disorders
Fatigue	5/140 (3.6%)	5	7/138 (5.1%)	7	3/95 (3.2%)	3
Infections and infestations
Influenza	13/140 (9.3%)	15	7/138 (5.1%)	7	2/95 (2.1%)	2
Nasopharyngitis	24/140 (17.1%)	31	24/138 (17.4%)	34	4/95 (4.2%)	4
Upper respiratory tract infection	6/140 (4.3%)	7	12/138 (8.7%)	16	2/95 (2.1%)	2
Urinary tract infection	11/140 (7.9%)	16	9/138 (6.5%)	13	4/95 (4.2%)	4
Injury, poisoning and procedural complications
Fall	9/140 (6.4%)	13	9/138 (6.5%)	15	4/95 (4.2%)	4
Musculoskeletal and connective tissue disorders
Arthralgia	6/140 (4.3%)	6	8/138 (5.8%)	10	6/95 (6.3%)	8
Back pain	15/140 (10.7%)	17	12/138 (8.7%)	15	5/95 (5.3%)	5
Pain in extremity	8/140 (5.7%)	8	6/138 (4.3%)	6	1/95 (1.1%)	2
Nervous system disorders
Headache	16/140 (11.4%)	28	14/138 (10.1%)	16	15/95 (15.8%)	18

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.