Clinical trial NCT02284568: 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
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Primary Progressive Multiple Sclerosis
Keywords: multiple sclerosis
primary progressive multiple sclerosis
oral immunomodulator
Lead sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Sponsor class: INDUSTRY
First posted: 2014-11-06
Enrollment: 374
Sex: ALL
Minimum age (years): 25
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Eligibility criteria: 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:

    1. 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)
    2. rituximab, ocrelizumab, or ofatumumab, if B cell count (CD19, as per medical history) is higher than 80 cells/μL
12. 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.
13. Previous use of laquinimod.
14. 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.
15. Previous use of cladribine or alemtuzumab (LEMTRADA®, Sanofi).
16. Previous total body irradiation or total lymphoid irradiation.
17. Previous stem cell treatment, cell-based treatment, or bone marrow transplantation of any kind.
18. Patients who underwent endovascular treatment for chronic cerebrospinal venous insufficiency (CCSVI) within 12 weeks prior to baseline.
19. Use of moderate/strong inhibitors of cytochrome P450 (CYP) 3A4 within 2 weeks prior to baseline.
20. Use of inducers of CYP3A4 within 2 weeks prior to baseline.
21. Pregnancy or breastfeeding.
22. Serum levels ≥3× upper limit of the normal range (ULN) of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at screening.
23. Serum direct bilirubin which is ≥2×ULN at screening.
24. 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.
25. A known history of hypersensitivity to gadolinium (Gd).
26. Glomerular filtration rate (GFR) \< or equal 60 mL/min at screening visit.
27. Inability to successfully undergo MRI scanning, including claustrophobia.
28. Known drug hypersensitivity that would preclude administration of laquinimod, such as hypersensitivity to mannitol, meglumine or sodium stearyl fumarate.

Primary outcomes:
measure: Percent Brain Volume Change (PBVC) From Baseline to Week 48 Using a Repeated Measures ANCOVA Model
timeFrame: Baseline (at least 14 days but not more than 6 weeks prior to Day 1), Weeks 24, 48 and including early termination visits
measure: Percent Brain Volume Change (PBVC) From Baseline to Weeks 24 and 48
timeFrame: Baseline (at least 14 days but not more than 6 weeks prior to Day 1), Weeks 24, 48
Secondary outcomes:
measure: Percentage of Participants With 12-Week Confirmed Disability Progression (CDP) As Measured by Expanded Disability Status Scale (EDSS) up to Week 48
timeFrame: Baseline (Week 0), Weeks 12, 24, 36, 48 (end if treatment if < 48 weeks)
measure: 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
timeFrame: Baseline (Week 0), Weeks 12, 24, 36, 48 (end if treatment if < 48 weeks)
measure: Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48
timeFrame: Baseline (Week 0), Weeks 12, 24, 36, 48
measure: Number of New T2 Brain Lesions at Week 48
timeFrame: Baseline (Week 0), 48 weeks
measure: Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Day 1 up to Week 130 (longest duration of treatment)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Teva Investigational Site 12966
state: Arizona
city: Newport Beach
country: United States
facility: Teva Investigational Site 12967
state: California
city: San Francisco
country: United States
facility: Teva Investigational Site 12962
state: California
city: Aurora
country: United States
facility: Teva Investigational Site 12964
state: Colorado
city: Northbrook
country: United States
facility: Teva Investigational Site 12973
state: Illinois
city: Kansas City
country: United States
facility: Teva Investigational Site 12975
state: Kansas
city: Lenexa
country: United States
facility: Teva Investigational Site 12969
state: Kansas
city: Golden Valley
country: United States
facility: Teva Investigational Site 12977
state: Minnesota
city: Golden Valley
country: United States
facility: Teva Investigational Site 13010
state: Minnesota
city: Chesterfield
country: United States
facility: Teva Investigational Site 12965
state: Missouri
city: Saint Louis
country: United States
facility: Teva Investigational Site 12968
state: Missouri
city: New York
country: United States
facility: Teva Investigational Site 12963
state: New York
city: Charlotte
country: United States
facility: Teva Investigational Site 12971
state: North Carolina
city: Columbus
country: United States
facility: Teva Investigational Site 12976
state: Ohio
city: Uniontown
country: United States
facility: Teva Investigational Site 12970
state: Ohio
city: Calgary
country: Canada
facility: Teva Investigational Site 11089
state: AL
city: Halifax
country: Canada
facility: Teva Investigational Site 11084
state: Nova Scotia
city: Ottawa
country: Canada
facility: Teva Investigational Site 11081
state: Ontario
city: Toronto
country: Canada
facility: Teva Investigational Site 11087
state: Ontario
city: Montreal
country: Canada
facility: Teva Investigational Site 11082
state: Quebec
city: Quebec
country: Canada
facility: Teva Investigational Site 11088
city: Bad Mergentheim
country: Germany
facility: Teva Investigational Site 32505
city: Bamberg
country: Germany
facility: Teva Investigational Site 32512
city: Berlin
country: Germany
facility: Teva Investigational Site 32510
city: Bochum
country: Germany
facility: Teva Investigational Site 32522
city: Dresden
country: Germany
facility: Teva Investigational Site 32509
city: Dusseldorf
country: Germany
facility: Teva Investigational Site 32517
city: Goettigen
country: Germany
facility: Teva Investigational Site 32543
city: Hamburg
country: Germany
facility: Teva Investigational Site 32514
city: Hannover
country: Germany
facility: Teva Investigational Site 32507
city: Munchen
country: Germany
facility: Teva Investigational Site 32513
city: Munchen
country: Germany
facility: Teva Investigational Site 32504
city: Rostock
country: Germany
facility: Teva Investigational Site 32516
city: Trier
country: Germany
facility: Teva Investigational Site 32523
city: Ulm
country: Germany
facility: Teva Investigational Site 32503
city: Wurzburg
country: Germany
facility: Teva Investigational Site 32511
city: Cefalu
country: Italy
facility: Teva Investigational Site 30106
city: Firenze
country: Italy
facility: Teva Investigational Site 30110
city: Gallarate
country: Italy
facility: Teva Investigational Site 30105
city: Genova
country: Italy
facility: Teva Investigational Site 30108
city: Milano
country: Italy
facility: Teva Investigational Site 30102
city: Orbassano
country: Italy
facility: Teva Investigational Site 30107
city: Padova
country: Italy
facility: Teva Investigational Site 30103
city: Rome
country: Italy
facility: Teva Investigational Site 30101
city: Rome
country: Italy
facility: Teva Investigational Site 30104
city: Amsterdam
country: Netherlands
facility: Teva Investigational Site 38068
city: Nijmegen
country: Netherlands
facility: Teva Investigational Site 38067
city: Sittard
country: Netherlands
facility: Teva Investigational Site 38069
city: Bialystok
country: Poland
facility: Teva Investigational Site 53262
city: Bydgoszcz
country: Poland
facility: Teva Investigational Site 53250
city: Gdansk
country: Poland
facility: Teva Investigational Site 53253
city: Katowice
country: Poland
facility: Teva Investigational Site 53257
city: Katowice
country: Poland
facility: Teva Investigational Site 53258
city: Katowice
country: Poland
facility: Teva Investigational Site 53256
city: Kielce
country: Poland
facility: Teva Investigational Site 53255
city: Lublin
country: Poland
facility: Teva Investigational Site 53260
city: Olsztyn
country: Poland
facility: Teva Investigational Site 53261
city: Warsaw
country: Poland
facility: Teva Investigational Site 53252
city: Kaluga
country: Russian Federation
facility: Teva Investigational Site 50285
city: Kazan
country: Russian Federation
facility: Teva Investigational Site 50288
city: Kazan
country: Russian Federation
facility: Teva Investigational Site 50290
city: Kirov
country: Russian Federation
facility: Teva Investigational Site 50294
city: Krasnoyarsk
country: Russian Federation
facility: Teva Investigational Site 50292
city: Moscow
country: Russian Federation
facility: Teva Investigational Site 50287
city: Nizhny Novgorod
country: Russian Federation
facility: Teva Investigational Site 50291
city: Novosibirsk
country: Russian Federation
facility: Teva Investigational Site 50286
city: Perm
country: Russian Federation
facility: Teva Investigational Site 50295
city: Saint Petersburg
country: Russian Federation
facility: Teva Investigational Site 50293
city: St. Petersburg
country: Russian Federation
facility: Teva Investigational Site 50289
city: Barcelona
country: Spain
facility: Teva Investigational Site 31108
city: Barcelona
country: Spain
facility: Teva Investigational Site 31106
city: El Palmar
country: Spain
facility: Teva Investigational Site 31105
city: Lleida
country: Spain
facility: Teva Investigational Site 31111
city: Madrid
country: Spain
facility: Teva Investigational Site 31112
city: Madrid
country: Spain
facility: Teva Investigational Site 31192
city: Malaga
country: Spain
facility: Teva Investigational Site 31101
city: San Sebastian
country: Spain
facility: Teva Investigational Site 31104
city: Sevilla
country: Spain
facility: Teva Investigational Site 31102
city: Valencia
country: Spain
facility: Teva Investigational Site 31100
city: Dnipropetrovsk
country: Ukraine
facility: Teva Investigational Site 58158
city: Ivano-Frankivsk
country: Ukraine
facility: Teva Investigational Site 58159
city: Kharkiv
country: Ukraine
facility: Teva Investigational Site 58157
city: Kyiv
country: Ukraine
facility: Teva Investigational Site 58160
city: Lutsk
country: Ukraine
facility: Teva Investigational Site 58152
city: Lviv
country: Ukraine
facility: Teva Investigational Site 58154
city: Lviv
country: Ukraine
facility: Teva Investigational Site 58153
city: Zaporizhzhia
country: Ukraine
facility: Teva Investigational Site 58156
city: Zaporizhzhya
country: Ukraine
facility: Teva Investigational Site 58150
city: Zaporizhzhya
country: Ukraine
facility: Teva Investigational Site 58151
city: Bristol
country: United Kingdom
facility: Teva Investigational Site 34190
city: Edinburgh
country: United Kingdom
facility: Teva Investigational Site 34188
city: Exeter
country: United Kingdom
facility: Teva Investigational Site 34189
city: Liverpool
country: United Kingdom
facility: Teva Investigational Site 34182
city: London
country: United Kingdom
facility: Teva Investigational Site 34181
city: Nottingham
country: United Kingdom
facility: Teva Investigational Site 34183
city: Oxford
country: United Kingdom
facility: Teva Investigational Site 34184
city: Plymouth
country: United Kingdom
facility: Teva Investigational Site 34186
city: Stoke-on-Trent
country: United Kingdom
facility: Teva Investigational Site 34185
city: Swansea
country: United Kingdom
facility: Teva Investigational Site 34187
Study officials:
affiliation: Teva Branded Pharmaceutical Products R&D, Inc.
name: Teva Medical Expert, MD
role: STUDY_DIRECTOR
References:
citation: Giovannoni G, Knappertz V, Steinerman JR, Tansy AP, Li T, Krieger S, Uccelli A, Uitdehaag BMJ, Montalban X, Hartung HP, Pia Sormani M, Cree BAC, Lublin F, Barkhof F. A randomized, placebo-controlled, phase 2 trial of laquinimod in primary progressive multiple sclerosis. Neurology. 2020 Aug 25;95(8):e1027-e1040. doi: 10.1212/WNL.0000000000010284. Epub 2020 Jul 10.