Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 1 of 1 for:    laquinimod and primary progressive multiple sclerosis
Previous Study | Return to List | Next Study

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 (ARPEGGIO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02284568
Recruitment Status : Completed
First Posted : November 6, 2014
Results First Posted : November 2, 2018
Last Update Posted : November 2, 2018
Sponsor:
Information provided by (Responsible Party):
Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products, R&D Inc. )

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 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

Layout table for study information
Study Type : Interventional  (Clinical Trial)
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 : January 12, 2015
Actual Primary Completion Date : May 4, 2017
Actual Study Completion Date : October 1, 2017

Resource links provided by the National Library of Medicine


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 Name: 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 Name: TV-5600




Primary Outcome Measures :
  1. Percent Brain Volume Change (PBVC) From Baseline to Week 48 Using a Repeated Measures ANCOVA Model [ 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 ]
    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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   25 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02284568


  Hide Study Locations
Locations
Layout table for location information
United States, Arizona
Teva Investigational Site 12966
Phoenix, Arizona, United States, 85018
United States, California
Teva Investigational Site 12967
Newport Beach, California, United States, 92663
Teva Investigational Site 12962
San Francisco, California, United States, 94158
United States, Colorado
Teva Investigational Site 12964
Aurora, Colorado, United States, 80045
United States, Illinois
Teva Investigational Site 12973
Northbrook, Illinois, United States, 60062
United States, Kansas
Teva Investigational Site 12975
Kansas City, Kansas, United States, 66160-7314
Teva Investigational Site 12969
Lenexa, Kansas, United States, 66214
United States, Minnesota
Teva Investigational Site 12977
Golden Valley, Minnesota, United States, 55422
Teva Investigational Site 13010
Golden Valley, Minnesota, United States, 55422
United States, Missouri
Teva Investigational Site 12965
Chesterfield, Missouri, United States, 63017
Teva Investigational Site 12968
Saint Louis, Missouri, United States, 63110
United States, New York
Teva Investigational Site 12963
New York, New York, United States, 10016
United States, North Carolina
Teva Investigational Site 12971
Charlotte, North Carolina, United States, 28207
United States, Ohio
Teva Investigational Site 12976
Columbus, Ohio, United States, 43221
Teva Investigational Site 12970
Uniontown, Ohio, United States, 44685
Canada, Nova Scotia
Teva Investigational Site 11084
Halifax, Nova Scotia, Canada, B3H 4K4
Canada, Quebec
Teva Investigational Site 11082
Montreal, Quebec, Canada, H3A 2B4
Canada
Teva Investigational Site 11089
Calgary, Canada, T2N 4Z1
Teva Investigational Site 11081
Ottawa, Canada, K1H 8L6
Teva Investigational Site 11088
Quebec, Canada, G1J 1Z4
Teva Investigational Site 11087
Toronto, Canada, M5B-1W8
Germany
Teva Investigational Site 32505
Bad Mergentheim, Germany, 97980
Teva Investigational Site 32512
Bamberg, Germany, 96049
Teva Investigational Site 32510
Berlin, Germany, 10117
Teva Investigational Site 32522
Bochum, Germany, 44791
Teva Investigational Site 32509
Dresden, Germany, 01307
Teva Investigational Site 32517
Dusseldorf, Germany, 40225
Teva Investigational Site 32543
Goettigen, Germany, 37075
Teva Investigational Site 32514
Hamburg, Germany, 20099
Teva Investigational Site 32507
Hannover, Germany, 30625
Teva Investigational Site 32513
Munchen, Germany, 81675
Teva Investigational Site 32504
Munchen, Germany, D-81377
Teva Investigational Site 32516
Rostock, Germany, 18057
Teva Investigational Site 32523
Trier, Germany, 54292
Teva Investigational Site 32503
Ulm, Germany, 89081
Teva Investigational Site 32511
Wurzburg, Germany, 97080
Italy
Teva Investigational Site 30106
Cefalu, Italy, 90015
Teva Investigational Site 30110
Firenze, Italy, 50134
Teva Investigational Site 30105
Gallarate, Italy, 21013
Teva Investigational Site 30108
Genova, Italy, 16132
Teva Investigational Site 30102
Milano, Italy, 20127
Teva Investigational Site 30107
Orbassano, Italy, 10043
Teva Investigational Site 30103
Padova, Italy, 35128
Teva Investigational Site 30101
Rome, Italy, 00133
Teva Investigational Site 30104
Rome, Italy, ?00152
Netherlands
Teva Investigational Site 38068
Amsterdam, Netherlands, 1081 HV
Teva Investigational Site 38067
Nijmegen, Netherlands, 6532 SZ
Teva Investigational Site 38069
Sittard, Netherlands, 6162 BG
Poland
Teva Investigational Site 53262
Bialystok, Poland, 15-402
Teva Investigational Site 53250
Bydgoszcz, Poland, 85-795
Teva Investigational Site 53253
Gdansk, Poland, 80-803
Teva Investigational Site 53257
Katowice, Poland, 40-635
Teva Investigational Site 53258
Katowice, Poland, 40-684
Teva Investigational Site 53256
Katowice, Poland, 40-749
Teva Investigational Site 53255
Kielce, Poland, 25-726
Teva Investigational Site 53260
Lublin, Poland, 20-954
Teva Investigational Site 53261
Olsztyn, Poland, 10-560
Teva Investigational Site 53252
Warsaw, Poland, 02-957
Russian Federation
Teva Investigational Site 50285
Kaluga, Russian Federation, 248007
Teva Investigational Site 50288
Kazan, Russian Federation, 420021
Teva Investigational Site 50290
Kazan, Russian Federation, 420103
Teva Investigational Site 50294
Kirov, Russian Federation, 610006
Teva Investigational Site 50292
Krasnoyarsk, Russian Federation, 660022
Teva Investigational Site 50287
Moscow, Russian Federation, 127018
Teva Investigational Site 50291
Nizhny Novgorod, Russian Federation, 603126
Teva Investigational Site 50286
Novosibirsk, Russian Federation, 630007
Teva Investigational Site 50295
Perm, Russian Federation, 614990
Teva Investigational Site 50293
Saint Petersburg, Russian Federation, 197022
Teva Investigational Site 50289
St. Petersburg, Russian Federation, 194044
Spain
Teva Investigational Site 31108
Barcelona, Spain, 08036
Teva Investigational Site 31106
Barcelona, Spain, 8035
Teva Investigational Site 31105
El Palmar, Spain, 30120
Teva Investigational Site 31111
Lleida, Spain, 25198
Teva Investigational Site 31112
Madrid, Spain, 28040
Teva Investigational Site 31192
Madrid, Spain, 28223
Teva Investigational Site 31101
Malaga, Spain, 29010
Teva Investigational Site 31104
San Sebastian, Spain, 20014
Teva Investigational Site 31102
Sevilla, Spain, 41009
Teva Investigational Site 31100
Valencia, Spain, 46026
Ukraine
Teva Investigational Site 58158
Dnipropetrovsk, Ukraine, 49005
Teva Investigational Site 58159
Ivano-Frankivsk, Ukraine, 76014
Teva Investigational Site 58157
Kharkiv, Ukraine, 61068
Teva Investigational Site 58160
Kyiv, Ukraine, ?03110
Teva Investigational Site 58152
Lutsk, Ukraine, 43005
Teva Investigational Site 58154
Lviv, Ukraine, 79010
Teva Investigational Site 58153
Lviv, Ukraine, 79044
Teva Investigational Site 58156
Zaporizhzhia, Ukraine, 69068
Teva Investigational Site 58150
Zaporizhzhya, Ukraine, 69035
Teva Investigational Site 58151
Zaporizhzhya, Ukraine, 69600
United Kingdom
Teva Investigational Site 34190
Bristol, United Kingdom, BS10 5NB
Teva Investigational Site 34188
Edinburgh, United Kingdom, EH4 2XU
Teva Investigational Site 34189
Exeter, United Kingdom, EX2 5DW
Teva Investigational Site 34182
Liverpool, United Kingdom, L9 7LJ
Teva Investigational Site 34181
London, United Kingdom, E1 2AT
Teva Investigational Site 34183
Nottingham, United Kingdom, NG7 2UH
Teva Investigational Site 34184
Oxford, United Kingdom, OX3 9DU
Teva Investigational Site 34186
Plymouth, United Kingdom, PL6 8DH
Teva Investigational Site 34185
Stoke-on-Trent, United Kingdom, ST4 6GQ
Teva Investigational Site 34187
Swansea, United Kingdom, SA6 6NL
Sponsors and Collaborators
Teva Branded Pharmaceutical Products, R&D Inc.
Investigators
Layout table for investigator information
Study Director: Teva Medical Expert, MD Teva Pharmaceuticals USA
  Study Documents (Full-Text)

Documents provided by Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products, R&D Inc. ):
Study Protocol  [PDF] February 1, 2016
Statistical Analysis Plan  [PDF] June 1, 2017


Layout table for additonal information
Responsible Party: Teva Branded Pharmaceutical Products, R&D Inc.
ClinicalTrials.gov Identifier: NCT02284568     History of Changes
Other Study ID Numbers: TV5600-CNS-20006
2014-001579-30 ( EudraCT Number )
First Posted: November 6, 2014    Key Record Dates
Results First Posted: November 2, 2018
Last Update Posted: November 2, 2018
Last Verified: October 2018

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products, R&D Inc. ):
multiple sclerosis
primary progressive multiple sclerosis
oral immunomodulator

Additional relevant MeSH terms:
Layout table for MeSH terms
Sclerosis
Multiple Sclerosis
Multiple Sclerosis, Chronic Progressive
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases