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A Clinical Study in Participants With Huntington's Disease (HD) to Assess Efficacy and Safety of Three Oral Doses of Laquinimod (LEGATO-HD)

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ClinicalTrials.gov Identifier: NCT02215616
Recruitment Status : Completed
First Posted : August 13, 2014
Results First Posted : June 19, 2019
Last Update Posted : June 19, 2019
Sponsor:
Information provided by (Responsible Party):
Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products, R&D Inc. )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Huntington's Disease
Interventions Drug: Laquinimod
Drug: Placebo
Enrollment 352
Recruitment Details A total of 468 participants were screened, of whom 116 participants were screen failures and 352 participants were enrolled. Of 352 enrolled participants, 123 participants were randomized in 1:1:1:1 ratio to receive laquinimod 0.5, 1.0, 1.5 milligrams/day (mg/day), or matching placebo prior to 10 January 2016.
Pre-assignment Details As of 10 January 2016; following recommendation of Data Safety Monitoring Board (DSMB), treatment of laquinimod 1.5 mg dose arm was discontinued as a proactive safety measure. After 10 January 2016; additional eligible participants, who were enrolled, were randomized in 1:1:1 ratio to receive laquinimod 0.5 mg/day, 1.0 mg/day, or matching placebo.
Arm/Group Title Placebo Laquinimod 0.5 mg Laquinimod 1.0 mg Laquinimod 1.5 mg
Hide Arm/Group Description Participants received 3 capsules of matching laquinimod placebo, orally once daily for 52 weeks. Participants received 1 capsule of laquinimod 0.5 mg and 2 capsules of matching placebo, orally once daily for 52 weeks. Participants received 2 capsules of laquinimod 0.5 mg (total 1.0 mg laquinimod) and 1 capsule of matching placebo, orally once daily for 52 weeks. Participants received 3 capsules of laquinimod 0.5 mg (total 1.5 mg laquinimod), orally once daily. The treatment of this high dose arm was discontinued as of 10 January 2016.
Period Title: Overall Study
Started 108 107 107 30
Received at Least 1 Dose of Study Drug 108 107 106 29
Completed 97 90 93 17
Not Completed 11 17 14 13
Reason Not Completed
Sponsor requested to stop study drug             0             0             1             4
Death             1             0             0             0
Adverse Event             7             4             9             2
Withdrawal by Subject             1             8             2             5
Non-compliance             0             2             1             0
Protocol Violation             0             2             0             0
Lost to Follow-up             1             1             0             1
Other than specified             1             0             1             1
Arm/Group Title Placebo Laquinimod 0.5 mg Laquinimod 1.0 mg Laquinimod 1.5 mg Total
Hide Arm/Group Description Participants received 3 capsules of matching laquinimod placebo, orally once daily for 52 weeks. Participants received 1 capsule of laquinimod 0.5 mg and 2 capsules of matching placebo, orally once daily for 52 weeks. Participants received 2 capsules of laquinimod 0.5 mg (total 1.0 mg laquinimod) and 1 capsule of matching placebo, orally once daily for 52 weeks. Participants received 3 capsules of laquinimod 0.5 mg (total 1.5 mg laquinimod), orally once daily. The treatment of this high dose arm was discontinued as of 10 January 2016. Total of all reporting groups
Overall Number of Baseline Participants 108 107 107 30 352
Hide Baseline Analysis Population Description
Intent-to-treat (ITT) population included all randomized participants.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 108 participants 107 participants 107 participants 30 participants 352 participants
43.8  (7.76) 43.3  (7.75) 44.0  (7.83) 45.5  (6.03) 43.9  (7.64)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 108 participants 107 participants 107 participants 30 participants 352 participants
Female
56
  51.9%
52
  48.6%
54
  50.5%
11
  36.7%
173
  49.1%
Male
52
  48.1%
55
  51.4%
53
  49.5%
19
  63.3%
179
  50.9%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
White Number Analyzed 108 participants 107 participants 107 participants 30 participants 352 participants
104
  96.3%
103
  96.3%
105
  98.1%
28
  93.3%
340
  96.6%
Black Number Analyzed 108 participants 107 participants 107 participants 30 participants 352 participants
0
   0.0%
1
   0.9%
1
   0.9%
0
   0.0%
2
   0.6%
Asian Number Analyzed 108 participants 107 participants 107 participants 30 participants 352 participants
2
   1.9%
0
   0.0%
0
   0.0%
1
   3.3%
3
   0.9%
Other Number Analyzed 108 participants 107 participants 107 participants 30 participants 352 participants
0
   0.0%
1
   0.9%
0
   0.0%
0
   0.0%
1
   0.3%
Missing Number Analyzed 108 participants 107 participants 107 participants 30 participants 352 participants
2
   1.9%
2
   1.9%
1
   0.9%
1
   3.3%
6
   1.7%
Unified Huntington’s Disease Rating Scale - Total Motor Score (UHDRS-TMS)   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 108 participants 107 participants 106 participants 30 participants 351 participants
26.4  (14.63) 24.0  (13.23) 22.1  (10.74) 26.8  (13.75) 24.4  (13.12)
[1]
Measure Description: The UHDRS TMS assesses all the motor features of HD and includes maximal chorea, maximal dystonia, ocular pursuit, saccade initiation and velocity, dysarthria, tongue protrusion, finger tapping, hand pronation and supination, luria, rigidity, bradykinesia, gait, tandem walking, and retropulsion pull test. Each of these was rated on a scale of 0 (normal motor function) to 4 (severely impaired motor function). TMS score is a sum of individual scores ranging from 0 (normal motor function) to 124 (severely impaired motor function). Lower TMS scores indicate better motor function.
[2]
Measure Analysis Population Description: 'Number analyzed' signifies participants evaluable for this parameter.
Normalized Caudate Volume   [1] 
Mean (Standard Deviation)
Unit of measure:  Milliliters (mL)
Number Analyzed 106 participants 103 participants 102 participants 28 participants 339 participants
6.06  (1.857) 5.78  (1.818) 6.02  (1.781) 5.39  (1.218) 5.90  (1.781)
[1]
Measure Analysis Population Description: 'Number analyzed' signifies participants evaluable for this parameter.
1.Primary Outcome
Title Change From Baseline in UHDRS-TMS at Week 52
Hide Description UHDRS is a research tool developed by Huntington Disease (HD) Study Group to provide a uniform assessment of the clinical features and course of HD. Components of the full UHDRS assess motor function, cognition, behaviour, functional abilities, independence scale and total functional capacities. Motor function assessment includes TMS and Total Functional Capacity (TFC) score. The UHDRS TMS assesses all the motor features of HD and includes maximal chorea, maximal dystonia, ocular pursuit, saccade initiation and velocity, dysarthria, tongue protrusion, finger tapping, hand pronation and supination, luria, rigidity, bradykinesia, gait, tandem walking, and retropulsion pull test. Each of these was rated on a scale of 0 (normal motor function) to 4 (severely impaired motor function). TMS score is a sum of individual scores ranging from 0 (normal motor function) to 124 (severely impaired motor function). Lower TMS scores indicate better motor function.
Time Frame Baseline, Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) included all participants in the ITT population (all randomized participants) who received at least 1 dose of study drug and had at least 1 post-baseline TMS assessment. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
Arm/Group Title Placebo Laquinimod 0.5 mg Laquinimod 1.0 mg Laquinimod 1.5 mg
Hide Arm/Group Description:
Participants received 3 capsules of matching laquinimod placebo, orally once daily for 52 weeks.
Participants received 1 capsule of laquinimod 0.5 mg and 2 capsules of matching placebo, orally once daily for 52 weeks.
Participants received 2 capsules of laquinimod 0.5 mg (total 1.0 mg laquinimod) and 1 capsule of matching placebo, orally once daily for 52 weeks.
Participants received 3 capsules of laquinimod 0.5 mg (total 1.5 mg laquinimod), orally once daily. The treatment of this high dose arm was discontinued as of 10 January 2016.
Overall Number of Participants Analyzed 98 92 95 4
Mean (Standard Deviation)
Unit of Measure: units on a scale
1.3  (8.00) 1.4  (8.34) 2.0  (7.27) 11.0  (7.12)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Laquinimod 1.0 mg
Comments Analysis was performed using Mixed Model Repeated Measures model (MMRM) with treatment group (3 levels: placebo, laquinimod 0.5 mg and laquinimod 1 mg), categorical week (4 levels: Weeks 4, 13, 26, and 52), treatment by week interaction, country, TMS baseline value and TMS baseline by week interaction as fixed effects. Unstructured variance-covariance structure was used in the initial model.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4853
Comments Threshold for significance at 0.045 level.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Least square (LS) mean difference
Estimated Value 0.78
Confidence Interval (2-Sided) 95%
-1.42 to 2.98
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percent Change From Baseline in Caudate Volume (Brain Atrophy) at Week 52
Hide Description Brain atrophy was assessed using magnetic resonance imaging (MRI) measures of caudate volume. Caudate volume atrophy is a sensitive biomarker in very early HD and correlates with disease progression. Brain atrophy in the caudate refers to the shrinkage in volume, so that a decrease in volume is a positive value, while an increase in volume is a negative value. Percent change in caudate volume at Week 52 was calculated as the change in caudate volume since the baseline visit, divided by the baseline caudate volume and multiplied by 100.
Time Frame Baseline, Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all participants in the ITT population (all randomized participants) who received at least 1 dose of study drug and had at least 1 post-baseline TMS assessment. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
Arm/Group Title Placebo Laquinimod 0.5 mg Laquinimod 1.0 mg Laquinimod 1.5 mg
Hide Arm/Group Description:
Participants received 3 capsules of matching laquinimod placebo, orally once daily for 52 weeks.
Participants received 1 capsule of laquinimod 0.5 mg and 2 capsules of matching placebo, orally once daily for 52 weeks.
Participants received 2 capsules of laquinimod 0.5 mg (total 1.0 mg laquinimod) and 1 capsule of matching placebo, orally once daily for 52 weeks.
Participants received 3 capsules of laquinimod 0.5 mg (total 1.5 mg laquinimod), orally once daily. The treatment of this high dose arm was discontinued as of 10 January 2016.
Overall Number of Participants Analyzed 87 87 85 2
Mean (Standard Deviation)
Unit of Measure: percent change
5.13  (3.265) 4.03  (3.275) 3.14  (3.360) 4.11  (0.598)
Time Frame Baseline up to Week 56
Adverse Event Reporting Description Safety analysis set included all participants who had received at least 1 dose of study drug.
 
Arm/Group Title Placebo Laquinimod 0.5 mg Laquinimod 1.0 mg Laquinimod 1.5 mg
Hide Arm/Group Description Participants received 3 capsules of matching laquinimod placebo, orally once daily for 52 weeks. Participants received 1 capsule of laquinimod 0.5 mg and 2 capsules of matching placebo, orally once daily for 52 weeks. Participants received 2 capsules of laquinimod 0.5 mg (total 1.0 mg laquinimod) and 1 capsule of matching placebo, orally once daily for 52 weeks. Participants received 3 capsules of laquinimod 0.5 mg (total 1.5 mg laquinimod), orally once daily. The treatment of this high dose arm was discontinued as of 10 January 2016.
All-Cause Mortality
Placebo Laquinimod 0.5 mg Laquinimod 1.0 mg Laquinimod 1.5 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/108 (0.93%)      0/107 (0.00%)      0/106 (0.00%)      0/29 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Laquinimod 0.5 mg Laquinimod 1.0 mg Laquinimod 1.5 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   8/108 (7.41%)      7/107 (6.54%)      5/106 (4.72%)      1/29 (3.45%)    
Cardiac disorders         
Defect conduction intraventricular  1  0/108 (0.00%)  0 0/107 (0.00%)  0 0/106 (0.00%)  0 1/29 (3.45%)  1
Gastrointestinal disorders         
Gastrooesophageal reflux disease  1  0/108 (0.00%)  0 1/107 (0.93%)  1 0/106 (0.00%)  0 0/29 (0.00%)  0
Small intestinal obstruction  1  1/108 (0.93%)  1 0/107 (0.00%)  0 0/106 (0.00%)  0 0/29 (0.00%)  0
Hepatobiliary disorders         
Cholecystitis  1  0/108 (0.00%)  0 1/107 (0.93%)  1 0/106 (0.00%)  0 0/29 (0.00%)  0
Infections and infestations         
Burn infection  1  0/108 (0.00%)  0 1/107 (0.93%)  1 0/106 (0.00%)  0 0/29 (0.00%)  0
Diverticulitis  1  0/108 (0.00%)  0 0/107 (0.00%)  0 1/106 (0.94%)  1 0/29 (0.00%)  0
Gastroenteritis  1  1/108 (0.93%)  1 0/107 (0.00%)  0 0/106 (0.00%)  0 0/29 (0.00%)  0
Gastrointestinal viral infection  1  1/108 (0.93%)  1 0/107 (0.00%)  0 0/106 (0.00%)  0 0/29 (0.00%)  0
Osteomyelitis chronic  1  0/108 (0.00%)  0 0/107 (0.00%)  0 1/106 (0.94%)  1 0/29 (0.00%)  0
Injury, poisoning and procedural complications         
Fall  1  1/108 (0.93%)  1 1/107 (0.93%)  1 0/106 (0.00%)  0 0/29 (0.00%)  0
Femur fracture  1  1/108 (0.93%)  1 0/107 (0.00%)  0 0/106 (0.00%)  0 0/29 (0.00%)  0
Multiple injuries  1  1/108 (0.93%)  1 0/107 (0.00%)  0 0/106 (0.00%)  0 0/29 (0.00%)  0
Rib fracture  1  0/108 (0.00%)  0 1/107 (0.93%)  1 0/106 (0.00%)  0 0/29 (0.00%)  0
Road traffic accident  1  1/108 (0.93%)  1 0/107 (0.00%)  0 0/106 (0.00%)  0 0/29 (0.00%)  0
Skin abrasion  1  0/108 (0.00%)  0 1/107 (0.93%)  1 0/106 (0.00%)  0 0/29 (0.00%)  0
Traumatic liver injury  1  0/108 (0.00%)  0 1/107 (0.93%)  1 0/106 (0.00%)  0 0/29 (0.00%)  0
Musculoskeletal and connective tissue disorders         
Back pain  1  0/108 (0.00%)  0 1/107 (0.93%)  1 0/106 (0.00%)  0 0/29 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Breast cancer metastatic  1  1/108 (0.93%)  1 0/107 (0.00%)  0 0/106 (0.00%)  0 0/29 (0.00%)  0
Gastric cancer  1  0/108 (0.00%)  0 1/107 (0.93%)  1 0/106 (0.00%)  0 0/29 (0.00%)  0
Nervous system disorders         
Cluster headache  1  0/108 (0.00%)  0 0/107 (0.00%)  0 1/106 (0.94%)  1 0/29 (0.00%)  0
Product Issues         
Device dislocation  1  0/108 (0.00%)  0 0/107 (0.00%)  0 1/106 (0.94%)  1 0/29 (0.00%)  0
Psychiatric disorders         
Depression  1  0/108 (0.00%)  0 0/107 (0.00%)  0 1/106 (0.94%)  1 0/29 (0.00%)  0
Psychiatric decompensation  1  1/108 (0.93%)  1 0/107 (0.00%)  0 0/106 (0.00%)  0 0/29 (0.00%)  0
Psychotic disorder  1  1/108 (0.93%)  1 0/107 (0.00%)  0 0/106 (0.00%)  0 0/29 (0.00%)  0
Suicide attempt  1  0/108 (0.00%)  0 0/107 (0.00%)  0 1/106 (0.94%)  1 0/29 (0.00%)  0
Renal and urinary disorders         
Nephrolithiasis  1  0/108 (0.00%)  0 1/107 (0.93%)  1 0/106 (0.00%)  0 0/29 (0.00%)  0
Respiratory, thoracic and mediastinal disorders         
Chronic obstructive pulmonary disease  1  0/108 (0.00%)  0 0/107 (0.00%)  0 1/106 (0.94%)  1 0/29 (0.00%)  0
Mediastinal haematoma  1  0/108 (0.00%)  0 1/107 (0.93%)  1 0/106 (0.00%)  0 0/29 (0.00%)  0
Skin and subcutaneous tissue disorders         
Cutaneous lupus erythematosus  1  0/108 (0.00%)  0 1/107 (0.93%)  1 0/106 (0.00%)  0 0/29 (0.00%)  0
1
Term from vocabulary, MedDRA v19.0
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Laquinimod 0.5 mg Laquinimod 1.0 mg Laquinimod 1.5 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   62/108 (57.41%)      69/107 (64.49%)      58/106 (54.72%)      19/29 (65.52%)    
Gastrointestinal disorders         
Abdominal pain  1  1/108 (0.93%)  1 7/107 (6.54%)  10 2/106 (1.89%)  2 1/29 (3.45%)  1
Constipation  1  3/108 (2.78%)  3 3/107 (2.80%)  3 3/106 (2.83%)  3 2/29 (6.90%)  2
Diarrhoea  1  9/108 (8.33%)  9 12/107 (11.21%)  14 9/106 (8.49%)  11 3/29 (10.34%)  6
Nausea  1  4/108 (3.70%)  4 5/107 (4.67%)  10 5/106 (4.72%)  5 4/29 (13.79%)  4
Vomiting  1  3/108 (2.78%)  3 7/107 (6.54%)  10 4/106 (3.77%)  7 2/29 (6.90%)  2
Infections and infestations         
Influenza  1  7/108 (6.48%)  9 8/107 (7.48%)  8 7/106 (6.60%)  7 0/29 (0.00%)  0
Nasopharyngitis  1  19/108 (17.59%)  33 10/107 (9.35%)  12 10/106 (9.43%)  13 0/29 (0.00%)  0
Upper respiratory tract infection  1  7/108 (6.48%)  7 3/107 (2.80%)  5 2/106 (1.89%)  2 1/29 (3.45%)  1
Urinary tract infection  1  5/108 (4.63%)  5 1/107 (0.93%)  1 2/106 (1.89%)  2 2/29 (6.90%)  2
Injury, poisoning and procedural complications         
Contusion  1  6/108 (5.56%)  8 0/107 (0.00%)  0 1/106 (0.94%)  1 1/29 (3.45%)  3
Fall  1  9/108 (8.33%)  15 10/107 (9.35%)  12 5/106 (4.72%)  7 2/29 (6.90%)  6
Ligament sprain  1  2/108 (1.85%)  2 1/107 (0.93%)  1 1/106 (0.94%)  1 2/29 (6.90%)  4
Investigations         
Alanine aminotransferase increased  1  0/108 (0.00%)  0 2/107 (1.87%)  2 4/106 (3.77%)  5 2/29 (6.90%)  2
Amylase increased  1  0/108 (0.00%)  0 8/107 (7.48%)  10 6/106 (5.66%)  10 1/29 (3.45%)  1
Blood folate decreased  1  0/108 (0.00%)  0 1/107 (0.93%)  1 6/106 (5.66%)  6 1/29 (3.45%)  1
Haemoglobin decreased  1  0/108 (0.00%)  0 1/107 (0.93%)  1 3/106 (2.83%)  3 3/29 (10.34%)  3
Pancreatic enzymes increased  1  0/108 (0.00%)  0 2/107 (1.87%)  2 2/106 (1.89%)  2 2/29 (6.90%)  2
Musculoskeletal and connective tissue disorders         
Arthralgia  1  5/108 (4.63%)  5 5/107 (4.67%)  7 4/106 (3.77%)  4 2/29 (6.90%)  2
Back pain  1  7/108 (6.48%)  8 7/107 (6.54%)  7 8/106 (7.55%)  12 2/29 (6.90%)  2
Nervous system disorders         
Balance disorder  1  0/108 (0.00%)  0 1/107 (0.93%)  1 0/106 (0.00%)  0 2/29 (6.90%)  2
Chorea  1  3/108 (2.78%)  4 3/107 (2.80%)  3 0/106 (0.00%)  0 2/29 (6.90%)  2
Headache  1  7/108 (6.48%)  7 19/107 (17.76%)  22 14/106 (13.21%)  31 5/29 (17.24%)  5
Psychiatric disorders         
Anxiety  1  4/108 (3.70%)  4 3/107 (2.80%)  3 1/106 (0.94%)  1 2/29 (6.90%)  2
Depression  1  5/108 (4.63%)  7 0/107 (0.00%)  0 2/106 (1.89%)  2 2/29 (6.90%)  2
Insomnia  1  4/108 (3.70%)  4 4/107 (3.74%)  4 2/106 (1.89%)  2 2/29 (6.90%)  2
Irritability  1  4/108 (3.70%)  5 6/107 (5.61%)  7 3/106 (2.83%)  3 1/29 (3.45%)  2
Respiratory, thoracic and mediastinal disorders         
Cough  1  4/108 (3.70%)  5 3/107 (2.80%)  4 6/106 (5.66%)  7 0/29 (0.00%)  0
1
Term from vocabulary, MedDRA v19.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Name/Title: Director, Clinical Research
Organization: Teva Branded Pharmaceutical Products, R&D Inc.
Phone: 1-888-483-8279
Responsible Party: Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products, R&D Inc. )
ClinicalTrials.gov Identifier: NCT02215616     History of Changes
Other Study ID Numbers: TV5600-CNS-20007
2014-000418-75 ( EudraCT Number )
First Submitted: August 12, 2014
First Posted: August 13, 2014
Results First Submitted: May 29, 2019
Results First Posted: June 19, 2019
Last Update Posted: June 19, 2019