Unverricht-Lundborg Disease
Conditions
Keywords
Unverricht-Lundborg Disease, Baltic Myoclonus, Progressive Myoclonic Epilepsies, Myoclonus, Brivaracetam
Brief summary
The study will compare the efficacy and safety of Brivaracetam with placebo in patients with Unverricht- Lundborg Disease (ULD).
Interventions
OTHERPlacebo
* Pharmaceutical Form: Tablet * Concentration: 2.5 mg, 25 mg and 50 mg * Route of Administration: Oral use
DRUGBRV 2.5 mg
* Pharmaceutical Form: Tablet * Concentration: 2.5 mg * Route of Administration: Oral use
DRUGBRV 25 mg
* Pharmaceutical Form: Tablet * Concentration: 25 mg * Route of Administration: Oral use
DRUGBRV 50 mg
* Pharmaceutical Form: Tablet * Concentration: 50 mg * Route of Administration: Oral use
Sponsors
UCB Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
\- Subjects with diagnosed Unverricht-Lundborg disease (ULD) ascertained by appropriate genetic testing for a homozygous or compound heterozygous mutation in the CSTB gene- Subjects with moderate to severe myoclonus documented by an Action Myoclonussum score of ≥ 30 (evaluation by investigator)-Subjects currently being or having been treated with clonazepam up to the maximum recommended daily dose of 20 mg or up to their individual optimal dose as assessed by the investigator- Subjects currently being or having been treated with valproate up to the maximum recommended daily dose 60 mg/kg or serum levels of 100 mcg/ml or up to their individual optimal dose as specified by the investigator- Male/female subjects from 16 years onwards. Subjects under 18 years may only be included where legally permitted and ethically accepted
Exclusion criteria
\- Subjects currently on felbamate or having been on felbamate within less than 18 months prior to Visit 1- Subjects currently treated with phenytoin or having been on phenytoin in the last month prior to Visit 1- Subjects currently on vigabatrine. Subjects having been on vigabatrine if no visual fields examination report available including standard static (Humphrey or Octopus) or cinetic perimetry (Goldman)- Subject taking any drug with possible central nervous system (CNS) effects- Subjects taking any drug that may significantly influence the metabolism of BRV (CYP2C or CYP3A potent inducers/inhibitors)- Known clinically significant acute or chronic illness or illness which may impair reliable participation in the trial, necessitate the use of medication not allowed by protocol or represent a safety risk in the Investigator's opinion- Subjects with history of severe adverse hematological reaction to any drug- Impaired hepatic function: ALAT/SGPT, ASAT/SGOT, alkaline phosphatase, GGT value of more than three times the upper limit of the reference range- History of suicide attempt during the last 5 years- Subject with suicidal ideations within the last year or at risk of suicide attempt unless cleared by written confirmation from a psychiatrist and approved by the UCB physician- Ongoing psychiatric disorder other than mild controlled disorder
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to the End of Treatment Period on the Action Myoclonus Score (Unified Myoclonus Rating Scale (UMRS) Section 4) | From Baseline to End of Treatment Period (Week 14 or Early Discontinuation Visit) | The range for Action Myoclonus Score (centrally read) is 0 (best) - 160 (worst). Percent change from Baseline = 100 X ((Baseline UMRS4 - Treatment UMRS4) / Baseline UMRS4). Baseline is defined as the last non-missing value prior to or on Randomization Visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to the End of Treatment Period on the Functional Disability Score (Unified Myoclonus Rating Scale (UMRS) Section 5) | Baseline to End of Treatment Period (Week 14 or Early Discontinuation Visit) | The range for Functional Disability Score is 0 (best) to 28 (worst). Percent change from Baseline = 100 X ((Baseline UMRS5 - Treatment UMRS5) / Baseline UMRS5). Baseline is defined as the last non-missing value prior to or on Randomization Visit. |
| Percent Change From Baseline to the End of Treatment Period on the Stimulus Sensitivity Score (Unified Myoclonus Rating Scale (UMRS) Section 3) | Baseline to End of Treatment Period (Week 14 or Early Discontinuation Visit) | The range for Stimulus Sensitivity Score is 0 (best) to 17 (worst). Percent change from Baseline = 100 X ((Baseline UMRS3 - Treatment UMRS3) / Baseline UMRS3). Baseline is defined as the last non-missing value prior to or on Randomization Visit. |
| Percent Change From Baseline to the End of Treatment Period on the Myoclonus Patient Questionnaire (Unified Myoclonus Rating Scale (UMRS) Section 1) | Baseline to End of Treatment Period (Week 14 or Early Discontinuation Visit) | The range for Myoclonus Patient Questionnaire is 0 (best) to 44 (worst). Percent change from Baseline = 100 X ((Baseline UMRS1 - Treatment UMRS1) / Baseline UMRS1). Baseline is defined as the last non-missing value prior to or on Randomization Visit. |
| Global Evaluation Score (Investigator) at the End of Treatment Period | End of Treatment Period (Week 14 or Early Discontinuation Visit) | The Global Evaluation Scale Score (Investigator) ranges from 1 (Marked worsening) to 7 (Marked improvement). |
Countries
Canada, Finland, France, Israel, Russia, Serbia, Tunisia, United States
Participant flow
Recruitment details
72 subjects were screened, 56 subjects were randomized. Participant Flow refers to all subjects randomized who are identical with the Intent-To-Treat (ITT) Population, which consists of all randomized subjects who took at least one dose of study medication.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo twice a day (bid), 14 weeks (2 week Up-Titration Period + 12 week Maintenance Period) | 18 |
| Brivaracetam 5 mg/Day Brivaracetam (BRV) 5 mg/day 2.5 mg twice a day (bid) using 2.5 mg tablets for 12 weeks (after 2 week Up- Titration Period) | 20 |
| Brivaracetam 150 mg/Day Brivaracetam (BRV) 150 mg/day 75 mg twice a day (bid) using 25 mg and 50 mg tablets for 12 weeks (after 2 week Up-Titration Period) | 18 |
| Total Title | 56 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | AE, non-serious non-fatal | 0 | 0 | 1 |
| Overall Study | SAE, non-fatal | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Brivaracetam 5 mg/Day | Brivaracetam 150 mg/Day | Total Title |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 19 Participants | 17 Participants | 54 Participants |
| Age, Continuous | 34.3 years STANDARD_DEVIATION 9.2 | 35.8 years STANDARD_DEVIATION 10.9 | 33.7 years STANDARD_DEVIATION 11.4 | 34.65 years STANDARD_DEVIATION 10.38 |
| Region of Enrollment Canada | 4 participants | 3 participants | 2 participants | 9 participants |
| Region of Enrollment Finland | 3 participants | 4 participants | 2 participants | 9 participants |
| Region of Enrollment France | 3 participants | 2 participants | 3 participants | 8 participants |
| Region of Enrollment Israel | 0 participants | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Russian Federation | 2 participants | 3 participants | 3 participants | 8 participants |
| Region of Enrollment Serbia | 2 participants | 2 participants | 2 participants | 6 participants |
| Region of Enrollment Tunisia | 2 participants | 3 participants | 0 participants | 5 participants |
| Region of Enrollment United States | 2 participants | 3 participants | 4 participants | 9 participants |
| Sex: Female, Male Female | 12 Participants | 11 Participants | 9 Participants | 32 Participants |
| Sex: Female, Male Male | 6 Participants | 9 Participants | 9 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 13 / 18 | 13 / 20 | 15 / 18 |
| serious Total, serious adverse events | 2 / 18 | 3 / 20 | 2 / 18 |
Outcome results
Primary
Percent Change From Baseline to the End of Treatment Period on the Action Myoclonus Score (Unified Myoclonus Rating Scale (UMRS) Section 4)
The range for Action Myoclonus Score (centrally read) is 0 (best) - 160 (worst). Percent change from Baseline = 100 X ((Baseline UMRS4 - Treatment UMRS4) / Baseline UMRS4). Baseline is defined as the last non-missing value prior to or on Randomization Visit.
Time frame: From Baseline to End of Treatment Period (Week 14 or Early Discontinuation Visit)
Population: The number of subjects is equal to the number of subjects in the Intent-To-Treat (ITT) population having non-missing post-baseline results for the percent change from baseline on the functional disability score (UMRS section 5). In case a subject drops out, the result at Early Discontinuation Visit is used.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Percent Change From Baseline to the End of Treatment Period on the Action Myoclonus Score (Unified Myoclonus Rating Scale (UMRS) Section 4) | 17.45 Percent change |
| Brivaracetam 5 mg/Day | Percent Change From Baseline to the End of Treatment Period on the Action Myoclonus Score (Unified Myoclonus Rating Scale (UMRS) Section 4) | -4.60 Percent change |
| Brivaracetam 150 mg/Day | Percent Change From Baseline to the End of Treatment Period on the Action Myoclonus Score (Unified Myoclonus Rating Scale (UMRS) Section 4) | 12.34 Percent change |
Comparison: The first hypothesis for the primary efficacy variable compares placebo versus Brivaracetam (BRV) 150 mg/day.~The second hypothesis for the primary efficacy variable compares placebo versus BRV 5 mg/day. However, this second hypothesis will only be tested when all the hypotheses for placebo versus BRV 150 mg/day are significant for the primary three UMRS related secondary endpoints.~The hypotheses will be tested using nonparametric analysis. The study was designed to have 80 % power.p-value: =0.94295% CI: [-26.12, 24.96]stratified Wilcoxon Test
p-value: =0.10595% CI: [-39.31, 4.86]stratified Wilcoxon Test
Secondary
Global Evaluation Score (Investigator) at the End of Treatment Period
The Global Evaluation Scale Score (Investigator) ranges from 1 (Marked worsening) to 7 (Marked improvement).
Time frame: End of Treatment Period (Week 14 or Early Discontinuation Visit)
Population: The number of subjects is equal to the number of subjects in the Intent-To-Treat (ITT) population having non-missing post-baseline results for the Global Evaluation Score (I-GES). In case a subject drops out, the result at Early Discontinuation Visit (EDV) is used.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Global Evaluation Score (Investigator) at the End of Treatment Period | Marked improvement | 0 percentage of participants |
| Placebo | Global Evaluation Score (Investigator) at the End of Treatment Period | Slight improvement | 33.3 percentage of participants |
| Placebo | Global Evaluation Score (Investigator) at the End of Treatment Period | No change | 50.0 percentage of participants |
| Placebo | Global Evaluation Score (Investigator) at the End of Treatment Period | Slight worsening | 0 percentage of participants |
| Placebo | Global Evaluation Score (Investigator) at the End of Treatment Period | Moderate worsening | 0 percentage of participants |
| Placebo | Global Evaluation Score (Investigator) at the End of Treatment Period | Marked worsening | 5.6 percentage of participants |
| Placebo | Global Evaluation Score (Investigator) at the End of Treatment Period | Moderate improvement | 11.1 percentage of participants |
| Brivaracetam 5 mg/Day | Global Evaluation Score (Investigator) at the End of Treatment Period | Moderate improvement | 0 percentage of participants |
| Brivaracetam 5 mg/Day | Global Evaluation Score (Investigator) at the End of Treatment Period | No change | 50.0 percentage of participants |
| Brivaracetam 5 mg/Day | Global Evaluation Score (Investigator) at the End of Treatment Period | Marked worsening | 0 percentage of participants |
| Brivaracetam 5 mg/Day | Global Evaluation Score (Investigator) at the End of Treatment Period | Slight worsening | 10.0 percentage of participants |
| Brivaracetam 5 mg/Day | Global Evaluation Score (Investigator) at the End of Treatment Period | Moderate worsening | 0 percentage of participants |
| Brivaracetam 5 mg/Day | Global Evaluation Score (Investigator) at the End of Treatment Period | Marked improvement | 10.0 percentage of participants |
| Brivaracetam 5 mg/Day | Global Evaluation Score (Investigator) at the End of Treatment Period | Slight improvement | 30.0 percentage of participants |
| Brivaracetam 150 mg/Day | Global Evaluation Score (Investigator) at the End of Treatment Period | Moderate worsening | 5.6 percentage of participants |
| Brivaracetam 150 mg/Day | Global Evaluation Score (Investigator) at the End of Treatment Period | Slight improvement | 33.3 percentage of participants |
| Brivaracetam 150 mg/Day | Global Evaluation Score (Investigator) at the End of Treatment Period | No change | 33.3 percentage of participants |
| Brivaracetam 150 mg/Day | Global Evaluation Score (Investigator) at the End of Treatment Period | Marked improvement | 11.1 percentage of participants |
| Brivaracetam 150 mg/Day | Global Evaluation Score (Investigator) at the End of Treatment Period | Moderate improvement | 11.1 percentage of participants |
| Brivaracetam 150 mg/Day | Global Evaluation Score (Investigator) at the End of Treatment Period | Slight worsening | 5.6 percentage of participants |
| Brivaracetam 150 mg/Day | Global Evaluation Score (Investigator) at the End of Treatment Period | Marked worsening | 0 percentage of participants |
p-value: =0.931Stratified Wilcoxon test
Comparison: P-value for pairwise comparison of each Brivaracetam dose versus Placebo.p-value: =0.253Stratified Wilcoxon test
Secondary
Percent Change From Baseline to the End of Treatment Period on the Functional Disability Score (Unified Myoclonus Rating Scale (UMRS) Section 5)
The range for Functional Disability Score is 0 (best) to 28 (worst). Percent change from Baseline = 100 X ((Baseline UMRS5 - Treatment UMRS5) / Baseline UMRS5). Baseline is defined as the last non-missing value prior to or on Randomization Visit.
Time frame: Baseline to End of Treatment Period (Week 14 or Early Discontinuation Visit)
Population: The number of subjects is equal to the number of subjects in the Intent-To-Treat (ITT) population having non-missing post-baseline results for the percent change from baseline on the functional disability score (UMRS section 5). In case a subject drops out, the result at Early Discontinuation Visit is used.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Percent Change From Baseline to the End of Treatment Period on the Functional Disability Score (Unified Myoclonus Rating Scale (UMRS) Section 5) | 0.00 Percent change |
| Brivaracetam 5 mg/Day | Percent Change From Baseline to the End of Treatment Period on the Functional Disability Score (Unified Myoclonus Rating Scale (UMRS) Section 5) | 0.00 Percent change |
| Brivaracetam 150 mg/Day | Percent Change From Baseline to the End of Treatment Period on the Functional Disability Score (Unified Myoclonus Rating Scale (UMRS) Section 5) | 0.00 Percent change |
Comparison: If primary efficacy is proven for Brivaracetam (BRV) 150 mg/day, the following secondary endpoints will be tested for Placebo versus BRV 150 mg/day. The testing scheme will be hierarchical, thus statistical significance at 5 % on BRV 150 mg/day on a secondary endpoint is needed to continue testing BRV 150 mg/day at 5 % significance level for the next secondary endpoint.p-value: =0.67295% CI: [-21.9, 31.06]stratified Wilcoxon Test
Comparison: In case the three endpoints are significant for placebo versus Brivaracetam (BRV) 150 mg/day, the primary endpoint will be tested for Placebo versus BRV 5 mg/day. In case of significance, the three UMRS related secondary endpoints will be tested for Placebo versus BRV 5 mg/day, provided the previous is significant at 5 %. Secondary endpoints are tested in the following order:~* Functional Disability~* Stimulus Sensitivity~* Myoclonus Patient Questionnairep-value: =0.80695% CI: [-33.33, 18.75]stratified Wilcoxon Test
Secondary
Percent Change From Baseline to the End of Treatment Period on the Myoclonus Patient Questionnaire (Unified Myoclonus Rating Scale (UMRS) Section 1)
The range for Myoclonus Patient Questionnaire is 0 (best) to 44 (worst). Percent change from Baseline = 100 X ((Baseline UMRS1 - Treatment UMRS1) / Baseline UMRS1). Baseline is defined as the last non-missing value prior to or on Randomization Visit.
Time frame: Baseline to End of Treatment Period (Week 14 or Early Discontinuation Visit)
Population: The number of subjects is equal to the number of subjects in the Intent-To-Treat (ITT) population having non-missing post-baseline results for the percent change from baseline on the Myoclonus Patient Questionnaire (UMRS section 1). In case a subject drops out, the result at Early Discontinuation Visit (EDV) is used.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Percent Change From Baseline to the End of Treatment Period on the Myoclonus Patient Questionnaire (Unified Myoclonus Rating Scale (UMRS) Section 1) | -9.68 Percent change |
| Brivaracetam 5 mg/Day | Percent Change From Baseline to the End of Treatment Period on the Myoclonus Patient Questionnaire (Unified Myoclonus Rating Scale (UMRS) Section 1) | 0.00 Percent change |
| Brivaracetam 150 mg/Day | Percent Change From Baseline to the End of Treatment Period on the Myoclonus Patient Questionnaire (Unified Myoclonus Rating Scale (UMRS) Section 1) | 5.41 Percent change |
p-value: =0.03795% CI: [-1.76, 39.39]stratified Wilcoxon Test
p-value: =0.11195% CI: [-5.56, 30]stratified Wilcoxon Test
Secondary
Percent Change From Baseline to the End of Treatment Period on the Stimulus Sensitivity Score (Unified Myoclonus Rating Scale (UMRS) Section 3)
The range for Stimulus Sensitivity Score is 0 (best) to 17 (worst). Percent change from Baseline = 100 X ((Baseline UMRS3 - Treatment UMRS3) / Baseline UMRS3). Baseline is defined as the last non-missing value prior to or on Randomization Visit.
Time frame: Baseline to End of Treatment Period (Week 14 or Early Discontinuation Visit)
Population: The number of subjects is equal to the number of subjects in the Intent-To-Treat (ITT) population having non-missing post-baseline results for the percent change from baseline on the stimulus sensitivity score (UMRS section 3). In case a subject drops out, the result at Early Discontinuation Visit (EDV) is used.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Percent Change From Baseline to the End of Treatment Period on the Stimulus Sensitivity Score (Unified Myoclonus Rating Scale (UMRS) Section 3) | 0.00 Percent change |
| Brivaracetam 5 mg/Day | Percent Change From Baseline to the End of Treatment Period on the Stimulus Sensitivity Score (Unified Myoclonus Rating Scale (UMRS) Section 3) | 43.44 Percent change |
| Brivaracetam 150 mg/Day | Percent Change From Baseline to the End of Treatment Period on the Stimulus Sensitivity Score (Unified Myoclonus Rating Scale (UMRS) Section 3) | 0.00 Percent change |
p-value: =0.54995% CI: [-25, 100]stratified Willcoxon Test
p-value: =0.65495% CI: [-50, 66.67]stratified Wilcoxon Test