Cranial Dystonia, Oromandibular Dystonia
Conditions
Keywords
Levetiracetam, Cranial Dystonia, Oromandibular Dystonia
Brief summary
Background: \- People with dystonia cannot control their muscle contractions. This disorder can affect different body areas. When it affects the face, tongue, and jaw, it is called oromandibular dystonia (OMD) or cranial dystonia (CD). Researchers want to find out if a drug that treats seizures may help people with this kind of dystonia. Objective: \- To see if levetiracetam can improve symptoms of jaw or face dystonia. Eligibility: \- Adults ages 18 to 80 years with OMD or CD. Design: * Participants will be screened with a medical history and physical exam. Researchers will test how severe their dystonia is. * Participants will have blood drawn through a needle in the arm. * Participants will be assigned to take either levetiracetam or placebo. * Phase 1: * Participants will start with one 500-mg tablet twice daily. The dose will be increased by 500 mg every 3 days. The maximum dose will be 4000 mg a day over 3 weeks. Participants who cannot tolerate that will take the highest dose they can. * Participants will return for study visits at weeks 3 and 6. They will be asked about their health, side effects, and symptoms of depression. They will have a neurological examination and test of their dystonia. * After the week 6 visit, participants will taper and stop the study drug over about 1 week. * Phase 2 begins one week later. Participants will repeat phase 1, but with the other drug. * After phase 2, participants will return to their usual clinics. They will be told how to stop taking the drug. They will have a follow-up phone call 2 weeks later.
Detailed description
Objectives: --To determine the efficacy of levetiracetam (LVT) for reducing the symptoms of subjects with oromandibular dystonia (OMD) or cranial dystonia (CD) as assessed by dystonia rating scales and to report all adverse events in this study. Sample Size and Population: --We plan to recruit 10 subjects with either primary OMD or CD from the Movement Disorders and Botulinum Toxin (BoNT) Clinics of HMCS. Design: --This is a randomized, double-blind placebo controlled cross-over study. All subjects will receive a baseline evaluation and have their dystonia assessed by the eyes, mouth, speech and swallowing subscores of the Burke-Fahn-Marsden (BFM) dystonia scale, and the eyes and upper and lower face, jaw, and tongue subscores of the Global Dystonia Severity (GDS) rating scale. They will then be randomized into two groups. Either LVT or placebo with a titration schedule up to a total daily dose of 4000 mg will be prescribed for six weeks. After week 6, all subjects will undergo tapering and a wash-out period (one week for tapering off and one week for the washout). The two groups will then be switched to the opposite intervention (LVT or placebo), following the same titration and tapering pattern. We will evaluate both groups at weeks 3, 6, 11 and 14 using the same scales. This study requires six outpatient visits to the NIH CC; the total duration of this study will be 15 weeks. Outcome measurement: Primary outcome: The percent change of sum of the eyes, mouth, speech and swallowing subscores of BFM dystonia scale at weeks 6 and 14 comparing to the baseline. Secondary outcome: The percent change of the sum of the eyes, mouth, speech and swallowing subscores of BFM dystonia scale at weeks 3 and 11 and sum of eyes and upper face, lower face and jaw and tongue subscores of the GDS rating scale at weeks 3, 6, 11 and 14 comparing to baseline and all adverse events.
Interventions
DRUGLevetiracetam
Anticonvulsant
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA FOR THE PARTICIPANTS: 1. Be at least 18 years of age and less than or equal to 80 years of age. 2. Must be able to provide consent. 3. Primary OMD or CD diagnosed by movement disorders specialist. 4. No history of receiving LVT. 5. If the subject is using other medications for their dystonia such as anticholinergics, baclofen, benzodiazepines or tetrabenazine, the dosage must stay the same starting 4 weeks before participation and throughout the duration of the study. Subjects will also be prohibited from starting new medications for their dystonia. 6. If the subject was injected with BoNT, the latest dose must be injected at least 12 weeks before participation in this study. 7. Subject is willing to not receive any BoNT injections during the entire study.
Exclusion criteria
FOR THE PARTICIPANTS: 1. Psychiatric co-morbidities such as depression, psychosis or phobic disorders. 2. Has had a history of brain tumor, stroke, documented history of peripheral trauma to the mouth, jaw or face within a year from the onset of dystonia, epilepsy or seizures. 3. Secondary OMD or CD. 4. Postural instability, frequent falling, severe vertigo or dizziness and severe ataxia. 5. Inability to take medication via oral route due to severe degree of OMD. 6. An estimated creatinine clearance (eCrCL) less than 50 mL/min. 7. Pregnant, lactating or planning to become pregnant in 6 months. Women who are able to get pregnant must be willing to use an effective method of contraception from the time of enrollment until 3 months after the last dose of the study medication.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change of the Sum of the Eyes, Mouth, Speech and Swallowing Subscores of the Burke-Fahn-Marsden (BFM) Dystonia Scale. | 6 and 14 weeks compared to baseline | The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) is a measure of dystonia severity. The scale consists of evaluation of nine body parts (eyes, mouth, speech, swallowing, neck, trunk, right arm, right leg, left arm and left leg). The severity and provoking factors for each part are rated using a 5-point scale. These range from 0 (indicating no dystonia) to 4 (indicating the presence of dystonia at rest). The primary outcome measure includes the sum of the eyes, mouth, speech and swallowing subscores and represents the percent change from baseline to either 6 weeks or 14 weeks (representing the end of the 3 week period at the maximum tolerated dose for Levetiracetam or Placebo). The total range for these combined sub scores is 0-16, with higher scores indicating more severe dystonia and 0 indicating absence of dystonia. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change of the Sum of the Eyes, Mouth, Speech and Swallowing Subscores of Burke-Fahn-Marsten Dystonia Rating Scale (BFM) | 3 and 11 weeks compared to baseline | The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) is a measure of dystonia severity. The scale consists of evaluation of ten body parts (eyes, mouth, speech, swallowing, neck, trunk, right arm, right leg, left arm and left leg). The severity and provoking factors for each part are rated using a 5-point scale. These range from 0 (indicating no dystonia) to 4 (indicating the presence of dystonia at rest). The secondary outcome measure includes the sum of the eyes, mouth, speech and swallowing subscores and represents the percent change from baseline to either 3 weeks or 11 weeks (representing the end of the three week titration period up to the maximum tolerated dose for Levetiracetam or Placebo). The total range for these combined sub scores is 0-16, with higher scores indicating more severe dystonia and 0 indicating absence of dystonia. |
| Percent Change of the Sum of Eyes and Upper Face, Lower Face and Jaw and Tongue Subscores of the GDS Rating Scale | 3, 6, 11 and 14 compared to baseline | The Global Dystonia Severity Scale provides a severity rating for ten body regions, i.e.,1) eyes and upper face, 2) lower face, 3) jaw and tongue, 4) larynx, 5) neck, 6) shoulder and proximal arm, 7) distal arm and hand including elbow, 8) pelvis and upper leg, 9) distal leg and foot, and 10) trunk. Each body area is rated from 0 to 10, with 0 representing no dystonia present in that body area and 10 representing severe dystonia. The secondary outcome measure includes the sum of the eyes and upper face, lower face and jaw and tongue subscores of the GDS rating scale and represents the percent change from baseline to either 3 and 6 weeks or 11 and 14 weeks (representing the end of the three week titration period (3 weeks and 11 weeks) and the post-3 week period (6 weeks and 14 weeks) at the maximum tolerated dose for Levetiracetam or Placebo). The total range of these combined sub scores is 0-30, with higher scores indicating more severe dystonia and 0 indicating absence of |
Countries
United States
Participant flow
Recruitment details
Participants between the ages of 18 and 80 with a diagnosis of primary oromandibular or cranial dystonia were recruited from the Movement Disorders and Botulinum Toxin Clinics at the National Institutes of Health and from the Dystonia Global Registry and Dystonia Medical Research Foundation.
Pre-assignment details
Subjects were excluded if they had a history of depression, psychosis or phobic disorders. One subject was consented but did not participate due to abnormal laboratory finding noted during screening.
Participants by arm
| Arm | Count |
|---|---|
| Primary Oromandibular Dystonia or Cranial Dystonia All participants enrolled in the study. | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Misunderstood titration schedule | 1 | 0 |
| Overall Study | Suicidal Ideation | 0 | 1 |
Baseline characteristics
| Characteristic | Primary Oromandibular Dystonia or Cranial Dystonia |
|---|---|
| Age, Continuous | 65 years |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 5 | 0 / 5 |
| serious Total, serious adverse events | 1 / 5 | 0 / 5 |
Outcome results
Primary
Percent Change of the Sum of the Eyes, Mouth, Speech and Swallowing Subscores of the Burke-Fahn-Marsden (BFM) Dystonia Scale.
The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) is a measure of dystonia severity. The scale consists of evaluation of nine body parts (eyes, mouth, speech, swallowing, neck, trunk, right arm, right leg, left arm and left leg). The severity and provoking factors for each part are rated using a 5-point scale. These range from 0 (indicating no dystonia) to 4 (indicating the presence of dystonia at rest). The primary outcome measure includes the sum of the eyes, mouth, speech and swallowing subscores and represents the percent change from baseline to either 6 weeks or 14 weeks (representing the end of the 3 week period at the maximum tolerated dose for Levetiracetam or Placebo). The total range for these combined sub scores is 0-16, with higher scores indicating more severe dystonia and 0 indicating absence of dystonia.
Time frame: 6 and 14 weeks compared to baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levetiracetam Group | Percent Change of the Sum of the Eyes, Mouth, Speech and Swallowing Subscores of the Burke-Fahn-Marsden (BFM) Dystonia Scale. | 12.16 percent change | Standard Deviation 29.07 |
| Placebo Group | Percent Change of the Sum of the Eyes, Mouth, Speech and Swallowing Subscores of the Burke-Fahn-Marsden (BFM) Dystonia Scale. | 31.25 percent change | Standard Deviation 26.86 |
Secondary
Percent Change of the Sum of Eyes and Upper Face, Lower Face and Jaw and Tongue Subscores of the GDS Rating Scale
The Global Dystonia Severity Scale provides a severity rating for ten body regions, i.e.,1) eyes and upper face, 2) lower face, 3) jaw and tongue, 4) larynx, 5) neck, 6) shoulder and proximal arm, 7) distal arm and hand including elbow, 8) pelvis and upper leg, 9) distal leg and foot, and 10) trunk. Each body area is rated from 0 to 10, with 0 representing no dystonia present in that body area and 10 representing severe dystonia. The secondary outcome measure includes the sum of the eyes and upper face, lower face and jaw and tongue subscores of the GDS rating scale and represents the percent change from baseline to either 3 and 6 weeks or 11 and 14 weeks (representing the end of the three week titration period (3 weeks and 11 weeks) and the post-3 week period (6 weeks and 14 weeks) at the maximum tolerated dose for Levetiracetam or Placebo). The total range of these combined sub scores is 0-30, with higher scores indicating more severe dystonia and 0 indicating absence of
Time frame: 3, 6, 11 and 14 compared to baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levetiracetam Group | Percent Change of the Sum of Eyes and Upper Face, Lower Face and Jaw and Tongue Subscores of the GDS Rating Scale | -10.36 Percentage of change | Standard Deviation 20.06 |
| Placebo Group | Percent Change of the Sum of Eyes and Upper Face, Lower Face and Jaw and Tongue Subscores of the GDS Rating Scale | 4.11 Percentage of change | Standard Deviation 32.31 |
| Placebo Group at 3 or 11 Weeks | Percent Change of the Sum of Eyes and Upper Face, Lower Face and Jaw and Tongue Subscores of the GDS Rating Scale | -16.93 Percentage of change | Standard Deviation 36.49 |
| Placebo Group at 6 or 14 Weeks | Percent Change of the Sum of Eyes and Upper Face, Lower Face and Jaw and Tongue Subscores of the GDS Rating Scale | -3.83 Percentage of change | Standard Deviation 24.8 |
Secondary
Percent Change of the Sum of the Eyes, Mouth, Speech and Swallowing Subscores of Burke-Fahn-Marsten Dystonia Rating Scale (BFM)
The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) is a measure of dystonia severity. The scale consists of evaluation of ten body parts (eyes, mouth, speech, swallowing, neck, trunk, right arm, right leg, left arm and left leg). The severity and provoking factors for each part are rated using a 5-point scale. These range from 0 (indicating no dystonia) to 4 (indicating the presence of dystonia at rest). The secondary outcome measure includes the sum of the eyes, mouth, speech and swallowing subscores and represents the percent change from baseline to either 3 weeks or 11 weeks (representing the end of the three week titration period up to the maximum tolerated dose for Levetiracetam or Placebo). The total range for these combined sub scores is 0-16, with higher scores indicating more severe dystonia and 0 indicating absence of dystonia.
Time frame: 3 and 11 weeks compared to baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levetiracetam Group | Percent Change of the Sum of the Eyes, Mouth, Speech and Swallowing Subscores of Burke-Fahn-Marsten Dystonia Rating Scale (BFM) | 14.80 percent change | Standard Deviation 55.76 |
| Placebo Group | Percent Change of the Sum of the Eyes, Mouth, Speech and Swallowing Subscores of Burke-Fahn-Marsten Dystonia Rating Scale (BFM) | 6.78 percent change | Standard Deviation 29.37 |