Comparison of Keppra and Clonidine in the Treatment of Tics

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Brief Title

Comparison of Keppra and Clonidine in the Treatment of Tics

Official Title

Comparison of Keppra and Clonidine in the Treatment of Tics in Children With Tourette Syndrome

Brief Summary

      The goal of this study is to confirm that levetiracetam has a better tic-suppressing profile
      than that of the widely used tic-suppressing medication, clonidine. More specifically, the
      investigators hypothesize that in a 15 week placebo run-in, double-blind, medication
      cross-over trial; levetiracetam will be more effective and have fewer side-effects than
      clonidine.
    

Detailed Description

      This is a randomized, double-blind, 15 week (two treatment phase), 1 week run-in, cross-over
      study, in which the same patient receives 6 weeks of treatment with levetiracetam and a 6
      week treatment course with clonidine, separated by a two week medication wash-out. The
      investigators plan to enroll twenty patients between the ages of 7 to 19 years with moderate
      to moderately-severe Tourette syndrome or chronic motor/vocal tics. The recruitment period is
      expected to be approximately 12 months (total study length of about 18 months). The study
      will begin with a screening evaluation to ensure that each subject satisfies all eligibility
      criteria, to allow subjects to become familiar with our assessment procedures, and to obtain
      informed consent. Following a baseline visit, there will be a one week "run-in" treatment
      period in order to screen for high placebo responders, in which all subjects will receive
      placebo. If the patient's tic severity score fails to improve he/she will begin the double
      blind treatment period (levetiracetam/clonidine), that will last for six weeks followed by a
      two week wash out period, and then by a second double blind treatment period
      (clonidine/levetiracetam) for an additional six weeks. A statistician not involved with the
      care of the subjects will be responsible for randomization. A six week trial treatment was
      chosen to allow for an adequate drug response period. Patients will be followed by phone at
      weekly intervals throughout the study and will be formally evaluated at the beginning and end
      of each treatment phase. At the completion of the study, patients/parents will be given the
      opportunity to continue a successful treatment.

      The primary outcome measure is the Yale Global Tic Severity Scale (YGTSS): A semi-structured
      clinical interview designed to measure current tic severity. Other outcome measures will
      include the Clinical Global Impression-Improvement Scale (CGI-I), the Child Yale-Brown
      Obsessive-Compulsive Scale (CYBOCS), the DuPaul Attention Deficit Hyperactivity Disorder
      (ADHD) Rating Scale, Child Depression Inventory (CDI), Multi-Dimensional Anxiety Scale for
      Children (MASC), and an expanded Pittsburgh Side-Effect Scale.

      Subjects will be recruited from the Tourette Syndrome Clinic at the Johns Hopkins Hospital.
      This clinic, directed by Dr. Harvey Singer, currently follows more than 1000 chronic tic
      patients and averages 4 new referrals every week. The clinic staff has a longstanding
      successful record of designing and completing therapeutic protocols for the treatment of
      tics.

      Inclusion Criteria: see below

      Exclusion Criteria: see below

      Procedures:

      i) Screening visit: Determination of diagnostic eligibility criteria (medical history and
      complete physical examination; evaluation of tic severity, screening of females who have
      begun to menstruate with a urine pregnancy test, familiarization with assessment procedures,
      and obtaining informed consent. The urine pregnancy test will be obtained in females over 12
      years of age. Parents will be told the results of these tests. If the patient is
      uncomfortable with our telling the results of the pregnancy test to her parent(s), then they
      may decide not to take part in this study.

      ii) Baseline Visit (Day 0): Evaluation prior to the run-in (placebo) phase will include
      weight, heart rate, blood pressure, respiratory rate, rating scales for: tics, the Yale
      Global Tic Severity Scale (YGTSS) and Childhood Global Impression-TS (CGI-TS); adverse
      effects, the Pittsburgh Side-Effect Rating Scale; obsessive-compulsive problems, Child
      Yale-Brown Obsessive Compulsive Scale (CY-BOCS; attention deficit hyperactivity disorder,
      DuPaul ADHD Rating Scale, depression, Child Depression Inventory- Short Version (CDI-S);
      anxiety, the Multidimensional Anxiety Scale for Children (MASC; and episodic outbursts, Rage
      Attack Rating Scale.

      iii) Run-in Placebo Phase (days 0-7): Immediately after the baseline visit, the subject is
      started on placebo treatment for a one week period. All subjects will receive 1 capsule twice
      a day; capsules will be similar in appearance to that used in the drug treatment phase. The
      Run-in phase has been added to eliminate subjects whose treatment outcome could be influenced
      by only a transient exacerbation of tics or by the exposure to non-pharmacologic treatment.

      a) Post- Run in Period Evaluation (day 8): Subjects will return for a re-evaluation of
      symptoms, emphasis will be placed on rating scales for: tics, the Yale Global Tic Severity
      Scale (YGTSS) and Childhood Global Impression-TS (CGI-TS); and adverse effects, the
      Pittsburgh Side-Effect Rating Scale. If there is no tic improvement following the receipt of
      placebo, the patient will move on to the treatment phase of the study. In contrast, if tic
      symptoms are reduced by more than 15% or significant side effects are reported, all treatment
      will be discontinued and the subject will be withdrawn from the study.

      iv) Treatment phases (days 8 50 and days 65 107): A computer generated unequal randomized
      scheme will be used to assign patients to either levetiracetam or clonidine in the initial
      treatment phase. Research Pharmacy at Johns Hopkins will be responsible for packaging
      levetiracetam (supplied by UCB) and clonidine (purchased), randomizing its allocation, and
      distributing the medication. Levetiracetam and clonidine will be repackaged in look-alike
      capsules with different dosage levels: levetiracetam, 250 milligrams (mg) or 500 mg and
      clonidine, 0.05 mg or 0.1 mg. Patients will receive a six week supply of medication at the
      first treatment phase visit (day 8) and at the beginning of the second treatment phase (day
      63). A study physician (Dr. Harvey Singer) will be responsible for changing medication dosage
      and monitoring side-effects. A Safety Monitoring Board has been established to oversee
      medication use and monitor side-effects.

        1. Levetiracetam: The starting dose of levetiracetam will be 10 mg/kg/day for one week;
           administered as 5 mg/kg twice a day (B.I.D.)(rounded to the closest unit of 250 mg). If
           needed for tic suppression, the dose will be increased weekly by 5-10
           mg/killigrams(kg)/day. The maximum dose will be 50 mg/kg/day (administered as 25 mg/kg
           BID), with a maximum dose of 2,500 milligrams per day. For reference, doses from 10 to
           60 mg/kg/day of levetiracetam are currently being used in pediatric studies for the
           treatment of seizures and up to 2000 mg in TS children with a mean age of 12 years. In
           any individual subject, dose escalation may proceed more slowly, or the dose may be
           reduced if necessary. No changes in dosage will be made during the final week of both
           treatment phases.

        2. Clonidine: The starting dose of clonidine will be 0.05mg BID for one week. If needed for
           tic suppression, the dose will be increased weekly by 0.05-0.1 mg. The maximum dose will
           be 0.4 mg (administered as 0.2 mg BID).

      iv) Wash out phase: Between the two treatment phases, medication will be tapered over a ten
      day period. Levetiracetam will be tapered at the end of each treatment phase by 5-10
      mg/kg/day every third day. The half life of levetiracetam is approximately 7-8 hours in
      healthy volunteers, 5 8 hours in epileptic patients, and about 10 hours in the elderly.
      Clonidine will be tapered by 0.05 - 0.1 mg every third day. Subjects will be off medication
      for 5 days before starting the second phase of the cross over study.

      v) End of study drug taper: At the completion of the second treatment phase, medication will
      be tapered over a ten-day period, reducing the medications in equal proportions every third
      day.

      vi) Early stopping rules: Subjects may be withdrawn from the study at any time at the
      discretion of the subject, attending physician, or investigator.

        1. The investigator decides the subject should be withdrawn. This decision could be made
           because of an adverse effect or a failure to comply with the study protocol.

        2. The subject or his/her personal physician requests that the subject be withdrawn from
           the study.

        3. The subject, for any reason, requires treatment with another therapeutic agent that
           could conflict with the use of levetiracetam or clonidine.

        4. A Drug Safety Monitoring Board will monitor side effects and assist in determining
           whether a subject should be withdrawn from the trial. Members of this board are full
           time Johns Hopkins Hospital faculty members and epilepsy fellows with experience in the
           use of levetiracetam. The Board will have access to the randomization codes maintained
           by the statistician. A quarterly update meeting will be scheduled for the Monitoring
           Board with topics to be reviewed including the number of subjects, dosage schedules,
           side effects, and therapeutic responses. Significant adverse events will be reported to
           the sponsor Union chimique belge, Inc (UCB, Inc), Johns Hopkins Joint Committee on
           Clinical Investigation (JCCI), and Food and Drug Administration (FDA) within 24 hours.

      vii) Evaluations: This is a 15 week study. Telephone evaluations will be performed by the
      blinded Research Assistant on day 14, 21, 28, 35, 42, 70, 77, 84, 91, and 98. At each
      telephone session clinical response, possible side effects, drug compliance, and medication
      adjustment will be discussed. Subjects will be formally evaluated at 4 separate times
      including baseline (day 0), at end of the run-in phase (day 8), end of the first treatment
      phase (day 49), at end of the drug wash out period (day 63), and at end of the study (day
      105). Evaluations at each visit by the Research Assistant will include vital signs, weight,
      and an assessment of side effects using the Pittsburgh side effects scale. The blinded
      outcome evaluator, Dr. Harvey Singer, will administer and score the YGTSS, CGI I, DuPaul ADHD
      scale, CY BOCS, CDI S, and MASC. In addition, at each visit a pill count will be done to
      assure compliance.

      C. Outcomes Measures:

      i) Yale Global Tic Severity Scale (YGTSS): The YGTSS is a semi-structured clinical interview
      designed to measure current tic severity [Leckman et al., 1989]. This scale consists of the
      separate rating of severity for motor (total motor, 0 to 25) and vocal (total vocal, 0 to 25)
      tics. Ratings are made along 5 discriminant dimensions, on a scale of 0 to 5 for each
      including number, frequency, intensity, complexity, and interference. Summation of these
      scores (i.e., 0 to 50) provides a Total Tic Score (TTS) which will be the primary outcome
      measure. The YGTSS also contains a separate ranking of impairment (Tic Impairment Score or
      TIS), with a maximum of 50 points, based on the impact of the tic disorder on areas such as
      self esteem, family life, social acceptance, and school scores. Because the focus of this
      study is to evaluate the impact of levetiracetam and clonidine on tics and because the TIS
      may incorporate other components of TS, the Total Tic Score (TTS) has been selected as the
      primary outcome measure.

      ii) Clinical Global Impression-Improvement (CGI-I): The CGI-I is used to compare current
      severity to baseline. A score of 1 corresponds to "very much improved; @ 2 equals "much
      improved;" 3 denotes minimal change; and 4 represents "no change." Scores above 4 are used to
      indicate deterioration, i.e., 5 equals "minimally worse;" 6 is "much worse;" and 7 is "very
      much worse."

      iii) Child Yale-Brown Obsessive Compulsive Scale: The severity of OCD will be evaluated using
      the Child Yale-Brown Obsessive Compulsive Scale (CY-BOCS) [Scahill et al, 1997]. Obsessions
      and compulsions are rated on 5 separate scales yielding three summary scores: Obsessions
      (0-20), Compulsions (0-20) and a Total score (0-40). The CY-BOCS is the most widely used
      instrument to assess the severity of obsessive-compulsive symptoms in research studies
      involving children. It includes a checklist of specific obsessions and compulsions followed
      by examiner ratings of time spent, interference, distress, resistance and control over the
      obsessions and compulsions assessed independently. The CY-BOCS has well established
      psychometric properties.

      iv) DuPaul ADHD Rating Scale: The presence of ADHD symptoms will be assessed using the DSM-IV
      version of the ADHD rating scale developed by DuPaul. This scale incorporates the symptom
      items for ADHD from the DSM into a rating scale format that quantifies symptom severity. Each
      item is rated as not at all, just a little, pretty much, and very much (0, 1, 2, and 3). This
      scale has been normed in large clinical and community samples and has excellent psychometric
      properties including a test-retest reliability over a 2-week period of 0.93 and significant
      correlations with direct observations of classroom behavior.

      v) Child Depression Inventory-Short Version (CDI-S): Depression severity will be rated by
      using the Child Depression Inventory-Short Version (CDI-S. This 10 item scale takes about 5
      minutes to complete. It has excellent psychometric properties and is designed for repeated
      administrations over time.

      vi) Multidimensional Anxiety Scale for Children (MASC): The child's anxiety will be followed
      using the multidimensional Anxiety Scale for Children (MASC) and is now considered the
      preferred instrument for rating childhood anxiety.

      vii) Adverse effects: Side effects will be assessed by an expanded Pittsburgh Side Effect
      Scale modified to include side effects of levetiracetam and clonidine. Significant adverse
      events will be reported to the UCB, JCCI, and FDA within 24 hours.

      D. Open Label Continuation:

      At the completion of the study the subject will be given the option of continuing either
      levetiracetam or clonidine in an open labeled fashion. This will be enabled by having the
      subject seen by another physician who will have access to the study codes. This physician
      will continue to follow the subject until the entire study is completed. For members of the
      research team, the treatment code will not be broken until all subjects have completed the
      protocol.

      IV. Analytical Strategies A. Inclusion of a Run-in phase: The Run-in phase has been added to
      eliminate subjects whose treatment outcome could be influenced by a transient exacerbation of
      tics or by the exposure to non-pharmacologic treatment.

      B. Power calculations: As described, this is a pilot randomized, double-blind,
      placebo-controlled, cross-over project in which the investigators plan to enroll twenty
      patients between the ages of 7-19 years with Tourette Syndrome. Subjects with moderate to
      severe TS will be enrolled in this treatment protocol. Data from randomized, double-blind,
      placebo-controller trials of tics suggest that 6.0 points in the YGTSS total tic score is a
      reasonable estimate of the standard deviation of this outcome variable in the population of
      interest. The investigators estimate that approximately 19 subjects will provide a desired
      power of 0.9 to detect a difference of 4.2 points in the mean 6-week change in YGTSS total
      tic score between the two treatment arms, using a two-tailed t-test and a 5% level of
      significance.

      C. Statistical evaluations: The primary outcome measure is effective tic suppression as
      determined by the difference in Total Tic scores between treatment arms for levetiracetam and
      clonidine. Secondary outcome measures include the Tic Impairment Score, the Total YGTSS
      score, and the CGI-I. Data will be compared both as a change in absolute test score and as a
      percentage from baseline. Unpaired Student's t-tests will be used to compare treatment and
      placebo groups across all clinical variables at baseline. A paired t-test with a 95%
      confidence interval will be used to compare changes in outcome measures from baseline to
      endpoint between the two treatment groups (levetiracetam and clonidine) regardless of
      treatment order. Using a secondary assessment (Analysis of Variance (ANOVA) with levels
      within respective classes containing subjects completing study, 2 treatments, and 2 periods),
      the investigators will analyze each outcome measure as a two-period (days 8 to 49 or 63 to
      105), two-treatment, two-sequence design with a test for the effects of treatment, first or
      second period, and treatment by period interaction. To evaluate the effect of levetiracetam
      and clonidine on blood pressure, pulse, weight, DuPaul ADHD scale, CYBOCS, CDI-S, and MASC,
      the investigators will conduct a series of repeated measures ANOVA to examine differences in
      each group across time. Statistical significance for all analyses will be set at alpha=0.05
      for a two-tailed test. This protocol format has been used effectively in a prior study of
      baclofen and levetiracetam.
    

Study Phase

Phase 4

Study Type

Interventional


Primary Outcome

Yale Global Tic Severity Scale (YGTSS):

Secondary Outcome

 Clinical Global Impression-Improvement (CGI-I):

Condition

Tic Disorders

Intervention

Levetiracetam

Study Arms / Comparison Groups

 Levetiracetam
Description:  Levetiracetam (Keppra) is used in one phase of this cross-over study.
The initial dose of levetiracetam was 10 mg/kg/day, divided twice daily (rounded to the closest unit of 250 mg). The dose was increased weekly by 5-10 mg/kg/day, to a maximum dose of 50 mg/kg/day (or 2,500 mg/day), if deemed necessary for tic suppression. In any individual, dose escalation may have proceeded more slowly, or the dose may have been reduced as necessary. No changes in dosage occurred during the final week of either treatment phase.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

12

Start Date

February 2007

Completion Date

June 2009

Primary Completion Date

July 2008

Eligibility Criteria

        Inclusion Criteria:

        Patients will be included in this study if they meet the following criteria:

          -  Tourette syndrome criteria based on the TS Classification Study Group [1993], which
             includes onset before 18 years, multiple involuntary motor tics, one or more vocal
             tics, a waxing and waning course, the gradual replacement of old symptoms with new
             ones, the presence of tics for more than one year, the absence of other medical
             explanations for tics, and observation of tics by a reliable examiner;

          -  Age 7 to 19 years, either gender;

          -  Observable tics, achieving a minimum score of > 22 on the Total Tic score of Yale
             Global Tic Severity Scale (YGTSS);

          -  Tic symptoms severe enough to warrant therapy;

          -  The concurrent use of other tic-suppressing medications will be permitted, if the
             subject has been on a stable dose for more than three weeks and agrees to maintain a
             constant dosage throughout the study;

          -  Tics are not controlled with current medication or individuals are tic suppressing
             drug naive.

        Exclusion Criteria:

        Exclusion criteria include the following:

          -  Secondary tics;

          -  Significant medical illness

          -  Current major depression, generalized anxiety disorder, separation anxiety disorder,
             psychotic symptoms (based on clinical evaluation), pervasive developmental disorder,
             autism, mental retardation (I.Q. less than 70), anorexia/bulimia, or substance abuse.
             Subjects with co-morbid ADHD, obsessive compulsive disorder (OCD), and conduct
             disorder will not be excluded;

          -  pregnancy;

          -  Hypersensitivity to levetiracetam or clonidine;

          -  baseline weight of less than 25 kilograms.
      

Gender

All

Ages

7 Years - 19 Years

Accepts Healthy Volunteers

No

Contacts

Harvey S Singer, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00370838

Organization ID

TSkepclon


Responsible Party

Sponsor-Investigator

Study Sponsor

Harvey S. Singer

Collaborators

 UCB Pharma

Study Sponsor

Harvey S Singer, MD, Principal Investigator, Johns Hopkins University


Verification Date

September 2011