Ziprasidone in Children With Autism: A Pilot Study
Condition: Autism
MeSH terms: Autistic Disorder
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to see if the drug, ziprasidone, is effective in treating
      problems in adolescent associated with autism.
    

Detailed description: 
      I. SPECIFIC AIMS

        1. To investigate the safety of clinical use of ziprasidone in children

        2. To investigate the dosages that have been employed clinically.

      II. BACKGROUND AND SIGNIFICANCE

      Ziprasidone, a recently released atypical agent is likely to be as effective as other
      neuroleptics in treating psychiatric symptoms in children, but may have the considerable
      health advantage of not causing weight gain. Ziprasidone administration has been associated
      with prolongation of the QTc interval (mean=20 msec), an electrocardiographic measure of
      ventricular repolarization (Federal Drug Administration, 2000). There are no reports
      regarding the use of ziprasidone in autism, and data regarding the safety and efficacy of
      ziprasidone in children is extremely limited. The only published study of ziprasidone in
      children found that it was safe and effective in treating Tourette's syndrome in children
      aged 7 to 17 years of age (Sallee et al, 2000). Because children are being treated with
      ziprasidone despite a paucity of safety data, it is important to begin to collect and review
      available data, including that from clinical usage. Some children who receive services within
      the Child and Adolescent Psychiatric Services of Drexel University College of Medicine have
      been treated with ziprasidone. The charts of the children and adolescents will contain data
      regarding exposure to ziprasidone and laboratory data and ECG's that can be reviewed to
      determine whether ziprasidone treatment has been associated with changes in weight,
      laboratory values and ECG's. We propose to review the charts of patients who have been
      treated with our services since March 1, 2001 XXX because such patients may have been exposed
      to ziprasidone (ziprasidone received FDA approval on February 5, 2001).

      III. DESIGN AND METHODS

      A. Setting: The setting for this study will be the Specialty Clinic for Pervasive
      Developmental Disorders, part of the Child and Adolescent Psychiatry Outpatient Clinic at
      Eastern Pennsylvania Psychiatric Institute.

      B. Subjects: Subjects will be 15 children and adolescents who meet the DSM-IV Criteria for
      Pervasive Developmental Disorder.

      C. Design: This is a 6-week pilot study employing open treatment with ziprasidone. Subjects
      will be rated at baseline and thereafter assessed weekly.

      D. Medication: Subjects will be treated openly with ziprasidone. Should untoward effects
      occur, the dosage of the medication will be reduced or the medication will be discontinued,
      as clinically appropriate. Subjects will not receive other concomitant psychotropic
      medication during the study. Medication will be taken concomitant with food.

      Ziprasidone Dosing Strategy: Ziprasidone tablets (5, 10, and 20 mg) will be employed for the
      study. The dosage range for ziprasidone will be 5 mg/day to 40 mg/day. Every effort will be
      made to reach and maintain a therapeutic dosage by week four of the treatment phase.

        1. For subjects who weigh less than 25 kg, starting dosage will be 5 mg/every other day.
           After 3 days, the dosage can be increased to 5 mg. By week 2, subjects can be increased
           to 20 mg/day. Thereafter, dosage increases can be made in up to 20 mg increments weekly.

        2. For subjects who weigh greater than 25 kg, the starting dosage will be 5 mg/day. After
           three days, the dosage can be increased to 10 mg/day. By week two, subjects can be
           increased to 20 mg/day. Thereafter, dosage increases can be made in up to 20 mg
           increments weekly as needed.

      Note: Should 5 mg tablets not be available, the dosing schedule will be altered to have a
      starting dosage of 10 mg, and dosage increases will be made in 10 mg increments.

      F. Measures

        1. Primary efficacy measure: The Clinical Global Impressions (CGI; Psychopharmacology
           Bulletin, 1985). The efficacy of treatments can be judged on their ability to enhance
           global functioning, an assessment that is particularly relative in a pilot study. The
           CGI consists of three global scales measuring severity of illness, global improvement,
           and drug effect, and has been useful in measuring drug treatment effect in this
           population (see Campbell and Palij, 1985). The PI and another trained rater will
           complete this scale. Although only members of the research team generally complete this
           scale, it will additionally be completed by the subject's parent/caretaker. Having it
           completed by the parent/caretaker will take only minutes and may result in useful data.
           This measure will be completed weekly beginning at baseline.

        2. Secondary efficacy measure: Children's Psychiatric Rating Scale (Psychopharmacology
           Bulletin, 1985). The CPRS was developed by the Psychopharmacology Branch of the NIMH to
           rate childhood psychopathology. Each of the items is rated from "1" (not present) to "7"
           (extremely severe). The first 28 items of this scale require no verbal response on the
           part of the subject, making them appropriate for rating children and adolescents with
           Pervasive Developmental Disorder. Of these 28 items, 14 are particularly relevant in
           autism (see Campbell and Palij, 1985): they assess the symptoms for which drug treatment
           is indicated including hyperactivity, aggression, self-abusive behavior, temper
           tantrums, lability of mood, irritability, social withdrawal, and stereotypies. A
           composite sum of these 14 items, the CPRS-14, will be constructed and employed as a
           secondary outcome measure, a procedure used by a number of investigators (Anderson et
           al, 1989; Campbell et al, 1986, 1989, 1993; Findling et al, 1997; Sanchez et al, 1996).
           We analyzed our data using the CPRS-14; the ICC was 0.8978. In addition, 4 factors
           derived from these 14 items will be examined. They include: autism,
           anger/uncooperativeness, hyperactivity, and speech deviance (Overall and Campbell,
           1988). This measure will be completed at baseline and at the end of treatment.

        3. Safety measures: (1) A physical exam will be completed at baseline. (2) Height, weight,
           blood pressure, and pulse will be obtained and recorded at baseline and at each visit
           during the study. (3) The following laboratory measures will be obtained at baseline and
           repeated at the end of the treatment phase: complete blood count with differential,
           liver functions, and electrocardiogram. Serum prolactin will be obtained at baseline and
           at the end of the treatment phase. These laboratory studies will be repeated at the end
           of the treatment phase of the study. Any other clinically appropriate tests and
           evaluations will also be completed whenever needed.

      Untoward effects will be measured and recorded at each visit employing the following
      measures: (1) Dosage Record and Treatment Emergent Symptom Scale (DOTES); (2) Treatment
      Emergent Symptoms Scale (TESS); (3) Abnormal Involuntary Movement Scale (AIMS) (all from
      Psychopharmacology Bulletin, 1985); and (4) the Neurologic Rating Scale (Simpson and Angus,
      1970). The DOTES and TESS measure a wide range of possible untoward effects. The AIMS
      measures dyskinesias. The Neurologic Rating Scale measures other forms of extrapyramidal
      effects that can occur with neuroleptics such as dystonias, parkinsonian effects, and
      akathisia.

      G. Procedures: All patients appropriate to the study and their parent/caretakers will be
      approached and informed consent and assent (in subjects under 14 years) will be obtained.
      Subjects meeting the Inclusion Criteria, but not the Exclusion Criteria, will enter the
      baseline period of the study.

      Baseline (week 0): Subjects will be rated at baseline employing the CGI and the CPRS.

      End of Treatment (week 6): At the end of the treatment period, subjects will again be rated
      employing the CGI and the CPRS (selected items).

      In addition, each subject will be rated on the CGI at each visit so that data from the last
      visit is available should the subject terminate the study prematurely. If it is known that a
      subject will terminate the study at a visit before week 6, the subject will be rated with the
      CGI and the CPRS at that visit.

      All safety measures will be completed at each visit. Laboratory measures and EKG will be
      obtained in the morning.

      I. Analysis: This is a pilot study whose purpose is to get initial safety and efficacy data
      with ziprasidone in children with autism. We will perform an ANOVA, repeated measures, for
      CGI severity scores, the CPRS-14 and the CPRS factors. Similar analyses will be performed for
      safety measures including for weight, prolactin and other laboratory measures, and EKG
      indices.
    

Intervention name(s): Ziprasidone
Intervention type(s): Drug
Intervention description(s): Ziprasidone 40mg to 60mg per day, individually titrated
Other intervention name(s): Geodon
Intervention MeSH terms: Ziprasidone
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Autism; Pervasive Developmental Disorder; Ziprasidone; Adolescents