Janssen Asperger's MRS (Magnetic Resonance Spectroscopy Risperidone Study

STUDY DESIGN

This study will be an open-label, 12-week trial of risperidone in subjects with Asperger's Disorder, according to DSM-IV Criteria. The study has two arms, one involving pre- and post-treatment MRS studies, and one without MRS. The MRS arm will study 18-20 subjects ages 6 and above, with a target of 14 completing patients. For both arms, we plan to a enroll at total of 30 patients to achieve completion for 24 patients. The non-MRS arm of the study will include subjects 6-18 years of age, the bulk of which have completed the study as of the writing of this updated revision.

Subjects will first undergo a screening visit during which safety and diagnostic assessments are completed, and a minimum of 3 days will be allowed to evaluate the screening results. Then, the subjects will complete one or two practice sessions to provide training to achieve the necessary stillness for a duration that is sufficient to complete a MRS session. Upon completion of successful practice sessions, subjects will then be scheduled for a MRS visit. Once the MRS is successfully completed, subjects will be assigned to receive risperidone 0.25 mg at their baseline visit.

Response to risperidone will be measured at weeks 3, 6, 9, and 12 by the Scale for Assessment of Negative Symptoms (SANS). Additional secondary outcome measures are shown below (figure 1). A post-treatment MRS will be conducted after the Week 12 or early termination visit. Subjects will be given adequate medication supply to cover through the day of the final MRS visit.

Study Medication. Because Asperger's Disorder is diagnosed in childhood and is considered a childhood disease, our previous phase of the study focused on subjects ages 6 - 18. Published dosages of risperidone used in child, adolescent, and adult studies ranges from 0.25 to 11 mg per day. Most studies in children and adolescents begin with a starting dose of 0.25 mg bid, which is also appropriate for adults, and will be the starting dose planned for this study. The study progresses from a fixed to a titrated dose paradigm. After Week 6, dose will be increased (based on response and tolerability), ranging from one to two tablets twice daily (either 1 or 2 mg of risperidone daily). Again at Week 9, dose will be increased (based on response and tolerability), ranging from 1 mg to 4 mg per day of risperidone, one to four tablets twice a day of risperidone. Patients who have any trouble tolerating the starting dose may have their dose reduced to 0.25 mg per day and continue in the study. Patients who cannot tolerate the 0.25 mg dosage would discontinue the study in order to receive alternative treatment.

Schedule of Events and Observations

Screening Visit: A Structured Clinical Interview for Diagnosis (SCID) in conjunction with DSM-IV criteria and a psychiatric history, will allow the study physicians to establish and confirm a diagnosis of Asperger's disorder. Medical history, vital signs, clinical labs {chemistry, complete blood count (CBC), thyroid function, urinalysis, urine drug screen, and blood pregnancy test (fecund females only)}, a physical exam, and an EKG will be performed to determine patient safety.

Blood Draws: Additional lab samples will be collected at both screening and end of study to explore 1) the effects of diet on treatment outcomes with risperidone, and 2) effects of risperidone treatment on levels of Brain Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF). The additional blood will amount to an approximate total of 8 tablespoons of blood collected during the study.

MRS Visits and Practice Sessions: Subjects enrolling in the MRS arm, will be scheduled for a pretreatment MRS which will take place after the screening visit but before the baseline visit and prior to starting risperidone. Subjects will also have a post-treatment MRS within 7 days of their week 12 visit or at study termination. Patients will be supplied with enough medication to continue treatment until the MRS measures are complete.

Subjects may be required, based on the investigator's discretion, to complete one or two sessions during the screening period for Practice Sessions for MRS studies to better prepare subjects for the level of stillness needed for MRS studies. The practice sessions will last approximately one hour and will be performed at the Medical College of Georgia (MCG) Office of Clinical Investigative Services, located at 1521 Pope Ave, Suite FF-100. Practice Sessions may also be performed at the MRI suite at MCG to allow the subject to see or lie in the MRI machine, depending on availability.

Rationale for practice sessions: We have learned that these sessions may be necessary to help subjects achieve the stillness required for MRS. During the sessions, subjects will be trained to remain still while lying on a padded stretcher, using behavioral and relaxation training techniques performed by a qualified investigator. Other efforts will be made to simulate the MRS environment that may include playing recorded sounds of a MRI machine and simulation of the padded head supports.

In most cases the Practice Sessions, would be all done prior to the MRS visit, but in some cases of a failed MRS visit, the investigator may choose to schedule another practice session prior to re-trying the MRS visit. The practice session will supplement the standard efforts used to support patients' compliance during MRI procedures. For example, part of the hospital's usual care during MRI studies includes the option of having the patient wear video goggles and headphones. Subjects in our study may view a calming video of neutral content to aid in problems affecting stillness.

Behavioral reinforcement and subject payments during practice sessions. Part of the payment for practice sessions will be used as a behavioral reinforcement plan, and this will be in addition to the $20 payment for clinic visits, reimbursement for travel over 25 miles one-way @ .28/mile, and $50 for the MRS visit (paid regardless of success or failure).

The additional subject payment in the practice session will be used as incentive and behavioral reinforcement for achieving stillness. Specifically, subjects will receive a token (such as a poker chip or printed paper token) worth $5.00 for each 5-minute period they remain still. If a subject's head moves during a period, they will be told they have to begin a new period. The achievement of stillness will be determined by the investigator at the time, taking into account the actual observed stillness and the need to encourage and reward the subjects' efforts.

The actual stillness practice will last up to 40 minutes, and the subject will receive a token for each 5 minute period they remain still, for up to 8 periods. The total additional payment for behavioral reinforcement will range from $5.00 to $40.00, to be paid in the same way as other subject payments. In the case of adolescent subjects, parents will be encouraged to consider the additional practice session payments to go to the child as a reward for the child's efforts.

Baseline Visit: Subjects will be scheduled for baseline procedures when lab results and MRS values are reviewed and approved by the study physician, in most cases expected to be a period of 7 days. This visit will consist of medical-psychiatric interviews and neurocognitive testing. A urine pregnancy test (done previously at screening) may be repeated at baseline based on the judgement of the investigator.