low enrollment

This study will assess the efficacy of topiramate in the treatment of pathological gambling. Pathological gambling (PG) is a debilitating disorder, generally leading to severe personal, familial, financial, social, and occupational impairments. In PG, the patient experiences a progressive inability to resist impulses to gamble, and gambling significantly disrupt the patient's functioning in the personal, familial, and/or vocational spheres. Topiramate has shown preliminary evidence of efficacy in some impulse control disorders.

This is a 14-week, outpatient, multicenter, randomized, double-blind, placebo-controlled, flexible-dose study of topiramate in subjects with pathological gambling. After giving informed consent, subjects who meet all the inclusion and exclusion criteria may be enrolled. The study will consist of three phases:

• Washout/Screening Phase (up to 28 days prior to randomization or longer for those medications requiring a longer washout period;
• Double-Blind Phase (Titration: up to 6 weeks; Maintenance: 8 weeks); and
• Taper Phase (approximately 1 week).

The study medication will be titrated to 300 mg/day or the subject's maximum tolerated dose (MTD). Subjects must reach a minimum dose of 50 mg/day by Week 2. The taper phase will last approximately one week where subjects gradually reduce their medication until they are no longer taking study medication.

Patient may also give an optional blood sample for pharmacogenomic testing

Inclusion Criteria:

• Subjects must have a current DSMV-IV-TRTM diagnosis of pathological gambling supported by the Structured Clinical Interview for Pathological Gambling (SCI-PG).

• Subjects must have a severity score of ³ 4 (moderately ill) on the Clinical Global Impressions Scale - Severity (CGI-S) at Visit 1A (Day -28).

• Subjects must have a severity score of ³5 on the South Oaks Gambling Screen (SOGS) at Visit 1B (Day -7).

• Subjects must have a score of ³2 for item number 1 on the Gambling Symptom Assessment Scale (G-SAS) at Visit 1B (Day -7) and Visit 2 (Day 1).

• Subjects must have a minimum score of >10 on the obsession subscale (questions 1-5) of the Pathological Gambling - Yale Brown Obsessive Compulsive Scale (PG-Y-BOC) at Visits 1B (Day -7) and 2 (Day 1).

• Subjects must score ≤15 on the Young Mania Rating Scale (YMRS) at Visits 1B (Day -7) and 2 (Day 1).

• Subjects must be between 18 and 70 years of age, inclusive.

• Subjects must provide contact information for themselves to be used by the site in case of a missed appointment.

• Subjects may be male or female and must be in generally good health as confirmed by medical history and physical examination, laboratory tests and vital signs.

• Female subjects must be:

  • postmenopausal for at least one year, or
  • surgically sterile, or
  • practicing an effective method of birth control (e.g., oral contraceptives, contraceptive injections, intrauterine device, spermicide with barrier, contraceptive patch, contraceptive vaginal ring, male partner sterilization, or abstinence and agree to continue abstinence or to use an acceptable method of contraception, as listed above, should sexual activity commence) before entry and throughout the study; have a negative urine pregnancy test at Visits 1B (Day -7) and 2 (Day 1).

• Subjects must be able to take oral medication, adhere to the medication regimens and be willing to return for regular visits.

• Subjects must be able and willing to read written instructions and complete all scales and inventories required by the protocol.

• Subjects must have signed an informed consent form indicating that they understand the purpose of and procedures required for the study and are willing to participate.

Exclusion Criteria:

• Subjects with any current Axis I psychiatric disorder as defined by DSM-IV-TRä supported by the SCID-I/P, other than pathological gambling, that in the investigator's judgment might require intervention with either pharmacological or non-pharmacological therapy over the course of the study.
• Subjects with a history of personality disorder (e.g., schizotypal or borderline) considered by the investigator to likely interfere with assessment or compliance with treatment.
• Subjects who have a current or recent (within 3 months of Visit 2, Day 1) DSM-IV-TRTM diagnosis of substance abuse or dependence, with the exception of nicotine and caffeine abuse or dependence.
• Subjects receiving formal psychotherapy for pathological gambling (with the exception of Gamblers Anonymous) within the 4 weeks prior to Visit 1B (Day -7).

Note: Formal psychotherapy is defined as behavioral therapy, cognitive therapy, cognitive-behavioral therapy, psychoanalysis, etc. for the treatment of a clinical diagnosis or for which a healthcare professional is billing for such therapy.

- Subjects who have begun to receive formal psychotherapy for a psychiatric disorder, other than pathological gambling, within 3 months prior to Visit 1B (Day -7).

Note: Subjects who have been engaged in formal psychotherapy for a condition other than pathological gambling for >3 months and plan to maintain therapy throughout the study will be considered on a case-by-case basis.

• Subjects with a score of >24 on the Montgomery-Asberg Depression Rating Scale (MADRS) at Visit 1B (Day -7) and Visit 2 (Day 1).
• Subjects who are expected to stay in a restricted environment.
• Subjects who have taken a prohibited medication described in the Concomitant Therapy section of the protocol and who have not met the washout criteria specified in Attachment 15.
• Subjects with a positive urine drug screening [benzodiazepines, phencyclidine, cocaine, amphetamines, tetrahydrocannabinol (THC), and opiates] at Visit 1B (Day -7).

Note: Subjects with a positive urine drug screen for THC may be retested in 7 days and enrolled if they a) continue to meet inclusion/exclusion criteria and b) have a negative urine drug screen upon retest.

• Subjects who are pregnant or lactating.

• Subjects who are members of the same household.

• Subjects with a history of nephrolithiasis.

• Subjects known to have clinically significant medical conditions, including but not limited to:

  1. symptomatic coronary artery disease or peripheral vascular disease;
  2. malignancy or history of malignancy within the past 5 years (except basal cell carcinoma);
  3. renal disease and/or impaired renal function as defined by subjects with an estimated creatinine clearance of £60 mL/min;
  4. diseases of the gastrointestinal system including active liver disease;
  5. subjects with AST and/or ALT >2 times the upper limit of the normal range and/or an increased serum bilirubin > 2.0 mg/dL at Visit 1B (Day -7); Note: if these values are abnormal they can be re-tested prior to enrollment. If the repeat study is within the limits of the protocol the subject may be randomized.
  6. pulmonary disorders including subjects with active tuberculosis;
  7. endocrinological disorders;
  8. neurological disorders including subjects with seizure disorders and subjects with progressive or degenerative neurological disorders (e.g., multiple sclerosis); or I. any disease or condition that compromises the function of those body systems that could result in altered absorption, excess accumulation, or impaired metabolism or excretion of topiramate.

• Subjects who have previously been treated with topiramate for any reason and discontinued treatment due to an adverse event or a hypersensitivity reaction to topiramate.

• Subjects with prior non-response to topiramate for the treatment of pathological gambling following an adequate trial.

• Subjects who in the opinion of the investigator should not be enrolled in the study because of the precautions, warnings or contraindications outlined in the topiramate investigator brochure and/or package insert.

• Employees of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the investigator or study center employees.

Pathological Gamblers meeting criteria

Small sample size and short study duration. Selection bias - sample unrepresentative of PG in the community due to exclusion criteria.