Open-Label Pilot Study to Examine the Value of Substituting Quetiapine for Benzodiazepines
Open-Label Pilot Study to Examine the Value of Substituting Quetiapine for Benzodiazepines
The hypothesis of this study is that symptoms of anxiety, depression and insomnia; and
 indices of psychosocial function will all improve, while BZ use will decrease significantly
 during a twelve-week trial period of substituting quetiapine for benzodiazepines.
1.1 Background Numerous patients having depression or anxiety appear to use benzodiazepines
 chronically and respond incompletely to conventional antidepressants. These patients are more
 likely to request or incur frequent changes of medication because of non-response, incomplete
 response or intolerance. The hypothesis of this study is that symptoms of anxiety, depression
 and insomnia; and indices of psychosocial function will all improve, while BZ use will
 decrease significantly during a twelve-week trial period of substituting quetiapine for
 benzodiazepines.

 1.2 Rationale for this study The scientific rationale for this derives from a combination of
 clinical observation and a review of the literature. Anecdotal clinical experience with
 numerous patients having depression or anxiety suggested to me that patients with chronic
 benzodiazepine use were less likely to respond or remit with conventional antidepressants and
 more likely to request or incur frequent changes of medication because of non-response,
 incomplete response or intolerance. Although most of these patients were not drug abusers and
 the doses they took were within ranges recommended in the package inserts for these drugs
 (e.g., 5-20mg/ day of diazepam or equivalent), they were "dependent" in the sense that they
 took the BZ daily or almost daily, would not give it up in spite of "good responses"
 (although often with residual symptoms of anxiety or insomnia) to antidepressants or mood
 stabilizers, and were determined to get their prescription refills on time and often upset if
 they could not. I hypothesized that chronic benzodiazepine use created circadian or ultradian
 cycles of sedation, which might be experienced as fatigue or amotivation, and withdrawal,
 which might be experienced as anxiety or insomnia. Patients often tinkered with the doses and
 timing of the doses in an attempt to smooth out these cycles. The current study will
 determine whether symptoms of anxiety, depression and insomnia; and indices of psychosocial
 function improve, while BZ use decreases during a twelve-week trial period of substituting
 quetiapine for benzodiazepines. This would be a proof of concept study in a unique
 subpopulation with MDD or GAD.

 2. STUDY OBJECTIVES 2.1 Primary objective For MDD:The primary efficacy measures will be
 change from baseline to endpoint in the MADRAS and the change in mean daily benzodiazepine
 dose in diazepam equivalents during the past week.

 For GAD: The primary efficacy measures will be change from baseline to endpoint in the HAM-A
 and the change in mean daily benzodiazepine dose in diazepam equivalents during the past
 week.

 2.2 Secondary objectives Secondary efficacy measures will include response and remission
 rates and self-rated scales of symptoms and psychosocial function (the IDS-SR for depressive
 symptoms, the SAS-SR for social/vocational function and the Q-LES-Q for quality of life).

 3. STUDY PLAN AND PROCEDURES 3.1 Overall study design and study plan Subjects will be
 followed to assure a stable regimen of antidepressant medications and BZ for at least 8
 weeks. Patients will then be treated with flexible doses of quetiapine-ER up to 300mg/day for
 8 weeks. Dosing will begin with Seroquel 50 mg. at bedtime and will escalate weekly to
 Seroquel 100mg., Seroquel-XR 200mg. and Seroquel-XR 300 mg depending on clinical response and
 side effects. BZ doses will be gradually tapered at the equivalent of 5mg/day/week of
 diazepam equivalents where possible. This is not a forced titration schedule.

 3.2 Rationale for study design, doses and control groups The design is an open-label, proof
 of concept study. The dosing is based on my prior clinical experience with this patient
 population. There are no control groups.

 3.4 Treatments 3.4.1 Identity of investigational product and comparators Seroquel-XR 50 mg.,
 Seroquel-XR100mg., Seroquel-XR 200mg. and Seroquel-XR 300 mg.

 3.4.2 Doses and treatment regimens Dosing will begin with Seroquel-XR 50 mg. at bedtime and
 will escalate weekly to Seroquel-XR 100mg., Seroquel-XR 200mg. and Seroquel-XR 300 mg
 depending on clinical response and side effects.

 3.5 Pre-study, concomitant and post-study treatment(s)

 Prohibited medication during the study:

 -  Potent cytochrome P450 inhibitors (including but not limited to ketoconazole,
 itraconazole, fluconazole, erythromycin, clarithromycin, troleandomycin, indinavir,
 nelfinavir, ritonavir, fluvoxamine and saquinavir)

 -  potent cytochrome P450 inducers (including but not limited to phenytoin, carbamazepine,
 barbiturates, rifampin, St. John's Wort, and glucocorticoids)

 -  Any psychotropic besides quetiapine, antidepressant or benzodiazepine.

 Other medication, which is considered necessary for the subject's safety and well-being, may
 be given at the discretion of the investigator(s). The administration of all medication
 (including investigational products) must be recorded in the appropriately.

 4. OUTCOME AND VARIABLES 4.1 Primary Variable For MDD: The primary efficacy measures will be
 change from baseline to endpoint in the MADRAS and the change in mean daily benzodiazepine
 dose in diazepam equivalents during the past week.

 For GAD: The primary efficacy measures will be change from baseline to endpoint in the HAM-A
 and the change in mean daily benzodiazepine dose in diazepam equivalents during the past
 week.

 4.2 Secondary Variables Secondary efficacy measures will include response and remission rates
 and self-rated scales of symptoms and psychosocial function (the IDS-SR for depressive
 symptoms, the SAS-SR for social/vocational function and the Q-LES-Q for quality of life).

 4.3 Efficacy Variable(s) For MDD: The primary efficacy measures will be change from baseline
 to endpoint in the MADRAS and the change in mean daily benzodiazepine dose in diazepam
 equivalents during the past week.

 For GAD: The primary efficacy measures will be change from baseline to endpoint in the HAM-A
 and the change in mean daily benzodiazepine dose in diazepam equivalents during the past
 week.

 An overdose is not regarded as an AE. All symptoms associated with the overdose should
 however be reported as AEs. For further information regarding overdose, see section 11.2.

 Pregnancy in itself is not regarded as an AE unless there is a suspicion that an
 investigational product may have interfered with the effectiveness of a contraceptive
 medication. For further details regarding pregnancy, see section 11.3.

 4.4.1.3 Reporting of serious adverse events Investigators and other site personnel must
 inform the FDA, via a Medwatch form, of any unexpected and possibly Study Drug-related
 serious adverse events (SAEs) according to the FDA reporting requirement timelines. The
 Investigator must also inform appropriate AstraZeneca representatives of any SAE that occurs
 in the course of the study within one day (ie, immediately but no later than the end of the
 next business day) of when he or she becomes aware of it. The investigator must also report
 follow-up information on SAEs within one day. A copy of the MedWatch report must be faxed to
 AstraZeneca at the time the event is reported to the FDA. Reporting to the FDA is recommended
 regardless of whether an IND is required for the study.

 Additionally, the Investigator shall provide AstraZeneca with a report of all other SAEs that
 did not qualify for expedited reporting to the FDA (e.g., considered to be expected and/or
 not related) on at least a quarterly basis in order for AstraZeneca to meet its regulatory
 reporting obligations.

 If the Study is blinded, the Institution shall provide AstraZeneca with the code break
 information with the initial SAE report or a copy of the randomization schedule at the start
 of the Study, so that AstraZeneca may un-blind SAE reports to the extent necessary to meet
 global regulatory reporting requirements.

 A complete written SAE report must be sent with a cover page indicating the following:

 Drug Name (Seroquel); this is an Investigator Sponsored Study (ISS) Research (Protocol) and
 AstraZeneca Tracking Number [IRUSQUET0483] Principal Investigator's IND number assigned by
 the FDA (if applicable) Principal Investigator's full name and address Unblinding information
 (if applicable) Send by way of fax to Seroquel ISS Safety Representative (302) 885-3043

 If a non-serious AE becomes serious, this and other relevant follow-up information must also
 be provided to AstraZeneca and the FDA within 1 day as described above. All SAEs have to be
 reported to AstraZeneca, whether or not considered causally related to the investigational
 product. All SAEs will be documented. The investigator is responsible for informing the IRB
 and/or the Regulatory Authority of the SAE as per local requirements.

 4.4.2 Other safety measurements and variables Safety assessments will include vital signs at
 each visit and hematology, chemistries, pregnancy testing and urine drug screening prior to
 and at the end of treatment.

 4.5 Volume of blood sampling and handling of biological samples The total volume of blood
 that will be drawn from each subject in this study is as follows: 30 cc 5. DATA MANAGEMENT We
 will develop standardized paper forms for collecting all data needed on study subjects
 including eligibility, demographic and other baseline data, sequential clinical assessments,
 dosing information, side effects, and outcome measures. all data required to explore the
 study hypotheses will be collected and entered into a database in the appropriate format for
 data analysis.

 6. STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 6.1 Description of analysis
 populations All analyses will be conducted on the intention-to-treat population. 6.2 Method
 of statistical analysis The Wilcoxon signed-rank test will be applied to the mean scores
 available at weeks 0 vs. endpoint for the primary outcome measures: MADRS, HAM-A & daily BZ
 dose, and for the secondary outcome measures IDS-SR, SAS-SR and Q-LES-Q respectively to test
 the questions of whether there is a difference from pre- to post-quetiapine treatment.
 Separate tests will be conducted for the two diagnostic groups (MDD and GAD), but there is no
 intent to compare the two.

 The proportions of a priori-defined responders and remitters during the study will be
 reported in descriptive statistics.

 6.3 Determination of sample size NA The N of 20 per group is dictated by budget and
 feasibility considerations. This is a pilot study with no control or comparison groups. Under
 a 2-tailed α value of .05, we will have the power to detect a large effect size.
Inclusion Criteria:

 For inclusion in the study subjects must fulfil all of the following criteria:

 1. Provision of written informed consent

 2. A diagnosis of a current major depressive episode (n =20) or generalized anxiety
 disorder (n = 20) of at least 4 weeks duration, as defined by Diagnostic and
 Statistical Manual of Mental Disorders- Fourth Edition (DSM-IV) and assessed on the
 SCID. Subjects may be included if they meet criteria for double depression, i.e.,
 current major depression with antecedent dysthymic disorder, major depression in
 partial remission or bipolar depression. MDD subjects must have a 24 item Hamilton
 Depression Rating Scale Score (HAM-D) at intake >/= 20. GAD subjects must have a
 Hamilton Anxiety Rating Scale Score (HAM-A) at intake >/= 20. Patients who meet
 criteria for current GAD only during a current episode of MDD will be considered to
 have MDD, according to DSM-IV convention.

 3. Females and/or males aged 18-65 years

 4. Female patients of childbearing potential must be using a reliable method of
 contraception and have a negative urine human chorionic gonadotropin (HCG) test at
 enrolment

 5. Able to understand and comply with the requirements of the study

 6. All subjects must report BZ use more days than not persistent for more than 6 months
 and a stable regimen of mood stabilizers and/or antidepressant medication for at least
 8 weeks.

 -

 Exclusion Criteria:

 -  Any of the following is regarded as a criterion for exclusion from the study:

 1. Pregnancy or lactation

 2. Any DSM-IV Axis I disorder not defined in the inclusion criteria

 3. Axis II diagnosis of antisocial, schizotypal or severe borderline personality
 disorder(defined as patients who are high risk for being unable to complete the
 study due to hospitalization, suicide attempts, significant self-mutilation, or
 other self-injurious or destructive behavior).

 4. Patients who, in the opinion of the investigator, pose an imminent risk of
 suicide or a danger to self or others

 5. Known intolerance or lack of response to quetiapine fumarate as judged by the
 investigator

 6. Use of any of the following cytochrome P450 3A4 inhibitors in the 14 days
 preceding enrolment including but not limited to: ketoconazole, itraconazole,
 fluconazole, erythromycin, clarithromycin, troleandomycin, indinavir, nelfinavir,
 ritonavir, fluvoxamine and saquinavir

 7. Use of any of the following cytochrome P450 inducers in the 14 days preceding
 enrollment including but not limited to: phenytoin, carbamazepine, barbiturates,
 rifampin, St. John's Wort, and glucocorticoids

 8. Administration of a depot antipsychotic injection within one dosing interval (for
 the depot) before randomisation

 9. Substance or alcohol dependence at enrolment (except dependence in full
 remission, and except for caffeine or nicotine dependence), as defined by DSM-IV
 criteria

 10. Opiates, amphetamine, barbiturate, cocaine, cannabis, or hallucinogen abuse by
 DSM-IV criteria within 4 weeks prior to enrolment

 11. Medical conditions that would affect absorption, distribution, metabolism, or
 excretion of study treatment

 12. Unstable or inadequately treated medical illness (e.g. diabetes, angina pectoris,
 hypertension) as judged by the investigator

 13. Involvement in the planning and conduct of the study

 14. Previous enrolment or randomisation of treatment in the present study.

 15. Participation in another drug trial within 4 weeks prior enrolment into this
 study or longer in accordance with local requirements