| Study Summary: |
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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.
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| Criteria: |
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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.
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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
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