| City: |
|
Bethesda |
|
State:
|
|
MD |
| Zip Code: |
|
20892 |
| Conditions: |
|
Depression - Anxiety Disorder |
| Purpose: |
|
This study will examine the safety and effectiveness of an experimental drug called AZD2327
for treating anxious major depressive disorder. Studies in animals and humans have shown
that the drug causes changes in certain body chemicals that may make it an effective
antidepressant and antianxiety medication.
People 18 to 65 years of age who are diagnosed with anxious major depressive disorder
without psychotic features may be eligible for this study. Candidates are screened with a
psychiatric and medical history, diagnostic interview, physical examination,
electrocardiogram (ECG), electroencephalogram (EEG) and blood and urine tests.
Participants are tapered off any medications, including antidepressants, that are prohibited
during the study and remain drug-free for 2 weeks. They are then randomly assigned to take
the study medication or placebo and are hospitalized for 7 days for monitoring while taking
the medication. They are then discharged from the hospital to continue the medication at
home for 4 weeks, returning to the clinic once a week for evaluation of anxiety and
depression, vital signs check and blood and urine tests. In addition, three EEGs are done
during this period.
After the treatment period, subjects have a physical exam, ECG and blood tests. They receive
short-term (up to 3 months) standard clinical treatment and are then transferred to the care
of an outside clinician for long-term treatment.
In addition to the above procedures, subjects may participate in the following optional
tests before starting treatment and at three other times during the study:
- Eyeblink test: This test measures the eyeblink reflex in response to a puff of air
delivered to the eye. It is an indirect measure of the functioning of the part of the
brain responsible for muscle coordination. During the test, the subject hears tones
through earphones. Weak air puffs are delivered to the corner of the eye through a
small plastic tube connected to a headband. It is not painful, uncomfortable, or
dangerous in any way. Changes in heart rate, sweat, and eyeblink are measured with
electrodes taped to the skin on two fingers, on the inside of each wrist, and under
each eye.
- Emotional pictures: This test examines an individual's reactivity to emotional
pictures. The subject's physiological responses to viewing pictures with emotional
content are recorded. The pictures may be neutral, pleasant, or unpleasant. Pleasant
pictures may include baby faces, ice cream, puppies, fireworks, and mildly erotic
pictures. Unpleasant pictures may include guns, surgery, tumors, and bleeding faces.
|
| Study summary: |
|
There is increasing evidence that patients with anxious major depressive disorder (AMDD)
have a greater depressive severity, functional impairment, increased risk of suicidality,
worse social distress, higher incidence of alcohol and drug abuse, and poorer treatment
response and outcome than patients with non-anxious depression. A recent report by STAR*D
emphasizes the worse outcome of patients with this type of depression. The investigators
found that remission was significantly less likely and to taker longer to occur in patients
with anxious versus nonanxious depression. Current antidepressants are largely me too
drugs in as much as they exert their primary biochemical effects by increasing the
intrasynaptic levels of monoamines, and as such, there has been limited (if any) progress in
developing medications with improved efficacy.
There is increasing literature of the involvement of the endogenous opioid system in major
depression and its treatment. Identification of delta-opioid receptor as a possible target
in the treatment of depression and anxiety began with clinical observations that a
heightened anxiety state and depressive-like behaviors were consistently noted in the
delta-opioid receptor knockout mouse. A number of investigators have found that selective
delta-opioid receptor agonists have antidepressant-like properties in models such as the
forced swim test. In a search for a selective delta-opioid receptor agonist to test in a
proof-of-concept clinical study in AMDD, AZD2327 is a potent, first in class, high-affinity
enkephalinergic agonist that possesses anxiolytic and antidepressant activity in animal
models. AZD2327 has efficacy comparable to diazepam and imipramine in rodent models of
anxiety and depression, respectively. Phase I studies have been completed and have indicated
an acceptable safety profile.
In summary, clear preclinical signals for efficacy and an acceptable safety profile in Phase
I studies to date have been seen with the enkephalinergic agonist AZD2327, suggesting that
it might be a highly novel and effective therapy in both anxiety and depression.
Furthermore, understanding the mechanism of action of enkephalinergic agonists'
antidepressant effect may ultimately lead to further insight into the pathophysiology of
mood disorders in general.
Male and female patients, ages 18 to 65, with a diagnosis of major depression (without
psychotic features) meeting criteria for AMDD, will be randomized to double-blind treatment
to receive either AZD2327 (3 mg BID) or placebo in a 2:1 ratio for a period of 4 weeks. In
addition, a series of surrogate neurobiological markers will be obtained to establish
whether they are capable of predicting therapeutic response. Approximately 96 patients with
acute major depression will be enrolled in the study. |
| Criteria: |
|
- INCLUSION CRITERIA:
For inclusion in the study, patients must fulfill all of the following criteria:
- Provision of written informed consent before initiation of any study related
procedures.
- Male and female patients aged 18 to 65 years old, both inclusive. Women must be
either of non-childbearing potential or if of childbearing potential, agree to use a
highly effective form of birth control as well as double barrier method
contraception. Women of child bearing potential must have a negative serum pregnancy
test. Highly effective forms of birth control include but are not limited to: true
sexual abstinence, a vasectomized sexual partner, Implanon, female sterilization by
tubal occlusion, IUD/IUS (copper coils), Depo-Provera injections, low dose combined
oral contraceptive only if used in TriCycle regime, and Evra Patch or Nuvaring use in
TriCycle regime. Women should be on a stable method of birth control for a minimum
of 3 months prior to study entry.
- Documented clinical diagnosis meeting criteria from the DSM-IV for the following:
296.22 Major Depressive Disorder, Single Episode, Moderate or
296.23 Major Depressive Disorder, Single Episode, Severe Without Psychotic Features,
duration at least 1 year or
296.32, Major Depressive Disorder, Recurrent, Moderate or
296.33, Major Depressive Disorder, Recurrent, Severe Without Psychotic Features.
- HRSD17 total score greater or equal to 20; HAM-A total score greater or equal to 16;
CGI-S score greater or equal to 4 at both screening and randomization (an interval of
at least 2 weeks).
- Patient must agree to voluntary hospitalization for a minimum of 4 days.
- Patient must be able to understand and comply with the requirements of the study, as
judged by the investigator.
- Patient must be compliant with the self-administration of medication. No structured
psychotherapy will be permitted during the study.
EXCLUSION CRITERIA:
Any of the following is regarded as a criterion for exclusion from the study:
- Patients with current DSM-IV Axis II disorder which has a major impact on the
patient's current psychiatric status.
- Patients with current DSM-IV Axis I bipolar disorder (I or II), psychotic disorder,
or major depressive disorder with psychotic features.
- Patients with symptoms of psychosis within the past 6 months.
- Patients with a current DSM-IV clinical diagnosis of Obsessive-Compulsive Disorder
(300.3), Posttraumatic Stress Disorder (309.81) or have experienced a Panic Disorder
within 1 year prior to randomization.
- Patient whose current depressive episode is less than 8 weeks or greater than 24
months.
- History of substance or alcohol abuse in the past 6 months or dependence within 1
year of enrollment (except for caffeine or nicotine dependence), as defined in DSM IV
criteria. Patients with a positive urine drug screen (UDS) for methamphetamines
(including ecstasy), benzodiazepines, cocaine and/or metabolites, amphetamines,
tetrahydrocannibinol (THC), and opiates will be excluded except for patients testing
positive for prescribed medications. Patients can be retested if the initial UDS is
positive, but should be excluded if the results are still positive, at the second
test. Patients with a positive UDS for a drug(s) legally available by prescription
must provide evidence of the prescription for the drug(s).
- Any history of seizure including one febrile seizure. Patients with a family history
of epilepsy will also be excluded from participation.
- History of head trauma, including closed head injury in which loss of consciousness
occurred greater than one minute.
- Treatment with ECT within the past 3 months prior to randomization.
- EEG with evidence of epileptiform activity on initial baseline screening or after
medication washout (4-7 days prior to randomization).
- Patients who pose a serious suicidal or homicidal risk in the opinion of the
investigator as assessed by clinical evaluation and suicidality measures. Patients
with a suicide or homicide attempt within the past 6 months.
- Women that are pregnant or lactating.
- Positive HIV, Hepatitis B or Hepatitis C test or acquired immunodeficiency syndrome
(AIDS).
- Serious unstable medical illness (e.g., asthma, hypertension, poorly controlled
diabetes, unstable angina) or illness that, in the opinion of the investigator, would
be negatively impacted by the study medication. Hypothyroidism permitted if
corrected and on stable regimen for a minimum of 3 months.
- History of pancreatitis.
- QT interval corrected by the Fredericia Formula (QTcF) on screening ECG of greater
than 450 (msec).
- Systolic blood pressure less than 95 mm Hg or elevated greater than 140 mm Hg on 3
consecutive measurements at screening.
- Heart rate less than 50 beats per minute or greater than 100 beats per minute on 3
consecutive measurements at screening.
- Conditions that could affect metabolism of study medication (e.g., liver disease).
- Current diagnosis of cancer (except basal or squamous cell skin carcinoma), unless in
remission for at least 10 years.
- Current or past diagnosis of stroke or Transient Ischemic Attack (TIA).
- Clinically significant deviation from the reference range in clinical laboratory test
results as judged by the investigator including: absolute neutrophil count less than
or equal to 1.5X 109/L, ALT or AST greater than or equal to 2 times the upper limit
of normal for the reference range; creatinine greater than or equal to 1.8 units.
- Known history of intolerance or hypersensitivity to any medication required by this
protocol (or 3 or more classes of pharmaceuticals) or current manifestation of any
allergic disorder (other than seasonal allergies) as judged by the investigator.
- Use of antidepressant antipsychotic or mood stabilizing drugs within 2 weeks prior to
randomization. Use of anxiolytic or hypnotics within 4 days prior to randomization.
Patients on chronic benzodiazepine treatment within past 3 months will be excluded.
Use of fluoxetine within 28 days before randomization. Use of monoamine oxidase
inhibitors within 14 days prior to randomization. Use of depot neuroleptics within 2
months prior to randomization.
- Use of drugs that induce or inhibit the hepatic metabolizing cytochrome P450 3A4
enzymes within 2 weeks prior to randomization: e.g., inducers: carbamazepine,
phenytoin, barbiturates, rifampin, rifabutin, glucocorticoids, thioridazine and St.
John's Wort; e.g., inhibitors: ketoconazole (except for topical use), itraconazole,
fluconazole, erythromycin, clarithromycin, fluoxetine, nefazodone, troleandomycin,
indinavir, nelfinavir, ritonavir, and saquinavir.
- Enrollment in a concurrent investigational study or intake of an investigational drug
within 30 days of randomization.
- Inability to understand or cooperate with study procedures due to mental function,
visual or hearing impairment or lack of fluency in English or Spanish.
- Involvement or involvement of a family member in either the planning or conduct of
the study. |
|
|
|
|
|
|
|
|
If you are interested in this clinical trial please use the contact information above. If you would like to get additional information about this clinical trial please visit ClinicalTrials.gov.
|
| Trials Alerts: |
|
If you would like to be
notified of new clinical trials as they become available please
register for a free account.
|
|
| Data Source: |
|
ClinicalTrials.gov |
| Date Processed: |
|
April 13, 2010 |
Modifications to
this listing: |
|
Only selected fields are shown, please use the link
above to view all information about this clinical trial. |
|
|
|
|
|
|
|
|