A Definitive Estrogen Patch Study (ADEPT)
|First Received Date ICMJE||July 26, 2006|
|Last Updated Date||May 7, 2015|
|Start Date ICMJE||July 2006|
|Primary Completion Date||October 2011 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Positive and Negative Syndrome Scale (PANSS) [ Time Frame: Baseline and week 8 ]
The Positive and Negative Syndrome Scale (PANSS) is a well validated, standardized method of evaluating and monitoring psychotic symptoms. The PANSS assesses: positive (hallucinations, delusions, thought disorder), negative (blunted affect, abstract thinking and general symptomatology. The positive and negative subscale each consist of 7 items rated from 1(absent) - 7(extreme) with a minimum score = 7, maximum score = 49. The general subscale consists of 16 items with a minimum score = 16, maximum score = 112. A Total PANSS score (positive+ negative + general scores) has a minimum of 30 and maximum of 210. Higher scores represent more severity in symptoms.
|Original Primary Outcome Measures ICMJE
||Positive and Negative Syndrome Scale (PANSS), which will be taken at weeks 1, 2, 4 and 8 of the trial.|
|Change History||Complete list of historical versions of study NCT00357006 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||A Definitive Estrogen Patch Study (ADEPT)|
|Official Title ICMJE||Multisite Double-Blind Randomized Controlled Study of Estradiol Plus Antipsychotic Versus Placebo Plus Antipsychotic in the Treatment of Psychotic Symptoms in Women With Schizophrenia|
To test the use of adjunctive estrogen in a 8 week, three-arm, double-blind, placebo-controlled study in the treatment of psychotic symptoms in women with schizophrenia.
That women receiving adjunctive estrogen will demonstrate significantly greater improvements in the symptoms of schizophrenia than women receiving adjunctive placebo.
180 women will be recruited over a three-year period across three sites. Participant will be of potential child-bearing age (Pre-menopausal and Post-menarche) with a current diagnosis of Schizophrenia, Schizophreniform Disorder, or Schizoaffective Disorder (not in manic phase)according to the Mini International Neuropsychiatric Interview (MINI).
Estradiol. One third of the participants (n=60) will be randomised to receive adjunctive 100mcg Estradiol; one third of the participants (n=60) will be randomised to receive adjunctive 200mcg Estradiol n=60; and, one third of the participants (n=60) will be randomised to receive adjunctive placebo n=60). All patches will be covered with identical adhesive contact to ensure the "blind" is maintained.
Data will be collected over a two-month period for each participant. Visits will be performed at baseline, and then at weekly or fortnightly intervals. A total of six visits will be completed for each participant. The following evaluations will be performed:
i) Inclusion/exclusion checklist. (Baseline visit only)
ii) Informed consent. (Baseline visit only)
iii)psychiatric evaluation to determine diagnosis. (Baseline visit only)
iv) General clinical evaluation including medical history, current conditions and a non-invasive physical examination, body weight, vital signs. (Baseline and endpoint visits)
v) Medication history. (Baseline and evaluation visits)
vi) Demographics. (Baseline visits only)
vii) The primary outcome measures will be the Positive and Negative Syndrome Scale (PANSS), which will be taken at weeks 1, 2, 4 and 8 of the trial. Cognitive testing will take place at baseline and 8 weeks. Side effects will be assessed at weeks 1, 2, 4, 6, and 8 to measure changes in subject's reported side effects during the trial.
viii) Laboratory tests including; Serum levels of mood stabiliser, LH, FSH, Estrogen, Progesterone, Prolactin, DHEA,Testosterone and(Baseline and evaluation visits).
This research protocol outlines a multi-site clinical trial of adjunctive estradiol in women with Schizophrenia. We propose to recruit 180 women into this study from 3 Australian sites - The Alfred Hospital, Barwon Health, and Dandenong Hospital.
1.1 Literature Review
Schizophrenia is a severe mental disorder that affects up to 2% of the adult population. Patients present with a variety of symptoms including hallucinations, delusions and bizarre behaviour while some develop additional "negative" symptoms such as amotivational states and poverty of thought.
Schizophrenia is generally thought to be an organic brain disorder with psychosocial determinants for course and outcome. The illness appears to be heterogenous with groups of patients presenting with distinct and differing patterns of psychopathology and illness course. Part of this heterogeneity includes distinct male and female subtypes of schizophrenia.
In recent times, gender differences in schizophrenia have received some attention, in particular from an epidemiological and psychopathological perspective. Hormonal studies have been utilised to investigate underlying neuroendocrine disturbances in schizophrenia, but information from these studies has not been used in the development of new gender specific treatment strategies. Overall the treatment of schizophrenia has remained gender-blind. The main gender differences observed in schizophrenia that have international consensus include the later age of onset in women; better response to antipsychotics in women; and more treatment resistant negative symptoms in men. Women have also demonstrated vulnerability to psychotic episodes during menopause, the post-partum period and at low estrogen phases of the menstrual cycle.
From these clinical observations, Seeman and Lang (1990) hypothesised that estrogen may provide "protection" against early onset of severe schizophrenia in women, thereby accounting for increased vulnerability during both lifetime and monthly low estrogen phases. Seeman and Lang (1990) further hypothesised that estrogen may provide protection against early onset of severe treatment resistant schizophrenia through an anti-dopaminergic effect by modulating the sensitivity of the dopamine receptor thereby potentiating the effect of antipsychotics.
Evidence for estrogen having a modulating effect on dopaminergic systems comes from studies in rats in which estrogens can enhance antipsychotic-induced cataplexy (Behrens et al. 1992; Fields et al 1982) and reduce amphetamine and apomorphine-induced behaviour such as stereotypies (Ferretti et al., 1992; Clopton et al., 1986). In humans, the presence of estrogen receptors in the limbic system indicates that estrogens may have a neuromodulatory function (Foreman, et al., 1980; Koller, et al., 1980; Gordon et al., 1980). Estrogens have been shown to reduce the dopamine concentration in the striatum (Dupond et al., 1981; Bedard et al., 1984) and modulate the sensitivity as well as the number of dopamine receptors (Di Paolo, et al., 1981; McDermott, et al., 1994). There are clinical case reports of women whose schizophrenic symptomatology is exacerbated at low estrogen phases of the menstrual cycle (Endo et al., 1978). Similarly there are clinical case reports of women with chronic schizophrenia improving during pregnancy - when estrogen levels are extremely high (Seeman, 1986). After delivery, when estrogen levels drop, increased vulnerability to psychosis is observed (Seeman, 1996). A recent study investigating the relationship between schizophrenia psychopathology and low estrogen phases of the menstrual cycle revealed that symptoms improved when natural estradiol levels increased (Riecher-Rossler et al., 1994). This study also showed that all 32 patients studied had markedly reduced serum estradiol levels compared with the normal population and that fluctuations throughout the cycle were dampened.
1.2 Justification for Project
The findings from both basic and clinical research reviewed in section 1.1 above warrant further investigation of the hypothesis that estrogen has a protective effect in women, not only over the female life cycle, but also over the menstrual cycle. Case reports have appeared in the literature in which clinicians detail improvement in one or two female patients following administration of synthetic combined estrogen and progesterone. A study conducted by Klaiber and colleagues' (1979) reported that large doses of estrogen assisted in the treatment of depression in women. We have been conducting clinical trials in patients with schizophrenia using estrogen as a treatment for many years, and have an international reputation for work in this area. Initially, we conducted an open clinical trial with acutely ill schizophrenic women (Kulkarni et al., 1996) and added 0.02mg of oral estradiol to the antipsychotic drug treatment of 11 women. Their response was compared to seven women who received antipsychotic drugs alone. The estrogen adjunct group showed dramatic earlier improvement, with significant reduction in positive psychotic symptoms by day 3 of treatment. This suggests that estradiol may act as a catalyst for treatment and could prove to be an important adjunctive treatment in the therapy of schizophrenia. Subsequent to this early pilot study, we conducted a double blind placebo controlled 3-arm study of 100mcg, 50mcg estradiol and placebo transdermal adjunctive patches. Published in Schizophrenia Research (Kulkarni et al., 2003), our results showed that the 100mcg estrogen adjunct afforded the best outcomes. We then conducted a "proof of concept" study to examine the effect of adding 100mcg transdermal estrogen versus transdermal placebo to antipsychotic drug treatment in 90 women with schizophrenia. For the results of this 'proof of concept' study please refer to Appendix G.
1.3 Review of Estradiol and its Uses
Estrogen is one of a group of hormonal steroid compounds that promote the development of female secondary sex characteristics. Human estrogen is produced by the ovaries, adrenal cortices, testes, and feto-placental unit. Along with progesterone, estrogen plays a major role in the regulation of the menstrual cycle and is regulated by levels of Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) released from the anterior pituitary gland in the brain. These two gonadotropin hormones are in turn regulated by the actions of the hypothalamus. Pharmaceutical preparations of estrogen are used in oral contraceptives, to palliate post-menopausal breast cancer and prostatic cancer, to inhibit lactation, and to treat threatened abortion, osteoporosis and ovarian disease. Estrogen is also given to relieve the discomforts of menopause. Types of estrogen are conjugated estrogen, esterified estrogen, estradiol, estriol and estrone (Mosby, 1986). Delivery of estrogen by transdermal patches provides more natural and physiologically equivalent replacement of estradiol levels.
2. RESEARCH OBJECTIVES
To conduct a three-arm, double-blind, randomized, placebo-controlled, trial across three sites, to investigate the 'estrogen-protection' hypothesis in women with schizophrenia. The study aims to:
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Completion Date||December 2013|
|Primary Completion Date||October 2011 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||18 Years to 50 Years (Adult)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Australia|
|Removed Location Countries|
|NCT Number ICMJE||NCT00357006|
|Other Study ID Numbers ICMJE||202/04
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|Plan to Share Data||Not Provided|
|IPD Description||Not Provided|
|Responsible Party||Jayashri Kulkarni, Professor, The Alfred|
|Study Sponsor ICMJE||The Alfred|
|Collaborators ICMJE||Stanley Medical Research Institute|
|Information Provided By||The Alfred|
|Verification Date||May 2015|
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