Ignite Creation Date:
2024-05-05 @ 4:58 PM
Last Modification Date:
2024-10-26 @ 9:26 AM
Study NCT ID:
NCT00357006
Status:
COMPLETED
Last Update Posted:
2015-05-12
First Post:
2006-07-26
Brief Title:
A Definitive Estrogen Patch Study ADEPT
Sponsor:
The Alfred
Organization:
The Alfred
Study Overview
Official Title:
Multisite Double-Blind Randomized Controlled Study of Estradiol Plus Antipsychotic Versus Placebo Plus Antipsychotic in the Treatment of Psychotic Symptoms in Women With Schizophrenia
Status:
COMPLETED
Status Verified Date:
2015-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
OBJECTIVE
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
HYPOTHESIS
That women receiving adjunctive estrogen will demonstrate significantly greater improvements in the symptoms of schizophrenia than women receiving adjunctive placebo
STUDY POPULATION
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 phaseaccording to the Mini International Neuropsychiatric Interview MINI
STUDY MEDICATION
Estradiol One third of the participants n60 will be randomised to receive adjunctive 100mcg Estradiol one third of the participants n60 will be randomised to receive adjunctive 200mcg Estradiol n60 and one third of the participants n60 will be randomised to receive adjunctive placebo n60 All patches will be covered with identical adhesive contact to ensure the blind is maintained
STUDY EVALUATIONS
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 Inclusionexclusion checklist Baseline visit only
ii Informed consent Baseline visit only
iiipsychiatric 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 subjects reported side effects during the trial
viii Laboratory tests including Serum levels of mood stabiliser LH FSH Estrogen Progesterone Prolactin DHEATestosterone andBaseline and evaluation visits
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
HYPOTHESIS
That women receiving adjunctive estrogen will demonstrate significantly greater improvements in the symptoms of schizophrenia than women receiving adjunctive placebo
STUDY POPULATION
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 phaseaccording to the Mini International Neuropsychiatric Interview MINI
STUDY MEDICATION
Estradiol One third of the participants n60 will be randomised to receive adjunctive 100mcg Estradiol one third of the participants n60 will be randomised to receive adjunctive 200mcg Estradiol n60 and one third of the participants n60 will be randomised to receive adjunctive placebo n60 All patches will be covered with identical adhesive contact to ensure the blind is maintained
STUDY EVALUATIONS
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 Inclusionexclusion checklist Baseline visit only
ii Informed consent Baseline visit only
iiipsychiatric 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 subjects reported side effects during the trial
viii Laboratory tests including Serum levels of mood stabiliser LH FSH Estrogen Progesterone Prolactin DHEATestosterone andBaseline and evaluation visits
Detailed Description:
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
11 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
12 Justification for Project
The findings from both basic and clinical research reviewed in section 11 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 002mg 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
13 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
1 replicate previous research thereby providing proof of concept for the potential use of estradiol as a treatment in women with schizophrenia
2 investigate the effect of an increased dose of estradiol 200mcg transdermal
3 investigate the duration of the antipsychotic effect of estradiol
The aims will be met by comparing changes in psychopathology and cognition over an 8-week period between three groups of participants 1 a group of participants receiving standard antipsychotic treatment and a placebo 2 a matched group receiving standard antipsychotic treatment plus 100mcg estradiol patches and 3 a matched group receiving standard antipsychotic treatment plus 200mcg estradiol patches
3 ETHICS REVIEW AND INFORMED CONSENT
31 Ethics Review
The protocol for this study was approved by the Alfred Research Ethics Committee on 6th January 2005 at the Barwon site on 01032006 and at the Dandenong site on 12052006
32 Issues Related to the Use of Estradiol Skin Patches
The study involves the addition of 100mcg200mcg estradiol to standard antipsychotic treatment for 8 weeks This dose of estradiol is commonly used in hormone replacement therapy for postmenopausal women without side effects The length of the trial is 2 menstrual cycles which is a short period of estrogen use Most side effects commonly associated with estrogen use are related to long term administration and are thus not applicable in this study Basic medical precautions will be taken prior to the commencement of estrogen therapy ie physical examination routine investigations and pregnancy testing In our large study of 90 women 100mcg transdermal estradiol was used and the treatment was well tolerated Subjects will be counselled with regard to the lack of contraceptive effect of using estradiol patches
33 Use of a Placebo
All subjects will be informed that there is a two-in-three chance that they will receive estradiol patches and a one-in-three chance they will receive placebo patches As well as the study medication all subjects will receive standard antipsychotic medication and thus will not be disadvantaged in any way by placement in the placebo group Subjects who are entered into the trial will be on a relatively stable treatment regime having had no change of medication in the prior 30 days and there will be no future change in medication anticipated By controlling this variable we are able to create a true placebo group as there should be no modification of antipsychotic medication over the trial period that could potentially affect the psychopathology results Both subjects and researchers will be unaware of which group a subject is in However if the need arises researchers will be able to break the code to reveal the group to which the subject belongs Subjects allocated to the placebo group will be offered open-label adjunctive treatment with 200mcg estradiol for two months proceeding the trial thereby ensuring all participants receive the potential benefits of adjunctive estradiol
34 Standard Antipsychotic Treatment
As the proposed study is an adjunctive trial all participants will continue to receive standard antipsychotic treatment whilst in the trial Antipsychotic medication will be measured in risperidone equivalents which involves converting the dose of their current antipsychotic treatment to its equivalent dose of risperidone To be included in the trial participants must meet the following criteria 2-10mg daily risperidone equivalents for at least 4 weeks with residual symptoms as defined by a PANSS positive score greater than 15 andor a PANSS negative score greater than 15
35 Informed Consent
Only participants who are able to give informed consent ie able to demonstrate an understanding of the objectives of the study and the implications of their role in it will be recruited into the study Involuntary patients who are able to give informed consent will be able to participate and where possible a guardian or relative will be contacted and notified of the patients involvement Participants will be advised that their participation is voluntary and that they are free to withdraw from the study at any stage
36 Confidentiality
Participants identity will remain anonymous at all times Once a participant agrees to participate in the study she will be assigned a code number to ensure anonymity Information about the subject will be restricted to the researchers directly involved unless there are clear management issues in which case the information will be shared with the treatment team Participants files will be stored in locked filing cabinets with access only available to researchers on the project All test results will be shared with the participant and their family guardian
4 METHOD
41 Participants
A target number of 180 participants 60 from The Alfred 60 from Barwon and 60 from Dandenong will be recruited over a three-year period with equal numbers being allocated to each group 100mcg Estradiol n60 200mcg Estradiol n60 Placebo n60 Participants will be recruited from both inpatient and outpatient settings and participants may be recruited from other centres providing that approval has been gained from the appropriate controlling bodies The total number of subjects will allow results to be analysed by subgroups based on factors such as menstrual cycle phase
42 Materials
demographic information
diagnosis according to the Mini International Neuropsychiatric Interview MINI - modules L psychotic disorders and D maniahypomania
inclusionexclusion criteria check
medical history non-invasive general physical examination
Laboratory tests to determine pregnancy status menstrual cycle phase and neuroendocrine status
Breast scan mammogram at Alfred and Dandenong sites or breast screens ultrasounds at Barwon site to check for breast abnormalities in participants to be conducted when informed consent is provided
hormone measurements of estrogen progesterone prolactin testosterone LH FSH and DHEA
A menstrual cycle questionnaire MCQ to gain a menstrual history
Assessment of psychopathology PANSS MADRS and cognitive function RBANS
Hormone assays will be repeated at weeks 4 and 8 A menstrual calendar will be used to record the onset and cessation of menses during the trial 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 subjects reported side effects during the trial
43 Procedures
Participants will be screened as soon after identification as possible to assess eligibility for entry into the study The diagnostic instrument to be used will be the Mini International Neuropsychiatric Interview MINI The details of the project and requirements of participation will be explained to eligible participants and a Plain Language Statement provided If a potential participant is identified to be a current client of The Alfred Psychiatric Service Southern Health Dandenong site or Barwon Health Barwon site the researcher will contact a member of the individuals treating team to discuss the suitability of approaching the client and to gain an indication of the persons ability to give informed consent A member of the treating team will then approach the potential participant and ask if they are willing to talk to the researcher about the study This discussion will involve providing a detailed verbal explanation of the study and the written Participant Information and Consent Form PICF as approved by the applicable Human Research Ethics Committee The potential participant will be asked to read through the PICF or have it read to them by the researcher The potential participant will be encouraged to discuss the PICF and the possibility of participating in this study with a significant other or support person
Once the potential participant has read the PICF the researcher will have another discussion with this person preferably in the presence of a witness The researcher will ask the potential participant to provide a verbal explanation about what they think the study is about and what is involved in their participation The researcher may draw attention to particular parts of the PICF to ensure that the potential participant is fully aware of all aspects involved The potential participant will be asked if heshe has any questions about the study which will be answered by the researcher At this point if the researcher believes that the potential participant understands the information provided to them about the study and has had the opportunity to ask questions and have them answered then the consent form can be signed The consent form will be signed and dated by the project participant by the researcher who explained the project to the participant and by a witness
Participants who provide informed written consent will undergo a full psychiatric and medical history and will receive a non-invasive physical examination as well as a breast scan or screen dependant on site specific regulatory advice Baseline hormone levels will be measured via a blood test and a menstrual cycle questionnaire will be administered to determine menstrual status Baseline psychopathology rating scales PANSS will then be administered After a participant has been deemed eligible to enter the trial and baseline measurements have been performed the participant may be randomised to one of three groups for the duration of the eight-week double blind phase The three groups are 1 100mcg estradiol patches 2 200mcg estradiol patches and 3 placebo patches
Upon entry into the double-blind phase each participant will be allocated an identification number and will be randomly assigned to a treatment regimen as generated by The Alfred Clinical Trials Pharmacy who will be aware of which treatment group the participant is allocated to but will not be directly involved in the trial The Clinical Trials Pharmacy coordinator will not disclose the randomisation codes to any of the investigators or data collectors involved with the project
Day one of the trial will be the first day that the participant receives the study medication Study medication is dispensed via the pharmacy department at each site Baseline measurements must be taken the day before the first day of the trial and thus baseline is considered to be Day 0 Evaluation of adverse events and medication compliance will be performed at regular intervals for the duration of the trial Psychopathology rating scales will be completed at baseline and weeks 1 2 4 and 8 Hormone assays will be completed at baseline and weeks 4 and 8 Cognitive assessment will be completed at baseline and at week 8 The week 8 visit must fall on the last day of the trial medication
44 Clinical Follow-up
For ethical reasons upon completion of the active phase of the trial each participant will be unblinded and made aware of which treatment they had received Participants who were receiving placebo will be offered an open label trial of the 200mg estradiol patches This is so that no one is disadvantaged by their participation in the trial and are all able to take the active medication if they so wish Participants who opt to have an open label trial of the estradiol patches will be monitored for side effects for a further 8 weeks whilst they are using the patches This data will not be included in the research trial database
All participants will be followed up for 3 months following the completion of the active phase of the trial including the open-label treatment This follow-up will consist of monthly telephone contact to check participants progress as well as determine the duration of the antipsychotic effect of estrogen
5 STUDY MANAGEMENT
51 Data Management
Source data from each site will be transferred to The Alfred site for data entry and analysis A copy of the source data for each site will be archived at each site according to local ethics committee guidelines A Contract Research Organisation CRO will monitor each of the sites to ensure high quality data and adherence to study recruitment and retention targets Inter-rater reliability training will be performed annually for all staff at each site or when new staff commence
11 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
12 Justification for Project
The findings from both basic and clinical research reviewed in section 11 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 002mg 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
13 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
1 replicate previous research thereby providing proof of concept for the potential use of estradiol as a treatment in women with schizophrenia
2 investigate the effect of an increased dose of estradiol 200mcg transdermal
3 investigate the duration of the antipsychotic effect of estradiol
The aims will be met by comparing changes in psychopathology and cognition over an 8-week period between three groups of participants 1 a group of participants receiving standard antipsychotic treatment and a placebo 2 a matched group receiving standard antipsychotic treatment plus 100mcg estradiol patches and 3 a matched group receiving standard antipsychotic treatment plus 200mcg estradiol patches
3 ETHICS REVIEW AND INFORMED CONSENT
31 Ethics Review
The protocol for this study was approved by the Alfred Research Ethics Committee on 6th January 2005 at the Barwon site on 01032006 and at the Dandenong site on 12052006
32 Issues Related to the Use of Estradiol Skin Patches
The study involves the addition of 100mcg200mcg estradiol to standard antipsychotic treatment for 8 weeks This dose of estradiol is commonly used in hormone replacement therapy for postmenopausal women without side effects The length of the trial is 2 menstrual cycles which is a short period of estrogen use Most side effects commonly associated with estrogen use are related to long term administration and are thus not applicable in this study Basic medical precautions will be taken prior to the commencement of estrogen therapy ie physical examination routine investigations and pregnancy testing In our large study of 90 women 100mcg transdermal estradiol was used and the treatment was well tolerated Subjects will be counselled with regard to the lack of contraceptive effect of using estradiol patches
33 Use of a Placebo
All subjects will be informed that there is a two-in-three chance that they will receive estradiol patches and a one-in-three chance they will receive placebo patches As well as the study medication all subjects will receive standard antipsychotic medication and thus will not be disadvantaged in any way by placement in the placebo group Subjects who are entered into the trial will be on a relatively stable treatment regime having had no change of medication in the prior 30 days and there will be no future change in medication anticipated By controlling this variable we are able to create a true placebo group as there should be no modification of antipsychotic medication over the trial period that could potentially affect the psychopathology results Both subjects and researchers will be unaware of which group a subject is in However if the need arises researchers will be able to break the code to reveal the group to which the subject belongs Subjects allocated to the placebo group will be offered open-label adjunctive treatment with 200mcg estradiol for two months proceeding the trial thereby ensuring all participants receive the potential benefits of adjunctive estradiol
34 Standard Antipsychotic Treatment
As the proposed study is an adjunctive trial all participants will continue to receive standard antipsychotic treatment whilst in the trial Antipsychotic medication will be measured in risperidone equivalents which involves converting the dose of their current antipsychotic treatment to its equivalent dose of risperidone To be included in the trial participants must meet the following criteria 2-10mg daily risperidone equivalents for at least 4 weeks with residual symptoms as defined by a PANSS positive score greater than 15 andor a PANSS negative score greater than 15
35 Informed Consent
Only participants who are able to give informed consent ie able to demonstrate an understanding of the objectives of the study and the implications of their role in it will be recruited into the study Involuntary patients who are able to give informed consent will be able to participate and where possible a guardian or relative will be contacted and notified of the patients involvement Participants will be advised that their participation is voluntary and that they are free to withdraw from the study at any stage
36 Confidentiality
Participants identity will remain anonymous at all times Once a participant agrees to participate in the study she will be assigned a code number to ensure anonymity Information about the subject will be restricted to the researchers directly involved unless there are clear management issues in which case the information will be shared with the treatment team Participants files will be stored in locked filing cabinets with access only available to researchers on the project All test results will be shared with the participant and their family guardian
4 METHOD
41 Participants
A target number of 180 participants 60 from The Alfred 60 from Barwon and 60 from Dandenong will be recruited over a three-year period with equal numbers being allocated to each group 100mcg Estradiol n60 200mcg Estradiol n60 Placebo n60 Participants will be recruited from both inpatient and outpatient settings and participants may be recruited from other centres providing that approval has been gained from the appropriate controlling bodies The total number of subjects will allow results to be analysed by subgroups based on factors such as menstrual cycle phase
42 Materials
demographic information
diagnosis according to the Mini International Neuropsychiatric Interview MINI - modules L psychotic disorders and D maniahypomania
inclusionexclusion criteria check
medical history non-invasive general physical examination
Laboratory tests to determine pregnancy status menstrual cycle phase and neuroendocrine status
Breast scan mammogram at Alfred and Dandenong sites or breast screens ultrasounds at Barwon site to check for breast abnormalities in participants to be conducted when informed consent is provided
hormone measurements of estrogen progesterone prolactin testosterone LH FSH and DHEA
A menstrual cycle questionnaire MCQ to gain a menstrual history
Assessment of psychopathology PANSS MADRS and cognitive function RBANS
Hormone assays will be repeated at weeks 4 and 8 A menstrual calendar will be used to record the onset and cessation of menses during the trial 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 subjects reported side effects during the trial
43 Procedures
Participants will be screened as soon after identification as possible to assess eligibility for entry into the study The diagnostic instrument to be used will be the Mini International Neuropsychiatric Interview MINI The details of the project and requirements of participation will be explained to eligible participants and a Plain Language Statement provided If a potential participant is identified to be a current client of The Alfred Psychiatric Service Southern Health Dandenong site or Barwon Health Barwon site the researcher will contact a member of the individuals treating team to discuss the suitability of approaching the client and to gain an indication of the persons ability to give informed consent A member of the treating team will then approach the potential participant and ask if they are willing to talk to the researcher about the study This discussion will involve providing a detailed verbal explanation of the study and the written Participant Information and Consent Form PICF as approved by the applicable Human Research Ethics Committee The potential participant will be asked to read through the PICF or have it read to them by the researcher The potential participant will be encouraged to discuss the PICF and the possibility of participating in this study with a significant other or support person
Once the potential participant has read the PICF the researcher will have another discussion with this person preferably in the presence of a witness The researcher will ask the potential participant to provide a verbal explanation about what they think the study is about and what is involved in their participation The researcher may draw attention to particular parts of the PICF to ensure that the potential participant is fully aware of all aspects involved The potential participant will be asked if heshe has any questions about the study which will be answered by the researcher At this point if the researcher believes that the potential participant understands the information provided to them about the study and has had the opportunity to ask questions and have them answered then the consent form can be signed The consent form will be signed and dated by the project participant by the researcher who explained the project to the participant and by a witness
Participants who provide informed written consent will undergo a full psychiatric and medical history and will receive a non-invasive physical examination as well as a breast scan or screen dependant on site specific regulatory advice Baseline hormone levels will be measured via a blood test and a menstrual cycle questionnaire will be administered to determine menstrual status Baseline psychopathology rating scales PANSS will then be administered After a participant has been deemed eligible to enter the trial and baseline measurements have been performed the participant may be randomised to one of three groups for the duration of the eight-week double blind phase The three groups are 1 100mcg estradiol patches 2 200mcg estradiol patches and 3 placebo patches
Upon entry into the double-blind phase each participant will be allocated an identification number and will be randomly assigned to a treatment regimen as generated by The Alfred Clinical Trials Pharmacy who will be aware of which treatment group the participant is allocated to but will not be directly involved in the trial The Clinical Trials Pharmacy coordinator will not disclose the randomisation codes to any of the investigators or data collectors involved with the project
Day one of the trial will be the first day that the participant receives the study medication Study medication is dispensed via the pharmacy department at each site Baseline measurements must be taken the day before the first day of the trial and thus baseline is considered to be Day 0 Evaluation of adverse events and medication compliance will be performed at regular intervals for the duration of the trial Psychopathology rating scales will be completed at baseline and weeks 1 2 4 and 8 Hormone assays will be completed at baseline and weeks 4 and 8 Cognitive assessment will be completed at baseline and at week 8 The week 8 visit must fall on the last day of the trial medication
44 Clinical Follow-up
For ethical reasons upon completion of the active phase of the trial each participant will be unblinded and made aware of which treatment they had received Participants who were receiving placebo will be offered an open label trial of the 200mg estradiol patches This is so that no one is disadvantaged by their participation in the trial and are all able to take the active medication if they so wish Participants who opt to have an open label trial of the estradiol patches will be monitored for side effects for a further 8 weeks whilst they are using the patches This data will not be included in the research trial database
All participants will be followed up for 3 months following the completion of the active phase of the trial including the open-label treatment This follow-up will consist of monthly telephone contact to check participants progress as well as determine the duration of the antipsychotic effect of estrogen
5 STUDY MANAGEMENT
51 Data Management
Source data from each site will be transferred to The Alfred site for data entry and analysis A copy of the source data for each site will be archived at each site according to local ethics committee guidelines A Contract Research Organisation CRO will monitor each of the sites to ensure high quality data and adherence to study recruitment and retention targets Inter-rater reliability training will be performed annually for all staff at each site or when new staff commence
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 05T-742 | None | None | None |