Clinical trial NCT04093518: Estradiol as add-on to Antipsychotics
Official title: A Randomized Trial Administering Estradiol Patch vs. Placebo Patch as add-on to Antipsychotics in Female Patients Above the Age of 38 With Schizophrenia, Schizoaffective or Schizophreniform Disorder
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Schizophrenia
Schizoaffective Disorder
Schizophreniform Disorders
Lead sponsor: Tangent Data
Sponsor class: OTHER
Collaborators: name: Stanley Medical Research Institute
name: MediStat Ltd.
name: PCI pharma services (formerly BIOTEC SERVICES INTERNATIONAL LIMITED)
name: S.C. IMUNOTEHNOMED S.R.L.
name: Tangent Data Srl
First posted: 2019-09-18
Enrollment: 100
Sex: FEMALE
Minimum age (years): 38
Maximum age (years): 48
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, add-on to anti-psychotics, double blind, placebo-controlled, parallel group clinical trial
Primary purpose: TREATMENT

Brief summary: The objective of the study is to evaluate the efficacy of Estradiol patch compared to placebo, as add-on to anti-psychotics in the treatment of women 38 and older with schizophrenia, schizoaffective or schizophreniform disorder.

Detailed description: Several lines of evidence suggest that estrogen affects the course of schizophrenia. The onset of schizophrenia is 2-4 years later in women than in men, and women have a lower incidence of schizophrenia until menopause, after which women have an increased incidence, so that the lifetime prevalence is similar in both genders. Women are more likely to have their first schizophrenic episode during an estradiol trough in the menstrual cycle. These gender differences in the natural course of schizophrenia are well replicated and provide a major lead to understanding and treating the illness, and have led to several randomized controlled trials administering oral estradiol to patients with schizophrenia. Studies on transdermal estradiol have been more encouraging, and four RCTs, have shown that estradiol patches are efficacious in treating schizophrenia The most recent study was performed our group and showed that overall estradiol patches were efficacious with an effect size of 0.41 for total PANSS, with significant improvements in PANSS positive, negative and general-psychopathology scores. Post hoc analyses showed that the improvements in symptoms were found almost exclusively in women who were 38 and older, in whom the effect of estrogen patches vs placebo reached an effect size of 0.58 for PANSS total.

The currently proposed study is based on the post-hoc finding of improvement in participants aged 38 and above, and we will a-priori recruit women with schizophrenia 38 and above, in order to test the efficacy of 200 µg estradiol patches vs placebo in these woman.

Eligibility criteria: Inclusion Criteria:

1. Female above 38, up to 45 years of age, inclusive
2. Willing and able to provide informed consent, after the nature of the study has been fully explained
3. Current DSM-V diagnosis of schizophrenia, schizoaffective or schizophreniform disorder as confirmed by modified SCID.
4. Total PANSS score \> 70 and (PANSS positive subscale \>15 and/or PANSS negative subscale \>15)
5. Must be on a stable dose of any antipsychotic drug, for at least 2 weeks prior to the baseline visit, at doses within the PORT criteria, whenever possible. Patients receiving higher doses will have their records reviewed to ensure that their dose is required and, if possible, will be stabilized on a lower dose prior to study entry.
6. Patients who are physically and endocrinologically healthy,
7. Not menopausal as assessed by asking patients if they are menstruating
8. Inpatients or outpatients. Inpatients will be randomized 3 days or more after admission

Exclusion Criteria:

1. Unwilling or unable, in the opinion of the Investigator, to comply with study instructions
2. Pregnant or breast-feeding
3. Women who are menopausal.
4. Patients treated with oral estrogen preparations containing estradiol greater than 30 mcg.
5. Women who have known severe abnormalities in the hypothalamo-pituitary gonadal axis, thyroid disorders, severe medical conditions and disorders that would contraindicate estrogen use (breast cancer, migraine with aura or stroke)
6. History of endometrial cancer or breast cancer, history of breast or uterine cancer, no history of 1st and 2nd grade family with breast or uterine cancer, vaginal bleeding between periods.
7. Likely allergy or sensitivity to estradiol.
8. Schizoaffective disorder in the manic phase.
9. At significant risk of committing suicide, or in the opinion of the Investigator, currently at imminent risk of suicide or harming others.
10. Patients with a current DSM-V substance or alcohol abuse. Patients with a history of and/or current recreational use of cannabinoids or alcohol, and/or patients who smoke cigarettes can be included.
11. Concurrent delirium, mental retardation, drug-induced psychosis, or history of clinically significant brain trauma documented by CT or MRI.
12. Patients receiving phenobarbital, phenytoin, carbamazepine, rifampicin, rifabutin, nevirapine, efavirenz, ritonavir and nelfinavir,or Hypericum perforatum.

Primary outcomes:
measure: Change in total PANSS scores at the end of the trial
timeFrame: Change from Baseline at 16 weeks
Secondary outcomes:
measure: Positive and Negative Syndrome Scale (PANSS) and general psychopathology scales
timeFrame: through study, 16 weeks
measure: Clinical Global Impression Scale-Severity (CGI-S) and Global Impression Scale-Improvement (CGI-I),
timeFrame: through study, 16 weeks
measure: Montgomery-Asberg Depression Rating Scale
timeFrame: through study, 16 weeks
measure: Rates of drop outs before the end of the trial
timeFrame: through study completion, an average of 1 year
Other outcomes:
Locations:
city: Chisinau
country: Moldova, Republic of
facility: Centrul Comunitar de Sănătate Mintală Botanica
Study officials:
affiliation: Sheba Medical Center
name: Mark Weiser, M.D.
role: PRINCIPAL_INVESTIGATOR
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