Effectiveness of Escitalopram in Preventing or Reducing Depressive Symptoms in People Receiving Interleukin-2 Treatment

Study Overview
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Brief Summary
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This study will determine the effectiveness of an antidepressant in preventing or reducing depressive symptoms in people with melanoma who are receiving Interleukin-2 (IL-2) treatment.

Detailed Description
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Melanoma is the most serious type of skin cancer, affecting nearly 54,000 people in the United States each year. Melanomas often develop in pre-existing moles or as new moles on the body. If left untreated, the cancerous cells can spread throughout the body. Fortunately, melanoma can be cured if a person is diagnosed and treated early. Typical treatments include surgery, amputation, chemotherapy, and immunotherapy. Interleukin-2 (IL-2) treatment, a type of immunotherapy, uses the body's immune system to slow or stop the spread of cancer cells to other parts of the body. However, IL-2 treatment is typically associated with severe side effects, including depression, fatigue, and difficulty thinking. This study will evaluate whether escitalopram, an antidepressant, can help improve treatment-related depressive symptoms, reduce stress hormone levels, and increase the number of treatment cycles among people with metastatic melanoma who are receiving IL-2 treatment. Participation in this double-blind study will last up to 18 weeks and will include 5 to 14 study visits. Participants will complete four 1-week cycles of IL-2 treatment over a 12-week period. Two weeks prior to starting IL-2 treatment, participants will undergo a psychiatric interview; a computerized thinking test; questionnaires; and blood, urine, and saliva collection. Participants will also be randomly assigned to start receiving either escitalopram or placebo for the entire duration of the study. The dosage of escitalopram or placebo will vary depending on the symptom severity of each participant. Immediately prior to IL-2 treatment, participants will undergo preliminary IL-2 procedures, which will include a medical history review, physical exam, and blood collection. These same procedures will occur every day that the participant is in the hospital for IL-2 treatment. Participants will stay in the hospital when receiving all four IL-2 treatment cycles. During these hospital stays, participants will complete repeat questionnaires and computerized tasks. Blood collection will occur at selected times as well. A follow-up visit will occur 4 weeks after the final treatment dose of IL-2.

Official Title
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IL-2 Neuropsychiatric Symptoms: Mechanism and Prevention

Conditions
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Depression

Intervention / Treatment
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* Drug: Escitalopram
* Drug: Placebo
* Drug: IL-2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with cancer and beginning Interleukin (IL)-2 treatment Willing to use an effective form of birth control throughout the study if sexually active Exclusion Criteria: Diagnosed with major depression or experiencing significant depressive symptoms or a Hamilton Rating Scale-Depression score of 18 or higher Brain metastases, history of a brain injury, or seizure disorders Meets Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for substance abuse or dependence within 3 months of study entry Suicidal, psychotic, or received psychiatric hospitalization within 12 months of study entry Past or current history of schizophrenia or bipolar disorder Pregnant or planning on becoming pregnant within 1 to 2 years Evidence of untreated or poorly controlled infectious, hormone, heart, blood, kidney, liver, or neurological disease Use of antidepressants, glucocorticoids, guanethidine, centrally acting alpha-antagonists, beta-blockers, or anticonvulsants Clinically significant eye abnormalities A score lower than 28 on the Mini Mental Status Exam (MMSE) Prior history of severe adverse events associated with escitalopram or other selective serotonin reuptake inhibitor (SSRI) antidepressants Diagnosed with type 1 or type 2 diabetes Any condition that might make the participant unsuitable for enrollment or that could interfere with study participation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Escitalopram<br>Participants will receive escitalopram and IL-2 treatment | Drug: Escitalopram<br>* Participants will begin medication approximately 2 weeks before their first scheduled IL-2 treatment. The dosage for the first week will be 10 mg per day. If 10 mg is well tolerated by the participant, the dosage will be increased to 20 mg per day. The dosage for the remainder of the study will be 20 mg per day.<br>* Other names: Lexapro;Drug: IL-2<br>* IL-2 is a 12-week treatment regimen with intravenous (IV) IL-2. There will be one cycle every 3 weeks for a total of four cycles. One cycle is 720,000 units/kg every 8 hours for 5 days.<br>|
| Placebo Comparator: Placebo<br>Participants will receive placebo and IL-2 treatment | Drug: Placebo<br>* Participants will begin the placebo approximately 2 weeks before their first scheduled IL-2 treatment. The dosage for the first week will be 1 pill per day, if 1 pill is well tolerated by the participant the dosage will be increased to 2 pills per day. Two pills per day will be the dosage for the reminder of the study.<br>* Other names: Sugar pill;Drug: IL-2<br>* IL-2 is a 12-week treatment regimen with intravenous (IV) IL-2. There will be one cycle every 3 weeks for a total of four cycles. One cycle is 720,000 units/kg every 8 hours for 5 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of IL-2 Treatments Tolerated | The mean number of IL-2 doses tolerated (out of the possible 60 total doses) are presented for each study arm. The standard high dose regimen of IL-2 includes 15 doses per cycle. The dose of IL-2 is reduced, or treatment is stopped entirely, if the side effects become severe. This analysis includes the total number of doses taken at the end of Cycle 4, by all participants who began the trial, regardless of how many cycles each participant completed. | Cycle 4 (up to 12 weeks of IL-2 treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentrations of Adrenocorticotropic Hormone (ACTH) | Adrenocorticotropic hormone (ACTH) is a stress hormone that is synthesized by the pituitary in response to corticotropin-releasing hormone (CRH). ACTH stimulates adrenal cortisol production. ACTH levels vary throughout the day and are highest between 6am and 8am. A typical reference range is 10-50 picograms per milliliter (pg/ml) from blood drawn in the morning. Low levels of ACTH can indicate adrenal insufficiency (including adrenal cancers) while high levels may indicate several diseases or stress. IL-2 treatment stimulates the release of ACTH and this stimulation is dose dependent (rising as the dose of IL-2 increases) and tends to increase further with repeated exposure to IL-2. Blood was drawn for measuring ACTH at screening (baseline value) and once during days 1-3 of each cycle of the four IL-2 treatments. | Screening and Cycles 1 - 4 (up to 14 weeks) | 
| Plasma Concentrations of Interleukin 6 (IL-6) | Immune system functioning was assessed by measuring plasma concentrations of interleukin 6 (IL-6). IL-6 is a proinflammatory cytokine that is elevated during times of inflammation, infection, in patients with advanced or metastatic cancer, and is also implicated in mood disorders. IL-2 treatments are associated with increased IL 6 levels, in a dose response manner. IL-6 values in healthy individuals are generally less than 16 pg/ml. Blood was drawn for measuring IL-6 at screening (baseline value) and once during days 1-3 of each cycle of the four IL-2 treatments. | Screening and Cycles 1 - 4 (up to 14 weeks) | 
| Plasma Concentrations of Cortisol | Cortisol is a steroid hormone made in the adrenal glands in response to fear or stressful situations. A typical reference range is 6-23 micrograms/deciliter (mcg/dL) from blood drawn in the morning. Low levels of cortisol can indicate Addison's disease or a problem with the pituitary gland, while high levels may indicate tumors of the adrenal gland, among other illnesses, or increased stress. Chronic elevation of cortisol is associated with reduced immune function and increased risk of heart disease. IL-2 treatment stimulates the release of cortisol and this stimulation is dose dependent (rising as the dose of IL-2 increases) and tends to increase further with repeated exposure to IL-2. Blood was drawn for measuring cortisol at screening (baseline value) and once during days 1-3 of each cycle of the four IL-2 treatments. | Screening and Cycles 1 - 4 (up to 14 weeks) | 
| Hamilton Depression Rating Scale (HAM-D) Score | Hamilton Depression Rating Scale (HAM-D) is a 21-item, observer-rated scale which quantifies the severity of depressive symptoms, including depressed mood, loss of interest in usually pleasurable activities, insomnia, anorexia, fatigue, weight loss, and psychomotor retardation or agitation. Participants rate the severity of their symptoms on a scale of 0-2 or 0-4 (depending on the item), where 0 means that the symptom is absent. Total scores are calculated by summing the first 17 items for a total score between 0 and 50. For this study a score of 0-6 indicates a normal state, a score of 7-17 indicates mild depression, a score of 18-24 indicates moderate depression, and a score of greater than 25 indicates severe depression. The HAM-D was administered at screening (baseline value) and once during days 1-3 of each cycle of the four IL-2 treatments. | Screening and Cycles 1 - 4 (up to 14 weeks) | 
| Genetic Polymorphisms |  | Screening and After Cycle 4 (up to 14 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, IL-2 therapy, Antidepressant, Immune system, Neuroendocrine response