Fluoxetine Prevention Trial

Study Description

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Brief Summary:

Many cancer survivors are experiencing problems with memory and other cognitive abilities following cancer treatment. Little is known concerning the contributions of potentially preventive therapies on cognitive function, but animal studies have pointed to the potential value of the medication fluoxetine in this context. We aim to determine whether six months of fluoxetine therapy can preserve brain function in patients who have undergone chemotherapy, and examine potential biological mechanisms for its protective effects in humans. If use of fluoxetine in cancer patients can be validated in this manner, it will represent the first drug demonstrated to prevent cerebral dysfunction associated with exposure to chemotherapy. Moreover, as this involves an agent that is already FDA-cleared for other indications, widely commercially available throughout the U.S. and other parts of the world, and relatively inexpensive since it is obtainable in generic formulations, it would represent a pharmacologic approach that is amenable to rapid translation to the clinical setting.

Condition or disease	Intervention/treatment	Phase
Cognitive Dysfunction	Drug: Fluoxetine; Other: Placebo	Early Phase 1

Detailed Description:

Systematic studies of adverse cognitive and neurobiological changes subsequent to chemotherapy for lymphoma, breast, and other cancers have attracted substantial interest in the past decade. Little is known, however, concerning the feasibility and effects of potentially protective therapies on cerebral function in patients undergoing chemotherapy. Animal models have recently proved useful in examining some of the toxic effects of chemotherapy agents on working memory and other abilities, as well as on biological properties such as proliferation and survival of neuronal precursors involved in hippocampal neurogenesis. Such models have also proved useful for testing potential neuroprotective properties of agents given before, during and/or after chemotherapy. For example, impairment in spatial working memory and decreased hippocampal neurogenesis is induced in rats by the chemotherapy agent methotrexate, but co-administration of the (FDA-cleared and commercially available) drug fluoxetine has been shown to counteract the negative long-term effects on memory and hippocampal neurogenesis otherwise occurring after methotrexate administration. To determine whether such a strategy could be effective in counteracting effects that chemotherapy may have on cerebral function in humans, well-controlled experimental data obtained with cancer patients is needed.

This investigation will employ a prospective, randomized, double-blinded, placebo-controlled design, to provide a rigorous test of whether fluoxetine, a drug with a long-standing excellent safety profile in humans most commonly marketed as an antidepressant, can offer protection to breast cancer or lymphoma patients against changes in cerebral function occurring after chemotherapy (Specific Aim 1). It will further provide a test of the durability of any protective effects beyond the period during which fluoxetine is used, by re-assessing function approximately 6 months after completion of the regimen (Specific Aim 2). Cerebral function will be assessed by determining distributions of regional cerebral metabolism, previously demonstrated to sensitively detect functional alterations and closely reflect diminished cognitive abilities with high statistical power, using positron emission tomography with the glucose analog radiotracer [F-18]fluorodeoxyglucose. Neuropsychologic testing will be conducted in parallel with neuroimaging studies and, as a step towards understanding mechanisms underlying neurotoxic effects of chemotherapy and potentially related to protective effects of fluoxetine, peripheral markers of inflammatory cytokines will be measured in blood samples drawn at the time of neuroimaging (Specific Aim 3). If use of fluoxetine in cancer patients can be validated in this manner and lead to its adoption in the clinical setting, it will constitute the first drug with demonstrated utility for the prevention of cerebral dysfunction associated with exposure to chemotherapy. Moreover, as this involves an agent that is already FDA-cleared for other indications, widely commercially available throughout the U.S. and other parts of the world, and relatively inexpensive since it is obtainable in generic formulations, it would represent a pharmacologic approach that is amenable to rapid translation to the clinical setting.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	376 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Prevention
Official Title:	Prevention of Cognitive Decline After Chemotherapy, With Fluoxetine Treatment
Estimated Study Start Date :	June 2018
Estimated Primary Completion Date :	October 2020
Estimated Study Completion Date :	October 2020

Arms and Interventions

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm	Intervention/treatment
Experimental: Fluoxetine tablets	Drug: Fluoxetine; 20-40 mg fluoxetine po qd for 6 months; Other Name: Prozac
Placebo Comparator: Placebo tablets	Other: Placebo; 20-40 mg pharmacologically inactive tablets for 6 months; Other Name: "sugar" pill

Outcome Measures

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Primary Outcome Measures :

1. Change from baseline in regional cerebral metabolism [ Time Frame: Baseline and 6 months ]

Secondary Outcome Measures :

1. Durability of the protective effect of fluoxetine [ Time Frame: 6 months and 1 year ]
2. Change from baseline in neuropsychological (cognitive, functional) test results [ Time Frame: Baseline, 6 months, and 1 year ]
3. Correlation between cognitive functioning and cerebral metabolism by correlating neuropsychological testing results with PET imaging [ Time Frame: Baseline, 6 months, and 1 year ]
4. Correlation between inflammatory cytokines and cerebral metabolism by correlating blood cytokine marker levels with PET imaging [ Time Frame: Baseline, 6 months, and 1 year ]

Eligibility Criteria

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Ages Eligible for Study:	21 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Scheduled to undergo chemotherapy, or has completed chemotherapy no more than a month prior to enrollment, for breast cancer or lymphoma
• Age 21 or above
• Geographically accessible for follow-up in one year
• English language proficient
• Able to provide informed consent

Exclusion Criteria:

• Pregnant
• Evidence of current or past disorder/disease of the central nervous system or any medical condition that might be expected to impact cognitive functioning (e.g. multiple sclerosis)
• History of head trauma with loss of consciousness greater than 30 minutes
• Epilepsy, dementia, or severe learning disability
• Current psychotic-spectrum disorder (e.g. schizophrenia, bipolar disorder, major affective disorder) or current substance abuse or dependence
• History of whole brain irradiation or surgery
• Active diagnosis of autoimmune disorder e.g., systemic lupus erythematosis, rheumatoid arthritis, vasculitis
• Insulin dependent diabetes
• Uncontrolled allergic condition or asthma
• Chronic use of oral steroid medication
• Hormone therapy (estrogen, progestin compounds) other than vaginal estrogen
• Due to the subtleties of neuropsychological test evaluation, including necessity for repeated administration with alternate forms, we must also exclude non-English language proficient subjects.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Daniel H. Silverman, M.D., Ph.D.	310-825-4257	dsilver@ucla.edu

Locations

United States, California
City of Hope	Not yet recruiting
Duarte, California, United States, 91010
Contact: Arti Hurria, M.D.
UCLA Medical Center	Not yet recruiting
Los Angeles, California, United States, 90024
Contact: Daniel H. Silverman 310-825-4257

Sponsors and Collaborators

University of California, Los Angeles

City of Hope Medical Center

Investigators

Principal Investigator:	Daniel H. Silverman, M.D., Ph.D.	University of California, Los Angeles

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Daniel H. Silverman, Professor, Medical and Molecular Pharmacology, University of California, Los Angeles
ClinicalTrials.gov Identifier:	NCT01615055 History of Changes
Other Study ID Numbers:	12-000568
First Posted:	June 8, 2012
Last Update Posted:	October 31, 2017
Last Verified:	October 2017

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		Yes
Device Product Not Approved or Cleared by U.S. FDA:		No

Keywords provided by Daniel H. Silverman, University of California, Los Angeles:

Chemotherapy; Cognitive; Prozac	Fluoxetine; FDG; PET

Additional relevant MeSH terms:

Fluoxetine; Cognitive Dysfunction; Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action	Neurotransmitter Agents; Serotonin Agents; Physiological Effects of Drugs; Antidepressive Agents, Second-Generation; Antidepressive Agents; Psychotropic Drugs; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors