Fluoxetine Prevention Trial

Prevention of Cognitive Decline After Chemotherapy, With Fluoxetine Treatment

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.

Study Overview

• Status: Withdrawn
• Conditions: Cognitive Dysfunction
• Intervention / Treatment: Drug: Fluoxetine; Other: Placebo

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 Type: Interventional
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Los Angeles, California, United States, 90024
      • UCLA Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change from baseline in regional cerebral metabolism	Baseline and 6 months

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of California, Los Angeles
• Collaborators: City of Hope Medical Center
• Investigators: Principal Investigator: Daniel H. Silverman, M.D., Ph.D., University of California, Los Angeles

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2018
• Primary Completion (Anticipated): October 1, 2020
• Study Completion (Anticipated): October 1, 2020

Study Registration Dates

• First Submitted: June 6, 2012
• First Submitted That Met QC Criteria: June 7, 2012
• First Posted (Estimate): June 8, 2012

Study Record Updates

• Last Update Posted (Actual): October 15, 2018
• Last Update Submitted That Met QC Criteria: October 10, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: PET; Chemotherapy; Cognitive; FDG; Fluoxetine; Prozac
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Fluoxetine
• Other Study ID Numbers: 12-000568

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes