16-week Comparative Effectiveness Trial of Lamotrigine vs. Fluoxetine for Bipolar Depression (FLAME)

June 17, 2019 updated by: Mark Frye, Mayo Clinic

16-week Open Randomized Comparative Effectiveness Trial of Lamotrigine vs. Fluoxetine for Bipolar Depression: Pharmacogenomic and Biomarker Predictors of Response

The FLAME Study is a 16-week clinical trial to study treatment with lamotrigine or fluoxetine in bipolar I, II and bipolar schizoaffective depressed adults. The purpose of the trial is to have a better understanding of whether individuals with a particular gene type and other inherited biological markers will have a good response to fluoxetine or lamotrigine, or alternatively, would be more likely to have side effects to this medication.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Depression is the predominant prevailing mood state of bipolar disorder and it is associated with substantial morbidity and mortality. However, in comparison to acute mania, bipolar depression is understudied both from the standpoint of its pathophysiology as well as clinical trials and treatment development. Given the lack of evidence-based guidelines, clinicians and participants enter a treatment phase with little guidance.

The FLAME Study is a 16-week, open randomized comparative effectiveness trial evaluating genomic predictors and biomarkers of response and adverse events to treatment with lamotrigine (n=200) and fluoxetine (n=200) for bipolar I, II and bipolar schizoaffective depressed adults (18-65). Participants will be recruited over a 5-year period.

It is known that functionally significant genetic polymorphisms of pharmacokinetics and pharmacodynamic pathways can influence individual differences in repose to specific medications. We propose to evaluate the contribution of these pharmacogenomic variations to lamotrigine and fluoxetine treatment response and adverse events. We will correlate clinical phenotypes of response and adverse events to treatment with genotype and haplotype variations of drug metabolism, neurotransmitter biosynthesis, (metabolism, storage, release, reuptake), receptor and intracellular signaling-that have been previously implicated to either lamotrigine or fluoxetine. These initial steps will be complemented with genome-wide analysis (GWA), pathway analysis and other candidate gene studies.

Based on our results we aim to develop a translational treatment algorithm of bipolar depression that may help individualized treatment for bipolar depression. This algorithm for participants could potentially increase the likelihood of successful treatment interventions, deliver the "right treatment, for the right participant at the right time", and decrease the number of ineffective treatments and/or risk for serious adverse events.

Study Type

Interventional

Enrollment (Actual)

2

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Adult participants, age 18-65.
  • Outpatients or inpatients with a diagnosis of bipolar I, II or schizoaffective bipolar disorder, depressed phase, non-psychotic, (DSM-5 criteria, Structured Clinical Interview for the Diagnostic and Statistical Manual for Mental Disorders Module D confirmed)
  • At least mild symptom severity of depression as defined by the Clinical Global Impression for Bipolar Disorder (CGI-BP, Spearing et al. 1997) >2.
  • Bipolar I participants must be on conventional mood stabilizing treatment [lithium, divalproex or valproate, or an atypical antipsychotic]. Participants with a bipolar II disorder may pursue the FLAME Study as monotherapy.
  • Negative urine pregnancy test.
  • Participants not planning pregnancy in the near future (6 months).
  • Negative urine toxicology screen (except cannabis).
  • No evidence of clinically significant laboratory screening tests (complete blood count (CBC); electrolytes; thyroid stimulating hormone (TSH); creatinine/blood urea nitrogen, Aspartate Aminotransferase (AST)/ALT). Clinical laboratory evaluation within the last three months is acceptable.

Exclusion Criteria:

  • Inability or unwilling to provide informed consent.
  • Inability to understand English.
  • Actively suicidal participants at screening or enrollment visit as defined by a response of 3 or 4 on question 4 of the Bipolar Inventory of Symptoms Scale (BISS).
  • Active delusions or hallucinations defined as a score of 3 or 4 on the BISS question 40 (persecutory ideas) or 41 (delusions or hallucinations).
  • Impaired insight as defined as a score of 3 or 4 on BISS question 42 (insight).
  • Hypomania defined by a BISS manic subscore of ≥15.
  • Axis I or II comorbidity that by referring mental health professional and/or study psychiatrist is primary need of treatment. (This will be assessed by the site principal investigator, who has >10 years clinical experience with this population. Hospital discharge summaries and outpatient medical records may be reviewed (i.e., adequate trials of mood stabilizing treatments with minimal to no response, prominent self-injurious behavior in the absence of significant mood symptomatology, or atypical cycle patterns) to make this decision.
  • Pregnant participants
  • Unwilling or unable to taper any current antidepressant therapy
  • Participants currently breastfeeding
  • Female not practicing a reliable form of birth control (condom, intrauterine device (IUD), Depo-Provera injection)
  • Due to lamotrigine pharmacokinetics, female subjects wishing to commence oral contraceptive therapy (OCT) within 3 months of enrollment date or anticipate discontinuing OCT during study (stable oral contraceptive therapy exception).
  • History of active substance abuse disorder within the last 3 months (other than caffeine or cannabis)
  • Participants with medical contraindications that preclude lamotrigine or fluoxetine treatment
  • History of severe adverse reaction to lamotrigine and/or fluoxetine
  • Current carbamazepine or oxcarbazepine treatment
  • Unstable active medical illness

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Lamotrigine
Subjects on this arm will be randomized to Lamotrigine.
Drug: Lamotrigine
Lamotrigine dosing: 25 mg daily x 2 weeks, 50 mg daily x 2 weeks, 100 mg daily x 2 weeks, 200 mg (100 mg bid)) x 4 weeks. If patient still has at least mild depressive symptoms, the dose can be increased to 300 mg daily for 2 weeks and 400 mg for 4 weeks. Dose will be held for treatment response and can be reduced for side effects.
Other Names:
  • Lamictal
Active Comparator: Fluoxetine
Subjects on this arm will be randomized to Fluoxetine.
Drug: Fluoxetine
Fluoxetine dosing: 20mg for month 1, 40mg for month 2, and if still depressed (CGI ≥ 3) 60mg for month 3 and 4. Lower doses of fluoxetine will be prescribed for those with side effects. For known Cytochrome P450 2D6 poor metabolizers, fluoxetine will not be dosed > 40mg.
Other Names:
  • Prozac

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Inventory for Depressive Symptoms
Time Frame: 12 weeks
12 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Mayo Clinic

Collaborators

J Willard and Alice S. Marriott Foundation

Investigators

  • Principal Investigator: Mark A Frye, MD, Mayo Clinic

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2015

Primary Completion (Actual)

May 23, 2018

Study Completion (Actual)

May 23, 2018

Study Registration Dates

First Submitted

March 10, 2015

First Submitted That Met QC Criteria

March 16, 2015

First Posted (Estimate)

March 17, 2015

Study Record Updates

Last Update Posted (Actual)

June 19, 2019

Last Update Submitted That Met QC Criteria

June 17, 2019

Last Verified

June 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 13-003545-1
  • UL1TR000135 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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