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

Primary Purpose

Bipolar Disorder

Status

Terminated

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Lamotrigine

Fluoxetine

About this trial

This is an interventional treatment trial for Bipolar Disorder focused on measuring Bipolar Disorder, Mayo Clinic

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Mayo Clinic

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Lamotrigine

Fluoxetine

Arm Description

Subjects on this arm will be randomized to Lamotrigine.

Subjects on this arm will be randomized to Fluoxetine.

Outcomes

Primary Outcome Measures

Inventory for Depressive Symptoms

Secondary Outcome Measures

Full Information

NCT ID

NCT02389712

First Posted

March 10, 2015

Last Updated

June 17, 2019

Sponsor

Mayo Clinic

Collaborators

J Willard and Alice S. Marriott Foundation

1. Study Identification

Unique Protocol Identification Number

NCT02389712

Brief Title

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

Acronym

FLAME

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2019

Overall Recruitment Status

Terminated

Why Stopped

Difficulties with recruitment

Study Start Date

March 2015 (undefined)

Primary Completion Date

May 23, 2018 (Actual)

Study Completion Date

May 23, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Mayo Clinic

Collaborators

J Willard and Alice S. Marriott Foundation

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Bipolar Disorder

Keywords

Bipolar Disorder, Mayo Clinic

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

2 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Lamotrigine

Arm Type

Active Comparator

Arm Description

Subjects on this arm will be randomized to Lamotrigine.

Arm Title

Fluoxetine

Arm Type

Active Comparator

Arm Description

Subjects on this arm will be randomized to Fluoxetine.

Intervention Type

Drug

Intervention Name(s)

Lamotrigine

Other Intervention Name(s)

Lamictal

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Fluoxetine

Other Intervention Name(s)

Prozac

Intervention Description

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.

Primary Outcome Measure Information:

Title

Inventory for Depressive Symptoms

Time Frame

12 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Mark A Frye, MD

Organizational Affiliation

Mayo Clinic

Official's Role

Principal Investigator

Facility Information:

Facility Name

Mayo Clinic

City

Rochester

State/Province

Minnesota

ZIP/Postal Code

55905

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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