Determining Optimal Treatment Sequences in Anxious Depression (DOTS-AD)

Study Overview
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Brief Summary
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Acute, double-blind, adaptively randomized treatment with duloxetine or escitalopram, followed by double-blind, randomized adjunctive treatment with clonazepam or pregabalin for persistent symptoms.

Detailed Description
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The study will consist of 2 phases (Figure 1). Eighty-four adults will be enrolled in Phase 1 and will be adaptively randomized (initially 1:1) to acute, double-blind treatment with escitalopram or duloxetine for 11 weeks. Remission status will be determined at week 10. Remitting patients (CGI-S ≤2) will resume treatment as usual, which may consist of outpatient referral. Non-remitting patients (CGI-S ≥3), will continue into Phase 2 and will be randomized to adjunctive clonazepam or pregabalin for 8 weeks. Twenty adults treated with escitalopram (or its racemic equivalent, citalopram) or duloxetine for ≥6 weeks (at screening) will be enrolled into Phase 2 and will be randomized to receive adjunctive clonazepam or pregabalin for 8 weeks.

Official Title
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Determining Optimal Treatment Sequences in Anxious Depression (DOTS-AD)

Conditions
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Anxious Depression, Depression

Intervention / Treatment
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* Drug: Escitalopram
* Drug: Duloxetine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written, informed consent. Patients must be fluent in the English. 18 to 50 years of age, inclusive, at Visit 1. Patients must meet DSM-5 criteria for generalized, social and/or separation anxiety disorder and/or panic disorder, confirmed by the MINI.99 Patients may also meet criteria for persistent depressive disorder or major depressive disorder however, these may not be the primary focus of treatment. HAM-A score ≥20 at Visits 1 and 2. Clinical Global Impressions- Severity (CGI-S) score ≥4 at Visits 1 and 2. No clinically significant abnormalities on physical examination and EKG. Negative pregnancy test at Visit 1 in females. Negative urine drug screen at Visit 1. Sexually active patients must practice a reliable method of contraception (Section 15.0) that will continue for the duration of the study and for a minimum of 30 days following the end of study participation. Reliable methods of contraception are defined below; other forms of contraceptives (pharmacological and/or non-pharmacological) are not accepted: Surgical sterilization Oral contraceptives (e.g. estrogren-progestin combination or progestin) Transdermally-delivered contraceptives (e.g., Ortho-Evra), depot injections (e.g., Depo-Provera) Vaginal contraceptive ring (e.g., NuvaRing), contraceptive implants (e.g., Implanon, Norplant II/Jadelle) An intrauterine device Diaphragm plus condom. For patients directly enrolling into Phase 2: treatment with escitalopram (or its racemic equivalent citalopram) or duloxetine for ≥6 weeks, at time of screening. Exclusion Criteria: DSM-5 diagnosis other than generalized anxiety, social anxiety, separation anxiety or panic disorder(s) that is the primary focus of treatment. A history of intellectual disability. Suicide risk as determined by either: (1) any suicide attempt within the past 6 months and/or (2) significant risk at Visit 1 (Screening) or Visit 2 (Baseline), as judged by the Investigator. Allergy, intolerance, non-response or hypersensitivity to escitalopram, duloxetine, pregabalin or clonazepam. Subjects taking other medications that require a taper or washout of more than 5 days. Patients who have initiated/terminated psychotherapy/behavior therapy within 1 month before Visit 2 (Baseline) will be excluded; if the patient is engaged in psychotherapy, it must have been stable for 1 month prior to baseline. A clinically-significant medical illness. QTc >450 in males or >460 in females (prolonged QTc based on American Heart Association recommendations for Standardization and Interpretation of the EKG100 Alcohol or substance use disorder within 6 months of baseline (nicotine use is permitted). Positive urine pregnancy test/pregnancy or breast feeding. A positive urine drug screen. Patients who are unable to swallow capsules.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Escitalopram<br>Adaptively randomized, double-blind treatment with escitalopram for 11 weeks in Phase 1. Non-remitting patients will be randomized in Phase 2 to adjunctive clonazepam or pregabalin for 8 weeks. Additionally, adults who are already treated with escitalopram or citalopram for at least 6 weeks prior to screening, may enter Phase 2 and be randomized to adjunctive clonazepam or pregabalin for 8 weeks. | Drug: Escitalopram<br>* Escitalopram, a SSRI, commercially known as LexaproTM, is commonly prescribed for anxiety disorders and is FDA-approved for acute and maintenance treatment of MDD and GAD.<br>* Other names: Lexapro;|
| Active Comparator: Duloxetine<br>Adaptively randomized, double-blind treatment with duloxetine for 11 weeks in Phase 1. Non-remitting patients will be randomized in Phase 2 to adjunctive clonazepam or pregabalin for 8 weeks. Additionally, adults who are already treated with duloxetine for at least 6 weeks prior to screening, may enter Phase 2 and be randomized to adjunctive clonazepam or pregabalin for 8 weeks. | Drug: Duloxetine<br>* Duloxetine, a SNRI, commercially known as CymbaltaTM, is FDA-approved for the treatment of GAD, MDD, diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain in adults.<br>* Other names: Cymbalta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Hamilton Anxiety Rating Scale (HAM-A) total score | The HAM-A rating scale is a test of 14 items measuring the severity of anxiety symptoms. Each item is rated on a 5-point ordinal scale, ranging from 0 (not present) to 4 (severe). Total scores range from 0 to 56. A lower score is favorable. | Week 2 to 20 | 
| Change from Baseline in the Clinical Global Impression of Severity (CGI-S) | CGI-S is a seven point scale where 1=Normal and 7=Among the most extremely ill patients. | Week 2 to 20 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anxious Depression