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

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

Study Overview

• Status: Recruiting
• Conditions: Depression; Anxious Depression
• Intervention / Treatment: Drug: Escitalopram; Drug: Duloxetine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 84
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Heidi K Schroeder, BS; Phone Number: (513) 558-4422; Email: heysehk@uc.edu
• Study Contact Backup: Name: Zoe N Neptune, BS; Phone Number: (513) 558-2866; Email: neptunza@uc.edu

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Recruiting
      • University of Cincinnati, Department of Psychiatry & Behavioral Neuroscience
      • Contact: Jeffrey R Strawn, MD, FAACAP; Phone Number: 513-558-4315; Email: strawnjr@ucmail.uc.edu
      • Contact: Heidi K Schroeder, BS; Phone Number: (513) 558-4422; Email: heysehk@uc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No

Description

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:

  1. Surgical sterilization
  2. Oral contraceptives (e.g. estrogren-progestin combination or progestin)
  3. Transdermally-delivered contraceptives (e.g., Ortho-Evra), depot injections (e.g., Depo-Provera)
  4. Vaginal contraceptive ring (e.g., NuvaRing), contraceptive implants (e.g., Implanon, Norplant II/Jadelle)
  5. An intrauterine device
  6. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Escitalopram; 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; 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.; Other Names: Lexapro
Active Comparator: Duloxetine; 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; 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.; Other Names: Cymbalta

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Cincinnati
• Investigators: Principal Investigator: Jeffrey R Strawn, MD, FAACAP, University of Cincinnati

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2020
• Primary Completion (Estimated): July 30, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: January 27, 2020
• First Submitted That Met QC Criteria: January 27, 2020
• First Posted (Actual): January 29, 2020

Study Record Updates

• Last Update Posted (Actual): September 14, 2023
• Last Update Submitted That Met QC Criteria: September 13, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Anxious Depression
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Dopamine Agents; Serotonin and Noradrenaline Reuptake Inhibitors; Selective Serotonin Reuptake Inhibitors; Duloxetine Hydrochloride; Escitalopram
• Other Study ID Numbers: Strawn DOTS-AD

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No