Theophylline for Depression Study (T-DEP)

• ClinicalTrials.gov Identifier: NCT04309877
• Recruitment Status: Not yet recruiting
• First Posted: March 16, 2020
• Last Update Posted: October 22, 2020
• Sponsor: University of California, Los Angeles
• Information provided by (Responsible Party): Hyong Jin Cho, University of California, Los Angeles

Tracking Information

• First Submitted Date: March 10, 2020
• First Posted Date: March 16, 2020
• Last Update Posted Date: October 22, 2020
• Estimated Study Start Date: March 2021
• Estimated Primary Completion Date: June 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 12, 2020)

Change in depressed mood from baseline [ Time Frame: At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration ]

Short Form of the Profile of Mood States (POMS-SF) Depression Subscale with higher scores indicating more severe depressed mood (range 0-32)

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 12, 2020)

• Change in tension/anxiety from baseline [ Time Frame: At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration ]
  Short Form of the Profile of Mood States (POMS-SF) Tension Subscale with higher scores indicating more severe tension/anxiety (range 0-24)
• Change in depressive symptoms from baseline [ Time Frame: At baseline and then at 2, 4, and 6 hours after LPS (or saline) administration ]
  Montgomery-Asberg Depression Rating Scale (MADRS): a clinician-rated questionnaire of depressive symptoms with scores ranging from 0 to 60, with higher scores indicating more severe depressive symptoms
• Change in feelings of social disconnection from baseline [ Time Frame: At baseline and then at 2, 4, and 6 hours after LPS (or saline) administration ]
  Feelings of Social Disconnection Scale: a self-report questionnaire of feelings of social disconnection with scores ranging from 0 to 28, with higher scores indicating more severe feelings of social disconnection
• Change in fatigue from baseline [ Time Frame: At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration ]
  Short Form of the Profile of Mood States (POMS-SF) Fatigue Subscale with higher scores indicating more severe fatigue (range 0-20)
• Change in confusion from baseline [ Time Frame: At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration ]
  Short Form of the Profile of Mood States (POMS) Confusion Subscale with higher scores indicating more severe confusion (range 0-20)
• Change in verbal memory from baseline [ Time Frame: At baseline and then 3 hours after LPS (or saline) administration ]
  Verbal memory measured using computerized tests from CNS Vital Signs™
• Change in visual memory from baseline [ Time Frame: At baseline and then 3 hours after LPS (or saline) administration ]
  Visual memory measured using computerized tests from CNS Vital Signs™
• Change in executive function from baseline [ Time Frame: At baseline and then 3 hours after LPS (or saline) administration ]
  Executive function measured using computerized tests from CNS Vital Signs™
• Change in attention from baseline [ Time Frame: At baseline and then 3 hours after LPS (or saline) administration ]
  Attention measured using computerized tests from CNS Vital Signs™

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: March 12, 2020)

• Subjective Sensitivity to Social Rejection [ Time Frame: 2 hours after LPS (or saline) administration ]
  Cyberball Social Exclusion Task
• Negative Bias in Facial Emotion Recognition [ Time Frame: 2 hours after LPS (or saline) administration ]
  Emotional Face Recognition Task
• Reward [ Time Frame: 2 hours after LPS (or saline) administration ]
  Reward Learning Task
• Change in proinflammatory cytokines from baseline [ Time Frame: At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration ]
  Plasma proinflammatory cytokines (interleukin-1 receptor antagonist, interleukin-6, tumor necrosis factor-α, and soluble tumor necrosis factor receptor)
• Change in kynurenine Metabolites from baseline [ Time Frame: At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration ]
  Plasma tryptophan, kynurenine, quinolinic acid, and kynurenic acid
• Change in gene expression from baseline [ Time Frame: At baseline and 30 minutes after LPS (or saline) administration ]
  Genome-wide transcriptional profiling with focus on the percentage increase from baseline to 30 minutes after LPS (or saline) administration in activities of transcription factors related to immune activation, sympathetic activation, and glucocorticoid insensitivity: respectively, nuclear factor kappa-B (NF-kB), cAMP response element-binding protein (CREB), and glucocorticoid receptor (GR).

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Theophylline for Depression Study
• Official Title: Pilot Randomized Controlled Trial of Theophylline for Attenuation of Lipopolysaccharide-Induced Depressive Symptoms
• Brief Summary: Depression is very common and poses a huge disease burden. About 20% of the US population suffers from depression at least once in their lifetime. Inflammations that are hidden inside our body as a result of aging, obesity, chronic diseases, or certain treatments (e.g., interferon for hepatitis C) appear to cause depressive symptoms and even clinical depression. Individuals with such inflammations are more likely to suffer from depression and are less likely to respond to currently available antidepressant medications. This study will test theophylline, a medication currently used for asthma treatment, as a new way to mitigate depressive symptoms in response to such inflammations. This study begins with a 90-minute screening session to determine whether participants are eligible to join the main study. Those who meet the eligibility criteria will then join the main study, which will consist of taking theophylline or methylcellulose (i.e., oral placebo) for 2 weeks at home and an 8-hour session at the UCLA Medical Center. Approximately 20 healthy adults will be recruited for participation in the study. During the course of the study, participants will take theophylline or methylcellulose for 2 weeks at home and then will be injected either lipopolysaccharide (LPS) or saline (i.e., intravenous placebo) at the UCLA Medical Center. LPS is a bacterial substance that can initiate chemical reactions that are similar to those seen in individuals with mild sickness symptoms, such as a slight increase in body temperature, muscle aches, or tiredness. It is a safe way of investigating the body's response to inflammation and how these changes may alter cognitive, emotional, or neural function. It has been given thousands of times to healthy volunteers - both younger and older adults - without any serious side effects.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Early Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Factorial Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Basic Science
• Condition: Depression

Intervention

• Drug: Theophylline ER
  Capsules of theophylline ER
• Other: PO placebo
  Capsules of methylcellulose
• Biological: Lipopolysaccharide (LPS)
  Purified bacterial wall component as an inflammatory challenge
• Other: IV placebo
  Normal (0.9%) saline

Study Arms

• Experimental: PO theophylline & IV LPS
  Oral (PO) theophylline 400 mg/day for 2 weeks followed by a single intravenous (IV) bolus of lipopolysaccharide (LPS) 0.8 ng/kg of body weight
  Interventions:

  • Drug: Theophylline ER
  • Biological: Lipopolysaccharide (LPS)
• Experimental: PO placebo & IV LPS
  PO methylcellulose (placebo) daily for 2 weeks followed by a single intravenous (IV) bolus of lipopolysaccharide (LPS) 0.8 ng/kg of body weight
  Interventions:

  • Other: PO placebo
  • Biological: Lipopolysaccharide (LPS)
• Experimental: PO theophylline & IV placebo
  PO theophylline 400 mg/day for 2 weeks followed by a single IV bolus of 0.9% saline
  Interventions:

  • Drug: Theophylline ER
  • Other: IV placebo
• Placebo Comparator: PO placebo & IV placebo
  PO methylcellulose (placebo) daily for 2 weeks followed by a single IV bolus of 0.9% saline
  Interventions:

  • Other: PO placebo
  • Other: IV placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: March 12, 2020): 20
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 2021
• Estimated Primary Completion Date: June 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• in good general health (as evaluated during the phone and in-person screening sessions)
• aged 18-65 years
• if female, using adequate birth control

Exclusion Criteria:

• history of hypersensitivity to xanthine derivatives (a contraindication to theophylline treatment)
• pregnant or planning to become pregnant in the next 6 months
• current breastfeeding
• chronic diseases such as cardiovascular disease, hepatic impairment, peptic ulcer disease, and seizure disorders
• current use of prescription medications such as steroids, non-steroid anti-inflammatory drugs, immune modifying drugs, opioid analgesics, and psychotropics
• Axis I psychiatric disorders including current major depressive disorder
• current depressive symptoms assessed by the Patient Health Questionnaire (PHQ-9 ≥ 5)
• heavy smoking (1 pack or more per day)
• excessive caffeine use (>600 mg/day)
• Body-mass index > 35 due to the effects of obesity on cytokine activity
• evidence of recreational drug use from urine test
• evidence of pregnancy from urine test
• evidence of clinically significant rhythm abnormality on a resting electrocardiogram (ECG)
• clinically significant abnormalities on screening laboratory tests

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Ariya Mahbod, MD; 310-267-4389; Amahbod@mednet.ucla.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04309877
• Other Study ID Numbers: 20-000005
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Hyong Jin Cho, University of California, Los Angeles
• Study Sponsor: University of California, Los Angeles
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: University of California, Los Angeles
• Verification Date: October 2020