Peripheral Neuroimmune Mechanisms of Hyperthermia

• ClinicalTrials.gov Identifier: NCT05366270
• Recruitment Status: Recruiting
• First Posted: May 9, 2022
• Last Update Posted: March 10, 2023
• Sponsor: Massachusetts General Hospital
• Collaborator: National Institute of General Medical Sciences (NIGMS)
• Information provided by (Responsible Party): Simmie L. Foster, MD, Massachusetts General Hospital

Study Description

Brief Summary:

The goal of this study is to examine how whole-body hyperthermia affects the thermoinflammatory profile, which includes the combined immune and heat shock response, in patients with depression and whether these changes correlate with decreased depression in individuals with Major Depressive Disorder.

Condition or disease	Intervention/treatment	Phase
Hyperthermia; Major Depressive Disorder; Inflammation	Device: WBH; Device: Sham	Not Applicable

Detailed Description:

The study is a maximum of 42-day randomized controlled trial (RCT) of Whole Body Hyperthermia (WBH) vs. Sham for subjects with depressive symptoms at the Depression Clinical Research Program (DCRP) at Massachusetts General Hospital (MGH). 60 subjects with Major Depressive Disorder (MDD), males and females, between the ages of 18 and 65 years will be recruited and undergo a screening visit prior to being randomized to receive a single treatment of WBH or sham. The primary endpoint will be measurement of Interleukin-6 (IL-6) and other inflammation associated proteins (cytokines and heat shock proteins) in the plasma at one hour, 24h and one-week post WBH. A further endpoint is treatment response defined by a decrease of 50% or more in the Inventory of Depressive Symptomatology, Clinician-Rated (IDS-CR) score at 7 days post-intervention, 2 weeks post-intervention, and 4 weeks post-intervention.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Subjects are randomized to Control/Sham and Intervention groups
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Masking Description: Participant and clinician assessors will be blinded until study completion. The PI will only be unblinded in the event of an adverse event.
• Primary Purpose: Basic Science
• Official Title: Peripheral Neuroimmune Mechanisms of Hyperthermia
• Actual Study Start Date: November 1, 2022
• Estimated Primary Completion Date: June 2024
• Estimated Study Completion Date: June 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Whole Body Hyperthermia (WBH); A single treatment of Whole Body Hyperthermia will be administered using the Heckel Hyperthermia device. During this procedure, participants' core body temperature will be elevated to 38.5 degrees Celsius.	Device: WBH; Hyperthermia exposure using Heckel Hyperthermia Device; Other Name: Whole Body Hyperthermia
Sham Comparator: Sham; Under the sham condition, participants will enter the Heckel Hyperthermia device as in the active treatment condition, but will not receive the whole body hyperthermia treatment, and will instead only receive mild heating.	Device: Sham; Sham (mild heating) using Heckel Hyperthermia Device

Outcome Measures

Primary Outcome Measures :

1. Changes in serum levels of Interleukin-6 from baseline to post-treatment [ Time Frame: baseline (pre-intervention), one hour post-intervention, 24 hours post-intervention, one week post-intervention ]
   Changes in serum levels of Interleukin-6 from baseline to post-treatment, measured by immunoassay
2. Decreases in depressive severity, as measured by the Inventory of Depressive Symptomatology, Clinician-Rated (IDS-CR) [ Time Frame: baseline (pre-intervention), one week post-intervention, two weeks post-intervention, four weeks post-intervention ]

   The Inventory of Depressive Symptomatology is a valid and reliable 30-item measure that is designed to assess severity of depression. The questions focus on neurovegetative and other depressive symptoms experienced over the past seven days. Possible values range from 0 to 84, with lower scores indicating lower depressive severity. A decrease of 50% or more in the IDS-CR score is considered to be a positive response to treatment, while a final score of 11 or less is considered typical remission.

   Depressive severity will be measured at baseline and at three timepoints post-intervention using the IDS-CR.

3. Decreases in depressive severity, as measured by the Symptoms of Depression Questionnaire (SDQ) [ Time Frame: baseline (pre-intervention), 24 hours post-intervention, one week post-intervention, two weeks post-intervention, four weeks post-intervention ]
   The Symptoms of Depression Questionnaire (SDQ) assesses irritability, anger attacks, and anxiety symptoms together with the commonly considered symptoms of depression. Depressive severity will be measured at baseline and at four timepoints post-intervention using the SDQ. Possible values range from 44 to 264, with lower scores indicating lower depressive severity.

Secondary Outcome Measures :

1. Changes in mental and physical functioning, as measured by the Patient Rated Outcome Measure Information System, 29-Item (PROMIS-29) [ Time Frame: baseline (pre-intervention), one week post-intervention, two weeks post-intervention, four weeks post-intervention ]
   The PROMIS-29 is a short form assessment containing four items from each of seven domains (Depression, Anxiety, Physical Function, Pain Interference, Fatigue, Sleep Disturbance, and Ability to Participate in Social Roles and Activities) plus one pain intensity question (0-10 numeric rating scale). Possible values range from 4 to 20, with lower scores indicating better functioning.
2. Changes in mood, as measured by the Positive and Negative Affect Schedule (PANAS) [ Time Frame: baseline (pre-intervention), 24 hours post-intervention, one week post-intervention, two weeks post-intervention, four weeks post-intervention ]
   The Positive and Negative Affect Schedule (PANAS) is a self-report measure that is made up of two mood scales, one measuring positive affect and the other measuring negative affect. Number of items: 10-items measuring positive affect, 10-items measuring negative affect. Scoring is broken down into a positive affect score and a negative affect score; possible values range from 10 to 50, with higher positive scores indicating higher positive affect, and higher negative scores indicating higher negative affect.
3. Changes to quality of life, as measured by the World Health Organization Wellbeing Index (WHO-5) [ Time Frame: baseline (pre-intervention), one week post-intervention, two weeks post-intervention, four weeks post-intervention ]
   The World Health Organization-Five Well-Being Index (WHO-5) is a short self-reported measure of current mental wellbeing. Possible values range from 0 to 25, with lower scores indicating lower quality of life.
4. Changes to quality of life, as measured by the Quality of Life, Enjoyment, and Satisfaction Questionnaire [ Time Frame: baseline (pre-intervention), one week post-intervention, two weeks post-intervention, four weeks post-intervention ]
   The Quality of Life Enjoyment and Satisfaction Questionnaire is a self-report measure designed to enable investigators to easily obtain sensitive measures of the degree of enjoyment and satisfaction experienced by subjects in various areas of daily functioning. Possible values range from 14 to 70, with lower scores indicating lower quality of life.
5. Reduction in perceived stress, as measured by the Perceived Stress Scale (PSS) [ Time Frame: baseline (pre-intervention), one week post-intervention, two weeks post-intervention, four weeks post-intervention ]
   The Perceived Stress Scale (PSS) is the most widely used psychological instrument for measuring the perception of stress. It is a measure of the degree to which situations in one's life are appraised as stressful. Items were designed to tap how unpredictable, uncontrollable, and overloaded respondents find their lives. Possible values range from 0 to 40, with lower scores indicating lower levels of perceived stress.
6. Decreases in depressive severity, as measured by the Hamilton Depression Rating Scale 6-Item Self-Report (HAMD-6) [ Time Frame: baseline (pre-intervention), 24 hours post-intervention, one week post-intervention, two weeks post-intervention, four weeks post-intervention ]
   The Hamilton Depression Rating scale (self-report, 6-item) is specific to the core depressive symptoms of depressed mood, guilt, work and activities, psychomotor retardation, psychic anxiety, and general somatic symptoms (energy and physical pain), and it is unidimensional. Possible values range from 0 to 22, with lower scores indicating lower levels of depressive severity.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Females and Males ages 18-65
2. English language proficiency
3. Ability to provide informed consent
4. Have a current primary psychiatric diagnosis of major depressive disorder (MDD) of at least 4 weeks duration, as defined by Diagnostic & Statistical Manual, 5th Edition (DSM-5) criteria using the MINI.
5. Score of ≥ 24 on the Inventory of Depressive Symptomatology - Clinician Rated (IDS-CR)
6. Individuals of childbearing potential must use an acceptable form of birth control.

Exclusion Criteria:

1. Pregnancy or planned pregnancy during study
2. Current breastfeeding
3. History of psychiatric hospitalization within the past year
4. Active suicidal intent ("yes" on item 4 or 5 on the Columbia-Suicide Severity Rating Scale)
5. History of bipolar disorder, psychotic disorders, eating disorders, and/or substance abuse or dependence (within the last year), as per the Mini-International Neuropsychiatric Interview (MINI)
6. Meeting DSM-5 criteria at screening for current obsessive compulsive disorder
7. A ≥25% drop in IDS-CR score from screen (V1) to baseline (V1b)
8. Positive urine toxicology screen due to illicit drug use or other exclusionary medications. (Potential false positives will be addressed on a case-by-case basis at the discretion of the investigator)
9. Serious unstable medical condition including cardiovascular, neurological, neoplastic, autoimmune, infectious or endocrine.
10. Morbid obesity (BMI > 40) and/or body shape that might increase the risk of cutaneous burning from the Heckel hyperthermia device (because of truncal skin being too close to the infrared lights).
11. Any history of or current diagnosis of thrombosis or thrombophilia; if it is unclear whether a subject has received this diagnosis, a signed release will be obtained to contact the subject's treating physician and obtain accurate diagnostic information. Depending on the recommendation of the treating physician, the subject may undergo appropriate testing with the treating physician to verify the diagnosis, and if the tests produce negative findings, the subject may be allowed to enter the study
12. Has a history of or an increased risk for gastrointestinal perforation such as a history of diverticulitis, stomach or intestinal ulcers or abdominal pain that does not go away
13. Using medication that might impact thermoregulatory capacity within 3 days of receiving WBH treatment, including: diuretics, barbiturates, beta-blockers, antipsychotic agents, anti-cholinergic agents or chronic use of antihistamines, aspirin (other than low-dose for prophylactic purposes), non-steroidal anti-inflammatory drugs (NSAIDs), systemic corticosteroids, or cytokine antagonists.
14. Use of any medication that could interact in such a way as to potentiate the sedative effect of lorazepam or ondansetron, or otherwise deemed unsafe per physician judgment.
15. Fever (Temp > 99) of unknown origin at the time of screen
16. Breast Implants
17. Unsafe cardiac status as defined by abnormal ECG reading at screening visit as determined by medical monitor, study doctor, or subject's primary care physician or cardiologist
18. Claustrophobia of sufficient severity to interfere with ability to enter/remain in Heckel device
19. A subject who in the opinion of the Principal Investigator would not be able to safely complete the study or would jeopardize study integrity

Contacts and Locations

Contacts

Contact: Simmie Foster, MD PhD; 617-643-7427; sfoster4@partners.org

Contact: Maren Nyer, PhD; 617-643-4897; mnyer@mgh.harvard.edu

Locations

United States, Massachusetts

Massachusetts General Hospital Depression Clinical & Research Program; Recruiting

Boston, Massachusetts, United States, 02114

Contact: Study Coordinator 617-724-3222 mgh-wbh@partners.org

Principal Investigator: Simmie Foster, MD, PhD

Sponsors and Collaborators

Massachusetts General Hospital

National Institute of General Medical Sciences (NIGMS)

More Information

• Responsible Party: Simmie L. Foster, MD, Psychiatrist, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT05366270
• Other Study ID Numbers: 2019P001103; 5K23GM129630-03 ( U.S. NIH Grant/Contract )
• First Posted: May 9, 2022
• Last Update Posted: March 10, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by Simmie L. Foster, MD, Massachusetts General Hospital:

Depression; Major Depressive Disorder; Inflammation; Hyperthermia; Mood Disorders

Additional relevant MeSH terms:

Depressive Disorder; Depression; Depressive Disorder, Major; Inflammation; Hyperthermia; Fever; Pathologic Processes; Mood Disorders; Mental Disorders; Behavioral Symptoms; Body Temperature Changes; Heat Stress Disorders; Wounds and Injuries