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Mild-Intensity Whole Body Hyperthermia (WBH) for Major Depressive Disorder (WBHforMDD)

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ClinicalTrials.gov Identifier: NCT03787290
Recruitment Status : Not yet recruiting
First Posted : December 25, 2018
Last Update Posted : December 25, 2018
Sponsor:
Collaborator:
heckel medizintechnik GmbH
Information provided by (Responsible Party):
David Mischoulon, MD, Massachusetts General Hospital

Brief Summary:
Overall, the objective of this pilot study is to utilize the IL-6 receptor antagonist tocilizumab to prospectively evaluate the role of IL-6 in the antidepressant and immunological effects of whole body hyperthermia (WBH). The study seeks to replicate findings thus far that WBH has an antidepressant effect by administering the intervention at two sites not involved in studies to date. Moreover, the current proposal may help the investigators better understand the role of IL-6 in the pathogenesis and treatment of depression which might point to novel immune-based interventions for Major Depressive Disorder (MDD). Finally, the current proposal holds promise for better understanding of a novel treatment for MDD, which is among the leading causes of health-related disability in the world.

Condition or disease Intervention/treatment Phase
Major Depressive Disorder Drug: Tocilizumab Drug: Placebo Device: Whole-Body Hyperthermia Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Intervention Model Description: Randomization will be conducted by randomly permuted blocks of 4 with separate randomization schedules for each site. The randomization schedule for each site will be created by a statistician who has no other role in the study data collection or analysis. The randomization schedules will be sent directly from the statistician to each site's Research Pharmacy which will maintain the list. Qualifying study subjects will be assigned the next sequential treatment assignment on the randomization schedule, in the order they are randomized. Participants will be randomized on a 1-to-1 allocation to one of two study arms: 1) tocilizumab followed by whole body hyperthermia (WBH); or 2) placebo followed by whole body hyperthermia (WBH). At the time of randomization, the study coordinator will contact the Research Pharmacy at the site to complete the coded treatment assignment described below.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: The randomization list maintained by the Research Pharmacies will contain the treatment assignment, along with a letter code (A or B) corresponding to the two treatment groups. During the study period and continuing until the major hypotheses have been tested and reported, the correspondence of letter-coded treatment assignment to actual treatment (tocilizumab or placebo) will be known only by pharmacy staff. The study principal investigators (PIs), study coordinators, clinicians conducting outcome assessments, and study statistician, as well as research assistants interacting with patients or entering study data and laboratory technicians performing/reporting biomarker assays, will have no access to any subject's treatment assignment. Only after the study statistician has completed and reported analyses by coded treatment assignment for the study aims articulated in this protocol will the correspondence between letter codes and actual treatment be revealed to study personnel.
Primary Purpose: Treatment
Official Title: Examining Immune-Based Mechanisms of Action for Mild-Intensity Whole Body Hyperthermia (WBH) in the Treatment of Major Depressive Disorder
Estimated Study Start Date : March 1, 2019
Estimated Primary Completion Date : February 1, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Fever
Drug Information available for: Tocilizumab

Arm Intervention/treatment
Experimental: Tocilizumab
Participants will receive tocilizumab followed by whole-body hyperthermia
Drug: Tocilizumab
participants will receive a single subcutaneous injection of tocilizumab (162 mg)

Device: Whole-Body Hyperthermia
subjects' core temperature will be increased to 38.5 degrees Celsius (typically 60-120 minutes) then they will begin a 60-minute cool-down phase
Other Name: Heckel HT3000

Active Comparator: Placebo
Participants will receive a placebo followed by whole-body hyperthermia
Drug: Placebo
participants will receive a single subcutaneous injection of saline
Other Name: Saline

Device: Whole-Body Hyperthermia
subjects' core temperature will be increased to 38.5 degrees Celsius (typically 60-120 minutes) then they will begin a 60-minute cool-down phase
Other Name: Heckel HT3000




Primary Outcome Measures :
  1. Inventory of Depressive Symptomatology Self-Report (IDS-SR) [ Time Frame: Week 0 (Visit 2) to Week 1 (visit 3) [approximately 7 days] ]
    The IDS-SR is a self-administered questionnaire assessing depressive severity. 30 questions focus on depressive symptoms experienced over the past 7 days. Each question is scored from 0-3, for a total minimum score of 0 and a total maximum score of 84 (appetite and weight items are split into two questions each, one for increase and one decrease, but counted once only, so there are effectively 28 items). Higher scores indicate more severe depression. Ranges correspond to depressive severity as follows: 0-13 = no or minimal depression; 14-25 = mild depression; 26-38 = moderate depression; 39-48 = severe depression; 49-84 = very severe depression. A decrease of 50% or more in the score is considered to be a response to treatment, while a final score of 11 or less is considered remission. Primary study outcomes will be between-group differences (tocilizumab vs. placebo) in total IDS-SR score change from Week 0 (Visit 2) to Week 1 (visit 3).



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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. Ability to provide informed consent for study participation.
  2. Males and females between the age of 18 and 65 years.
  3. Have a current primary psychiatric diagnosis of major depressive disorder (MDD) of at least 4 weeks duration, as defined by Diagnostic and Statistical Manual of the American Psychiatric Association-5th Edition (DSM-5) criteria using the Mini International Neuropsychiatric Interview (MINI) v.7.0.
  4. A Screening and Baseline visit Clinician-Administered Inventory of Depressive Symptomatology Questionnaire (IDS-C30) score ≥ 25.
  5. Screening visit high-sensitivity C-reactive protein (CRP) concentration ≤ 5 mg/L (based on evidence that cytokine antagonism has an independent antidepressant effect in depressed patients with elevated CRP above this cut-off).

Exclusion Criteria:

  1. Any of the following medical conditions:

    • cardiovascular disease (other than controlled hypertension)
    • seizure disorder, history of cerebrovascular accident (CVA) or other serious neurological condition (e.g., Parkinson's disease, multiple sclerosis, seizure disorder [except childhood febrile seizures], dementia or delirium)
    • presence or history of neoplasia (other than resected non-melanotic skin cancer)
    • endocrinopathies (diabetes mellitus types I and II, Cushing's disease, Addison's disease)
    • active autoimmune disease (e.g., rheumatoid arthritis, Hashimoto's thyroiditis, inflammatory bowel disease)
    • chronic infection (e.g., hepatitis B or C or human immunodeficiency virus [HIV] infection)
    • Any history 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.
    • Any history of recurrent or recurring Herpes Simplex Virus infection (HSV)
    • any active enclosed infection (e.g., dental abscess, joint infection)
    • hemophilia or other cause for excessive bleeding (e.g., platelet disorder)
    • fever (Temp > 99) of unknown origin at the time of screen
    • Laboratory evidence of undiagnosed hypothyroidism or any change in treatment for hypothyroidism in the 3 months prior to screening.
    • Significant electrocardiogram abnormalities
    • Plan to receive surgery or medical procedure during the study
  2. Any other medical condition that in the judgment of the PI would increase the risk of study participation or introduce excessive physiological variance into the study population
  3. Morbid obesity and/or body shape that might increase the risk of cutaneous burning from the Heckel HT3000 hyperthermia device (because of truncal skin being too close to the infrared lights defined as 3 inches or less)
  4. Breast implants (because these increase the risk of burning)
  5. Known hypersensitivity to hyperthermia and/or infrared exposure
  6. Evidence of sunburn at time of treatment intervention
  7. Use of any medication that might impact thermoregulatory capacity within 5 days of receiving whole body hyperthermia (WBH) treatment, including: stimulants, diuretics, barbiturates, beta-blockers, antipsychotic agents, anti-cholinergic agents or chronic use of antihistamines, aspirin (other than low-dose aspirin for prophylactic purposes), non-steroidal anti-inflammatory drugs (NSAIDs), systemic corticosteroids, cytokine antagonists
  8. Use of any other medication that in the judgment of the principal investigator (PI) would increase risk of study participation or introduce excessive variance into physiological or behavioral responses to WBH
  9. Breastfeeding or pregnant women, women intending to become pregnant within 6 months of the screening visit, or sexually-active women of child bearing potential who are not using a medical accepted means of contraception (defined as oral contraceptive pill or implant, condom, diaphragm, intrauterine device (IUD), status-post tubal ligation, or partner with vasectomy)
  10. Any of the following exclusionary conditions for treatment with tocilizumab:

    • Taking immunosuppressive drugs including but not limited to:

      • Disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate
      • Corticosteroids such as prednisone
      • Monoclonal antibodies such as anti-cluster of differentiation antigen-20 (CD20) monoclonal antibodies
    • Taking selective co-stimulation modulators
    • Regularly taking nonsteroid anti-inflammatory drugs (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors in the 24 hours prior to WBH treatment and/or biomarker assessment
    • Absolute neutrophil count (ANC) below 2000 per mm3 or a history of neutropenia
    • Platelet count below 100,000 per mm3 or a history of thrombocytopenia
    • Elevated alanine transaminase (ALT) or aspartate transaminase (AST) levels above 1.5 times the upper limit of normal (ULN)
    • Known hypersensitivity to tocilizumab or other ingredients in ACTEMRA
    • History of tuberculosis (TB), past exposure to TB, positive TB test result, residence or travel to areas of endemic TB or endemic mycoses within previous 6 months, meets TB risk factors after evaluation
    • History of having received the Bacillus Calmette-Guérin (BCG) vaccine
    • Has an underlying condition that may predispose them to infection (e.g., human immunodeficiency virus [HIV], autoimmune disorders, on chemotherapy, etc)
    • 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
    • History of demyelinating disorders such as multiple sclerosis or chronic inflammatory demyelinating polyneuropathy
    • Have received a live vaccination in the one month prior to the scheduled administration of tocilizumab
  11. A lifetime history of any Psychotic Disorder, bipolar I or II disorder, anorexia nervosa
  12. Meeting DSM-5 criteria at screening for current obsessive compulsive disorder or bulimia nervosa.
  13. Patients who have failed to respond during the course of their current major depressive episode to >4 adequate antidepressant trials, defined as six weeks or more of treatment with the Food and Drug Administration (FDA)-defined minimally effective dose, as assessed by the Antidepressant Treatment Response Questionnaire (ATRQ).
  14. A concurrent anxiety disorder (e.g., obsessive compulsive disorder, panic disorder, posttraumatic stress disorder) that appears to be an individual's primary clinical problem (with the result that depressive symptoms are judged to either result from this primary condition or to be secondary to it)
  15. A concurrent personality disorder (e.g., borderline personality disorder, narcissistic personality disorder, histrionic personality disorder) that appears to be an individual's primary clinical problem (with the result that depressive symptoms are judged to either result from this primary condition or to be secondary to it)
  16. Meets criteria for any substance use disorder in 3 months previous to screening (except for nicotine or caffeine use disorder)
  17. Lifetime history of antisocial personality disorder
  18. Use of antidepressant or other psychotropic medications (other than benzodiazepine or non-benzodiazepine sleeping aids, e.g., zolpidem at a stable dose for at least 4 weeks) within 4 weeks of screening (8 weeks for fluoxetine due to its extended half-life)
  19. Participation in ongoing psychotherapy unless it has been stable for at least 3 months and individual has not improved (i.e., still meets criteria for MDD per MINI)
  20. Commencement of any psychotropic or psychotherapeutic intervention between screening and study completion
  21. A score of 5 on the Columbia Suicide Rating Scale (C-SSRS), consistent with active suicidal ideation with specific plan and intent, or suicide attempt within 3 months of screening per self-report
  22. Claustrophobia of sufficient severity to interfere with ability to enter/remain in Heckel HT3000 device

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03787290


Contacts
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Contact: David Mischoulon, MD, PhD 617-72405198 dmischoulon@partners.org
Contact: Maren Nyer, PhD 617-643-4897 mnyer@partners.org

Sponsors and Collaborators
Massachusetts General Hospital
heckel medizintechnik GmbH

Publications:
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Responsible Party: David Mischoulon, MD, Professor, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT03787290     History of Changes
Other Study ID Numbers: 2018P000285
First Posted: December 25, 2018    Key Record Dates
Last Update Posted: December 25, 2018
Last Verified: December 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
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Disease
Depressive Disorder
Depression
Depressive Disorder, Major
Fever
Pathologic Processes
Mood Disorders
Mental Disorders
Behavioral Symptoms
Body Temperature Changes
Signs and Symptoms