<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03787290</url>
  </required_header>
  <id_info>
    <org_study_id>2020P002424</org_study_id>
    <nct_id>NCT03787290</nct_id>
  </id_info>
  <brief_title>Mild-Intensity Whole Body Hyperthermia (WBH) for Major Depressive Disorder</brief_title>
  <official_title>Examining Immune-Based Mechanisms of Action for Mild-Intensity Whole Body Hyperthermia (WBH) in the Treatment of Major Depressive Disorder</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>heckel medizintechnik GmbH</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Massachusetts General Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Overall, the objective of this pilot study is to utilize the IL-6 receptor antagonist&#xD;
      tocilizumab to prospectively evaluate the role of IL-6 in the antidepressant and&#xD;
      immunological effects of whole body hyperthermia (WBH). The study seeks to replicate findings&#xD;
      thus far that WBH has an antidepressant effect by administering the intervention at a site&#xD;
      not involved in studies to date. Moreover, the current proposal may help the investigators&#xD;
      better understand the role of IL-6 in the pathogenesis and treatment of depression which&#xD;
      might point to novel immune-based interventions for Major Depressive Disorder (MDD). Finally,&#xD;
      the current proposal holds promise for better understanding of a novel treatment for MDD,&#xD;
      which is among the leading causes of health-related disability in the world.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Major depressive disorder (MDD) is among the leading causes of overall global disease burden.&#xD;
      Much of this burden derives from the fact that currently available pharmacologic modalities&#xD;
      suffer from important shortcomings, including limited efficacy, delayed onset of action, and&#xD;
      significant side effects that impair quality of life and promote treatment non-adherence&#xD;
      and/or discontinuation. These factors provide ample incentive to continue the search for&#xD;
      novel antidepressant methodologies that might maximize the benefits of these newer treatment&#xD;
      modalities while minimizing their limitations. It is within this context that discoveries&#xD;
      regarding the use of whole body hyperthermia (WBH) are of significant potential clinical&#xD;
      relevance. The investigators' studies to date suggest that WBH produces a rapid and sustained&#xD;
      antidepressant response with an extremely favorable side effect profile in medically-healthy&#xD;
      patients with MDD. To follow up on evidence of the antidepressant effect of hyperthermia&#xD;
      observed in animal models, the investigators conducted an open trial of WBH in humans. In 16&#xD;
      medically-healthy adults with MDD, the investigators found that a single session of WBH&#xD;
      induced a rapid, robust and sustained reduction in depressive symptom scores (Hanusch et al.&#xD;
      2013). Thirteen of the study participants received no other pharmacologic or&#xD;
      psychotherapeutic intervention during the study period (pre-treatment and 5 days&#xD;
      post-treatment), whereas 3 participants were receiving a stable dose prior to treatment with&#xD;
      a selective serotonin reuptake inhibitor (SSRI) antidepressant (with no change in dosage&#xD;
      during the study period). Interestingly, when looked at separately, WBH appeared to have no&#xD;
      effect in these 3 individuals, and, in fact, worsened depressive symptoms in one of them.&#xD;
      These findings are consonant with animal data from the investigators' group demonstrating&#xD;
      that therapeutic doses of an SSRI (citalopram 20 mg/kg) obviated the antidepressant-like&#xD;
      effects of WBH (Hale et al. 2017).&#xD;
&#xD;
      The investigators' group followed-up positive findings from this initial open trial with a&#xD;
      randomized, double-blind, sham-controlled study of WBH. Confirming the investigators primary&#xD;
      study hypothesis, participants in the active WBH group showed significantly reduced Hamilton&#xD;
      Depression Rating Scale (HDRS) scores at one week post-treatment when compared to&#xD;
      participants in the sham group. A similar advantage for active WBH at one week post-treatment&#xD;
      was apparent based on self-reported Inventory of Depressive Symptomatology Self-Report&#xD;
      (IDS-SR) scores which indicated that active WBH separated from sham beginning on day 3&#xD;
      post-treatment. Contrary to the investigators' a priori hypothesis, the antidepressant effect&#xD;
      of active WBH remained apparent out to 6 weeks post treatment when compared to sham. Based on&#xD;
      HDRS scores, 60% (9 of 15) of the active WBH group met criteria for response and 40% (6 of&#xD;
      15) met criteria for remission during at least one post-intervention assessment, compared&#xD;
      with 7% (1 of 14) and 0% respectively for sham. Rates of adverse events were very low in both&#xD;
      WBH and sham groups, with no differences between groups, except for increased adverse events&#xD;
      at post-intervention week two in the sham group (Janssen et al. 2016).&#xD;
&#xD;
      With regards to the immunosuppressive effects of WBH, much of the investigators' prior work&#xD;
      has focused on the role of inflammation in the etiology and treatment of MDD. Given this, in&#xD;
      the investigators' initial randomized, sham-controlled, double-blind trial of WBH they&#xD;
      examined the impact of WBH on inflammatory cytokines (tumor necrosis factor [TNF],&#xD;
      interleukin (IL)-6, IL-1-beta). Based on extensive data from the investigators' group and&#xD;
      many others indicating that the cytokines TNF and IL-6 have depressogenic potential and are&#xD;
      elevated in MDD, the investigators sought to test the hypothesis that WBH would reduce plasma&#xD;
      concentrations of these cytokines and that these reductions would be associated with improved&#xD;
      mood. However, when compared to sham, WBH produced a striking acute increase in IL-6 that&#xD;
      resolved completely by one-week post-intervention, while having no acute or chronic effect on&#xD;
      TNF.&#xD;
&#xD;
      Because IL-6 can come from multiple cell types in the body, and may have more of a&#xD;
      pro-inflammatory vs. anti-inflammatory effect depending on whether it comes from immune cells&#xD;
      (pro-inflammatory) or other tissues (i.e. adipocytes, muscle fibers, skin cells)&#xD;
      (anti-inflammatory), the investigators measured plasma neopterin concentrations prior to, and&#xD;
      following, the study interventions and at post-intervention weeks 1 and 4 simultaneous with&#xD;
      the measurement of IL-6.&#xD;
&#xD;
      The investigators next explored whether acute changes in IL-6 and/or neopterin were&#xD;
      associated with the antidepressant effects of WBH. The investigators found that acute&#xD;
      increases in both IL-6 and neopterin in response to WBH were associated with reduced&#xD;
      self-reported depressive symptoms one week following the treatment. Smaller but similar&#xD;
      associations were observed between this immune signal and reductions in clinician-rated HDRS&#xD;
      scores at one-week post-treatment. Increased IL-6 and neopterin in response to WBH were also&#xD;
      associated with increased positive emotion from beginning to conclusion of the procedure.&#xD;
&#xD;
      Overall, the objective of this pilot study is to utilize the IL-6 receptor antagonist&#xD;
      tocilizumab to prospectively evaluate the role of IL-6 in the antidepressant and&#xD;
      immunological effects of WBH. The study will seek to replicate findings thus far that WBH has&#xD;
      an antidepressant effect by administering the intervention at a site not involved in studies&#xD;
      to date. Moreover, the current proposal may help the investigators better understand the role&#xD;
      of IL-6 in the pathogenesis and treatment of depression which might point to novel&#xD;
      immune-based interventions for MDD . Finally, the current proposal holds promise for better&#xD;
      understanding a novel treatment for MDD, which is among the leading causes of health-related&#xD;
      disability in the world.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">December 1, 2023</start_date>
  <completion_date type="Anticipated">March 1, 2025</completion_date>
  <primary_completion_date type="Anticipated">December 1, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Randomization will be conducted by randomly permuted blocks of 4. The randomization schedule will be created by a statistician who has no other role in the study data collection or analysis. The randomization schedule will be sent directly from the statistician to the 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 to complete the coded treatment assignment described below.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>The randomization list maintained by the Research Pharmacy 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 investigator (PI), 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.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Inventory of Depressive Symptomatology Self-Report (IDS-SR)</measure>
    <time_frame>Week 0 (Visit 2) to Week 1 (visit 3) [approximately 7 days]</time_frame>
    <description>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).</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">35</enrollment>
  <condition>Major Depressive Disorder</condition>
  <arm_group>
    <arm_group_label>Tocilizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive tocilizumab followed by whole-body hyperthermia</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants will receive a placebo followed by whole-body hyperthermia</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tocilizumab</intervention_name>
    <description>participants will receive a single subcutaneous injection of tocilizumab (162 mg)</description>
    <arm_group_label>Tocilizumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>participants will receive a single subcutaneous injection of saline</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Saline</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Whole-Body Hyperthermia</intervention_name>
    <description>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</description>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_label>Tocilizumab</arm_group_label>
    <other_name>Heckel HT3000</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Ability to provide informed consent for study participation.&#xD;
&#xD;
          2. Males and females between the age of 18 and 65 years.&#xD;
&#xD;
          3. Have a current primary psychiatric diagnosis of major depressive disorder (MDD) of at&#xD;
             least 4 weeks duration, as defined by DSM-5 criteria using the MINI v.7.0.&#xD;
&#xD;
          4. A Screening and Baseline visit Clinician-Administered Inventory of Depressive&#xD;
             Symptomatology Questionnaire (IDS-C30) score ≥ 25.&#xD;
&#xD;
          5. Screening visit high-sensitivity C-reactive protein (CRP) concentration ≤ 5 mg/L&#xD;
             (based on evidence that cytokine antagonism has an independent antidepressant effect&#xD;
             in depressed patients with elevated CRP above this cut-off).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any of the following medical conditions:&#xD;
&#xD;
               -  cardiovascular disease (other than controlled hypertension)&#xD;
&#xD;
               -  seizure disorder, history of cerebrovascular accident (CVA) or other serious&#xD;
                  neurological condition (e.g., Parkinson's disease, multiple sclerosis, seizure&#xD;
                  disorder [except childhood febrile seizures], dementia or delirium)&#xD;
&#xD;
               -  presence or history of neoplasia (other than resected non-melanotic skin cancer)&#xD;
&#xD;
               -  endocrinopathies (diabetes mellitus types I and II, Cushing's disease, Addison's&#xD;
                  disease)&#xD;
&#xD;
               -  active autoimmune disease (e.g., rheumatoid arthritis, Hashimoto's thyroiditis,&#xD;
                  inflammatory bowel disease)&#xD;
&#xD;
               -  chronic infection (e.g., hepatitis B or C or human immunodeficiency virus [HIV]&#xD;
                  infection)&#xD;
&#xD;
               -  acute kidney injury or Chronic Kidney Disease&#xD;
&#xD;
               -  any history of or current diagnosis of thrombosis or thrombophilia; if it is&#xD;
                  unclear whether a subject has received this diagnosis, a signed release will be&#xD;
                  obtained to contact the subject's treating physician and obtain accurate&#xD;
                  diagnostic information. Depending on the recommendation of the treating&#xD;
                  physician, the subject may undergo appropriate testing with the treating&#xD;
                  physician to verify the diagnosis, and if the tests produce negative findings,&#xD;
                  the subject may be allowed to enter the study.&#xD;
&#xD;
               -  any history of recurrent or recurring HSV (Herpes simplex)&#xD;
&#xD;
               -  any active enclosed infection (e.g., dental abscess, joint infection)&#xD;
&#xD;
               -  hemophilia or other cause for excessive bleeding (e.g., platelet disorder)&#xD;
&#xD;
               -  fever (Temp &gt; 99) of unknown origin at the time of screen&#xD;
&#xD;
               -  laboratory evidence of undiagnosed hypothyroidism or any change in treatment for&#xD;
                  hypothyroidism in the 3 months prior to screening.&#xD;
&#xD;
               -  significant electrocardiogram abnormalities&#xD;
&#xD;
               -  plan to receive surgery or medical procedure during the study&#xD;
&#xD;
               -  those with impaired sensation (e.g. diabetic polyneuropathy)&#xD;
&#xD;
               -  those with a deteriorated ability to express themselves&#xD;
&#xD;
               -  those in whom irradiating cold tissue, tissue badly supplied with blood or an&#xD;
                  area with low subcutaneous tissue (e.g. tibial border)&#xD;
&#xD;
          2. Any other medical condition that in the judgment of the PI would increase the risk of&#xD;
             study participation or introduce excessive physiological variance into the study&#xD;
             population&#xD;
&#xD;
          3. A positive score to C-SSRS items 4 or 5 is OR a suicide attempt in the past 12 months&#xD;
&#xD;
          4. Morbid obesity and/or body shape that might increase the risk of cutaneous burning&#xD;
             from the Heckel HT3000 hyperthermia device (because of truncal skin being too close to&#xD;
             the infrared lights defined as 3 inches or less)&#xD;
&#xD;
          5. Breast implants (because these increase the risk of burning)&#xD;
&#xD;
          6. Known hypersensitivity to hyperthermia and/or infrared exposure&#xD;
&#xD;
          7. Evidence of sunburn at time of treatment intervention&#xD;
&#xD;
          8. Use of any medication that might impact thermoregulatory capacity within 5 days of&#xD;
             receiving WBH treatment, including: stimulants, diuretics, barbiturates,&#xD;
             beta-blockers, antipsychotic agents, anti-cholinergic agents or chronic use of&#xD;
             antihistamines, aspirin (other than low-dose ASA for prophylactic purposes),&#xD;
             non-steroidal anti-inflammatory drugs (NSAIDs), systemic corticosteroids, cytokine&#xD;
             antagonists&#xD;
&#xD;
          9. Use of any other medication that in the judgment of the PI would increase risk of&#xD;
             study participation or introduce excessive variance into physiological or behavioral&#xD;
             responses to WBH&#xD;
&#xD;
         10. Breastfeeding or pregnant women, women intending to become pregnant within 6 months of&#xD;
             the screening visit, or sexually-active women of child bearing potential who are not&#xD;
             using a medical accepted means of contraception (defined as oral contraceptive pill or&#xD;
             implant, condom, diaphragm, IUD, status-post tubal ligation, or partner with&#xD;
             vasectomy)&#xD;
&#xD;
         11. Any of the following exclusionary conditions for treatment with tocilizumab:&#xD;
&#xD;
               -  Taking immunosuppressive drugs including but not limited to:&#xD;
&#xD;
                    -  Disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate&#xD;
&#xD;
                    -  Corticosteroids such as prednisone&#xD;
&#xD;
                    -  Monoclonal antibodies such as anti-CD20 monoclonal antibodies&#xD;
&#xD;
               -  Taking selective co-stimulation modulators&#xD;
&#xD;
               -  Regularly taking nonsteroid anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors&#xD;
                  in the 24 hours prior to WBH treatment and/or biomarker assessment&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) below 2000 per mm3 or a history of neutropenia&#xD;
&#xD;
               -  Platelet count below 100,000 per mm3 or a history of thrombocytopenia&#xD;
&#xD;
               -  Elevated ALT or AST levels above 1.5 times the upper limit of normal (ULN)&#xD;
&#xD;
               -  Known hypersensitivity to tocilizumab or other ingredients in ACTEMRA&#xD;
&#xD;
               -  History of tuberculosis (TB), past exposure to TB, positive TB test result,&#xD;
                  residence or travel to areas of endemic TB or endemic mycoses within previous 6&#xD;
                  months, meets TB risk factors after evaluation&#xD;
&#xD;
               -  History of having received the Bacillus Calmette-Guérin (BCG) vaccine&#xD;
&#xD;
               -  Has an underlying condition that may predispose them to infection (e.g., HIV,&#xD;
                  autoimmune disorders, on chemotherapy, etc)&#xD;
&#xD;
               -  Has a history of or an increased risk for gastrointestinal perforation such as a&#xD;
                  history of diverticulitis, stomach or intestinal ulcers or abdominal pain that&#xD;
                  does not go away&#xD;
&#xD;
               -  History of demyelinating disorders such as multiple sclerosis or chronic&#xD;
                  inflammatory demyelinating polyneuropathy&#xD;
&#xD;
               -  Have received a live vaccination in the one month prior to the scheduled&#xD;
                  administration of tocilizumab&#xD;
&#xD;
         12. A lifetime history of any Psychotic Disorder, bipolar I or II disorder, anorexia&#xD;
             nervosa&#xD;
&#xD;
         13. Meeting DSM-5 criteria at screening for current obsessive compulsive disorder or&#xD;
             bulimia nervosa.&#xD;
&#xD;
         14. Patients who have failed to respond during the course of their current major&#xD;
             depressive episode to &gt;4 adequate antidepressant trials, defined as six weeks or more&#xD;
             of treatment with the FDA-defined minimally effective dose, as assessed by the ATRQ.&#xD;
&#xD;
         15. A concurrent anxiety disorder (e.g., obsessive compulsive disorder, panic disorder,&#xD;
             posttraumatic stress disorder) that appears to be an individual's primary clinical&#xD;
             problem (with the result that depressive symptoms are judged to either result from&#xD;
             this primary condition or to be secondary to it)&#xD;
&#xD;
         16. A concurrent personality disorder (e.g., borderline personality disorder, narcissistic&#xD;
             personality disorder, histrionic personality disorder) that appears to be an&#xD;
             individual's primary clinical problem (with the result that depressive symptoms are&#xD;
             judged to either result from this primary condition or to be secondary to it)&#xD;
&#xD;
         17. Meets criteria for any substance use disorder in 3 months previous to screening&#xD;
             (except for nicotine or caffeine use disorder)&#xD;
&#xD;
         18. Lifetime history of antisocial personality disorder&#xD;
&#xD;
         19. Use of antidepressant or other psychotropic medications (other than benzodiazepine or&#xD;
             non-benzodiazepine sleeping aids, e.g., zolpidem at a stable dose for at least 4&#xD;
             weeks) within 4 weeks of screening (8 weeks for fluoxetine due to its extended&#xD;
             half-life)&#xD;
&#xD;
         20. Participation in ongoing psychotherapy unless it has been stable for at least 3 months&#xD;
             and individual has not improved (i.e., still meets criteria for MDD per MINI)&#xD;
&#xD;
         21. Commencement of any psychotropic or psychotherapeutic intervention between screening&#xD;
             and study completion&#xD;
&#xD;
         22. A score of 4 or 5 on the Columbia Suicide Rating Scale (C-SSRS), consistent with&#xD;
             active suicidal ideation with specific plan and intent, or suicide attempt within 12&#xD;
             months of screening per self-report&#xD;
&#xD;
         23. Claustrophobia of sufficient severity to interfere with ability to enter/remain in&#xD;
             Heckel HT3000 device&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>David Mischoulon, MD, PhD</last_name>
    <phone>617-724-5198</phone>
    <email>dmischoulon@partners.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Maren Nyer, PhD</last_name>
    <phone>617-643-4897</phone>
    <email>mnyer@partners.org</email>
  </overall_contact_backup>
  <reference>
    <citation>Janssen CW, Lowry CA, Mehl MR, Allen JJ, Kelly KL, Gartner DE, Medrano A, Begay TK, Rentscher K, White JJ, Fridman A, Roberts LJ, Robbins ML, Hanusch KU, Cole SP, Raison CL. Whole-Body Hyperthermia for the Treatment of Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2016 Aug 1;73(8):789-95. doi: 10.1001/jamapsychiatry.2016.1031. Erratum In: JAMA Psychiatry. 2016 Aug 1;73(8):878.</citation>
    <PMID>27172277</PMID>
  </reference>
  <reference>
    <citation>Hanusch KU, Janssen CH, Billheimer D, Jenkins I, Spurgeon E, Lowry CA, Raison CL. Whole-body hyperthermia for the treatment of major depression: associations with thermoregulatory cooling. Am J Psychiatry. 2013 Jul;170(7):802-4. doi: 10.1176/appi.ajp.2013.12111395. No abstract available.</citation>
    <PMID>23820835</PMID>
  </reference>
  <reference>
    <citation>Hale MW, Lukkes JL, Dady KF, Kelly KJ, Paul ED, Smith DG, Raison CL, Lowry CA. Whole-body hyperthermia and a subthreshold dose of citalopram act synergistically to induce antidepressant-like behavioral responses in adolescent rats. Prog Neuropsychopharmacol Biol Psychiatry. 2017 Oct 3;79(Pt B):162-168. doi: 10.1016/j.pnpbp.2017.06.006. Epub 2017 Jun 12.</citation>
    <PMID>28619470</PMID>
  </reference>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>October 27, 2018</study_first_submitted>
  <study_first_submitted_qc>December 22, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 26, 2018</study_first_posted>
  <last_update_submitted>March 6, 2023</last_update_submitted>
  <last_update_submitted_qc>March 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 7, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>David Mischoulon, MD, PhD</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>hyperthermia</keyword>
  <keyword>whole-body hyperthermia</keyword>
  <keyword>depression</keyword>
  <keyword>major depressive disorder</keyword>
  <keyword>cytokine</keyword>
  <keyword>inflammation</keyword>
  <keyword>immunological</keyword>
  <keyword>mechanism of action</keyword>
  <keyword>tocilizumab</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hyperthermia</mesh_term>
    <mesh_term>Fever</mesh_term>
    <mesh_term>Depressive Disorder</mesh_term>
    <mesh_term>Depression</mesh_term>
    <mesh_term>Depressive Disorder, Major</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03787290
org study id: 2020P002424
nct id: NCT03787290
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: Yes
is us export: No
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 a site
      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.
Major depressive disorder (MDD) is among the leading causes of overall global disease burden.
      Much of this burden derives from the fact that currently available pharmacologic modalities
      suffer from important shortcomings, including limited efficacy, delayed onset of action, and
      significant side effects that impair quality of life and promote treatment non-adherence
      and/or discontinuation. These factors provide ample incentive to continue the search for
      novel antidepressant methodologies that might maximize the benefits of these newer treatment
      modalities while minimizing their limitations. It is within this context that discoveries
      regarding the use of whole body hyperthermia (WBH) are of significant potential clinical
      relevance. The investigators' studies to date suggest that WBH produces a rapid and sustained
      antidepressant response with an extremely favorable side effect profile in medically-healthy
      patients with MDD. To follow up on evidence of the antidepressant effect of hyperthermia
      observed in animal models, the investigators conducted an open trial of WBH in humans. In 16
      medically-healthy adults with MDD, the investigators found that a single session of WBH
      induced a rapid, robust and sustained reduction in depressive symptom scores (Hanusch et al.
      2013). Thirteen of the study participants received no other pharmacologic or
      psychotherapeutic intervention during the study period (pre-treatment and 5 days
      post-treatment), whereas 3 participants were receiving a stable dose prior to treatment with
      a selective serotonin reuptake inhibitor (SSRI) antidepressant (with no change in dosage
      during the study period). Interestingly, when looked at separately, WBH appeared to have no
      effect in these 3 individuals, and, in fact, worsened depressive symptoms in one of them.
      These findings are consonant with animal data from the investigators' group demonstrating
      that therapeutic doses of an SSRI (citalopram 20 mg/kg) obviated the antidepressant-like
      effects of WBH (Hale et al. 2017).

      The investigators' group followed-up positive findings from this initial open trial with a
      randomized, double-blind, sham-controlled study of WBH. Confirming the investigators primary
      study hypothesis, participants in the active WBH group showed significantly reduced Hamilton
      Depression Rating Scale (HDRS) scores at one week post-treatment when compared to
      participants in the sham group. A similar advantage for active WBH at one week post-treatment
      was apparent based on self-reported Inventory of Depressive Symptomatology Self-Report
      (IDS-SR) scores which indicated that active WBH separated from sham beginning on day 3
      post-treatment. Contrary to the investigators' a priori hypothesis, the antidepressant effect
      of active WBH remained apparent out to 6 weeks post treatment when compared to sham. Based on
      HDRS scores, 60% (9 of 15) of the active WBH group met criteria for response and 40% (6 of
      15) met criteria for remission during at least one post-intervention assessment, compared
      with 7% (1 of 14) and 0% respectively for sham. Rates of adverse events were very low in both
      WBH and sham groups, with no differences between groups, except for increased adverse events
      at post-intervention week two in the sham group (Janssen et al. 2016).

      With regards to the immunosuppressive effects of WBH, much of the investigators' prior work
      has focused on the role of inflammation in the etiology and treatment of MDD. Given this, in
      the investigators' initial randomized, sham-controlled, double-blind trial of WBH they
      examined the impact of WBH on inflammatory cytokines (tumor necrosis factor [TNF],
      interleukin (IL)-6, IL-1-beta). Based on extensive data from the investigators' group and
      many others indicating that the cytokines TNF and IL-6 have depressogenic potential and are
      elevated in MDD, the investigators sought to test the hypothesis that WBH would reduce plasma
      concentrations of these cytokines and that these reductions would be associated with improved
      mood. However, when compared to sham, WBH produced a striking acute increase in IL-6 that
      resolved completely by one-week post-intervention, while having no acute or chronic effect on
      TNF.

      Because IL-6 can come from multiple cell types in the body, and may have more of a
      pro-inflammatory vs. anti-inflammatory effect depending on whether it comes from immune cells
      (pro-inflammatory) or other tissues (i.e. adipocytes, muscle fibers, skin cells)
      (anti-inflammatory), the investigators measured plasma neopterin concentrations prior to, and
      following, the study interventions and at post-intervention weeks 1 and 4 simultaneous with
      the measurement of IL-6.

      The investigators next explored whether acute changes in IL-6 and/or neopterin were
      associated with the antidepressant effects of WBH. The investigators found that acute
      increases in both IL-6 and neopterin in response to WBH were associated with reduced
      self-reported depressive symptoms one week following the treatment. Smaller but similar
      associations were observed between this immune signal and reductions in clinician-rated HDRS
      scores at one-week post-treatment. Increased IL-6 and neopterin in response to WBH were also
      associated with increased positive emotion from beginning to conclusion of the procedure.

      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 WBH. The study will seek to replicate findings thus far that WBH has
      an antidepressant effect by administering the intervention at a site 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 MDD . Finally, the current proposal holds promise for better
      understanding a novel treatment for MDD, which is among the leading causes of health-related
      disability in the world.
allocation: Randomized
intervention model: Single Group Assignment
intervention model description: Randomization will be conducted by randomly permuted blocks of 4. The randomization schedule will be created by a statistician who has no other role in the study data collection or analysis. The randomization schedule will be sent directly from the statistician to the 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 to complete the coded treatment assignment described below.
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: The randomization list maintained by the Research Pharmacy 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 investigator (PI), 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.
measure: Inventory of Depressive Symptomatology Self-Report (IDS-SR)
time frame: Week 0 (Visit 2) to Week 1 (visit 3) [approximately 7 days]
description: 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).
arm group label: Tocilizumab
arm group type: Experimental
description: Participants will receive tocilizumab followed by whole-body hyperthermia
arm group label: Placebo
arm group type: Active Comparator
description: Participants will receive a placebo followed by whole-body hyperthermia
intervention type: Drug
intervention name: Tocilizumab
description: participants will receive a single subcutaneous injection of tocilizumab (162 mg)
arm group label: Tocilizumab
intervention type: Drug
intervention name: Placebo
description: participants will receive a single subcutaneous injection of saline
arm group label: Placebo
other name: Saline
intervention type: Device
intervention name: Whole-Body Hyperthermia
description: 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
arm group label: Placebo
arm group label: Tocilizumab
other name: Heckel HT3000
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: David Mischoulon, MD, PhD
phone: 617-724-5198
email: dmischoulon@partners.org
last name: Maren Nyer, PhD
phone: 617-643-4897
email: mnyer@partners.org
citation: Janssen CW, Lowry CA, Mehl MR, Allen JJ, Kelly KL, Gartner DE, Medrano A, Begay TK, Rentscher K, White JJ, Fridman A, Roberts LJ, Robbins ML, Hanusch KU, Cole SP, Raison CL. Whole-Body Hyperthermia for the Treatment of Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2016 Aug 1;73(8):789-95. doi: 10.1001/jamapsychiatry.2016.1031. Erratum In: JAMA Psychiatry. 2016 Aug 1;73(8):878.
PMID: 27172277
citation: Hanusch KU, Janssen CH, Billheimer D, Jenkins I, Spurgeon E, Lowry CA, Raison CL. Whole-body hyperthermia for the treatment of major depression: associations with thermoregulatory cooling. Am J Psychiatry. 2013 Jul;170(7):802-4. doi: 10.1176/appi.ajp.2013.12111395. No abstract available.
PMID: 23820835
citation: Hale MW, Lukkes JL, Dady KF, Kelly KJ, Paul ED, Smith DG, Raison CL, Lowry CA. Whole-body hyperthermia and a subthreshold dose of citalopram act synergistically to induce antidepressant-like behavioral responses in adolescent rats. Prog Neuropsychopharmacol Biol Psychiatry. 2017 Oct 3;79(Pt B):162-168. doi: 10.1016/j.pnpbp.2017.06.006. Epub 2017 Jun 12.
PMID: 28619470
responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: David Mischoulon, MD, PhD
investigator title: Professor
mesh term: Hyperthermia
mesh term: Fever
mesh term: Depressive Disorder
mesh term: Depression
mesh term: Depressive Disorder, Major