Whole Body Hyperthermia (WBH) as a Rapid Treatment for Fibromyalgia

We will direct a clinical trial of Whole Body Hyperthermia (WBH) for the treatment
Fibromyalgia. Although we have not yet studied WBH for Fibromyalgia we have data indicating
that WBH is effective for the acute treatment of major depression (MDD). Given the high
overlap of symptoms between Fibromyalgia and Major Depressive Disorder (MDD), we have
reasons for expecting that WBH may also be of benefit for Fibromyalgia. The primary
objective of the proposed study is to determine if WBH produces improvement in core
Fibromyalgia symptoms, just as it appears to do in MDD. Indeed, in preliminary studies, a
single exposure to WBH resulted in a downward shift in body temperature (Figure 6) and a
decrease in depressive symptoms as measured using the Center for Epidemiologic Studies
Depression Scale (known as the ADS in Germany where this study was conducted) 5 days later
(Figure 7). In addition, following exclusion of one patient with bronchopulmonary
inflammation that did not show a decrease in body temperature following treatment, a
correlation between the shift in body temperature and ΔADS approached statistical
significance (Figure 9). These preliminary data are consistent with previous studies showing
that 1) patients with seasonal affective disorder in winter during depression have blunted
thermoregulatory cooling but have thermoregulatory cooling that is similar in efficiency to
control subjects after successful antidepressant response to phototherapy (the retina has
direct projections to DRVL serotonergic neurons), 2) ECT increases the circadian amplitude
of core body temperature, and decreases mean core body temperature, particularly during the
nighttime thermoregulatory cooling period, and 3) thermoregulatory cooling, as evidenced by
the number of active sweat glands in depressed patients, increases upon clinical recovery,
but not earlier, following ECT. We hypothesize that these relationships in preliminary data
and in previous studies are due to dysfunction of the afferent signaling arm of the
thermoregulatory system in MDD, specifically the warm afferent system projecting to the LPB
and, secondarily, to the DRVL/VLPAG and DRI subsets of serotonergic neurons that have been
implicated in anxiolytic and antidepressant actions, respectively, and to normalization of
warm afferent signaling following treatment. Again given the high degree of overlap between
Fibromyalgia and MDD, we expect that WBH may confer therapeutic benefits in Fibromyalgia as
it appears to do in MDD.

This clinical trial will only include individuals with Fibromyalgia (i.e. no normal
controls) in order to determine whether there is a significant effect of a single treatment
with WBH administered in an open manner on Fibromyalgia symptoms. Based on our data from
patients with MDD, we expect that if WBH has an effect on Fibromyalgia symptoms this will be
apparent immediately after the treatment and will persist for at least a week. Therefore we
will assess Fibromyalgia symptoms prior to and at 1 and 2 weeks following a single treatment
with WBH. To evaluate whether treatment effects are longer lasting we will also assess
symptoms two weeks following the WBH treatment.

Useful preliminary results were obtained from a pilot study comparing mildly to severely
depressed patients receiving hyperthermic treatment (N=11) to depressed patients receiving
psychotherapy as usual (N=3). Baseline scores on the German language ADS depression scale
were similar for the two groups (mean=30.64, sd=9.18, N=11, vs. mean =32.33, sd=17.04, N=3).
Raw change on the ADS was significantly greater for the hyperthermia group (mean=-11.91,
sd=6.55, N=11, vs. mean=-1.33, sd=4.51, N=3; t=2.60, df=12, P=0.023), resulting in a very
large standardized treatment difference (Cohen d) of 1.69 (95% CI=1.00 - 2.48). Percent
change was also significant (mean=-39.4, sd=18.9, N=11, vs. mean=-8.6, sd=17.0, N=3; t=2.54;
df=12, P=0.026), for a Cohen d of 1.66 (95% CI=0.93 - 2.39). The percentage of the
hyperthermia vs. psychotherapy group achieving a clinical response (>50% reduction from
baseline) was 27.3% vs. 0%, and the percentage achieving at least a partial response (>25%
improvement) was 81.8% vs. 33.3%.

These data suggest that our proposed sample size of 10 individuals with Fibromyalgia should
be sufficient to identify a potential therapeutic effect, assuming that such an effect would
be of similar magnitude to the effect seen in MDD. To obtain a cohort of 10 subjects with
complete baseline and post-treatment data we anticipate enrolling between 12 and 15
subjects.

Inclusion Criteria:

- Male or female aged 18-65.

- Able to understand the nature of the study and able to provide written informed
consent prior to conduct of any study procedures.

- A diagnosis Fibromyalgia based on a clinician's diagnosis.

- In the investigator's opinion, has met criteria for Fibromyalgia for at least 4 weeks
prior to signing consent.

- Able to communicate in English with study personnel.

- For women, must not be pregnant (per urine test)

Exclusion Criteria:

- Any of the following diagnoses, as identified by the psychiatric evaluation or study
assessments:

- A current DSM-IV-TR Axis I diagnosis of Dementia; or

- Any current DSM-IV-TR Axis II diagnosis (i.e. personality disorder) that would
suggest potential noncompliance with the protocol; or

- A lifetime history of Schizophrenia, Schizoaffective Disorder, or a Bipolar
Disorder Type 1; or

- A diagnosis claustrophobia severe enough that it would impair ability to be in
the Heckel HT3000 hyperthermia device

- A current (or within 12 months prior to the Screening visit) diagnosis of Anorexia
Nervosa or Bulimia Nervosa

- Subject has met DSM-IV criteria for Substance Abuse in the month prior to screening
visit

- A diagnosis of an anxiety or mood disorder that is considered by the investigator to
be of greater source of distress or functional impairment than the patient's
FIBROMYALGIA diagnosis. Subjects with comorbid anxiety and mood disorders not
excluded above and considered to be of secondary importance will be permitted in the
study.

- Participation in concurrent formal psychotherapy during the trial, or in the 2 weeks
prior to the screening visit.

- Subject has a medical condition or disorder that:

- Is unstable and clinically significant, or:

- Could interfere with the accurate assessment of safety or efficacy of treatment,
including:

- individuals who are using prescription drugs that may impair thermoregulatory
cooling, including diuretics, barbiturates, and beta-blockers, or
antihistamines,

- individuals with cardiovascular conditions or problems (uncontrolled
hypertension, congestive heart failure, or documented evidence of coronary
artery disease)

- individuals with chronic conditions/diseases associated with a reduced ability
initiate thermoregulatory cooling, including Parkinson's, multiple sclerosis,
central nervous system tumors, and diabetes with neuropathy,

- hemophiliacs/individuals prone to bleeding,

- individuals with a fever the day of study intervention (if so, they will be
rescheduled),

- individuals with hypersensitivity to heat,

- individuals with recent acute joint injury (i.e. arthritis),

- individuals with enclosed infections, be they dental, in joints, or in any other
tissues,

- Clinically significant, in the investigator's opinion, abnormal findings on screening
laboratory tests or physical exam.

- Use of any psychotropic medications for 2 weeks (8 weeks for fluoxetine) prior to
initiation of the study, with the exception of a stable dosage of benzodiazepine or
non-benzodiazepine hypnotic medications (e.g. zolpidem (Ambien), zaleplon (Sonata),
eszopiclone (Lunesta), lorazepam (Ativan), diazepam (Valium), clonazepam (Klonopin),
alprazolam (Xanax),

- Need for any non-protocol psychotropic medication once enrolled, with the exception
of benzodiazepine or non-benzodiazepine hypnotics used at a stable dosage.

- Women who are pregnant (HCG pregnancy test at screening, or lactating, or who plan to
become pregnant during the study.

- Current participation in any clinical trial that might impact results of this one,
which includes participation in another clinical trial, as well as drug trials with
agents that might affect mood or regulation of body temperature or core fibromyalgia
symptoms

- Reasonable likelihood for non-compliance with the protocol for any other reason, in
the opinion of the Investigator, prohibits enrollment of subject into the study.

- Obesity and overall size of subject. It will be up to the PI's discretion to consider
BMI, waist circumference, and body fat composition when determining eligibility and
safety of the individual.

- History of peripheral circulatory disease, for example peripheral vascular disease,
deep vein thrombosis (DVT), or lymphedema.

- History of a cerebral vascular accident

- History of stroke, epilepsy or cerebral aneurisms

- Cancer in the last five years, except for fully resected non-melanoma skin cancer.

- Diabetes mellitus types I or II.

- Any clinically significant autoimmune disease (compensated hypothyroidism allowed)