Patient-Partner Stress Management Effects on CFS Symptoms and Neuroimmune Process
Phase: NA
Conditions: Chronic Fatigue Syndrome
Sponsor: University of Miami

 
 
 
Patient-Partners Stress Management Effects of CFS Symptoms and 
Neuroimmune Processes 
 
NCT01650636 
 
04-23-2014 
 
 

to 9 month follow-up will be associated with greater reductions in the pro-inflammatory: anti-
inflammatory cytokine ratio and greater increases in the AM-PM salivary cortisol negative slope. 
AIM 3: To test whether reductions in total and specific CFS symptoms and neuorimmune 
process indicators in PP-T-CBSM are associated with greater improvements in patient/partner 
psychosocial functioning (decreased stress, depression and social disruption and increased 
social support). 
Hypoth 3.1 Patients/partners assigned to PP-T-CBSM will show greater reductions in stress, 
depression and social disruption, and greater increases in social support at 5- and 9-month 
follow-up compared to those assigned to T-HI. 
Hypoth 3.2 The magnitude of reductions in CFS symptoms and pro-inflammatory cytokines and 
increases in the AM-PM salivary cortisol slope from baseline to 9 month follow-up are associated 
with greater decreases in stress, depression and social disruption and greater increases in social 
support.  
 
Risk/benefits: The study involves very minimal risk associated with venipuncture and 
completiong psychosocial questionnaires. The potential benefits include learing techniques that 
can reduce stress and negative moods and improve the quality of life of chronic fatigue patients 
and their partners. 
 
4.2. * Research Background  
Provide background and previous studies supporting the study rationale.  Include a 
brief summary of existing knowledge relevant to the research.  Explain how the 
research may contribute to the advancement of knowledge.  
A. Background: 
1. Scope, Epidemiology, Etiology and Impact of CFS. According to the CDC (1) the overall 
prevalence of Chronic Fatigue Syndrome (CFS) in the U.S. is 235 per 100,000 persons (95% 
confidence interval, 142327 per 100,000 persons). Up to 80% of those affected are women (2). 
These individuals suffer from severe fatigue that impairs daily activity, diminishes quality of life 
for years and has no known cure (3). CFS symptoms bring about severe limitations in the 
lifestyle behaviors, and vocational activities of previously vital, productive and successful 
individuals (4). Symptoms include debilitating fatigue, low grade fever, lymph node pain and 
tenderness, pharyngitis, myalgias, arthralgias, cognitive difficulties and mood changes (5, 6, 7). 
Current medical treatments focus on symptom management (antidepressants, antifungals, 
antihistamines, antivirals, CNS depressants or stimulants, immunogobulins, anti-
inflammatories, anticonvulsants, macro-vitamin regimens) (8) but are not curative. Symptoms 
may emerge at unpredictable times, one of the features of CFS that makes it particularly 
stressful. CFS represents an economic burden for society (e.g., high rates of unemployment due 
to disability) and healthcare institutions (9). Hypothetical initiating events for CFS include 
infections, psychiatric trauma and exposure to toxins though etiology remains unknown (10). 
Many of the symptoms are inflammatory in nature and have prompted a theory of infection 
induced illness (11, 12) that presents with acute onset of illness, with systemic symptoms 
similar to influenza infection that do not subside (13). These observations have led to reports of 
associated microbial infection or reactivation of latent viral infections (11, 14, 15, 16). There is 
growing evidence that CFS patients reliably show abnormalities on several indices of immune 
functioning (e.g., elevated IgG, impaired natural killer cell activity, NKCA, 17), elevated levels 
of circulating cytokine peptides and/or mRNA (18), and abnormalities in the numbers and 
activation states of certain lymphocyte subpopulations (17, 19, 20, 21 – 25). Recent work in 
the U.S. isolating a gammaretrovirus virus (XMRV) in the etiologic pathway of CFS adds 
strength to the notion of a chronic immune system activation (26) though this XMRV finding has 
failed to replicate in a UK population study (27). 
2. Neuroimmune Model of CFS. CFS symptoms can be understood through a neuroimmune 
model elaborated by our group (28). CFS patients are hypothesized to have a Hypothalamic 
Pituitary Adrenal (HPA) axis dysregulation (13, 29, 30,31, 32) (which may be aggravated by 
stress), and altered Immunoregulation, which serve to maintain the symptom cluster of CFS 
such as fatigue, muscle pain, unrefreshing sleep and weakness. Patients may experience 
distress reactions that are secondary to these cytokine-induced flu-like symptoms (33). As CFS 
patients' ability to carry out activities of daily living decreases, anxiety, depression and 

irritability may increase (34). This distress cascade may further deplete energy resulting in 
additional decrements in attention and vigilance, thus worsening the fatigue symptoms. 
Distress reactions may further dysregulate the immune system since distress/depressive states 
are related to several pro-inflammatory cytokines possibly via alterations in HPA axis hormones 
such as cortisol (35,36). Because distress reactions appear to be a possible common 
denominator contributing to multiple abnormalities (fatigue, HPA axis alterations, immune 
dysfunction) characterizing this syndrome, we have reasoned that effective treatment would 
need to focus upon reduction of the patients' distress reactions in view of the interdependency 
among CFS symptom severity, psychological response processes, HPA functioning and the 
immune system. We propose to examine changes in these processes during a stress 
management intervention designed to modulate CFS patients’ distress responses (37, 38). 
3. Immune Dysregulation in CFS. Our model proposes that CFS involves an immunologic 
dysregulation (due to virus infection or unknown causes) characterized by chronic lymphocyte 
activation with elevated expression of lymphocyte activation markers, episodic increased 
expression of cytokines such as tumor necrosis factor (TNF)-a and b peptide and soluble 
receptor in serum/plasma, and mRNA in circulating lymphocytes, and associated decrements in 
cellular immune function, which may in turn, hamper anti-viral immunity and fail to eradicate 
viral infections thus promoting further immune activation (39, 28). We showed that CFS 
patients with the greatest fatigue severity and lowest vigor had lower NKCA and greater signs 
of lymphocyte activation (increased CD2+CD3+CD26+ T-cells). TNF-a and soluble TNF 
receptor-type I (sTNF-RI) were greater in the low NKCA group vs the normal NKCA group (40). 
Thus elevated pro-inflammatory cytokines such as TNF-a may accompany both decrements in 
antiviral immunity (via NKCA) and greater CFS symptom expression. TNF-a and b are primary 
modifiers of the inflammatory and immune reactivation in response to injury or infection, and 
are primarily produced by macrophages. Overproduction, inappropriate expression of TNF, and 
TNF injections have been associated with fever, slow-wave sleep induction and appetite 
suppression (41- 44), which may underlie the fatigue, lassitude and excessive sleepiness 
associated with CFS (45). We found that CFS patients show significantly elevated TNF- a and b 
levels compared to controls (20, 18). CFS symptoms may be part of a complex referred to as 
“sickness behavior” wherein fatigue, sleep disturbances, pain and other CFS-like symptoms are 
believed secondary to chronically elevated levels of pro-inflammatory cytokines (IL-1, IL-6, 
TNF) (46, 47). This pattern of increased pro-inflammatory cytokine production may be triggered 
by antigenic stimulation (e.g., viral infection) and maintained by stress/mood-related 
hypothalamic-pituiatry adrenal (HPA) axis alterations (e.g, flattened di-urnal secretion of 
glucocorticoids, and/or decreased glucocorticoid sensitivity in immune cells that produce pro-
inflammatory cytokines) (48). Sickness behavior symptoms and accompanying elevations in 
pro-inflammatory cytokines (e.g., TNF) are compatible with the symptom picture and cytokine 
patterns identified in CFS patients by our group (49).  
4. Stress and CFS symptom exacerbation. Given the neuroimmunologic association between 
HPA axis substances such as cortisol and pro-inflammatory cytokines (48), and our observation 
of altered cortisol di-urnal pattern and multiple CFS symptoms (32), it is plausible that stress-
induced exacerbations in CFS physical symptoms (50) are mediated by circulating cytokines. 
We showed that daily life event stress was associated with greater reports of symptom burden 
in persons with CFS and that stress effects were moderated by cognitive appraisals (more 
optimism, less frequent cognitive distortions), coping strategies (more active coping, planning 
and acceptance and less denial and disengagement), and social support (51). We next 
demonstrated prospectively that CFS patients who experienced the stress of Hurricane Andrew 
showed CFS exacerbations (compared to well-matched CFS patients sampled from adjacent 
counties not directly exposed to the hurricane (50). This included increased clinician-rated 
symptom relapses and increased severity and frequency of sleep disturbances, muscle 
weakness and fatigue after modest exercise; worse functional indicators such as work 
impairment and illness burden; and increased levels of circulating TNF-a. Greater perceived 
social support and an optimistic attitude (cognitive appraisal) were associated with less 
likelihood of a clinical relapse and lower reports of symptom burden. So, external stressors may 
exacerbate CFS symptoms and cognitive-behavioral-interpersonal factors such as cognitive 
appraisals, coping strategies and social support may moderate these stress effects.  
5, Behavioral Intervention in CFS. Meta-analyses find moderate effects for individual-based 
cognitive behavioral therapy (CBT) interventions focused on physical activity and deconditioning 

models in CFS, though drop-out rates range up to 42% (52). Group-based CBT combined with 
body awareness and exercise training has also been shown to be effective for CFS in recent 
work (53). In line with our stress model of CFS symptom exacerbation, our work has focused on 
testing group-based cognitive behavioral stress management (CBSM) intervention which is 
designed to reduce stress through relaxation, and depression by modifying participants' outlook 
and cognitive appraisals through CBT, teaching adaptive coping strategies and interpersonal 
skills such as assertiveness and anger management, and when conducted in a group format 
may also improve their perceptions of social support (54). Group-based CBSM improves mood 
and quality of life, modulates cortisol output, improves cellular immune functioning and 
decreases signs of herpesvirus reactivation among populations suffering from other 
immunomodulating illnesses or treatments (55- 60). Our conceptual model specifies the ways in 
which psychological distress, HPA axis functioning and immunologic abnormalities may act as 
mediators of stress-related exacerbation and/or maintenance of CFS physical symptoms (37). 
We hypothesize that CBSM affects symptoms through these mediators as well. Stress is 
experienced not only by the CFS patient but is likely to be also experienced by partners or 
family members who must make lifestyle adaptations to the patients illness—a well-established 
phenomenon in family members and caregivers of persons with chronic illness (61). Members of 
our team have argued for the importance of involving family members in psychosocial 
interventions for persons dealing with chronic illness (61). In prior work we showed that a 
patient-caregiver dual target psychosocial intervention improved depression and health 
symptoms in spinal cord injury patients when compared to either an inert control condition or a 
patient-focused intervention (62). We reasoned that a CBSM package—designed to reduce 
psychological stress (relaxation), alter cognitive appraisal aspects of CFS (via CBT), and teach 
interpersonal skills (assertiveness)—if taught simultaneously to CFS patients and their partners, 
may be effective in interrupting the biobehavioral mechanism maintaining or exacerbating some 
of the symptoms of CFS. This intervention may impact physical status and neuroimmune 
processes by way of stress/depression reduction, reduced social disruption, and improved social 
support. We propose that CBSM may affect CFS physical symptoms by first modulating a set of 
CBSM targets. Changes in these intervention targets are hypothesized to improve physical 
symptoms by improving psychosocial functioning and then reducing distress-related HPA axis 
dysregulation and modulating immune indicators.  
 
B. INNOVATION AND CONTRIBUTION 
Psychosocial Intervention Approach. Our work suggests that adding relaxation and interpersonal 
skills to CBT when done in groups (i.e., group-based CBSM) may improve multiple physical 
symptoms characterizing CFS (see preliminary studies). However, because of the nature of CFS, 
the debilitating and unpredictable course of the disease, it is difficult for participants to commit 
to clinic-based CBSM sessions. Of 365 individuals screened for a study of group-based CBSM, 
only 69 agreed to participate. Those who chose not to participate reported that they could not 
commit due to the fatigue burden as well as the unpredictability of their symptom flare-ups. We 
reasoned that modifying the delivery format of CBSM such that it can be accessed by even the 
least mobile CFS individuals might be a key innovation that addresses the special needs of this 
population. Accordingly we developed a Telephone-delivered CBSM (T-CBSM) protocol and 
demonstrated its efficacy in CFS (see Preliminary Studies section). Being a family member or 
partner of a person with a chronic illness affects both members of dyad and perpetuates stress 
and frustration, which may have exacerbating effects on CFS symptoms, which may occur 
through neuroimmune mechanisms (63). In prior work (see Prelim Studies section) we found 
that greater than 50% of our population of CFS patients is partnered and that partnered 
patients appeared to respond better to the T-CBSM protocol than unpartnered persons. We 
reasoned that a group-based T-CBSM intervention that actively incorporates the partner into 
group sessions as well as homework assignments would optimally reduce stress/distress and 
build social support for the patient, thus optimizing the effects of T-CBSM. However we were 
concerned that with multiple patient-partner dyads simultaneously involved on a conference call 
that it would be difficult for the group leader and members to discern who was speaking thus 
inviting confusion. We determined that the video-display of all dyads and the group leader 
would facilitate discussions. Thus, for the proposed work we will use a newly developed patient-
partner video-telephone delivered CBSM (PP-T-CBSM) intervention. Investigator Dr. Czaja, 
Director of the University of Miami Center on Aging, has demonstrated the feasibility and 

efficacy of videotelephone delivered patient-partner psychosocial support in the context of 
caregivers for patients with dementia (62). The proposed study is the first such trial in CFS and 
provides a model offering stress management skills in a videotelephone venue for chronic 
illness populations. 
 
Experimentally Elucidating Neuroimmune Mechanisms of CFS Symptoms- This is the first study 
to test a neuroimmune mechanism of CFS symptom changes in the context of a randomized 
trial using a videotelephone-based group CBSM intervention. The monitoring of changes in the 
di-urnal cycle of salivary cortisol secretion and a panel of pro- and anti-inflammatory cytokines 
in association with changes in CFS symptom frequency and severity before and after a stress 
management intervention will provide stronger evidence of a neuorimmune model of CFS than 
would be possible with a cross-sectional or longitudinal natural history study. Monitoring 
concomitant changes in stress/distress and psychosocial functioning in patient and partner will 
allow us to identify the contribution of cognitive, behavioral and interpersonal processes to 
neuroimmune and symptom changes so that future group-based interventions can be further 
refined. 
 
C. PRELIMINARY STUDIES SUPPORTING THIS STUDY 
Study 1. Effects Of Group-Based Cognitive Behavioral Stress Management in CFS 
The first intervention (1-U01 AI45940) study was designed to test the effects of group-based 
CBSM on stress, quality of life and symptoms in CFS. We hypothesized that participants 
randomized to CBSM would report improvements in perceived stress, mood, quality of life, and 
CFS symptoms from pre-post intervention (T1-T2) compared to those assigned to half a day 
psychoeducational (PE) seminar. Participants were mainly Caucasian women (76.8%) with a 
mean age of 45.9, high school diploma or greater (97%), on disability (44.5%), and a mean 
household income of $20,000-$30,000. They completed the Perceived Stress Scale (64), Profile 
of Mood States (POMS), Quality of Life Inventory (QOLI, 65), SF-36 health survey (66), and the 
Chronic Fatigue Immune Dysfunction Scale (CFIDS) at T1 and T2. We found a significant group 
x time interaction for PSS, POMS-total mood disturbance , QOLI , and SF-36 emotional 
wellbeing, such that those in CBSM showed greater T1 – T2 improvements than in PE. 
Significant CBSM effects were also found on CFS symptoms, including greater decreases in 
pain, sore throat severity , stomach pain , and frequency of unrefreshed sleep . 
Study 2. Neuroimmunologic Interactions and CFS Symptoms 
We next sought to identify neuroimmune associations that might explain CBSM effects on 
symptoms. We assessed CFS symptoms, HPA axis regulation (di-urnal salivary cortisol output), 
and circulating pro-inflammatory cytokines among 24 patients diagnosed with CFS. We 
observed symptoms such as un-refreshing sleep, unusual fatigue, muscle aches and pains, and 
general weakness in 92.8 – 100% of cases. Salivary cortisol collected across the di-urnal cycle 
(waking, 30 min post-waking, late afternoon and bed time, assayed by ELISA), for 2 days was 
used to represent HPA axis activity. Pro-inflammatory cytokines, interferon-alpha (IFN-a) and 
interleukin-1 (IL-1) in plasma were assayed by ELISA. The Cortisol Awakening Response (CAR) 
measured as the change between waking and 30 minutes post-waking was on average a 22% 
increase, which is lower than the normal value of 50 – 75% increase, but is in line with prior 
reports in CFS patients. Using established algorithms for analyzing salivary cortisol data (67), 
cortisol output was operationalized as: peak cortisol, average of the four waking cortisol 
measurements from each day (AVE), and area under the curve for the regression line fitted 
through raw cortisol values (AUR). Di-urnal cortisol regulation was indexed with: reactivity (RT) 
= total change in salivary cortisol during the observation period, slope of the regression line 
fitted through the data (SP), and area under the curve with respect to increase (AUCi). Greater 
levels of IL-1 were associated with lower cortisol output as indicated by lower AVE, and peak 
cortisol, and a less negative di-urnal cortisol slope as indicated by SP and RT. This suggested 
that poorer di-urnal regulation of cortisol was associated with greater circulating levels of pro-
inflammatory cytokines. We found that symptoms such as “feeling less pep” were associated 
with greater levels of IL-1 while greater fatigue in the past week and right now were associated 
with greater levels of IFN-a , another cytokine reflecting immune system activation. Lower 
cortisol output, reflected in AVE scores, was also associated with feeling more bushed, more 
fatigued, less vigor, less alert, and less energetic. A similar pattern of associations was found 
between these fatigue indicators and peak cortisol and AUR values. Poorer di-urnal cortisol 

regulation as indicated by lower negative slope (SP) values was associated with feeling less 
vigor, less alertness, less energetic, less clear-headed, poorer concentration due to fatigue, and 
feeling more worn-out, and more sluggish. Similar patterns were found in fatigue associations 
with other cortisol regulation indices (RT and AUCi). This pattern suggests that (1) CFS 
symptoms may be associated with greater levels of pro-inflammatory cytokines, and (2) these 
symptoms and cytokine levels were greater in cases with lower cortisol output and poorer di-
urnal regulation of cortisol. 
Study 3. Effects of a Telephone-Delivered CBSM Intervention in CFS  
Upon exit interviews from our first intervention study we learned that many patients found it 
difficult to attend structured CBSM groups at our site thus suggesting that we might be missing 
the population of CFS who are in greatest need of intervention. Because many CFS patients are 
not able to travel to and attend clinic-based groups we designed and tested a 10-session 
telephone-delivered CBSM (T-CBSM) program in a randomized controlled trial (NIH #1 R01 
NS055672-01). Because all of our prior CBSM studies had used a group-based intervention we 
decided to preserve the group format in the telephone delivery. To do so, we collaborated with 
the Dr. Sara Czaja, at the NIH-funded Center for Aging at the University of Miami Miller School 
of Medicine to adapt a teleconference system used for outreach and patient education and 
support in caregiver research. Since 1997, members of the proposed research team have been 
using the Computer-Telephone Integration System (CTIS) with caregivers of persons with 
dementia. Dr. Czaja, Senior Investigator in this application, has used the system with more 
than 150 persons caring for family members with dementia. This project was part of the 
Resources for Enhancing Alzheimer's Caregiver Health (REACH) study, a recently renewed five-
year multi-site project funded by the NIH (REACH-II). The investigators have demonstrated 
that the system is well accepted by caregivers and that it has a positive impact on patients and 
caregivers (62, 68).  
We adapted the CTIS by programming the phones with CBSM information (audio play back of 
all relaxation exercises, pull down screens for review of all CBSM module content, and speed 
dialing to group members, group leader and CFS Support organizations). The system presents 
text and voice recordings to the participants through the Analog Display Services Interface 
(ADSI) protocol and the system also has a conferencing feature to facilitate the group sessions 
and also allows for their monitoring. The phones were installed in the home, training was 
provided on site, and the phones were retrieved at the conclusion of the intervention. These 
phones recorded the total frequency and duration of usage of all features, allowing us to 
harvest information on dose of information consumed, all intra-group contacts, and access to 
support organizations. This system is very user-friendly and this telephone linkage allows 
participants to access information topics for both conditions 24-hours/day, 7-days/week. All 
participants may listen to the recorded information at their own pace. For example, participants 
in the T-CBSM may access the system to review information presented by the facilitator in the 
interactive group session. Those in the T-CBSM condition were provided the specially designed 
phone and connected to a once weekly, one hour CBSM conference call with up to 6 CFS 
patients and a clinically trained group leader, who led the group according to a 10- module 
manualized CBSM intervention protocol. The participant used the system to practice relaxation 
techniques presented in the session and/or listen to relaxation recordings (e.g., guided 
imagery, deep muscle relaxation scripts) at his or her leisure. Individuals assigned to the 
attention-matched control condition received 10 weekly sessions of health information (T-HI) 
delivered over a phone.  
Assessments were conducted pre-intervention and at 5 and 9-month follow-up. We found that 
adherence to the sessions was excellent (attendance rate > 90% on average). Using the 
recording system within the phones we measured in several cohorts, the frequency 
(times/month) and amount (minutes/month) of time participants have spent in reviewing and 
practicing pre-recorded audio-based intervention materials and techniques. Preliminary results 
indicate that modules receiving the greatest usage include relaxation, deep breathing, 
mindfulness meditation, and guided imagery as well as the following stress management 
modules: Anger Management, Stress Awareness, and Social Support. Results suggest that the 
T-CBSM program is well accepted by participants and they do engage the system outside of 
weekly telephone meetings. Of the first 70 cases enrolled in this trial 35 were assigned to T-
CBSM and 35 to T-HI. Patients (59 women, 11 men) had a mean age of 51.4 and were mostly 
non-Hispanic White or Hispanic. There were 44.3% of cases on disability, 14.3% unemployed 

and 28% worked full or part-time. The sample was middle class with 87.2% reporting a college 
education, 60% had an income > 30,000/yr. and 51% were partnered and 33% lived alone. At 
entry, over 95% reported unusual fatigue, unrefreshing sleep, or general weakness. The 
average frequency of CDC-based CFS symptoms was 3.3 times/wk. The Sickness Impact Profile 
(SIP) Recreational and Past-times and Social Interaction scales revealed that the majority of 
patients reported cutting back on social activities, hobbies, and spending time with other 
people. As in our pilot neuroimmune studies greater average severity of CDC-based symptoms 
was associated with greater IFN and TNF-a. 
Given the small sample size available for analyses of intervention effects the interim results will 
be expressed as paired t-tests within the T-CBSM and T-HI groups for the period from baseline 
to 5-month follow-up. For the primary outcome—CDC-based CFS symptoms—we found that 
patients assigned to T-CBSM showed significant declines in average symptom frequency 
compared to T-HI. Patients assigned to T-CBSM also showed greater reductions in diarrhea, 
muscle pain, unrefreshing sleep, sinus problems and general weakness (p’s = .02 - .08) 
compared to no changes in the T-HI group. Those in the T-HI condition also reported increases 
in joint pain and abdominal pain, which were not seen in the T-CBSM groups. Similarly the T-
CBSM patients showed decreases in SIP-Total Illness Burden Recreation and Pastimes compared 
with no similar change in the T-HI condition. In secondary analyses we observed changes in 
cytokine levels that mirrored these symptom findings. Here we found that those assigned to T-
CBSM showed decreases in pro-inflammatory cytokines, IL-1b and TNF-a and increases in the 
anti-inflammatory cytokine, IL-13, with no changes in T-HI. Greater decreases in TNF-a were 
associated with greater decreases in average CDC symptom severity over the pre-post 
intervention period. Greater TNF-x reductions also related to greater reduction in diarrhea, 
fatigue, muscle pain, joint pain, headache, and general weakness. Greater increases in the pitch 
of the negative AM-PM slope of salivary cortisol output (SP) were associated with greater 
decreases in TNF-a suggesting that a normalization of HPA axis function may relate to 
decreases in pro-inflammatory cytokines, which related to reduced CFS symptoms occurring 
during T-CBSM intervention.  
We also examined the relative effects of T-CBSM in partnered vs non-partnered patients. We 
found consistently larger magnitude of effects in the partnered group vs. the non-partnered 
group in CFS symptom frequency, plasma IL-1b, and fatigue symptoms and interference. 
Moreover we noted that partnered patients showed greater reductions in SIP interpersonal 
disruption scores and much greater increases in total, emotional and instrumental social 
support received on the Social Provisions Scale (SPS; 69). This suggests a synergy between the 
CBSM experience and the partner possibly due to: (a) partner support of the patient’s CBSM 
skill acquisition and practice, (b) informal transfer of CBSM skills to partner resulting in reduced 
partner stress and improved interpersonal skills leading to better ability to provide support to 
patient, or (c) some combination of these and other changes. This argues for formally including 
the partner in the CBSM process, including attending groups and joint patient-partner practicing 
of relaxation and cognitive-behavioral-interpersonal skill building assignments. Since all of our 
CBSM effects have been obtained in a group-based venue and due to the powerful effects of 
modeling that are likely operating, we reasoned that the next step was to develop and test the 
effects of a patient-partner dual focus group-based CBSM intervention. To optimize patient and 
partner engagement in the group we incorporated a state-of-the art teleconferencing system, 
making use of a videotelephone that we have been using successfully in patient-partner studies 
in the context of other chronic illnesses (68).  
 
Summary. The results of this study have major significance since they might offer an 
intervention approach that is efficacious in reaching a broader population of CFS patients who 
would not otherwise be able to benefit from these empirically supported techniques. This work 
is innovative in being the first RCT to test the effects of a patient-partner Telephone-delivered 
psychosocial intervention (PP-T-CBSM) for CFS patients while examining a neuroimmune 
mechanism (HPA axis-cytokine regulation) to explain the effects of this intervention on CFS 
symptoms.  
 

(only participants who live outside our catchment area) will be administered to screen for signs 
of gross intellectual impairment or attention problems that could threaten the validity of 
baseline and follow-up assessments. If participant is eligible an appointment will be made to 
proceed with the consent process and baseline interview instructions. During the face to face 
visit the interviewer will review and provide a copy of the consent form to both the CFS patient 
and their identified partner. Participants will be given time to carefully read the consent form 
and ask any questions about the study. If participants live outside our catchment area they will 
be sent an electronic copy of the consent forms. CFS patients and their partners will be 
contacted via telephone to review the consents and answer any questions pertaining to the 
study. If participants agree to participate they will be asked to sign the consent forms and send 
them to our office via email (pdf), fax or regular mail. Their consent date will be recorded in our 
records during the telephone call in which we review the consent and will later be reconfirmed 
by the signed hard copy. Once participants consent to participate in the study the participants 
will be provided with instructions on how to complete the baseline interview via Surveymonkey, 
a data collection program (please refer to section 4.4A). The core battery for the CFS patient 
will consist of the following focus areas: 1) Demographic information; 2) Lifestyle behaviors; 3) 
Physical factors related to CFS; 4) History of CFS; 5) Service utilization; 6) Perceived life 
stressors; 7) CFS symptoms; 8) Psychological functioning; 8) Social support; 9) Quality of 
patient-partner relationship; and 10) Changes in perceived CBSM skills. The core battery for the 
identified CFS partner will consist of demographic information, psychological functioning, social 
support, quality of patient-partner relationship, and changes in perceived CBSM skills. The time 
duration of the interviews is estimated to be 1-2 hours for the CFS participants and 30 minutes 
for the partner. Participants will be asked to complete a project evaluation questionnaire at the 
second (5 month) and third (9 month)interview and is estimated to take 15-20 minutes to 
complete. Participants (chronic fatigue patients only) will also be asked to collect four saliva 
samples on two consecutive days and provide us with a blood sample (about 2 ounces) at each 
measure point (baseline, about 5 month and about 9 month follow-ups). Chronic fatigued 
patients will be provided with a saliva kit and detailed instructions on how to collect the saliva 
and blood draw collection protocol (e.g. lab schedules and appointments and locations). For 
those participants who life outside our catchment area they will be sent a package via FedEx 
with instructions on how to collect the saliva samples and visit one of our contract labs near 
their area. Once they collect their samples they will send them to our lab processing center at 
the Papper Clinical Immunology Laboratory at the University of Miami (1600 NW 10 Avenue, 
Miami, Fl 33136). 
 
 
 
Intervention Protocol: 
After participants complete the interviews, and chronic fatigue patients complete the collection 
of saliva and blood, they will open an envelope that will advise them of the group they were 
randomly assigned to (PP-T-CBSM or T-HI). Participants who live outside our catchment area 
will be contacted to inform them of their randomization group. Randomization will occur in 
waves of eight, four dyads will be randomized to PP-T-CBSM and 4 to P-HI). Subjects 
randomized to PP-T-CBSM will receive 10 weeks of group intervention as described herein. A 
total of 4 dyads (CFS patient and their identified partner) will meet once weekly by videophone 
for approximately a one hour session at a mutually convenient set time. The content of the PP-
T-CBSM protocol will comprise two broad domains: Cognitive, behavioral and interpersonal 
skills training and relaxation/imagery. The Cognitive, Behavioral and Interpersonal skills 
component presents information concerning stressors and stress responses from a 
biopsychosocial perspective. The initial 5 weeks emphasize: (1) the importance of appraisals in 
the stress response and in symptom occurrence; (2) understanding automatic thoughts and 
cognitive distortions; (3) identifying and monitoring automatic thoughts; (4) disputing and 
restructuring cognitive distortions into more rational thoughts, and (5) learning adaptive 
problem-focused and emotion-focused coping skills. By monitoring automatic thoughts 
associated with negative emotions, participants increase their awareness of cognitive appraisals 
that precede changes in emotion. Stressors of primary importance in this study are those 
concerning the physical symptoms of CFS and the losses associated with the illness. Participants 
learn how automatic thoughts, including cognitive distortions may contribute to symptom 
magnification and ensuing feelings of loss of perceived control. The remaining 5 weeks focus on 

strategies to improve interpersonal communication, self-esteem, and quality of life, and to 
encourage appropriate emotional expression and assertion skills. During the sessions individual 
problems are addressed and homework is reviewed. Based on our experience, the combination 
of social support and self-reinforcement seems to increase participants’ use of these strategies 
and foster self-efficacy, self-esteem, and a sense of perceived personal control. The 
Relaxation/Imagery component includes targeting anxiety reduction through training in deep 
muscle relaxation. Participants use imagery of muscle groups rather than progressive muscle 
relaxation (tensing and relaxing muscle groups) because in our previous clinical work, we have 
found that tensing of muscle groups often increases joint and muscle pain-related symptoms 
that many CFS patients experience. In addition to reducing anxiety, relaxation training has 
been helpful for many of our participants in overcoming sleep problems associated with CFS. 
Autogenics, guided imagery, deep breathing and meditative techniques are taught in later 
weeks. We found that some members tend to learn and acquire skills better when presented in 
a didactic form while others may assimilate information better if it is introduced through images 
and metaphors. All sessions begin with a brief review of the previous meeting. The lively 
interactive format of our sessions enhances understanding and retention of the intervention 
materials through active participation. This multimodal/interactive approach should maximize 
the effectiveness of PP-T-CBSM in teaching stress reduction strategies simultaneously to 
patients and partners. Participants also receive a Participant Workbook, which contains a 
summary of the rationale for each module, outlines of each technique taught, and homework 
exercises and self-monitoring sheets to be completed by patient and partner. Finally, key points 
of all PP-T-CBSM strategies are available in text, audio and/or video form through pull-down 
screens in our Telecare system, which participants can access at any time. The video telephone 
is menu driven and has tri-modal output (text, speech, video).  
Subjects randomized to Telephone Health Information (T-HI) condition will receive 10 weeks of 
individual telephone sessions of approximately one hour. This control condition is designed to 
provide equal amounts of attention and contact time without any active treatment (CBSM) 
being given. T-HI is designed to control for common factors such as attention, supportiveness, 
empathy and enthusiasm. Social support processes (e.g., group cohesiveness) are an “active 
ingredient” in the T-CBSM intervention and social support changes will be tested as part of our 
hypothesized model. By providing T-HI in an individual format, we are controlling for 
facilitator’s time and attention, supportiveness, and empathy, but we retain the ability to test 
whether a supportive group intervention facilitates better quality of life and health outcomes. If 
we were to provide T-HI in a group format, we would be equalizing the groups on a factor that 
we are actually aiming to test. Moreover, once a group is assembled, it is very difficult to deter 
social processes as they may occur within the group or as part of ancillary group contact. The 
sessions cover the benefits of titrated physical and leisure activity, sleep, and proper nutrition 
(e.g., balanced diet, nutrition guidelines for adults), and the importance of receiving regular 
medical care and follow-up. Participants will be encouraged to ask questions and to discuss 
material at a personalized level to increase its relevance (e.g., asked to complete dietary log to 
increase awareness of eating habits; monitor physical activities; etc.). The material presented 
will be comprised of information that is commonly available and is designed to complement the 
ongoing medical care that participants receive from their medical treatment provider(s). Each 
session consists of a didactic presentation of the topics and activities to promote discussion. 
Patients report that they find the material to be useful. Participants will receive a Participant 
Workbook, which contains a summary of the information presented in each individual session 
and health resources. In addition, participants will be encouraged to inform their provider(s) 
about their study participation and to consult with provider(s) before initiating any health 
behavior changes (e.g., increasing physical activity). In addition to printed materials, 
participants will have access to system with recorded T-HI information. Usage of the system will 
be monitored as an indicator of dose. 
 
Treatment fidelity will be monitored by audio taping a random sample of the intervention 
sessions. Participants will be asked for their permission to be audio taped at the end of the 
consent form. If participants do not feel comfortable being audio taped this will not affect t their 
participation in the study. Those participants refusing to be audio taped will not be audio-taped 
at any point of the intervention. In addition audio tapes will be destroyed upon participant’s 
request.  

research study while incarcerated, the IRB Chairperson may determine that the 
subject may continue to participate in the research until the requirements of subpart 
C are satisfied. 
  
5.5. * What are the criteria for exclusion of participants from the research? 
Participants will be excluded from the study if: 
1. They do not have a current CDC case definition of having Chronic Fatigue Syndrome 
2. If they are under 21 years of age or over 75 years old. 
3. If they have a history of severe psychiatric disorders; DSM-IV diagnosis for panic attacks, 
substance dependency, psychoses or any expressed a current suicidal thoughts.  
4. If they do not identify a partner that will also agree to be part of the study. 
5. If they are unable to read, speak and write English (the program intervention is in English 
only) 
6. If they are receiving any treatment for a terminal condition or are diagnosed with Lyme's 
disease, Lupus, Rheumatoid arthritis, acute or chronic hepititis, HIV disease, or any other 
autoimmune disease. 
7. If they do not have internet capability (a broadband line). 
5.6. * Will any population be systematically excluded in this study? 
  
Yes 
No 
  
  
5.6.A. If yes, provide rationale/justification for this exclusion: 
 
 
  
5.7. * What are the criteria for inclusion of participants in the research? 
Participants are eligible to participate in the study if: 
1. Have a CDC diagnosis of Chronic Fatigue Syndrome. 
2. If they are 21 years or older and under 76 years old. 
3. They are fluent in English (the program intervention is only in English) 
4. Are able to identify a partner living together or separate and are willing to participate in the 
study for 9 months. 
5. Are willing to cooperate with the study's objectives and guidelines as reflected in the consent 
form. 
6. Have internet capability (broadband line) and are willing for us to install the study's 
equipment. 
5.8. * Will only one group of individuals be systematically selected and recruited for this 
study (e.g., welfare patients, racial and/or ethnic minorities, persons confined to 
institutions or persons determined to be incapacitated)? 
  
Yes 
No 
  
  
5.8.A. If yes, please state how this participant group will benefit from the results of 
the research and provide the reasons and justifications to target this group: 
Chronic fatigue syndrome patients and their identified partners. 
  
6. Subject Recruitment 

 
45 CFR 
46.117 
(c) (2) 
This research presents no more than minimal risk of harm to subjects 
and involves no procedures for which written consent is normally 
required outside of the research context. 
 
  
  
7.8.A. * Please state the justification for the criterion selected above: 
Potential participants will be asked for their permission to answer questions from a 
screening form to determine their eligibility in the study. 
  
7c. Informed Consent (cont'd) 
7.9. * Describe the specific steps for obtaining informed consent (e.g., by whom, his/her 
credentials, language, where, when, etc.): 
Not applicable 
Individuals who call our recruitment line or approach one of our staff member will be provided 
with information on the study. If the CFS person is interested in participating in the study, 
he/she will be asked for their verbal permission to proceed with a screening questionnaire that 
will determine their eligibility (please refer to preliminary screening uploaded in section 4.4A). 
If the CFS person is eligible she/he will be asked to indicate a convenient time and place to 
meet in order to proceed with the consent process and baseline interview of the CFS patient 
and their identified partner. Both CFS patient and their identified partner will be provided with 
thorough explanation of the study and consent process. If they agree to participate in the 
study the CFS and identified partner will be asked to sign the consent form and a copy will be 
provided for them to keep. The consent forms are written in simple language (non technical 
terms) and in English. 
 
Participants who live outside our catchment area will be sent an electronic copy of the consent 
form. CFS patients and their partners will be contacted via telephone to review the consents 
and answer any questions pertaining to the study. If participants agree to participate they will 
be asked to sign the consent forms and send them to our office via email (pdf), fax or regular 
mail. Their consent date will be recorded in our records during the telephone call in which we 
review the consent and will later be reconfirmed by the signed hard copy. 
7.10. Consent may be required from a parent, legal guardian, legal representative, court-
appointed representative, or health care surrogate where research involves 
children/minors, wards of the state, cognitively or developmentally impaired 
individuals, comatose or traumatized or emergency subjects, as well as any other 
subjects lacking capacity to consent. Such surrogate/representative/guardian can 
only consent if the IRB has approved the research under HHS or FDA regulations. For 
court-appointed guardians, court assent is required. 
If your study involves any of these groups, please specify below whether consent 
will be obtained from such surrogate/representative/guardian and describe the 
process for obtaining such consent: 
N/A 
7.11. * What protections will be offered to persons with cognitive impairment or to 
persons determined to be incapacitated?  Describe how capacity for consent will be 
determined, whether cognitive capacity is expected to change significantly during 
the study, whether a legally authorized representative or health surrogate  has been 
designated for purposes of obtaining informed consent, and whether court approval 

partner and dependent children own a total of $10,000 or 5% worth of equities in the sponsor, it 
should be reported below). 
"Conflicts of interest" apply to each investigator or other individuals listed as key personnel. Do not 
consider the combined ownership of all investigators/key personnel.  Do not consider compensation 
for the % effort on a study. 
 
15.1. * Does any person obtaining consent have any existing relationship (family, social, 
or professional, including physician-patient or student-teacher) with the 
subject(s)? 
  
Yes 
No 
  
  
15.1.A. If yes, describe the relationship(s) and how subjects will be protected 
against undue influence or coercion: 
 
 
  
15.2. * Will there be any programs, bonuses, rewards or other incentives that may be 
offered to this site and/or its faculty or staff by the sponsor or others for rapid 
enrollment?  
  
Yes 
No 
  
  
15.2.A. If yes, please describe: 
 
 
Note: Before accepting any awards, the IRB must be informed of the nature and value of these 
incentives. 
 
  
15.3. * Do any of the investigators or members of their immediate families receive from 
the sponsoring entity salaries, consulting fees, or other compensation for services 
that exceed $10,000 in any twelve month period? (Note: if the sponsoring entity is 
the full time employer of the investigator, co-investigator or key personnel (i.e. UM or JHS) 
then answer "No."   Do not consider compensation for the % effort on a study.") 
  
Yes 
No 
 
  
15.4. * Do any of the investigators or members of their immediate families serve as an 
officer, director, or as a member of any advisory board with the sponsoring entity? 
  
Yes 
No 
 
  
15.5. * Do any of the investigators or members of their immediate families have an 
equity interest that exceeds $10,000 in value or represents more than 5% 
ownership in the sponsoring entity? 
  
Yes 
No 
 
  

will be provided to the IRB upon the final formation and proposed operations of this 
Board. 
  
16.3. Has an external (non-UM or JHS) data safety monitor or board/committee been 
established to provide additional oversight or monitoring of this study for safety and 
adherence to the study protocol?  
  
Yes 
No 
  
  
16.3.A. If yes, describe the composition of the committee and how they will 
communicate findings to the IRB: