Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) Syndromes: A Mixed-methods Feasibility Study
Phase: NA
Conditions: Ehlers-Danlos Syndrome, Hypermobile EDS (hEDS), Hypermobility Syndrome, EDS
Sponsor: National University of Natural Medicine

  
 
Template Version 02.02.17 
Protocol  
Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) 
syndromes: A mixed-methods feasibility study (IMforHSDandEDS)  
PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
Version: 3.0 
1 
 
PROTOCOL 
 
Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos 
(EDS) syndromes: A mixed-methods feasibility study 
 
Principal Investigator:  
Douglas Hanes, PhD 
National University of Natural Medicine  
Helfgott Research Institute  
2220 SW 1st Ave 
Portland, OR 97201 
 
Clinical Investigator:  
Kerry Schaefer, MD 
Healthy Living Community 
3605 SE 26th Ave 
Portland, OR 97202 
 
Co-Investigator:  
Andrew Erlandsen, ND 
National University of Natural Medicine  
Helfgott Research Institute  
2220 SW 1st Ave 
Portland, OR 97201 
 
Staff:  
Sara Guedry  
Student Researcher 
National University of Natural Medicine 
Helfgott Research Institute  
2220 SW 1st Ave 
Portland, OR 97201 
 
Sponsor:  
Healthy Living Community 
3605 SE 26th Ave 
Portland, OR 97202 

  
 
Template Version 02.02.17 
Protocol  
Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) 
syndromes: A mixed-methods feasibility study (IMforHSDandEDS)  
PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
Version: 3.0 
2 
(971) 231-4536 
 
IRB #:  
 
Version #: 1.0 
 
Initial Document Approval Date:  
 
Research Sites: 
 
National University of Natural Medicine  
Helfgott Research Institute  
2220 SW 1st Ave 
Portland, OR 97201 
 
Healthy Living Community 
 
3605 SE 26th Ave 
Portland, OR 97202 
 
A. ABSTRACT 
 
Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos syndromes (EDS) are debilitating conditions 
of the connective tissue that manifest in musculoskeletal complaints, joint dislocations or instability, skin 
and soft tissue anomalies, chronic pain, fatigue, GI disorders, headaches, blood pressure dysregulation, 
and have a negative impact on the psychosocial lives of many patients that suffer from the disorders. No 
unique genetic origin for HSD has been identified. However, among Ehlers-Danlos syndromes (EDS),  the 
most common form of hypermobility, are 13 subtypes that are identifiable by their molecular defects.1 
Individuals afflicted with Hypermobility Spectrum Disorder (HSD) or Ehlers-Danlos syndromes (EDS) 
frequently remain undiagnosed for a significant length of time due to the variable symptoms of the 
disorder that overlap with other medical conditions. Treatments for HSD and EDS are inconsistent and 
lack a solid evidence base; in particular, the literature does not support the efficacy of physical 
rehabilitation.2 While HSD and EDS are not curable, current strategies for managing the disorders 
commonly include a combination of physical, supportive, and behavioral therapies (such as education 
and coping strategies for managing the condition) in addition to pain killers.3 There are no large studies 
on holistic care among patients living with HSD or EDS, nor is there any research on dietary intake and 
its impact on the disorder. 
 
The overall purpose of this study is to assess the feasibility of conducting a 9-week integrative medicine 
program that is comprised of a prescribed anti-inflammatory (Mediterranean) diet, as well as general 
behavioral and psychosocial support among patients with Hypermobility Spectrum Disorder (HSD) or 

  
 
Template Version 02.02.17 
Protocol  
Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) 
syndromes: A mixed-methods feasibility study (IMforHSDandEDS)  
PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
Version: 3.0 
3 
Ehlers-Danlos syndromes (EDS), in order to determine the recruitment potential in this population and 
to measure the ability of individuals to complete the program. Participants will be prescribed a food 
plan, and adherence to and feasibility of the food plan will be measured through participant food 
tracking and a subjective assessment of the food plan in a brief satisfaction survey. This study aims to 
recruit 20 patients with HSD or EDS and make preliminary observations regarding the effects of 
integrative medical care on pain reduction and improved quality of life. Participants will be given a 1-
week lead-in to track their general diet prior to starting their prescribed food plan, and associations will 
be recorded between symptom severity and diet as an exploratory analysis. Patient assessment of 
chronic illness care and living with a chronic illness will also be captured; to assess the experiences of 
patients with HSD or EDS, as well as their perceptions of previous medical care and patient-centered 
medicine, and any changes in these attitudes over the course of 9 weeks. Available studies assessing 
treatments for HSD or EDS provide insufficient evidence for treatment options; this project studies a 
novel intervention focused on nutrition and self-management counseling, developed in conjunction with 
a qualified physician, and would allow us to gain valuable information regarding the feasibility of 
employing the intervention as well as preliminary data on its effect on health outcomes. 
 
B. SPECIFIC AIMS  
 
B.1 Primary Aim: To investigate the feasibility of a 9-week integrative medicine intervention, as 
assessed by recruitment and retention in patients with Hypermobility Spectrum Disorder (HSD) or 
Ehlers-Danlos syndromes (EDS).  
• 
Outcome Measures 1: The recruitment rate will be assessed as the number of participants 
enrolled per month, over the duration of open recruitment. Our goal is to recruit 20 participants 
within a span of 4 months. Retention rate will be determined as the proportion of participants 
completing the mid-study or end-of-study visits, with a goal of 75% retention for each study 
visit.   
 
B.2 Secondary Aim: To evaluate the feasibility of and adherence to a prescribed food plan as well as the 
feasibility of food tracking as a part of a 9-week integrative medicine intervention in patients with 
Hypermobility Spectrum Disorder (HSD) or Ehlers-Danlos syndromes (EDS). 
• 
Outcome Measures 2: To assess the feasibility of the dietary recommendations, adherence will 
be assessed using estimated daily dietary intake recorded in MyFitnessPal, a food tracker app 
for mobile devices and computers. The participant’s reported macronutrient breakdown will be 
compared to the prescribed food plan to calculate an adherence score. Participants will also 
complete a food plan satisfaction survey at baseline, 5, and 9 weeks that will examine any 
physical side-effects, support needed, and any barriers to adherence, including food costs. The 
feasibility of food tracking will be measured by adherence to the recommended use of the app. 
A threshold of 3 days of reporting per week (including breakfast, lunch, dinner, and snacks) for 
the 9-week duration of the study will be considered adherent and should provide sufficient data 
to assess the observance of the recommended food tracking. 
 

  
 
Template Version 02.02.17 
Protocol  
Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) 
syndromes: A mixed-methods feasibility study (IMforHSDandEDS)  
PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
Version: 3.0 
4 
B.3 Tertiary Aim: To examine the effect of a 9-week integrative medicine intervention on overall 
perceived pain and quality of life in patients with Hypermobility Spectrum Disorder (HSD) or Ehlers-
Danlos syndromes (EDS).  
• 
Outcome Measures 3: Participants will complete a Visual Analog Scale for Pain (VAS Pain) and a 
29-Item profile HRQoL Survey (PROMIS-29) at baseline, 5, and 9 weeks.  
 
In order to better understand the needs of the patient population, we will also address the following 
exploratory aims, as far as we are able.  These aims can be considered to be independent of the effects 
of treatment. 
 
B.4 Exploratory Aim 1: To evaluate any associations between symptom severity, perceived pain, quality 
of life, and diet among patients with Hypermobility Spectrum Disorder (HSD) or Ehlers-Danlos 
syndromes (EDS). 
• 
Participants will be given a 1-week lead-in to establish baseline food patterns before starting the 
prescribed food plan. Associations of dietary composition, patient-reported symptoms, as well 
as overall perceived pain and quality of life scores will be examined, both cross-sectionally at 
intake and longitudinally over the 9 weeks of the intervention. 
 
B.5 Exploratory Aim 2: To assess the experiences of chronic illness care and living with chronic illness 
among patients with Hypermobility Spectrum Disorder (HSD) or Ehlers-Danlos syndromes (EDS).  
• 
Outcome Measure 5: Participants will complete a 26-item survey, Patient Assessment of Chronic 
Illness Care (PACIC+), that evaluates areas of patient self-management within the chronic care 
model of healthcare. The PACIC+ ascertains attitudes regarding patient-centered care, living 
with chronic illness, and chronic illness care; it will be completed by participants at baseline and 
9 weeks. 
 
C. BACKGROUND AND SIGNIFICANCE  
 
C.1. History and Prevalence 
 
Ehlers–Danlos syndromes (EDS) are a categorically distinctive set of connective tissue disorders with a 
varied range of symptoms characterized by generalized joint hypermobility, loose ligaments, and joint 
pain.4 Initially, the prevalence of EDS was thought to be 1 in 5,000 individuals; however, these figures 
have been disputed more recently, and it is proposed that there is a lack of screening and early 
detection for the disorder due to the misconception that it is rare, which may contribute to 
underreporting.5,6 There are 13 subtypes of EDS recognized by the International EDS Consortium that 
are genetically heritable; however, Hypermobile Ehlers–Danlos syndromes (hEDS) are heterogeneous, 
meaning the exact gene responsible for the disorder is unknown.4 Next-generation sequencing (NGS) 
has identified faulty collagen production as a potential genetic cause, however, not all EDS subtypes 
possess this mutation.7  
 

  
 
Template Version 02.02.17 
Protocol  
Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) 
syndromes: A mixed-methods feasibility study (IMforHSDandEDS)  
PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
Version: 3.0 
5 
Hypermobility Spectrum Disorder (HSD) is the umbrella term for joint hypermobility in 4 or more joints 
in the body for which a genetic mutation for the disorder is unknown. A diagnosis of HSD usually occurs 
after Ehlers–Danlos syndromes (EDS), which can be tested both genetically and clinically, have been 
ruled out. 
 
C.2 Signs and Symptoms 
 
HSD and EDS are often undiagnosed, even with regular recurrence of symptoms and repeated medical 
appointments over an extended period of time. The diagnosis for the condition relies solely on clinical 
observations, and the disorders are frequently associated with a range of comorbidities that vary widely 
among afflicted patients and can easily present as the main concern. In a retrospective cohort study of 
patients with EDS, they were found to be 7.38 times more likely to suffer from abdominal pain, 4.07 
times more likely to have neuropathic pain, 5.21 times more likely to have migraines, 2.85 times more 
likely to have joint pain, and 5.55 times more likely to have fatigue than those without the disorder.8  
 
Observed rheumatologic presentations of HSD and EDS include fatigue, musculoskeletal pain, joint 
instability, or dislocation resulting in subluxations, and muscle weakness.9 Cutaneous or symptoms 
related to the skin include sprains, abnormal wound healing, mitral valve prolapse, propensity for 
temporomandibular joint disorders (i.e TMJ), asthma as the result of lung atopy, constipation, 
gastroparesis, and other GI disorders related to motility.1 Skin hyperextensibility may also result in 
menstrual and sexual problems in women, often in conjunction with pelvic prolapse.1 Neurological 
disorders that accompany HSD and EDS include migraine headaches, loss of proprioception (sense of 
position), dysautonomia, or dizziness as the result of low blood pressure and an overly compensatory 
heart rate, depression, anxiety, and poor quality of life.1 Immunological disorders associated with HSD 
and EDS include mast cell disorders as the result of histamine dysregulation and auto-immune disorders 
related to the connective tissue in the body.10 
 
An often overlooked outcome of HSD and EDS, its psychosocial impacts were assessed through 
qualitative interviews, revealing common themes among patients with the disorder that included 
restricted daily activities due to fatigue or pain, feelings of burdening others, a lack of independence, 
healthcare limitations (including a lack of awareness of HSD or EDS from providers), social stigma, fear of 
the unknown, as well as reported difficulty with coping.11 In a prospective cohort study of 158 subjects, 
it was found that HSD was associated with a higher risk of developing panic disorders.12  
 
C3. Diagnosis 
 
For most patients suffering from HSD and EDS, receiving a diagnosis is problematic as manifestations of 
the disorder are often vague, multifactorial, or ubiquitous. Because of common comorbidities, many of 
the clinical findings frequently will not align with standard HSD and EDS signs and symptoms; 
consequently, the condition is not always assessed or identified by healthcare providers.13 There is no 
definitive biomarker for HSD and EDS. A diagnosis, however, can be validating and essential to 
management, treatment, and recovery. Since many patients with HSD and EDS have complex medical 

  
 
Template Version 02.02.17 
Protocol  
Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) 
syndromes: A mixed-methods feasibility study (IMforHSDandEDS)  
PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
Version: 3.0 
6 
histories, in conjunction with comorbidities such as depression and anxiety, they often feel discredited 
and alienated when they do seek out healthcare.11 It also remains unknown whether the chronic pain 
associated with HSD and EDS is the result of psychosocial impairment or whether it is a direct 
consequence of the disorder itself.13 
 
To diagnose joint hypermobility, a series of 9 maneuvers assess standard range of motion 
measurements; or angles on what is called a Beighton scale. For every motion for which hyperextension 
of the joint is present, a score of 1 point is documented.14 A score of 4/9 or more indicates the presence 
of generalized joint hypermobility. The term “joint hypermobility” represents laxity in the joint, and it is 
important to emphasize that HSD and EDS are not diseases, but are instead, the presentation of a 
connective tissue disorder.1  
 
A Beighton score may be negative after the age of 33, even in individuals with a previous EDS or HSD 
diagnosis, as joint laxity decreases with age, even when pain and other manifestations of the disorder 
remain from previous hypermobility.3 In a systematic review of the Beighton score, it was found to be a 
reliable but not a valid instrument; meaning it has demonstrated uniform measurement (carried out 
clinically), however, as a diagnostic tool for measuring hypermobility, it may not be conclusive.15  
 
C4. Treatment 
 
The most prominent symptom associated with HSD and EDS is pain that is often life-altering and 
disabling. Since subluxations are often involuntary and happen spontaneously, some patients may only 
have mild pain associated with these occurrences. Chronic pain unrelated to these frequent dislocations 
is strongly associated with HSD and EDS, however, and it is both physically and psychologically 
disabling.16 In a study among Dutch patients with ESD, 90% were reported to suffer from pain, with 
Hypermobile Ehlers–Danlos syndromes (hEDS) patients having the most elevated pain severity scores 
among the cohort.17 In a study of pressure pain thresholds, it was found that 50% of patients with 
Ehlers-Danlos syndrome hypermobility type (hEDS) experienced neuropathic pain when compared to 
healthy individuals.18 Another reported feature of HSD and EDS is hyperalgesia, or pain hypersensitivity, 
which may be an additional indication of central nervous system damage as a result of the disorder.18 
Taking into consideration that chronic pain can be neuropathic; or related to a potentially damaged 
nervous system or nociceptive, where the pain is linked to inflammation from a tissue injury, pain 
medications may be entirely ineffective.3  
 
Overall, pharmaceutical interventions and standard of care for HSD and EDS vary, and currently, there 
are no drugs that specifically target connective tissue defects. Along with pain management, patient-
centered medical care that supports effective coping strategies, as well as social support, might 
contribute to better management of the disorders. Previous studies have concluded that the social 
environment is essential for pain management, and by facilitating acceptance of their diagnosis, patients 
may gain the necessary coping techniques to establish a new ‘normal’ life.19 A mixed-methods study of 
38 patients with HSD and EDS receiving physical therapy found that patients had lower health-related 
quality of life (HRQoL) scores than the average American adult and a perceived a need for a “whole-

  
 
Template Version 02.02.17 
Protocol  
Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) 
syndromes: A mixed-methods feasibility study (IMforHSDandEDS)  
PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
Version: 3.0 
7 
body approach, long-term maintenance care, incorporation of multiple rehabilitation techniques, and 
patient-centered care that addresses safety and stability.”20 A shift to a patient-centered model of 
chronic illness care could provide patients with a more active role in their own treatment, validate their 
experiences, and provide emotional support for coping.  
 
C5. Anti-inflammatory (Mediterranean) diet 
 
Hypermobile Ehlers–Danlos syndromes (hEDS) are shown to be associated with rheumatological 
diagnoses, some of which are inflammatory, and cells with hEDS and HSD specificity appear to have 
inflammatory cytokines in vitro even though they are genetically distinct disorders.21, 22 Inflammatory 
cytokines are often targeted with an anti-inflammatory diet that avoids foods like wheat, sugar, refined 
oils, trans fats, fast food, or any other processed foods and meats. Anti-inflammatory diets encourage 
increasing whole fruits, vegetables, and grains as well as balancing macronutrients (proteins, 
carbohydrates, and fat) for every meal. The most researched anti-inflammatory diet, the Mediterranean 
diet, was shown in a systematic review of 46 observational studies to be associated with a reduction of 
inflammatory biomarkers.23 An anti-inflammatory food plan may provide some support for chronic pain 
that is associated with HSD and EDS. 
 
C6. Integrative Medicine Approach 
 
The complex nature of both HSD and EDS and the various comorbidities that arise may necessitate an 
intervention that incorporates more than pain management. Psychosocial support that is incorporated 
into coping approaches that were found in qualitative interviews among patients with HSD and EDS to 
provide support were acceptance, building social awareness, and education about joint hypermobility as 
well as physical modifications that could be made.11 Patient-based care may mitigate some of the 
complications that accompany chronic illnesses, and by facilitating effective coping strategies that 
incorporate social support, a patient can feel supported by a comprehensive care management team.11 
In a narrative review of Ehlers–Danlos syndrome (EDS), the four common psychosocial conditions that 
were found to be consistent in the literature were “cognitive problems (and attention to body 
sensations), negative emotions, and unhealthy patterns of activity (hypoactivity/hyperactivity).”24 The 
authors concluded that because chronic pain can be so invalidating, incorporating psychosocial support 
is essential to rehabilitation, especially when the patient is not responsive to conventional treatment.24 
 
Integrative medicine may provide some support for chronic illnesses, as it relies upon a patient-centered 
model of healthcare, one defined by the Academy of Integrative Health and Medicine (AHIM) as “an 
approach that rather than a disease-focused model, is instead a wellness and prevention 
model.  Integrative health must also include not only our individual selves, but our community, our 
environment and our planet.”25 As can be seen in Figure 1., in the Integrative Care Model, the patient is 
in control over their own illness, and the therapeutic relationship they establish with their healthcare 
providers promotes autonomy, decision-making, and being treated as a whole person. 
 
 

  
 
Template Version 02.02.17 
Protocol  
Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) 
syndromes: A mixed-methods feasibility study (IMforHSDandEDS)  
PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
Version: 3.0 
8 
 
 
Figure 1. Integrative Care Model 
 
D. Preliminary Data 
 
D.1 Preliminary Data  
 
No preliminary data exists at this time. 
 
E. RESEARCH DESIGN AND METHODS  
 
E.1. Overview  
 
This feasibility study will investigate the recruitment potential and retention rate among patients with 
Hypermobility Spectrum Disorder (HSD) or Ehlers-Danlos syndromes (EDS) participating in a 9-week 
integrative medicine intervention that involves a prescribed anti-inflammatory (Mediterranean) diet, as 
well as general behavioral and psychosocial support. The feasibility of the food plan will also be 
examined through participant food tracking as well as through a food plan assessment in a brief 
satisfaction survey. Up to 20 patients with HSD or EDS will be enrolled from the Portland Oregon area, 
and the in-person screening study visit and the 2 virtual follow-up visits will be conducted at or from the 
Healthy Living Community clinic. We will also obtain preliminary data on any effects that the 9-week 
integrative medicine intervention has on pain and health-related quality of life. Outcome measures will 
be collected at 5 and 9 weeks, with the exception of the patient assessment of care for chronic 
conditions (PACIC+), that will be collected at baseline and the close-out visit during week 9.  
 
Figure 2. Study Design 
Integrative  
Care  
Model
Patient-
centered 
care 
Patient is involved 
in their own 
treatment  
Supports autonomy 
Locus of control 
over illness 
Healthcare 
Team
Whole-person, holistic 
care 
Therapeutic relationship 
between practitioner and 
patient 
Supports coping and 
hope 
Comprehensive, many 
practitioners 

  
 
Template Version 02.02.17 
Protocol  
Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) 
syndromes: A mixed-methods feasibility study (IMforHSDandEDS)  
PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
Version: 3.0 
9 
 
Recruitment 
• Healthy Living Community 
• The Portland area EDS 
support group 
• Oregon Area Ehlers-Danlos 
Society 
• Flyers distributed at 
physical therapy and 
doctor’s oﬃces that 
specialize in HSD & EDS in 
the Portland Metro area 
Exclusion criteria  
• Pregnant or lactating women 
• Alcohol abuse 
• History of disordered eating 
or eating disorder  
• BMI <18.5 
• Metastatic cancer 
• Inability to make dietary 
changes 
• Major changes to diet, new 
medication, or new exercise 
routine in the last 90 days 
Inclusion criteria 
• Ability to provide informed consent 
• Beighton score of 4 +, VAS of 1+ 
• Aged 18-65 
• Willingness to participate in 
integrative medicine intervention  
• Willingness to attend in-person 
screening oﬃce visit and virtual 
follow-up oﬃce visits 
• Electronic device access 
• Not currently a HLC patient
Visit # 1: Screening 
• Obtain informed consent 
• Obtain baseline AE, VAS, PROMIS-29, 
PACIC+ surveys 
• Assist patient in downloading MyFitnessPal 
food tracker app 
• Informative ﬂyers, food plan satisfaction 
surveys will be distributed 
• Doctor will attend to patient in a clinical 
setting and obtain a complete and detailed 
medical history 
• Obtain BMI, weight, height, and Beighton 
score measurements 
• Discuss family and social support 
• Prescribe a food plan and assess current 
diet 
• Assess current self-management strategies 
for the following categories: self-care and 
mental health 
• Provide psychosocial support
Baseline
Lead-in time 
• Allow participant to adjust to 
MyFitnessPal food tracker app 
before starting dietary intervention 
• Obtain general baseline dietary 
information  
Analysis
Check-in # 1: Telephone call or email  
• Nutritional and psychosocial 
support to answer any questions 
• Monitor for any adverse events
Visit # 3: Follow-up 
• Obtain VAS, PROMIS-29, PACIC+ surveys 
• Obtain food plan satisfaction survey 
• Complete a multi-system screening for any 
adverse events 
• Doctor will attend to patient in a virtual 
clinical setting and document weight 
• Discuss family and social support 
• Assess food plan progress and advise 
discontinuation if patient desires 
• Assess current self-management 
strategies for the following categories: 
self-care and mental health 
• Provide psychosocial support 
5 weeks
9 weeks
1 week
2 weeks
6 weeks
Visit # 2: Follow-up 
• Obtain VAS, PROMIS-29 surveys 
• Obtain food plan satisfaction 
survey 
• Complete a multi-system 
screening for any adverse events 
• Doctor will attend to patient in a 
virtual clinical setting and 
document weight 
• Discuss family and social support 
• Assess food plan progress 
• Assess current self-management 
strategies for the following 
categories: self-care and mental 
health 
• Provide psychosocial support
Telephone 
screening to 
determine 
eligibility  
Check-in # 2: Telephone call or email  
• Nutritional and psychosocial 
support to answer any questions 
• Monitor for any adverse events

  
 
Template Version 02.02.17 
Protocol  
Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) 
syndromes: A mixed-methods feasibility study (IMforHSDandEDS)  
PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
Version: 3.0 
10 
 
E.2 Recruitment  
 
Participants will be recruited from a local nonprofit private medical practice in Portland, Oregon, 
Healthy Living Community. We will post advertisements via the Healthy Living Community email 
newsletter, Facebook page, as well as in the doctor’s office. (See Appendices 6A and 6B) 
 
We will also post flyers through the Portland area EDS support group, Oregon Area Ehlers-Danlos 
Society, as well as local physical therapy and doctor’s offices that specialize in HSD and EDS in the 
Portland Metro area. The flyers will invite patients who believe that they have HSD or EDS and are in 
pain to participate in the study.  
 
Healthy Living Community and Dr. Schaefer have a social media presence that may build trust among a 
more racially and ethnically diverse study population and help participants to research the practice and 
feel comfortable ahead of time. While it would greatly enhance generalizability of results, if we were 
able to stratify recruitment to specifically include minorities and diversify study participants, we do not 
consider this feasible in the current pilot study of a small local population, in which the primary barrier is 
to a sufficiently large sample of any demographic composition. 
 
E.3 Participant Population 
 
All participants will be required not to be current patients for Dr. Schaefer and Healthy Living 
Community. The Clinical Investigator, Dr. Schaefer, will confirm the HSD or EDS diagnosis during the in-
person screening visit, where range of motion measurements will be obtained. Up to 20 participants will 
be enrolled with a Beighton score of 4 or above, which indicates the presence of generalized joint 
hypermobility.14 A baseline Visual Analog Scale for Pain (VAS Pain) indicating pain at a level of 1 or above 
will also be required for enrollment. 
 
E.3.1 Inclusion Criteria  
• 
Age 18-65 
• 
Beighton score of 4 or more to confirm joint hypermobility diagnosis 
• 
Baseline VAS Score of 1 or more 
• 
Not currently, or already a patient of Dr. Schaefer and Healthy Living Community  
• 
Ability to provide written informed consent 
• 
Willingness to participate in 9-week integrative medicine intervention (and make dietary and 
lifestyle changes) 
• 
Willingness to attend 1 in-person screening visit and 2 virtual office visits (or 3 virtual visits, if 
medical documentation of Beighton score can be provided in advance of enrollment, and all 
other criteria are met). 
• 
Access to an electronic device for MyFitnessPal food-tracker use (i.e mobile device, tablet, 
laptop) 
 

  
 
Template Version 02.02.17 
Protocol  
Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) 
syndromes: A mixed-methods feasibility study (IMforHSDandEDS)  
PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
Version: 3.0 
11 
E.3.2 Exclusion Criteria 
• 
Pregnant and lactating women, or planned pregnancy over the next 3 months 
• 
Consumption of more than 14 (men) or 7 (women) alcoholic drinks per week  
• 
History of disordered eating or eating disorder 
• 
Body mass index (BMI) considered underweight (<18.5) 
• 
Weight loss from metastatic cancer 
• 
Unable to make dietary changes or participate in a 9-integrative medicine nutritional 
intervention  
• 
Those with significant dietary changes, new medications, or new exercise routines within the 
past 90 days 
• 
Currently, or already, a patient of Dr. Schaefer and Healthy Living Community  
 
E.4 Participant and Procedure Schedule 
 
E.4.1 Overview 
 
The study is comprised of 1 in-person screening, 2 follow-up visits, and 2 telephone or email check-in 
correspondences for additional support. The in-person screening and 2 virtual follow-up visits will take 
place at the Healthy Living Community clinic. Virtual follow-up study visits will take place via the Zoom 
video platform utilized by ChARM TeleHealth, a web-based and HIPAA compliant server maintained by 
the Healthy Living Community clinic and will occur at 5- and 9-weeks post-enrollment.  
 
During the in-office screening, participants will have their joint mobility measured in accordance with 
the Beighton Scoring System to confirm that they meet the diagnostic criteria for Hypermobility 
Spectrum Disorder. Participants who are diagnosed using the Beighton criteria and meet other eligibility 
criteria will then be asked to provide informed consent (E.4.3) and enrolled in the study if willing. The 
Clinical Investigator will capture a complete and detailed medical history of enrolled participants, discuss 
family and social support, as well as prescribe a food plan. The CI will also assess the patient’s current 
self-management strategies and provide general behavioral and psychosocial support. During the 2 
follow-up visits, the Clinical Investigator will revisit these self-management strategies. As scheduling 
visits may be difficult at precisely 5 and 9 weeks, we will leave some flexibility for these points in time to 
accommodate the schedules of the Clinical investigator, the student researcher, and the participants. 
 
At 2 and 6 weeks, the participants will be contacted by the student researcher to answer any questions, 
provide nutritional and psychosocial support, monitor for any adverse events, and offer solutions to any 
dietary challenges. Participants will also be assessed at all study visits for any adverse events. 
 
Participants will be asked to complete pain (VAS), and health-related quality of life (PROMIS-29) 
instruments at baseline, 5, and 9 weeks. Adherence to the dietary recommendations, as well as the 
feasibility of food tracking will be obtained using MyFitnessPal, a food tracker app throughout the 9 
weeks. A food plan satisfaction survey will be collected at 5 and 9 weeks. Participants will fill out the 

  
 
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Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) 
syndromes: A mixed-methods feasibility study (IMforHSDandEDS)  
PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
Version: 3.0 
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patient assessment of care for chronic conditions (PACIC+) at baseline and the close-out visit during 
week 9.  
 
E.4.2 Telephone Screening 
Prospective participants will be contacted via telephone prior to their first visit. A standardized 
telephone script will be used to determine, as far as possible, if the participants meet the inclusion 
criteria and are eligible to join the study (See Appendix 3A).  
 
In event that a prospective participant does not know if they have a Beighton score of 4 or more, a free 
screening will be required before scheduling the Screening visit. The medical assistant at Healthy Living 
Community clinic will confirm that prospective participants meet the eligibility requirements but will not 
record or capture any data. This will prevent prospective participants that are ineligible for the study 
from being scheduled for a screening visit. After the Beighton score is visually confirmed, the 
prospective participant will have the option to re-screen by telephone for the study and then be 
scheduled for a Screening Visit with the Clinical Investigator, if eligible.   
 
If a participant meets all other criteria but is unable to attend the baseline visit in person, then they will 
be informed that they may attend the visit virtually, as long as they can provide medical documentation 
of a Beighton score of at least 4. 
 
E.4.3 Informed Consent  
Informed consent paperwork will be sent to the participant before their first visit so that they can 
review the document, but they will not sign anything until the first study visit. The study participants will 
meet with the student researcher to answer questions and to look over the consent forms prior to 
signing the document. The signed informed consent paperwork will be captured electronically via 
REDCap, a secure and HIPAA compliant web-based application used to capture electronic data for 
research studies (See Appendix 2B). 
 
E.4.4 Visit # 1: Screening (baseline) 
During the in-person screening visit, CDC Coronavirus Disease 2019 (COVID-19) doctor visit regulations 
will be followed, and all participants, the student researcher, and the Clinical Investigator will be 
required to wear facial masks, maintain a physical distance at 6 feet apart, and wash hands after all 
contact.26 
 
Participants will review the informed consent form with the student researcher, who will answer any 
questions. A signed form will be collected prior to initiating study-related activities. The Clinical 
Investigator (CI) will take range of motion measurements that will be obtained in accordance with The 
Beighton Scoring System to confirm that the participant meets the diagnostic criteria for Hypermobility 
Spectrum Disorder. BMI, height, and weight will also be collected. Participants will be screened for a 
history of disordered eating or eating disorders; if present; the participant will be referred to a 
specialized physician for treatment and excluded from the study. Participants with a body mass index 
(BMI) considered to be underweight, or less than 18.5, will also be excluded from the study.27 The CI will 

  
 
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Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) 
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PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
Version: 3.0 
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calculate the daily caloric needs for each patient using the estimated energy requirements (EER) formula 
for each patient that takes into consideration their current physical activity level (i.e. sedentary or 
active), weight, and age.28 The CI will request consent to obtain the medical records of the participant. 
 
The Clinical Investigator will do a thorough review of the patient’s full medical history and listen to their 
entire background. They will discuss the social and familial support of the patient, assess their general 
diet, provide psychosocial support, and prescribe an anti-inflammatory food plan. The Clinical 
Investigator will also assess the patient’s current self-management strategies and provide general 
behavioral and psychosocial support. Any current medications or supplements being used for pain that 
the participant is taking will also be documented, but no changes in medications will be required by the 
study. Participants will be given portal access to their electronic health records through ChARM Patient 
Portal for the use only of this study. 
 
The student researcher will assist participants with logging into REDCap and collecting baseline pain 
(VAS), health-related quality of life (PROMIS-29) and patient assessment of care for chronic conditions 
(PACIC+) surveys. A baseline adverse events questionnaire will be obtained using the NUNM 
standardized multi-system survey for each participant, to document any current health conditions that 
may not be listed in the medical record. Participant demographic information will be collected, including 
age, sex, and gender 
 
The student researcher will provide flyers with advice and guidelines for following a meal plan that 
follows an anti-inflammatory eating pattern, including recommendations for meal planning and 
strategies for adding and reducing certain foods (See Appendices Gi through Giv). The macronutrient 
breakdown that will be recommended for the patients will be 40- 50 % carbohydrate, 15- 20 % protein, 
and 35- 40 % fat,29 which is aligned with the Mediterranean-style eating pattern and has been shown to 
be anti-inflammatory.23 Participants will be provided a food plan that is in accordance with their current 
average dietary consumption of either 1800 or 2200 calories. (See Appendices 2Gi through 2Giv) 
Participants will also be given a list of resources for online and local Mediterranean-style eating patterns 
to simplify their research options. (See Appendix 2Gvi) 
 
The student researcher will assist participants with downloading MyFitnessPal so that their estimated 
daily dietary intake can be captured. Participants will be assigned a MyFitnessPal username using an 
unidentifiable study number that will be recorded by the student researcher in a secure location, and 
the account will only be used for study purposes. Participants will be instructed that no identifiable 
health data related to the study will be shared on the MyFitnessPal app. The student researcher will also 
review the Sharing & Privacy settings in the MyFitnessPal app with participants to ensure that the 
privacy is protected as much as possible. 
 
They will also provide a handout for how to use the app or website (See Appendix 2Gv). Participants will 
be given an opportunity to practice using the app with support from the study coordinator. Participants 
will be encouraged to track their diet daily to the best of their ability and will be able to opt-out of 
tracking if they express concerns. Using the Friends feature on the app, participants will be able to share 

  
 
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Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) 
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PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
Version: 3.0 
14 
their daily food tracking with the student researcher, and the data will be collected at 5 and 9 weeks. 
Participants will be given a 1-week lead-in period so that they can adjust to tracking their dietary intake 
before starting the food plan and will be instructed to contact the student researcher with any 
questions. 
 
In the event that the baseline visit is conducted virtually, all procedures will be the same, except that the 
participant will provide medical documentation of a Beighton score of 4 or more, in lieu of a Beighton 
measurement being obtained at the visit. We will require informed consent prior to capturing this 
documentation.  The participant will be asked to report their own height and weight.  All other data will 
be captured electronically.  Any participant who completes the baseline visit remotely will be invited to 
complete the Week 5 visit in person, if possible; if the Week 5 visit is completed in person, then weight, 
height, and Beighton score will be confirmed at that visit. 
 
E.4.4.1 Food Plan Satisfaction Survey 
We will distribute food plan satisfaction surveys via REDCap to be completed by the participant prior to 
the patient’s next visit (5 weeks). The surveys will gather information regarding the overall cost-
effectiveness and feasibility of the diet and any obstacles that are faced with the food plan. (See 
Appendix 2Fi) 
 
E.4.5 Check-in #1 (2 weeks) 
Participants will receive a phone call or e-mail from the student researcher that will answer any 
questions, provide nutritional and psychosocial support, and offer solutions to any dietary challenges. 
The goal is to provide support with dietary adherence. This will occur 2 weeks after Visit # 1 and will be 
set up in advance at a time that works for the participant. If the participant is not available, we will send 
a check-in email and answer any questions, provide nutritional and psychosocial support, and offer 
solutions to any dietary challenges by email, if requested. The nutrition counseling script contains 
suggestions for a general healthy eating pattern but is not a part of food plan adherence. (See Appendix 
3B) 
 
Participants will be assessed for any adverse events with the following question, “Are you experiencing 
any new symptoms or side-effects that you may have noticed?” (See Appendix 3B) 
 
E.4.6 Visit # 2: Follow-up (5 weeks) 
During the second virtual clinical visit, the student researcher will collect VAS pain measurements, 
health-related quality of life scores (PROMIS-29) and will assess for any adverse events using the NUNM 
standardized multi-system questionnaire.  
 
The Clinical Investigator will discuss the social and familial support of the patient, provide psychosocial 
support, and address any concerns with the anti-inflammatory food plan. The CI will also assess the 
patient’s current self-management strategies and provide suggestions for any adjustments to general 
behavioral and psychosocial support recommendations. Any current medications or supplements being 

  
 
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Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) 
syndromes: A mixed-methods feasibility study (IMforHSDandEDS)  
PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
Version: 3.0 
15 
used for pain that the participant is taking will also be documented, but no changes in medications will 
be required by the study. Current self-reported weight will also be documented. 
 
E.4.6.1 Food Plan Satisfaction Survey 
We will distribute food plan satisfaction surveys via REDCap to be completed by the participant prior to 
Visit # 3. (See Appendix 2Fii) 
 
E.4.7 Check-in #2 (6 weeks) 
Participants will receive a phone call or e-mail from the student researcher that will answer any 
questions, provide nutritional and psychosocial support, and offer solutions to any dietary challenges. 
The goal is to provide support with dietary adherence. This will occur 2 weeks after Visit # 2 and will be 
set up in advance at a time that works for the participant. If the participant is not available, we will send 
a check-in email and answer any questions, provide nutritional and psychosocial support, and offer 
solutions to any dietary challenges by email, if requested. The Nutrition counseling script contains 
suggestions for a general healthy eating pattern but is not a part of food plan adherence. (See Appendix 
3B) 
 
Participants will be assessed for any adverse events with the following question, “Are you experiencing 
any new symptoms or side-effects that you may have noticed?” (See Appendix 3B) 
 
E.4.8 Visit # 3: Follow-up (9 weeks) 
During the final virtual visit, the student researcher will collect VAS pain measurements, patient 
assessment of care for chronic conditions (PACIC+), PROMIS-29 health-related quality of life scores and 
will assess participants for any adverse events using the NUNM standardized multi-system 
questionnaire.  
 
The Clinical Investigator will discuss the social and familial support of the patient, provide psychosocial 
support, and address any concerns with the anti-inflammatory food plan. The CI will also assess the 
patient’s current self-management strategies and provide suggestions for any adjustments to general 
behavioral and psychosocial support recommendations. Any current medications or supplements being 
used for pain that the participant is taking will also be documented, but no changes in medications will 
be required by the study. Current self-reported weight will also be documented. 
 
At the final visit, patients will be encouraged to continue to eat a healthy diet but will be reminded that 
the study is complete and that they may alter their diet in whatever way they wish. 
 
E.5 Intervention 
 
9-week integrative medicine intervention 
 
Enrolled participants will take part in a 9-week program that includes a novel integrative medicine 
intervention that is focused on patient-centered care. The patient will establish a therapeutic 

  
 
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PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
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relationship with a holistic healthcare provider team consisting of a medical doctor and a student 
researcher to support comprehensive care. Participants will attend a total of 3 visits with a medical 
doctor over the 9-week integrative medicine intervention.  
 
The Clinical Investigator has created a 9-week program that is composed of a prescribed anti-
inflammatory (Mediterranean) food plan as well as general behavioral and psychosocial support.  During 
the 3 consultations with the participant, the CI will: 1)   Capture a complete and detailed medical history 
and  background, 2)  Discuss familial and social support, 3)  Provide psychosocial support,  4) Assess the 
patient’s current self-management strategies for self-care, and 5) Assess the patient’s current self-
management strategies for mental health. Study personnel will also follow provide psychosocial and 
nutritional support to address any additional concerns and promote adherence to the food plan. 
 
Prescribing an anti-inflammatory food plan and assessment of current diet 
 
The Clinical Investigator will prescribe an anti-inflammatory food plan that consists of a high intake of 
fruits and vegetables (4-5 serving of each per day).30 The specific dietary requirements for adherence to 
the anti-inflammatory food plan incorporated in this 9-week integrative medicine intervention will 
include macronutrient levels similar to those of a Mediterranean diet, which breaks down to 40-50% 
carbohydrates, 15-20% protein, and 35-40 % fat.29 Such a diet is high in fiber, micronutrients, healthy 
fats, and antioxidants that may provide health benefits by reducing inflammation.23 The Clinical 
Investigator will present the macronutrient requirements, assess the current diet of the participant, and 
suggest modifications that will cause their diet to conform to study guidelines, such as reducing sugar as 
well as processed and fast foods. They will discuss removing trans fats and hydrogenated oils and 
replacing them with cold-pressed and unrefined oils. For simplicity and accuracy, participants will be 
advised to follow a “Mediterranean-style eating pattern,” which is very searchable among recipe 
databases and websites, and more specific than the term “anti-inflammatory.” 
 
Participants will be provided an anti-inflammatory food plan that includes recipes, a guide for adding 
and reducing certain foods, and obtaining targeted macronutrient levels (see above) if modification of 
their current diet seems infeasible, or if they so desire. The student researcher will assess the cooking 
skills of participants and provide resources, as needed (i.e. YouTube channels, websites). They will 
discuss meal-planning, meal-prepping, and making a grocery list on a budget as needed. Additionally, 
participants will be contacted twice via phone or email by the student researcher to provide nutritional 
and psychosocial support, answer any questions, and facilitate adherence. 
 
Capturing a complete and detailed medical history and background 
 
The Clinical Investigator will comprehensively intake the patient’s full medical history and listen to their 
entire background. Because HSD and ESD can be a frustrating and invalidating prognosis, extreme 
sensitivity and empathy will be used to build trust and develop a therapeutic relationship with the 
participants.  
 

  
 
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Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) 
syndromes: A mixed-methods feasibility study (IMforHSDandEDS)  
PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
Version: 3.0 
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Patients suffering from these conditions report that the limitations they receive within the healthcare 
system often involve a lack of awareness of HSD or EDS from providers, and hold similar perceptions 
that they have been ignored, belittled, or considered to have hypochondria when they do seek advice.11 
The Clinical Investigator will approach the participants by validating their experience with an emphasis 
on reinforcing the feeling that participants are and being heard, believed, and listed to attentively. 
 
Discussing familial and social support 
 
The Clinical Investigator will assess what and intrapersonal support the participants have, which can 
help influence long-term health changes. Motivational interviewing will be utilized and 
“include engaging with patients to help build rapport, focusing patients on the changes they want to 
make while offering advice and support, evoking the tools, and desires they possess within them to 
effect change, and planning to implement the goals and next steps patients identified through the 
encounter.”31 
 
The Clinical Investigator will assess the general support that the participants have in their home, or in 
the community where they live, to make dietary and lifestyle changes. This will involve discussing any 
barriers they have, such as grocery store and transportation access, and practical needs like having a 
kitchen, tools to cook, or time to prepare fresh food. Potential solutions to these barriers like 
community food pantries and cooking classes will be recommended depending on the location of the 
participant. The CI will also assess the social network of the participant for supportive relationships that 
are necessary to create healthy behavior changes. Recommendations will be made in accordance with 
the needs of the participant and may include referrals to the Portland area EDS support group, or 
Oregon Area Ehlers-Danlos Society if they require more assistance. 
 
Providing psychosocial support 
 
Psychosocial support will be provided by both the Clinical Investigator, the student researcher, 
and MyFitnessPal throughout the 9-week program. Participants will receive behavioral, lifestyle, and 
dietary counseling all through a total of 3 office visits with the medical doctor, and 2 phone calls or e-
mail check-in correspondences with the student researcher. 
 
The student researcher has personal experience with both hEDS and Postural Tachycardia Syndrome 
(POTS), and similar to another EDS study, this will be disclosed to participants at the beginning of the 
interview in an effort to mitigate the power imbalance that often accompanies research.11 This may also 
help “instill greater confidence in participants” to share their experiences with a researcher and EDS 
individual who is also in their “in-group.”11 It will also be “emphasized that it [is] their stories that 
matter” for the purpose of the study.11 
 
MyFitnessPal 
 

  
 
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PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
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MyFitnessPal, a food tracker available on both Apple and Android for mobile devices, as well as both 
Windows and Mac computer platforms, will be used to collect estimated daily dietary intake for 
participants. MyFitnessPal has a database of nutritional information for over 11 million foods that will 
allow participants to capture their general diet by manually adding individual ingredients, barcode 
scanning, or finding whole meals.32 In a comparison of micronutrients and calories between diet-tracking 
apps and the USDA database, MyFitnessPal was shown to have the best coding accuracy.33 Self-reported 
data, however, may  be subject to inaccuracies. When foods are entered into the Diary feature located 
in the app, the Nutrient Dashboard displays daily calories, as well as macronutrient proportions, broken 
down into carbohydrates, fats, and protein.  
 
Participants will be encouraged to track their daily diet to the best of their ability, and for weeks that 
there is missing data, a threshold of no less than 3 days of tracking (including breakfast, lunch, dinner, 
and snacks) per week for the 9-week study duration will be considered adherent and averaged 
appropriately. Individuals with previous disordered eating patterns, or discomfort with food tracking, 
will be able to opt-out; however, they will still be shown how to use MyFitnessPal to analyze dietary 
composition for adherence. A 1-week lead-in prior to introducing the food plan will be utilized to 
provide a baseline record of the participant’s general diet. MyFitnessPal data will allow us to track 
general adherence to dietary changes, the overall quality of the participant’s diet, and average 
macronutrient proportions. By measuring the participant’s reported macronutrient percentage scores 
and comparing them with the prescribed food plan, we will be able to calculate an adherence score. 
 
MyFitnessPal usage has been shown to have positive results for behavioral and health changes, and for 
meeting nutrition-related goals, and was found to be associated with higher levels of reported self-
efficacy among users that reported more frequent use.34 In a systematic review of dietary mobile app 
use and chronic diseases, it was concluded they may be effective self-monitoring tools and were shown 
to have positive effects on measured nutritional outcomes.35 Other small studies have shown that 
wearable technology may provide additional psychosocial support for dietary interventions and 
behavioral change.36 Most health and fitness apps have also been shown to incorporate health behavior 
theory, which is essential for behavioral change.37 In a focused review of smartphone diet-tracking 
apps, MyFitnessPal was shown to have better usability when compared to other apps; however, one 
disadvantage that the review cited for all diet-tracking apps was that users lack the ability to track their 
emotions.33 
 
Assessing the patient’s current self-management strategies for self-care 
 
The Clinical Investigator will assess each participant’s self-care regime and make recommendations. 
They will make the following mindfulness, sleep, and movement recommendations listed below. 
 
Practice mindfulness: Have some quiet time to yourself once a day. Listen to a guided meditation or 
grab a journal. Write down your thoughts. Let go of stress and try to relax. Try chanting, prayer, or using 
a mantra. 
 

  
 
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Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) 
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PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
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Mindful eating: Take some time to slow down and eat your food. This will help you tune in with your 
body. It might take time to listen to your body’s natural satiety cues to know when you are hungry or full 
at first. Try cooking, meal-prepping, and eating with others. Incorporate their support with the food plan 
to help you keep on track. 
 
Try to focus on having non-distracted eating during meals. This means silencing your cellphone, turning 
off your TV or computer, and savoring your food. 
 
Mindful eating 
Eat/drink with intention 
• 
How did the food make you feel? 
• 
Are you enjoying it? 
 
Listen to your hunger/thirst 
• 
Is your stomach growling?  
• 
Are you parched? 
 
Slow down 
• 
Slow down for a moment and enjoy your food. This will help you listen to your 
hunger and get pleasure out of eating. Take your time. 
 
 
Sleep: Try to sleep 7-8 hours at night. Practice good sleep hygiene by having a wind-down time at night 
without electronics (at least 2 hours before bedtime). Avoid eating a heavy meal or drinking alcohol 
before bed. 
 
Movement (light physical activity): Try to take your lunch break outside or go on a walk after work. It 
might take some time to build up the energy, so start slowly, maybe 15 minutes a day at first. 
 
Assessing the patient’s current self-management strategies for mental health 
 
The Clinical Investigator will determine the mental health needs of participants and make mental health 
provider referrals as needed. If additional support is required and a referral is made, the Clinical 
Investigator will revisit these needs and check on progress in follow-up visits. 
 
Patients will also be referred to mental health resources found at the Ehlers-Danlos Society website. 
 
E.6 Measures 
 
Primary Outcome measures: 
 
Feasibility 
• 
Retention rate (proportions of participants completing 5 and 9-week visits) 

  
 
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• 
Recruitment rate (average number of participants enrolled per month) 
• 
Dropout rate (proportions of participants failing to complete 5 or 9-week visits) 
 
Secondary Outcome measures: 
 
Dietary Adherence/Food Tracking Feasibility (MyFitnessPal food tracking): 
• 
Dietary adherence will be measured by self-reported food tracking through Daily Nutrition Goals 
in the MyFitnessPal app and will be documented at 5 and 9 weeks through the Friends feature. 
Daily macronutrient contributions will be obtained as percentages of total intake. The suggested 
macronutrient breakdown for the food plan is 40-50% calories from a carbohydrate source, 35-
40 % calories from fat, and 15-20% calories from protein. Weekly recorded consumption of the 
participant will be compared to this standard for an adherence score. For each of the three 
macronutrient categories, we will give 2 points if the percentage is within the required range 
and 1 point if the percentage is within 5% of the required range (maximum 6 points total).  A 
score of 4 and above will be considered adherent to the food plan. 
• 
The feasibility of food tracking will be measured by adherence to the recommended use of the 
app. A threshold of 3 days of reporting per week (including breakfast, lunch, dinner, and snacks) 
for the 9-week duration of the study will be considered adherent and should provide sufficient 
data to assess the observance of the recommended food tracking. 
 
Food Plan Feasibility (food plan satisfaction survey collection):  
• 
Any negative outcomes, overall cost-prohibitiveness, support needed, and barriers encountered 
will be assessed with a food plan satisfaction survey at 5 and 9 weeks that will examine the 
feasibility of the food plan. Qualitative data will be thematically summarized for representative 
quotes. 
 
Tertiary Outcome measures: 
 
Pain Visual Analog scale (VAS) collection: 
• 
We will collect subjective pain levels from participants over 9 weeks on a 10-point scale. A pain 
visual analog scale will give a numeric measurement of pain between “worst pain” and “no 
pain.” 
The Patient-Reported Outcomes Measurement Information System (PROMIS-29): 
• 
We will collect general perception of health status as well as quality of life scores over 9 weeks 
from participants. The PROMIS-29 is a survey that will give a numeric measurement of physical 
and mental health status on a scale of 0 to 10 that has been validated in adults with multiple 
chronic conditions.38 
 
Exploratory measures: 
 
Pain Visual Analog scale (VAS), The Patient-Reported Outcomes Measurement Information System 
(PROMIS-29), and Dietary Adherence associations: 

  
 
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PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
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• 
We will evaluate any associations between symptom severity, perceived pain, health-related 
quality of life, and dietary composition cross-sectionally and longitudinally over the course of 
the 9-week intervention. 
 
Patient Assessment of Chronic Illness Care+ scores (PACIC+) collection: 
• 
We will collect general perceptions and attitudes regarding the experiences of chronic illness 
care and living with chronic illness among patients with HSD and EDS at baseline and 9 weeks. 
• 
The Patient Assessment of Chronic Illness Care (PACIC+) is a validated survey shown to have 
good reliability, internal consistency, and better psychometric characteristics than other surveys 
on patient satisfaction.39, 40 It is designed to assess the experience and satisfaction within the 
chronic care model of healthcare, which often results in repeated appointments over a long 
time interval. It retrospectively assesses experiences of chronic illness care and living with 
chronic illness over the past 6 months. 
 
Health history and anthropometric measurements:  
• 
Biological information will be captured regarding the patients’ previous medical health history, 
age, sex, and gender at the baseline screening. We will also document BMI, weight, height, and 
estimated energy requirement measurements at baseline. We will record patient self-reported 
weight at 5 and 9 weeks and track any changes that occur. Any abnormal BMI values will be 
monitored appropriately for safety, and any changes in these measures will be analyzed in 
accordance with the overall effectiveness of the diet. 
• 
We will also document any other patient-reported symptoms that are experienced in addition to 
HSD or EDS throughout the 9 weeks and document any changes that occur. 
• 
Any current pain medications or supplements that the participants are taking for pain will also 
be recorded. 
 
Beighton score: range of motion measurements 
• 
A set of measurements that assess joint hypermobility through a 9-point scale will be 
documented during the in-office screening. For every joint that can be extended past a specified 
angle, 1 point is added to the patient’s Beighton score. A score of 4 or more indicates that 
generalized joint hypermobility is present.14 
• 
The Beighton score will be obtained during the baseline screening. 
 
NUNM Multi-system Adverse Event questionnaire: 
• 
A multi-system AE questionnaire will be administered at each visit. As HSD and EDS are 
associated with a considerable list of comorbidities, we will obtain a baseline measure of the AE 
questionnaire for each participant so that we have documented any pre-existing conditions. We 
will check on these conditions throughout the 9 weeks to ensure that symptoms have not 
worsened, in addition to noting any new occurrences. We will monitor these symptoms closely 
and recommend cessation of the food plan if a patient feels that any of their symptoms have 
been exacerbated. 

  
 
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Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) 
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PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
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• 
Participants will also be assessed for any adverse events during check-in calls with the following 
question, “Are you experiencing any new symptoms or side-effects that you may have noticed?” 
We will recommend cessation of the food plan if a patient feels that any of their symptoms have 
been exacerbated, or if they are experiencing any new symptoms. 
• 
Dietary alterations involving increased fats, protein, fruits, and vegetables may cause 
gastrointestinal distress. HSD and EDS are associated with motility issues that may result in 
constipation; however, adherence to a Mediterranean-style food pattern has been associated 
with improved gastrointestinal symptoms.41 We will monitor these symptoms closely and 
recommend cessation of the food plan if a patient is experiencing significant digestive distress. 
 
E.7 Data Collection and Sources 
 
E.7.1 Confidentiality and Data Storage 
There is a very small risk that information about a study participant could be inadvertently disclosed to 
non-study personnel. Throughout the study, measures to ensure the privacy of information on study 
subjects will be maintained. All study investigators and staff have been certified in the use of human 
subjects in research and have received training in HIPAA regulations. Participants and staff will be 
informed of the confidentiality of information and assured that data will be used only for statistical 
purposes and group analyses in which the individual cannot be identified. No data beyond what is stated 
in the informed consent will be sought without authorization from the participant. Information on 
illnesses and hospitalizations will not be sought from hospitals or doctors without a signed medical 
release from the subject. Conversely, no information on any individual will be released to anyone other 
than study personnel without a signed medical release from the participant, or where appropriate, the 
next of kin or a physician in case of a life-threatening emergency to the subject. All study personnel will 
be instructed not to discuss any participants with persons other than study personnel.  
 
Each participant will be assigned a unique alpha-numeric ID upon screening. All data resulting from 
study visits will be collected on standardized case report forms (CRFs). Data will be transferred from 
CRFs to a secure REDCap database for data management. Outcome data from MyFitnessPal will be 
entered into the REDCap database by the student researcher. Data will be downloaded only onto a 
password protected computer; upon download, data will be immediately entered into REDCap and 
deleted from the hard drive. Food VAS, Patient Assessment of Chronic Illness Care (PACIC+), and 
PROMIS-29 surveys will all be recorded utilizing the REDCap database. REDCap is a secure, web-based 
application that supports electronic data capture for research studies. REDCap features include: 1) 
intuitive data entry features; 2) audit trails for tracking data manipulation and export; 3) user-based 
privileges that support HIPAA compliance; 4) seamless data export to common statistical packages; and 
5) procedures for importing data from external sources. The REDCap database will be accessible only by 
the study team. The link between study IDs and protected health information will be kept as a single 
electronic file stored on a limited-access electronic folder on a secure server with select access limited to 
the study team. Data will be destroyed 3 years after completion of the study. Computer files will be 
deleted from the server, and paper files will be destroyed using a professional document shredding 
service.   

  
 
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IRB #: DH10320/PRAF 
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All completed forms will be kept in locked files to which only project personnel have access. These files 
will also be in locked rooms. Data from paper forms will be manually entered into REDCap and kept as 
electronic files. Paper forms will continue to be stored in a locked cabinet up to completion of data 
analysis, at which point they will be shredded.  Electronic files will be password protected with access 
given to study personnel only. All analyses will be conducted by study staff at the Helfgott Research 
Institute.  The study statistician will only access de-identified data exported from REDCap. Only de-
identified data will be presented in any reports, presentations, or manuscripts. 
 
E.8 Risks and Benefits  
 
In the USDA 2015-2020 Dietary Guidelines for Americans, the Mediterranean diet was listed among the 
Healthy Style Eating Pattern for its association with positive health outcomes.30 “The Healthy U.S.-Style 
Eating Pattern is designed to meet the Recommended Dietary Allowances (RDA) and Adequate Intakes 
for essential nutrients, as well as Acceptable Macronutrient Distribution Ranges (AMDR) set by the Food 
and Nutrition Board of the IOM. This eating pattern also conforms to limits set by the IOM or Dietary 
Guidelines, for other nutrients or food components and nutritional goals for almost all nutrients are 
met.”42 The anti-inflammatory food plan that will be recommended in this 9-week integrative medicine 
intervention reflects macronutrient levels that are similar to those of a Mediterranean diet, which 
breaks down to 40-50% carbohydrates, 15-20% protein, and 25-30 % fat.29 This macronutrient 
breakdown would still meet the requirements for carbohydrate restriction in conditions like type 2 
diabetes, which is usually around 50 grams per day.43  
 
The Mediterranean-style eating pattern is one of the most studied diets and has amassed a large 
evidence base for the treatment and prevention of many chronic diseases. In a meta-analysis of 50 
studies, the diet was associated with improved outcomes for reducing risk factors for cardiovascular 
disease, such as preventing metabolic syndrome, reducing blood pressure, lipid levels, and endothelial 
dysfunction; through both the antioxidant and anti-inflammatory properties of foods found in the 
Mediterranean dietary pattern.44 Adherence to a Mediterranean diet has also been shown to be 
beneficial for individuals with chronic kidney disease (CKD) and has been shown to improve both 
survival rates and renal function.45 In a holistic study of adherence to the Mediterranean diet, it was 
found to be associated with a 17-25% increase in overall survival rates as well as increased mortality 
rates for cancer, coronary artery disease, and cardiovascular disease.46  
 
Alteration of fats, protein, fruits, and vegetables may increase the risk of gastrointestinal distress that 
may result in gas, bloating, or constipation. Participants will be advised to discontinue the food plan if 
the patient is experiencing significant digestive distress. 
 
While the safety of integrative medicine is dependent on individual therapies or treatments, mind-body 
practices and light movement exercises are generally considered to be safe.47 The Clinical Investigator 
will evaluate the participant’s current supplements and medications before making food plan 
recommendations to prevent any drug interactions that could occur.47 

  
 
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PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
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Participants enrolled in the 9-week integrative medicine intervention will receive 3 complimentary office 
visits and 2 check-in calls from the student researcher. There may be little direct benefits to the 
participants other than the personal satisfaction of contributing to health research; however, if they 
respond positively to integrative care, and it was it effective in reducing pain and improving quality of 
life among patients, it is possible that some of the symptoms associated with the disorder could show 
some relief. 
 
E.9 Statistical Analysis  
 
All measures collected in the study, including baseline characteristics and outcome measures, will be 
summarized using mean and SD (biomarkers, anthropometrics), median and IQR (Beighton score), or 
percentage within each level, for categorical variables. All statistical analyses will be performed at the 
National University of Natural Medicine. 
 
For Specific Aim 1,  
 
Feasibility of the 9-week integrative medicine intervention will be measured through recruitment and 
retention at each follow-up visit. Recruitment rate will be presented as the mean number of participants 
enrolled per month, with enrolment ceasing either after 4 months, or when n=20 participants have been 
enrolled. Retention will be calculated as the percentage of enrolled participants from whom follow-up 
data is obtained, at either the 5-week or 9-week visit. 
 
For Specific Aim 2,  
 
Adherence to the recommended diet will be assessed in different ways and tracked by macronutrient 
levels and dietary composition. In particular, we will assess: 
• 
Percentage of days on which the diet recommendations were met; in order to satisfy this 
requirement, macronutrient distribution must meet all of the following: 
o Carbohydrates between 40-50% 
o Protein between 15-20%  
o Fat between 25-30 % 
• 
Number of weeks in which recommendations were met at least 5 days; 
• 
Whether recommendations were met on at least 75% of total days (Y/N) 
• 
Mean of weekly adherence scores calculated over the 9-week study period. 
 
Percentage of days and weeks adherent will be summarized across participants as median/IQR/range.  
We will also present the percentage of participants who met the threshold of 75% days adherent. 
 
Feasibility of the 9-week integrative medicine intervention will also be measured through self-reported 
food plan satisfaction surveys that assess any negative outcomes, overall cost-prohibitiveness or 

  
 
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Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) 
syndromes: A mixed-methods feasibility study (IMforHSDandEDS)  
PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
Version: 3.0 
25 
burden, support needed, and any barriers that are encountered with the recommended dietary 
modifications.   
• 
Because these measures are reported as open responses, they will be thematically summarized 
for representative quotes, at each time point measured.   
 
Adherence with dietary tracking will be assessed by: 
• 
Percentage of total days on which dietary intake was documented. Self-reporting of daily dietary 
intake on at least 50% of total days will be considered adherent. 
• 
Number of weeks on which intake was self-reported at least 3 days. 
 
For Specific Aim 3,  
 
We will test whether the integrative medicine education intervention reduced pain and improved 
health-related quality of life in patients with HSD or EDS. VAS pain scores and PROMIS-29 domain scores 
will be summarized across participants and time points as mean (SD). 
 
Analysis of pain and HRQoL outcomes for Aim 2 will use paired t-tests to assess mean changes unless 
investigation of distributions indicates a need for nonparametric testing, in which case changes will be 
analyzed using Wilcoxon signed-rank tests. 
 
For Exploratory Aim 1,  
 
Any associations between pain, HRQoL, and diet will be assessed both cross-sectionally and 
longitudinally over the course of treatment. Cross-sectional associations of VAS pain score, PROMIS-29 
domain scores, and dietary composition measures will be analyzed using Pearson correlations (or 
Spearman correlations for badly non-normal data). To assess associations of longitudinal changes, we 
will compute changes in each measure both from baseline to 5 weeks, and from baseline to 9 weeks, 
and we will similarly evaluate correlations between the changes over each time period. 
 
Cross-sectional correlations assess the association of participants’ ordinary diet with pain and health-
related quality of life, while correlations of changes assess the association of dietary changes, in 
response to the treatment recommendations, with changes in pain and HRQoL over the same time 
frame. 
 
We will also assess associations between age, race, sex, baseline symptoms, and changes in outcomes at 
follow-up, using Pearson correlations and independent t-tests, as appropriate. 
 
For Exploratory Aim 2,  
 
We will summarize Patient Assessment of Chronic Illness Care (PACIC+) scores in the sample, at both 
baseline and study end, and mean (SD). We will also test whether the scoring changed after 
participating in integrative medicine intervention, using a paired t-test. 

  
 
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Study Title: Integrative Medicine for Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos (EDS) 
syndromes: A mixed-methods feasibility study (IMforHSDandEDS)  
PI: Douglas Hanes, PhD 
IRB #: DH10320/PRAF 
Approval Date: 03.03.21 
Version: 3.0 
26 
 
F. Conclusion, Summary and/or Benefits of the Knowledge Gained  
 
Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos syndromes (EDS) are debilitating conditions 
of the connective tissue that can be both physically and psychologically disabling. For chronic care 
conditions, there is a need beyond the current healthcare model for patient-centered pain prevention 
and management programs. There are no current published scientific studies on holistic care among 
patients living with HSD or EDS, nor is there any research on dietary intake and its impact on the 
disorder. In order to better support rehabilitation, healthcare professionals should not only become 
more aware of both HSD and EDS and their related comorbidities, but they should also be educated in 
an effort to support the psychosocial needs that accompany chronic pain conditions. This project would 
allow us to study a novel integrative medicine intervention that is comprehensive, holistic, and patient-
centered. 
 
This study will allow us to capture the recruitment potential and retention rate among patients with 
Hypermobility Spectrum Disorder (HSD) or Ehlers-Danlos syndromes (EDS) participating in a 9-week 
integrative medicine intervention that is comprised of a prescribed anti-inflammatory (Mediterranean) 
food plan as well as general behavioral and psychosocial support. Both quantitative and qualitative 
measures obtained by participant food tracking and food satisfaction surveys will allow us to assess 
adherence to and feasibility of the prescribed food plan, as well as the feasibility of mobile device food 
tracking. This study aims to recruit 20 patients with HSD or EDS and make preliminary observations 
regarding the effects of integrative medical care on pain reduction and improved quality of life. We will 
capture current patient assessments of chronic illness care and living with a chronic illness among 
patients with HSD or EDS as well any associations between pain, quality of life, and diet. If the 9-week 
integrative medicine intervention shows the potential to be an appropriate program for patients with 
HSD or EDS, results from this study could be used to inform the healthcare community around ways to 
better support this unique population, and those same methods could be translated into a larger study 
and may contribute to further scientific research. 
 
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