An AHEI Dietary Intervention to Reduce Pain in Women With Endometriosis
Phase: NA
Conditions: Endometriosis
Sponsor: Fred Hutchinson Cancer Center

Version 6.0 Date 07.30.24 
 
 
 
 
 
 
 
 
 
An AHEI Dietary Intervention to Reduce 
Pain in Women with Endometriosis 
Protocol Version 6.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Version 6.0 Date 07.30.24 
 
 
Specific Aims 
Endometriosis is a disorder characterized by the presence of endometrial-like tissue outside of the 
uterine cavity. While it affects approximately 10% of reproductive age women in the U.S.,1 it is understudied. 
The etiology of this disorder has not been fully delineated, and few modifiable risk factors have been identified. 
Endometriosis incurs significant health care costs and high morbidity, and can also have significant social and 
psychological effects that impact quality of life (QOL).2,3 Over 80% of women with endometriosis report chronic 
pelvic pain (CPP).4 Among women with endometriosis who participated in the U.S. National Health Interview 
Survey, 50% reported an average of 18 days of bed rest in the previous year,5 estimated to cost the U.S. 
economy $14.7 million annually due to lost work productivity.6 Treatment options currently include hormonal 
suppression and surgery, but pain continues to persist in many women despite these interventions.7 The 
primary objective of our study is to investigate whether endometriosis symptomatology, specifically pain, poor 
QOL, and inflammation, can be reduced or alleviated through alterations in diet. 
Our research on diet and subsequent laparoscopic diagnosis of endometriosis in the Nurses’ Health 
Study II (NHSII) suggests that some dietary factors are more strongly associated with endometriosis diagnosed 
because of pain symptoms, compared to endometriosis diagnosed during an infertility work-up.8-11 Most 
recently, we observed that adherence to the Alternate Healthy Eating Index (AHEI-2010)12 was associated with 
a decreased risk of laparoscopically-diagnosed endometriosis among women experiencing pain symptoms.9 
These results support the hypothesis that diet may impact pelvic pain among women with endometriosis. 
Prostaglandin metabolism, cytokines and inflammation, and smooth muscle contractility are some of the 
factors that play a role in pain processes, and each of these can be influenced by diet.13-17  
Although there are multiple lay publications based primarily on anecdotal evidence about the 
effectiveness of dietary modifications for the treatment of endometriosis,18-22 there is no evidence from 
randomized controlled trials (RCTs) and few observational studies to support these claims. The few RCTs to 
modify endometriosis symptoms have focused on dietary supplements,23,24 and to our knowledge, no 
randomized interventions have assessed the effect of adherence to specific dietary guidelines on 
endometriosis symptoms. The lack of adequately designed RCTs is a critical barrier to our ability to provide 
evidence-based dietary advice for women with endometriosis-associated pain.  
The overall goal of this study is to evaluate the effects of a 12-week dietary intervention among 
premenopausal women aged 18-45 years, with laparoscopically-confirmed endometriosis who had a pain 
score of at least 6 out of 10 on the Visual Analog Scale (VAS) in the three months prior to study entry. Up to 
110 participants will be randomized to a 12-week dietary intervention (n=55) or a control group (n=55). The 
intervention will consist of a diet based on the AHEI-2010 guidelines. The intervention will be delivered by a 
behaviorally-trained dietitian including one baseline teaching session followed by weekly telephone-based 
phone support. The intervention group will receive meals, including preparation instructions, shipped directly to 
their home during the first 4 weeks of the intervention. For the remaining 8 weeks, meal plans and recipes will 
be provided. Adherence will be assessed using plasma carotenoid concentrations at baseline, 4 and 12 weeks, 
and analysis of 4-day food records. The control group will maintain their usual diet for the duration of the study. 
They will be offered the dietary intervention materials and one individual meeting with a study dietitian after 
completion of the 12-week study. Pain and quality of life will be assessed at baseline, 4, 8, and 12-weeks using 
validated questionnaires following the guidelines of the World Endometriosis Research Foundation (WERF) 
Endometriosis Phenome and Biobanking Harmonization Project (EPHect).25 Circulating levels of inflammatory 
markers will be assessed at baseline, 4, 8, and 12-weeks among a subset of participants. In addition, longer-
term effects of the intervention will be assessed by examining pain and QOL outcomes at 6 months and 1 year. 
The specific aims are to test the effect of a dietary intervention based on AHEI-2010 guidelines on: 
 
Aim 1. Pain measures among women with endometriosis. Pain will be measured with components of the 
EPHect participant questionnaire including the VAS pain score, the pain catastrophizing scale, and the 
mean number of analgesic and/or opiod pills taken per week.  
Aim 2. Physical and mental QOL components measured with the Endometriosis Health Profile 
Questionnaire and Short Form-12 Survey.   
Aim 3. Circulating levels of inflammatory markers (interleukin (IL)-6, IL-1β, high sensitivity-C-reactive 
protein, soluble tumor necrosis factor (TNF) -receptor 1, and soluble TNF -receptor 2).  
 
Impact: Many women with endometriosis experience poor QOL due to chronic pelvic pain and other physical 
and mental sequelae of endometriosis. As symptoms are often not sufficiently abated with hormonal 

Version 6.0 Date 07.30.24 
 
suppression or surgery, the identification of other evidenced-based, modifiable factors, that improve pain and 
QOL are critical to improving the lives of the tens of millions of women with endometriosis.   
 
Research Design and Methods 
Design overview 
The proposed RCT will test the effects of a diet intervention based on the AHEI-2010 guidelines compared to 
control (no dietary changes) on pain, QOL, and inflammatory markers in premenopausal individuals with 
laparoscopically-confirmed endometriosis. Up to 110 individuals will be randomized (55 each to intervention 
and control groups). Participants will be recruited primarily through Kaiser Permanente Washington, with 
additional patients recruited from Virginia Mason and Swedish Medical Centers, other clinical and research 
partners, Facebook, mass media, and community partners (numbers described in more detail under 
recruitment below). Potential participants will undergo several screening activities so that we select people who 
will be likely to succeed in the intervention, and for whom the outcome measures will be unbiased. The 
intervention will be 12-weeks long with pain, QOL, and inflammatory markers assessed at baseline, 4, 8, and 
12-weeks. Longer-term effects of the intervention will be assessed by examining pain and QOL outcomes at 6 
months and 1 year.   
 
Eligibility 
People will be eligible if they report laparoscopically-confirmed endometriosis, are premenopausal (at least one 
period in the past 6 months), aged 18-45, report a VAS pain score of at least 6 out of 10 in the previous 3 
months on the screening assessment, and score below 75 on the AHEI-2010. This age range is appropriate 
given that the symptoms of endometriosis continue throughout the reproductive years.26 People will be 
ineligible for enrollment if they are postmenopausal, pregnant, have had a hysterectomy or oophorectomy, 
have chronic illnesses that are known to affect gastrointestinal absorption of nutrients (celiac disease, Crohn’s 
disease, ulcerative colitis, or cystic fibrosis), or a history of kidney stones, cancer (except basal cell 
carcinoma), or diabetes. Those with a history of irritable bowel syndrome (IBS) will not be excluded. As there is 
no diagnostic test for IBS and as laparoscopy is required to definitively diagnosis endometriosis, the 
overlapping symptoms 27 often make it difficult to disentangle the two conditions. People with endometriosis 
may be misdiagnosed with IBS,28,29 especially prior to laparoscopic surgery to diagnosis endometriosis, and 
studies suggest a significant comorbidity between the two disorders.29,30 As the focus of our intervention is to 
alleviate pain among people with endometriosis, we have chosen not to exclude those who have been 
diagnosed with IBS.  
Participants must be able to come to fill out questionnaires in English or Spanish. Seattle metro area 
participants must be willing to come to in-person visits at the Fred Hutch Prevention Center at at baseline, 4, 8, 
and 12-weeks. In addition, all participants must be willing to be randomly assigned to intervention or control. 
This dietary trial will be testing adjuvant dietary treatment in addition to the participants’ current clinical 
standard of care. Participants will hence be allowed to continue medical treatment of their endometriosis 
throughout the trial per standard of clinical care, with medications such as combination estrogen and 
progesterone hormonal preparations, oral and injectable progesterone, intrauterine device, gonadotropin 
releasing hormone agonist, and pain medications as determined by their primary endometriosis-treating 
physician. However, participants will be required to discontinue all vitamins and nutritional supplements from 
the time of enrollment through the final 12-week evaluation. Participation will not begin sooner than 6 weeks 
following surgery for endometriosis. 
 
Recruitment 
Kaiser Permanent Washington 
Our primary recruitment strategy will be to approach people who are enrolled at Kaiser Permanente 
Washington, an integrated healthcare system headquartered in Seattle. Potentially eligible KPW members 
aged 18-45 years will be initially identified using KPWHRI electronic administrative and clinical data. 
International classification of Disease, 9th and 10th revisions (ICD-9 and ICD-10) diagnosis codes for 
endometriosis (ICD-9 codes 617.0-617.5, 617.8, 617.9, excluding 617.0 adenomyosis without endometriosis; 
ICD-10 codes N80.1-80.4, 80.8, N80.9, excluding N80.0) coupled with same-day Common Procedural 
Terminology (CPT) and ICD procedure codes for laparoscopy/laparotomy will be used to identify women who 
have undergone surgery likely for diagnosis of endometriosis. Hysterectomy/oophorectomy status will be 
ascertained using administrative data (CPT codes) and surgical history information from the Clarity reporting 
database of KPW’s EPIC electronic health record, and women with evidence of these surgeries will be 

Version 6.0 Date 07.30.24 
 
excluded. Based on preliminary data of KPW women residing in Western Washington, we anticipate 534 
people will meet these criteria during the proposed study. We will review the medical records of these 
potentially eligible individuals to confirm diagnosis of endometriosis from the pathology report associated with 
the laparoscopy/laparotomy surgery, and to confirm exclusion criteria (see Eligibility section). Individuals 
meeting these criteria after medical record review will be contacted via a mailed recruitment letter with study 
details and invited to participate in a 15-minute telephone interview. Consenting individuals who complete the 
telephone screening to confirm eligibility will be provided instructions to enroll in the study at Fred Hutch. We 
expect to send recruitment letters to ~500 eligible members of KPW, we expect ~400 to be interested.  
 
Social media recruitment 
We will work with Fred Hutch Communications to recruit participants through Facebook advertisements. 
Targeted Facebook and other social media advertisements have been successfully used for clinical trial 
recruitment31 including for studies of reproductive health32-34 and nutritional interventions,35,36 often at lower 
cost than traditional recruitment methods.32,35,37,38 We are confident this recruitment strategy will be even more 
effective for our younger target population as many endometriosis support organizations operate group pages 
through Facebook. In addition, this type of targeted advertising can be used to increase study diversity by 
offering the possibility of targeted ads by zipcode.31  
 
Clinical/Research partner recruitment 
We will also recruit women from health care providers (e.g., Virginia Mason, Swedish Medical Center affiliated 
providers) through fliers and brochures placed at clinics. We will also advertise the study to participants of 
ongoing endometriosis observational studies such as the Boston Center for Endometriosis Women’s Health 
Study: From Adolescence to Adulthood.  
 
Pilot study participants 
In addition, we will contact 114 women from our pilot study who provided contact information in order to be 
invited to participate in future studies. Fred Hutch Communications can also assist with recruitment by 
arranging timely news stories on local television channels and web-based news outlets. This strategy has been 
used successfully with previous studies of Dr. McTiernan.  
 
Racial/ethnic diversity 
To ensure adequate recruitment of minority individuals we will use the services of the Fred Hutch minority 
outreach department if we are not meeting our minority recruitment goals (12% Asian, 10% Hispanic, 8% 
Black) which have been set to reflect the racial and ethnic distribution of the Seattle area population while 
taking into account that the rate of surgically-confirmed endometriosis diagnosis observed among women of 
color is approximately ~2/3 that of non-Hispanic white women.26,39  
 
Screening 
A rigorous multi-level screening process is proposed to insure a highly motivated, adherent group of 
participants. The steps include:  
1) Phone screening questionnaire/interest survey: age, menopausal status, pain measures, medication 
use, medical history, current work schedule and other time commitments, and plans to remain in the 
local area for the ensuing 6 months, participation or planned participation in other dietary programs, 
and willingness to enter a randomized study. This screening will be conducted by KPW for preliminarily 
eligible KPW members who will then be connected with Fred Hutch for study enrollment. For 
participants recruited through all other recruitment methods Fred Hutch staff will conduct the initial 
screening. If individuals are deemed eligible they will be given instructions on a 3-day food diary to be 
further used as a screening tool to determine if the woman can self-monitor.  
2) Consent appointment and FFQ completion for screening prior to randomization: sign informed consent 
form, review 3-day food diary, and FFQ assessments.  
3) If randomized to the intervention they will also have an individual meeting with a dietitian following the 
baseline visit (described below).  
 
 
Randomization Procedures 
People will be randomized into one of the 2 study arms by permuted blocks randomization (N=55 to each arm) 
with block randomization by oral combination hormone therapy (CHT) use. Dr. Wang will create a 

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randomization program that will: 1) assess CHT use (yes/no), 2) within CHT group tables will contain a random 
sequence of 0 (control), 1 (intervention). The following study personnel will be masked to participant study arm: 
laboratory staff performing assays, study staff reviewing forms and entering data, and the study investigators. 
Only the statisticians, study manager, and research dietitian will be fully unblinded. After randomization, the 
intervention subjects will meet with the dietitian. Up to 110 participants will be randomized into the 2 study 
arms. Analysis of final outcomes will be determined by statisticans and investigators blinded to treatment 
groups. 
 
Dietary Intervention 
Recognizing the difficulty of achieving dietary change, the intervention is designed to maximize success by 
behavior modification skills combined with training in diet change; frequent contacts to provide support for 
behavior change; a dietary intervention that provides meals shipped directly to each participant’s home for the 
first 4 weeks, meal plans and restaurant recommendations for ease of adherence, multi-menu options that 
allow flexibility, and sensitivity to cultural differences; a combination of a structured protocol (in which all 
participants receive certain common information) and the flexibility to tailor strategies individually to help a 
specific participant achieve and maintain the study goals. Dr. Harris, in consultation with Drs. McTiernan and 
Duggan, will provide ongoing oversight, training, and support for nutrition intervention staff.   
 
AHEI-2010 Intervention 
Goals 
The AHEI-2010 intervention will be based on our modification of the DPP curriculum.40 The DPP was 
developed as a set of 16 sessions aimed at reducing weight and increasing exercise. We will modify the 
sessions as needed to correspond with our intervention goals by focusing on the diet modification components 
of the DPP (details below). The DPP Program emphasizes the importance of tailoring the intervention for 
different clinical populations to allow for flexibility within a common protocol. The overall goals for the 
intervention group will be:  
1) achievement of an AHEI-2010 score of 100 (maximum score=110; 90% score adherence) during the 
weeks when participants are provided two meals and one snack/day;  
2) achievement of an AHEI-2010 score of 90 (82% score adherence) when participants are responsible 
for preparing their own meals based on provided recipes.  
Approximately 80% adherence during weeks 5-12 of the intervention is consistent with adherence rates 
achieved in our previous studies.41,42 To our knowledge, no previous intervention studies have been based on 
the AHEI-2010, however, a dietary intervention among participants with type II diabetes reported a statistically 
significant change in AHEI score from baseline to 22-weeks among participants assigned to a vegan diet 
(mean increase in score=22.5),43 providing evidence that targeted dietary interventions can increase AHEI 
score. An average AHEI-2010 score of 69 was observed in our pilot study, indicating that among our target 
population (people suffering from painful endometriosis), ample room for AHEI-2010 score improvement exists.  
 
Behavioral modification 
The intervention utilizes strategies that have been shown to be most effective for dietary change. These 
include a multicomponent approach to intervention (including behavioral techniques and diet modification), and 
ongoing regular contact throughout the follow-up period. The diet intervention will be conducted by dietitians 
with training in behavior modification. The dietitian will hold one teaching session (either in-person, telephone, 
or video based [e.g., Microsoft Teams]) at baseline followed by weekly telephone-based or video based 
sessions/support and two additional teaching sessions at weeks 4 and 8. From the original DPP diet-focused 
sessions, we will create sessions with information about the AHEI-2010 diet components, diet and behavior 
strategies such as self-monitoring, goal setting, stimulus control, problem solving, as well as eating out 
strategies, managing stress, and motivational techniques. For goal setting we will replace the weight loss and 
fat intake goals from the original DPP with goals focused on AHEI adherence overall as well as adherence to 
each of the individual AHEI-2010 components. The AHEI-2010 is based on a 11 components with a 0-10 
scoring system for each component which allows for ease of self-monitoring. Specific to this intervention, we 
will not include brussels sprouts, cauliflower, or cabbage in our meal plans more than once per week per food 
serving (described below) since we observed an increased risk of laparoscopically-diagnosed endometriosis at 
levels that exceed 1/week with these individual food items in the NHSII.10 
In consultation with the study dietitian, participants can target individual AHEI-2010 components for 
daily/weekly goals. Importantly, as this is not a weight loss trial, the goal of intervention will be to focus on 

Version 6.0 Date 07.30.24 
 
meeting AHEI-2010 components, not on reducing caloric intake. To facilitate this the AHEI meal plan and meal 
delivery (described below) will be tailored to provide food and portion size recommendations that meet the 
estimated energy needs of individual participants. This strategy has been used in previous intervention 
studies.44,45 Of note, endometriosis is more common in lean women,46-48 thus in the event that unintended 
weight loss as a consequence of AHEI-2010 occurrence occurs, it is unlikely to unduly influence the study 
results. According to the DPP, self-monitoring is considered one of the most effective approaches to change 
dietary intake and thus will be a critical component of the intervention. Participants will be asked to record their 
food intake daily to encourage dietary behavior change and promote AHEI-2010 adherence (detailed below). 
Participants will be given self-monitoring tools including: list of common foods high in AHEI components (e.g., 
whole grains, long-chain (n-3) fats [EPA+DHA], PUFA) and low in AHEI components (e.g., trans fat, sodium), 
and a pocket-sized food log or recommended food tracking app if preferred.   
 
Procedures to Enhance Intervention Adherence 
One of the greatest challenges with dietary interventions is ensuring adherence to the prescribed 
intervention in order to enable the most accurate assessment of intervention effectiveness. An innovative 
aspect of this study is that for the first 4 weeks of the intervention we will provide shipped meals for intervention 
arm study participants. This will occur in two formats: 1) Seattle metro area based intervention participants will 
receive complete meals and preparation instructions for 2 meals/day, one snack, and one dessert to the 
participants shipped directly to their home (total of 56 meals received, 28 snacks, and 28 desserts received 
over 28 days). 2) Non-Seattle metro area based intervention participants will receive frozen meals and 
snacks/desserts shipped directly to their home along with instructions of for preparation of additional food items 
(total of 28 full meals and 28 snacks/desserts received over 28 days). This will strongly support adherence and 
will provide the participants with examples of AHEI-2010 based meals to use as a framework for future meals 
they will prepare for themselves during weeks 5-12. This meal delivery service will also substantially reduce 
participant burden in regards to travel time compared to controlled feeding studies which require participants to 
pick-up meals or consume meals at the study site. This will also allow for a wider geographic recruitment area. 
Data from our AHEI pilot study demonstrate that the dietary intervention is effective in improving AHEI score 
and lowering inflammatory biomarkers in the absence of meal shipment (where participants prepare their own 
meals the entire 12 weeks) thus both our meal shipment options will strongly support greater adherence to the 
intervention.  
Following the 4 weeks of meal delivery, to further facilitate adherence we will provide participants with a 
14-day meal plan (3 meals and 2 snacks) that adheres to the AHEI-2010 maximum score criteria. We will also 
provide suggestions of meals at local and chain restaurants that are most adherent to the AHEI-2010 and will 
suggest substitutions for popular consumed foods items that will help promote AHEI-2010 adherence. See an 
example of the meal plan in Table 2.  Culturally appropriate dietary options will be incorporated when 
appropriate by 
tailoring teaching 
and study materials. 
For example, 
dietitians will 
provide examples of 
food substitutions 
based on cultural 
dietary options and 
patient baseline 
FFQ responses 
(e.g. substituting 
mango for samosa 
as a snack for 
Asian Indian 
participants). As necessary, recipes will be adapted for minority partcipants as was done in the DPP’s lifestyle 
change program.  
 
 
Adherence Assessment 
Four methods will be used to assess and/or encourage adherence in the intervention group. 1) Daily 
completion of food logs (on-line or paper based on patient preference) will be encouraged to support 
Day 1
Day 2
Day 3
Day 4
Breakfast
Oatmeal
All bran cereal
Oatmeal
Sprouted Wheat toast
Suggested
Berries
Apple
Berries
Banana
Greek yogurt
Greek yogurt
Boiled egg
Nut butter
Lunch
Collard Wrap
Turkey Barley soup
Chicken salad sandwich
Tabouli/hummus
Shipped
Veg/hummus/sunflower seeds Green salad/HNL vinaigrette
Sprouted wheat bread
Veggie sticks
Soba noodles (buckwheat)
Parmesean cracker
Cucumber salad
Flax crackers
Orange
Kiwi
Dried mango
Apple
Dinner
Ginger chicken stir-fry
Cod, seasoned poached
Lentil/veggie marinara
Salmon, poached wine sauce
Shipped
Brown rice
Mexi Bowl/Quinoa pilaf
Whole grain pasta
Barley pilaf
Broc/Peppers/Carrots
Slaw/edamame/Crema sauce
Green salad/HNL vinaigrette
Green beans/red bell peppers
Dessert
Tropical fruit flan
Lemon chia pudding
Millett & PB buckeyes
Blueberry streusel
Snack
Nut butter
Almonds
Walnuts
Edamame
Shipped
Banana
Red grapes
Dried apricots
Green grapes
Table 2. AHEI-2010 4-day meal plan

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participant 
adherence.49 
Study 
dietitians will 
review 
participants’ 
food logs on 
a weekly 
basis. 
Ongoing 
individual 
contacts by 
phone and 
email will be 
an important 
mode of 
counseling in 
between individual sessions and will be adjusted as needed based on adherence. The dietitian will call or email 
all participants between the regular sessions with the following objectives: evaluation of success in meeting 
goals; problem solving of barriers to adherence; the development of specific plans for coping with problems; 
and the provision of reinforcement and social support. Importantly, we believe that women with endometriosis 
suffering from chronic pelvic pain are a highly-motivated group for a dietary intervention, and the high-
motivation of this group will be a strong asset in regards to participant adherence. The number of daily food 
logs completed will be expressed as a percentage of expected completions (total number of days of the 
intervention). This approach has been used successfully in our other studies.41 2) To more rigorously assess 
adherence by calculating the AHEI-2010 score, intervention participants will complete 3-day food records at 3-
time points (weeks 3, 7, and 11) during the 12-week study. Three time-points were chosen to balance accurate 
assessment of dietary intake with the documentation burden on participants.50 These records will be analyzed 
with the Nutrition Data System for Research Software. Measures of adherence to the AHEI-2010 will include 
mean, intervention-group AHEI-2010 score which will be compared to our study goals of the intervention arm 
(described above under Goals). 3) In both groups (intervention and control), plasma carotenoids will be 
measured at weeks 0, 4, and 12 as an objective measure of intervention adherence.51 4) FFQs will also be 
administered to both groups at baseline, 4, 8, and 12-weeks, 6 months, and 1 year in order to assess change 
in adherence during the intervention period and at 6 months and 1 year as participants will not be asked to 
complete food records at the later two timepoints (post-intervention follow-up described below). The 120-item 
FFQ was developed for the WHI and has been validated against 4-day food records and 24-hour dietary 
recalls.52 To calculate the AHEI-2010 score, each of the individual food items will be summed into 11 
components, described in Table 1 below. 
 
Controls 
During the 12-week study period the controls will not receive any intervention and will be asked to consume 
their usual diet as is considered appropriate for a trial of this type.53 After the study period is complete, 
including visits at baseline, 4, 8, and 12-weeks, the controls will be provided with study materials including the 
meal plan and suggestions of AHEI-2010 adherent meals at restaurants. In addition, we will offer them one 
individual meeting with a study dietitian and $100 after completing the study. Since no current dietary treatment 
standard exists for endometriosis having a ‘no active intervention’ control group is an appropriate and valid 
choice.54 
 
Baseline and Follow-up Assessments 
Outcomes will be measured at screening, baseline, 4, 8, and 12-weeks. In addition, longer-term effects of the 
intervention will be assessed by examining pain and QOL outcomes at 6 months and 1 year. All of the data will 
be collected following the guidelines of the World Endometriosis Research Foundation (WERF) Endometriosis 
Phenome and Biobanking Harmonization Project (EPHect). Importantly, the EPHect questionnaire 
development focused on selecting questions and rating scales that were validated in the literature and are 
recommended for use in women with endometriosis. In addition, EPHect researchers piloted these questions 
among endometriosis patients before finalizing the questionnaire.25,39  
Fruits (servings/day)
0
≥4
1 medium piece of fruit or 0.5 cup 
Vegetables1 (servings/day)
0
≥5
0.5 cup vegetables or 1 cup of leafy greens
Whole grains (grams/day)
0
75
0.5 cup of 100% whole grain product (≈15-20 g)
Sugar-sweetened beverages or fruit juice (servings/day)
≥1
0
8 oz
Nuts, legumes, and other vegetable protein2 (servings/day)
0
≥1
1 oz or 1 tablespoon (15mL) of nut butter
Red/processed meat (servings/day)
≥1.5
0
4 oz of unprocessed meat or 1.5 oz of processed meat
Trans fat (% of energy)
≥4
≤1.5
Long-chain (n-3) fats (EPA+DHA) (mg/day)
0
250
2 ≈4 oz servings of fish/week
PUFA3 (% of energy)
≤2
≥10
Sodium4 (mg/day)
Highest decile
Lowest decile
Alcohol (drinks/day)5
≥2.5
0.5-1.5
4 oz of wine, 12 oz of beer, or 1.5 oz of liquor
Total points
0
110
1Does not include potatoes. 2Includes tofu. 3Does not include EPA or DHA intake. 4Lowest decile ≤1112 mg/day and highest decile ≥3337 mg/day. 
5Non-drinkers receive a score of 2.5
Table 1. The AHEI-2010 components, scoring method, and serving sizes31
Minimum 
score criteria
Maximum 
score criteria Serving size
Component

Version 6.0 Date 07.30.24 
 
 
Pain (Aim 1) 
Pain will be measured with components of the EPHect questionnaire using the Visual Analogue Scale (VAS) 
pain score, the pain catastrophizing scale, and mean number of analgesic and opiod pills taken per week at 
baseline, 4, 8, and 12-weeks. The baseline questionnaire will ask about pain in the three months prior to 
baseline while all other questionnaires will refer to the preceding period (e.g., 4-week questionnaire will ask 
about pain between baseline and week 4). At baseline and weeks 4, 8, and 12 the questionnaires will be 
completed at a clinic visit. The 6 month and 1 year assessments will be completed on-line. The VAS pain score 
is a validated scale that measures pain on a scale of 0-10 with 10 being the greatest amount of pain.55 As 
women with endometriosis experience a variety of pain symptoms, including pain during their period 
(dysmenorrhea), noncyclical pelvic pain, and pain during vaginal intercourse/penetration (dyspareunia), we will 
assess a participant’s VAS pain score for both dysmenorrhea, pelvic pain not related to a participant’s period, 
and dyspareunia. Questions related to dysuria (painful urination) and dyschezia (painful defecation) are 
embedded in the questions for each of the pain types mentioned above. Pain catastrophizing, defined as “an 
exaggerated negative mental set brought to bear during actual or anticipated painful experience”56 will be 
assessed with the Pain Catastrophizing Scale, a validated measure of pain sensitivity.57 It will be evaluated on 
a scale of 0-52, with higher scores indicating a greater amount of catastrophizing (e.g., “I think that the pain will 
never improve”). As suggested by the EPHect guidelines we will place the pain catastrophizing questions 
before other pain related questions.25 Frequency of pain medication usage in the preceding period will be 
assessed including type of medication, days/week, tablets/week, and what type of pain this medication was 
used for (pelvic pain, other pain, or both).  
 
Quality of Life (Aim 2) 
Physical and mental QOL will be measured in participants at baseline and follow-up using the Endometriosis 
Health Profile (EHP-30) and Short Form Survey (SF-12). The EHP-30 is a reliable and valid instrument that 
has been designed specifically for use in women with endometriosis.58-60 It contains 30 items that we will use to 
address five domains (emotional well-being, control and powerlessness, social support, self image, and pain). 
Scores for the EHP-30 range from 0 to 100 with lower scores reflecting fewer symptoms and indicating better 
health status. The EHP-30 has been demonstrated to be sensitive to changes in health status and is suitable 
for detecting clinical changes in patients’ health status over time.60 The SF-12 is a validated survey that 
measures an individual’s perception of their general health status during the past four weeks using eight 
dimensions (physical functioning, social functioning, role limitations due to physical problems, role limitations 
due to emotional problems, mental health, energy and vitality, pain, and general perception of health).61,62 Two 
global scores are calculated, a physicial component summary (PCS) and a mental health component summary 
(MCS). The scores have a range of 0 to 100 with higher scores representing better health. While not created 
specifically for women with endometriosis the SF-12 is considered appropriate for use in these women 
according to the WERF EPHect guidelines.25 
 
Inflammatory markers (Aim 3) 
Among Seattle metro area based participants blood (50 ml) will be collected, labeled with study ID and date. 
Serum will be centrifuged after clot formation, and aliquoted into 1.8-ml aliquots and stored at -80 degrees C 
until time for analysis. Samples will be collected at baseline, 4, 8, and 12-weeks and all samples from the same 
participant will be assayed simultaneously to reduce inter-assay variation. Frozen serum aliquots will be 
shipped in sealed containers in dry ice to Boston Children’s Hospital in the CERLab, Department of Laboratory 
Medicine, that is certified by the National Heart, Lung, and Blood Institute/Centers for Disease Control and 
Prevention Lipid Standardization Program (see LOS). An equal number of intervention and control participants’ 
serum will be assayed at one time and all assays will be conducted without knowledge of intervention status. 
Each batch will include 10% blinded replicate samples for quality control. We will use a tracking system for all 
blood specimens based on ones developed for our previous studies. We will measure the following 
inflammatory cytokines: IL-6, IL-1β, CRP, sTNFR-1, and sTNFR-2. The sTNF receptors will be measured 
instead of TNF-α  as they are produced by the proteolytic cleavage of TNF cell surface receptors following 
induction by TNF or other cytokines. They have a longer half-life than TNF and are detected with a higher 
sensitivity. Levels of IL-6, IL-1β, sTNFR-1, and sTNFR-2 will be measured by immunoassay (R&D Systems, 
Minneapolis, MN). hsCRP levels will be measured using a high-sensitivity latex-enhanced 
immunonephelometric assay on a BNII analyzer (Dade Behring, Newark, DL). In repeated testing across 
several of our studies, this laboratory has been found to have consistently high precision in all of their assays 

Version 6.0 Date 07.30.24 
 
(all interassay coefficients of variation (CVs) <15%, <10% for IL-6, TNF-R1, and TNF-R2, and <5% for 
CRP), and this laboratory has previously carried out the assays specific to this proposal with great success. 
Although most inflammatory markers do not vary largely by menstrual cycle phase63 we will collect information 
on cycle day at blood collection, and conduct a sensitivity analyses stratifying by cycle phase.   
 
Carotenoids 
Blood collection procedures are described above. Plasma carotenoids will be measured in samples collected 
at weeks 0, 4, and 12 by the Harvard T. H. Chan School of Public Health Nutritional Biomarker Laboratory. 
Concentrations of alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene, lutein+zeaxanthin, retinol, 
alpha- and gamma-tocopherol will be measured as described by El-Sohemy et al64 using high-performance 
liquid chromatography. Because lutein and zeaxanthin co-elute on the chromatogram, the two are grouped and 
provided as lutein+zeaxanthin. The between-run CVs for alpha-carotene, beta-carotene, beta-cryptoxanthin, 
lycopene, lutein+zeaxanthin, and the tocopherols are generally ~5% in plasma. 
 
Covariates 
Participants will complete a questionnaire including epidemiologic variables and clinical information that is 
consistent with WERF EPHect recommendations.25  
 
Post-intervention Follow-up 
Participants will complete on-line follow-up questionnaires 6 and 12 months after randomization where the 
following will be assessed: pain measures (VAS pain score, pain catastrophizing scale, mean number of pain 
pills taken per week), QOL (EHP-30 and SF-12), and FFQ (to assess AHEI-2010 adherence). They will also 
complete a follow-up questionnaire that will update information on medical history, medication use, 
psychosocial variables, and other covariates. The purpose of the post-intervention follow-up is not to compare 
intervention and control groups but to assess: 1) if intervention participants chose to continue adhering to the 
AHEI-2010 after the 12-week intervention period is over; 2) assess how pain and QOL are affected by AHEI-
2010 adherence in a less supportive, non-intervention setting; 3) assess if the control group, who was provided 
with study materials and one individual meeting with a study dietitian, was able to improve their AHEI-2010 
score in the absence of the intensive intervention and if changes in AHEI-2010 adherence influenced pain and 
QOL measures at 6-months and 1 year.  
 
Protection of Human Subjects 
Risks to Human Subjects 
Sources of Material  
Study participants will donate blood, stool (optional), and saliva (optional) specimens for biomarker 
measurement. Participants will also report pain measurements, assess with components of the EPHect 
participant questionnaire including the VAS pain score, the pain catastrophizing scale, and mean number of 
analgesic and/or opiod pills taken per week. Physical and mental QOL components measured with the 
Endometriosis Health Profile Questionnaire and Short Form-12 Survey. They will also complete a self-
administered questionnaire including epidemiologic variables and non-surgical clinical information that is 
consistent with WERF EPHect recommendations. This includes information on endometriosis history including 
treatment(s), other medical and reproductive history, and psychosocial variables. In an optional sub-study 
participants will complete the Perceived Stress Scale.   
All enrolled participants are assigned a unique study ID. This number will be used on study paperwork 
rather than personal identifiers. Access to personal identifying information is determined by the principal 
investigator (and KPWHI site PI for KPW participants) and is limited to research staff responsible for direct 
patient contact, the study manager, and interviewer. Electronic data is maintained in a password-protected 
computer database. Hard copy records are stored in locked file cabinets. Blood and tissue specimens are 
collected and stored at -70 degrees C until time for analysis (in FHCRC CERC freezers). All human material 
referenced above is used expressly for research purposes. The following people and government agencies 
may get access to subject identities: (1) Authorized study research staff (2) NIH, and (3) Institutional Review 
Boards at FHCRC and KPWHRI. 
 
Potential Risks  
The potential risks of participation on this protocol involve the process of obtaining blood samples. 
Participants may experience some discomfort during the blood draw and may also develop a bruise or swelling 

Version 6.0 Date 07.30.24 
 
at the site of the needle puncture. There may also be an increased risk of light-headedness or fainting as a 
result of the draw. To minimize risk, a maximum of 50 ml of blood for research purposes will be obtained by a 
person experienced and certified in phlebotomy (i.e. study research nurse or specimen collection specialist) at 
each study visit (baseline, 4, 8, and 12-weeks). Individuals with medical conditions that contraindicate 
phlebotomy will not be included in this study. Risks will be described in detail in the study Consent Form and 
will be reviewed with the woman by a trained study staff member during the baseline visit prior to giving 
informed consent. Tubes of blood will be marked with a code identifying the blood by a study ID. There is a 
small risk to participants’ confidentiality. We will take measures described below to avoid this.  
Although the AHEI-2010 diet is a healthy diet which is likely to have a positive impact on the participant, 
unknown food intolerances/allergies are also a potential risks. Participants will be asked to report any potential 
adverse reactions to particular foods and study nutrionistis will make adjustment to meals/snacks as needed.  
Participants may feel slightly uncomfortable answering some of the questions about their endometriosis 
symptoms and treatment or collecting stool or saliva samples (optional). 
 
Adequacy of Protection Against Risks 
Recruitment and Informed Consent  
Up to 110 people will be recruited and randomized to a 12-week dietary intervention (n=55) or a wait-list 
control group (n=55), eligibility criteria include premenopausal individuals aged 18-45 years, with 
laparoscopically-confirmed endometriosis who had a pain score of at least 6 out of 10 on the Visual Analog 
Scale (VAS) in the three months prior to baseline. We will recuit individuals through a variety of mechanisms. 
Our primary recruitment strategy will be to approach individuals who are members of Kaiser Permanente 
Washington. People with laparoscopically-confirmed endometriosis who are potentially eligible first will be 
identified through the KPWHRI database using ICD and procedure codes followed by chart review to confirm 
eligibility and exclusion criteria. KPW members meeting eligibility criteria after medical record review will be 
contacted via a mailed recruitment letter with study details and invited to participate in a 15-minute telephone 
interview. Consenting individuals who complete the telephone screening to confirm eligibility will be provided 
instructions to enroll in the study at FHCRC. Secondary recruitment strategies include: 1) potentially eligible 
individuals from health clinics (e.g., Swedish Medical Center, Virginia Mason) and endometriosis observation 
studies (e.g., Boston Center for Endometriosis Women’s Health Study: From Adolescence to Adulthood). 2) 
FHCC Communications & Marketing Department will recruit participants through Facebook advertisements. 
People will be directed to our study website where they will complete a screening questionnaire and, if initially 
eligible, will be given the option to provide their contact information in order to have our study coordinator 
conduct a more detailed phone screening interview. The FHCC minority outreach department will also help 
identify community partners if we are not meeting our recruitment goals. 
 
The study coordinator will conduct the consent at the baseline clinic visit or virtually depending on the current 
COVID-19 situation and participant location and preference as follows: 
 
In-person consenting procedures 
• 
Provide an overall description of the study 
• 
Review the consent with the patient 
• 
Answer patient questions 
• 
Obtain the patient’s signature on the consent form  
 
Remote consenting procedures via phone or via video conference call 
The following remote consenting procedures will be offered to participants during the COVID-19 pandemic to 
reduce in-person time at the Prevention Center as well as to non-local participants. The participant will be 
notified via email (see separate email script) that we are conducting consenting remotely to reduce time at the 
Prevention Center. Once the potential participant has confirmed they can receive the consent via email, the 
study staff will schedule the video/phone consent session. On the scheduled day of the session, the consent 
form will be emailed to the participants. 
• 
At the beginning of the video/phone conference, the study staffer will verify the identity of the 
participant by visually checking a driver’s license or photo id on video conference or asking for the 
participant’s date of birth via phone. 
• 
After verification, the staffer will prompt the participant to follow along as we review the consent form. 

Version 6.0 Date 07.30.24 
 
• 
If the participant has any questions, the staffer will thoroughly answer the question before the consent 
is signed. 
• 
If the individual agrees to be a part of the study, she will sign the consent form and mail, fax, or scan 
the signed page(s) of the document to the study staff.  
• 
After the study staff receives the consent form, they will sign the consent document. 
• 
The staffer will then document that the consent was done via video or phone. The consent document 
will then be placed in the appropriate study file.  
 
If the participant choses to sign the informed consent for the main study they will be asked to donate a blood 
sample (for local participants only) and complete the baseline study questionnaires virtually or at their first 
study visit. The study coordinator will review the questionnaire results to confirm response completeness. 
Following completion of study questionnaires participants will be randomized. Those assigned to 
randomization group will then have their first individual meeting with a study nutritionist.  
 
Protections Against Risk  
Anxiety or Emotional Distress- The study activities will not put study participants at any significant level of risk 
for distress. Staff who will have direct contact with study participants will be given extensive training to prepare 
them to assist women with any concerns they may express. Participants may feel slightly uncomfortable 
answering some of the questions about their endometriosis symptoms and treatment but this is likely to be 
minimal. 
 
Blood Draw- To minimize this risk, a maximum of 50 ml of blood for research purposes will be obtained by a 
person experienced and certified in phlebotomy under the supervision of the Prevention Center medical staff. 
Individuals with medical conditions that contraindicate phlebotomy will not be included in this study. Attention 
will be taken to apply pressure following the procedure to reduce bleeding. There is little risk of anemia in these 
subjects due to the volume of blood drawn (50 ml). 
 
Diet- The diet program will be a diet based on the AHEI-2010, which is a healthy diet. Its key features include 
an emphasis on intake of fruits, vegetables, whole grains, nuts/legumes, long-chain (n-3) fatty acids, and 
polyunsaturated fats, and avoidance of red/processed meat, sugar-sweetened beverages/fruit drinks, and trans 
fats (see Table 1). The goal of the intervention will be to focus on meeting AHEI-2010 components, not on 
reducing caloric intake, so it is not a weight loss trial. Dietary intake will be carefully monitored by study 
nutritionists so little risk from this dietary program is anticipated.  
 
Confidentiality- Names and other personal identifying information about subjects are obtained only for subject 
contact. Personal identifiers will not appear in any computer files used for data analysis. Only study numbers 
will be recorded on each subject’s completed questionnaire and blood samples. Data presented in reports will 
be in the form of statistical summaries, and characteristics of individual participants will not be delineated. 
Only persons directly involved in the study will have access to data identifying individual subjects. All study 
staff with access to identifying information have signed confidentiality oaths and participate in on-going human 
subjects training. Records and forms will be kept in locked file cabinets when not in use. Access to information 
stored in computers will require simultaneous knowledge of data format, file name, and password. All patient 
identifying information (name, address, phone numbers, etc.) is maintained separately from the interview 
data. The only link to such identifying information will be the unique study number assigned to each subject, 
and only the study coordinators have access to this link. We do not share any participant data with other 
researchers without IRB approval. 
 
Adverse Events- Adverse events are not expected. Serious adverse events (death or injury) that could be 
related to study participation or to the intervention will be reported to the IRB using an Adverse Events form. 
The occurrence of serious adverse events more than expected may prompt changes in study protocol. Any 
such change will be approved by the IRB. 
 
Potential Benefits of the Proposed Research to Human Subjects and Others 
To be eligible for the study participants must be people with endometriosis who had a pain score of at least 6 
out of 10 on the Visual Analog Scale (VAS) in the three months prior to baseline as assessed on the screening 

Version 6.0 Date 07.30.24 
 
questionnaire. Participants in the study may may benefit directly from the study if the AHEI-2010 diet reduces 
pain or improves QOL in the participants. This benefit has the potential to apply to both intervention and control 
group since the control group will receive the AHEI intervention meal plan information and one individual 
meeting with a study nutritionist after the initial 12-week study period. However, all participants may not directly 
benefit from the study but their participation may aid in helping researchers gain knowledge in regards to how 
diet may influence endometriosis pain, QOL, and inflammatory markers. In our experience, the majority of 
study participants are happy that they were able to participate in studies such as this, feeling that they have 
made a contribution to our knowledge of endometriosis. In addition, society as a whole will benefit from any 
insight gained.  
 
Importance of Knowledge to be Gained 
To date, no randomized controlled trials of dietary interventions for endometriosis symptoms have been 
conducted. As endometriosis symptoms are often not sufficiently abated with hormonal suppression or surgery, 
the identification of modifiable dietary factors that are evidenced-based that improve pain and QOL are critical 
to improving the lives of people with endometriosis. Risk/benefit ratio. The risks associated with this study are 
minimal. All participants will be carefully screened, so that only people without contraindications to a dietary 
intervention will be enrolled. The risk of minor complications from the blood draw and slight discomfort from 
completing questionnaires on pain and QOL symptoms are described above. The information obtained from 
these measures will give unique information about the influence of the AHEI diet on endometriosis symtoms 
that could have important future impacts on addressing endometriosis related pain.  
 
 
 
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