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| Name | Class |
|---|---|
| University of Oxford | OTHER |
| DHR Health Institute for Research and Development | OTHER |
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The investigators propose to conduct a randomized behavioral trial that will produce a clinically useful multi-level integrative medicine model to be used in stress- and inflammation-related disorders that can easily be implemented with current pharmacological interventions to alleviate pain and improve QoL.
Endometriosis is a chronic inflammatory and painful condition that affects 176 million women in their reproductive years worldwide, and has substantial costs related to health care and loss in work productivity. The symptoms of endometriosis-chronic, incapacitating pain and infertility-cause high levels of stress, leading to poor quality of life (QoL) in affected women. Stress is known to affect the physiology of pelvic organs and to disturb the hypothalamic-pituitary-adrenal (HPA) axis leading to chronic, painful, inflammatory disorders. The team has documented a relationship between stress, HPA dysregulation and endometriosis. In an animal model the team demonstrated that stress exacerbates disease manifestations whereas the ability to control the level of stress results in smaller lesions and less inflammation. Further, the team has identified social support as one of the parameters that most significantly impacts QoL in women with endometriosis. Environmental enrichment (EE) can produce beneficial effects in models of chronic diseases improving anxiety and immune-related disturbances, and can block the effects of chronic stress on brain hippocampal integrity. The team recently found that EE can effectively minimize lesion size and numbers, and also decreased anxiety in this animal model. Together, these data support the basic premise of this proposal: EE interventions can overcome chronic stress thus reversing the negative influences on mental health status (depression/anxiety levels), inflammation/HPA axis (inflammatory cytokines, cortisol), and clinical course (pain levels) of endometriosis, leading to improved QoL. The central objective of this study is to refine and test a multi-modal intervention based on the EE paradigm tested in our animal model and translated it to the human scenario, to produce data on its effectiveness. The team hypothesizes that the EE interventions can be effectively adapted for women with endometriosis resulting in pain reduction and improved QoL. To test our hypothesis, our multidisciplinary team with combined expertise in endometriosis, psychology, physiology, neuroscience, gynecology, and stress management has adapted the experimental EE model to the human scenario. By applying a combined approach (systematic review of the literature, and input from a patient advisory committee) the team has developed six EE modules to be tested in human subjects. This study consists of two specific aims. In aim 1, the team will assess feasibility and acceptability of the EE interventions through a collaborative approach involving a patient population to refine EE modules. Under aim 2, the team will conduct a randomized clinical trial (RCT) of the EE intervention to determine its efficacy in improvement of pelvic pain and QoL (primary outcomes), and inflammation, HPA axis disturbances, and mental health (depression, anxiety) (secondary outcomes), measured before and after the intervention. With this purpose, the team will use a case control study design for the RCT where cases will receive the intervention as an adjuvant to standard gynecologic care for endometriosis, while controls will receive standard of care only. The proposed work will produce a clinically useful multi-level integrative medicine model to be used in stress- and inflammation-related disorders that can easily be implemented with current pharmacological interventions to alleviate pain and improve QoL.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Environmental enrichment | Experimental | Subjects randomized to the intervention condition will receive the environmental enrichment intervention (social support, open spaces, novel stress relief activities) as an adjuvant to standard gynecological care consisting of hormonal, analgesic or surgical treatment as necessary according to their symptoms during the study period. |
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| Controls | No Intervention | Participants randomized to the control condition will receive only standard care as necessary according to their symptoms during the study period plus an online patient training module. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Environmental enrichment | Behavioral | The experimental group will participate in six modules that mimic and integrate the three hallmarks of environmental enrichment: social interaction (more animals per cage = support group meetings, online support), novelty (toys and activities = exposure to new hands-on activities), and larger enclosures (larger cages = meetings in open environments). There will be 2 interventions per month, for three months, and a follow up 3 months after the end of the intervention |
| Measure | Description | Time Frame |
|---|---|---|
| Pain Perception | Mean level of maximum pain using the Visual Analog Scale (VAS), in which 1 is no pain and 10 is the worst pain imaginable. Categories: 1-4 low pain; 5-7 moderate pain; 8-10 severe pain. Therefore, the higher the score in the VAS the higher the pain level. | at baseline, at end of the intervention and 3 months after the end of intervention |
| Quality of Life (QoL) | QoL global impact scores measured using the Endometriosis Health Profile 30 (EHP-30), a disease-specific questionnaire to measure health related quality of life. The EHP-30 was developed by Jones et al., in 2001. Part 1 The first part contains 30 questions relevant to all women with endometriosis covering five areas: pain, emotional well-being, control and powerlessness, social support and self imaging scales. Each domain score is calculated by dividing the total scores of each item in the domain by the maximum possible score of all items in the domain multiplied by 100. Our outcome of interest is the global impact score, calculated as the mean of all completed subscale scores, with a range of 0 to 100. The global impact score ranges from 0 (indicating the best health status) to 100 (indicating the worst health status). No subscales are reported. | at baseline, at end of the intervention and 3 months after the end of intervention (for intervention); at baseline and end of intervention (for controls) |
| Measure | Description | Time Frame |
|---|---|---|
| Perceived Stress Levels 14 | Perceived stress levels will be measured using the Perceived Stress Scale 14 at baseline, end of interventions and 3 months from the end of intervention for the intervention group, but only at baseline and end of the intervention for the control group. The survey asks the following 14 questions about stressful situations and helps determine what stress is to the participant and how stressful they feel their life to be. Higher scores indicate higher levels of stress. The 14 items are scored from 0 to 4. Total scores range from 0 to 56. Score categories are: Low Stress (scores 0 - 18) Moderate Stress (scores 19 - 37) High Stress (scores 38 - 56) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Idhaliz Flores, PhD | Ponce Medical School Foundation | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ponce Medical School Foundation | Ponce | PR | 00732 | Puerto Rico |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36683601 | Result | Nieves-Vazquez CI, Detres-Marquez AC, Torres-Reveron A, Appleyard CB, Llorens-De Jesus AP, Resto IN, Lopez-Rodriguez V, Ramos-Echevarria PM, Castro EM, Flores I. Feasibility and acceptability of an adapted environmental enrichment intervention for endometriosis: A pilot study. Front Glob Womens Health. 2023 Jan 4;3:1058559. doi: 10.3389/fgwh.2022.1058559. eCollection 2022. | |
| 37885745 | Result | De Hoyos G, Ramos-Sostre D, Torres-Reveron A, Barros-Cartagena B, Lopez-Rodriguez V, Nieves-Vazquez C, Santiago-Saavedra F, Appleyard CB, Castro EM, Flores I. Efficacy of an environmental enrichment intervention for endometriosis: a pilot study. Front Psychol. 2023 Oct 10;14:1225790. doi: 10.3389/fpsyg.2023.1225790. eCollection 2023. |
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At this point, no individual patient data will be made available to other investigators
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We completed recruitment for both study cohorts of cases and controls. We started patient recruitment in September 2019 via a social media campaign and regular media (newspaper articles, radio, TV). Printed flyers and posters were distributed among local gynecology offices. Our targeted recruitment was 60 subjects per study group or 120 subjects total for both sessions. By the start of the study we recruited 29 patients in the intervention group and 27 in the control group.
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| ID | Title | Description |
|---|---|---|
| FG000 | Environmental Enrichment | Subjects randomized to the intervention condition will receive the Environmental Enrichment (EE) intervention (social support, open spaces, novel stress relief activities) as an adjuvant to standard gynecological care consisting of hormonal, analgesic or surgical treatment as necessary according to their symptoms during the study period. Environmental enrichment: The experimental group will participate in six modules that mimic and integrate the three hallmarks of Environmental Enrichment: social interaction (more animals per cage = support group meetings, online support), novelty (toys and activities = exposure to new hands-on activities), and larger enclosures (larger cages = meetings in open environments). There will be 2 interventions per month, for three months, and a follow up 3 months after the end of the intervention |
| FG001 | Controls | Participants randomized to the control condition will receive only standard care as necessary according to their symptoms during the study period in addition on participation in an online patient training module. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Environmental Enrichment | Subjects randomized to the intervention condition will receive the EE intervention (social support, open spaces, novel stress relief activities) as an adjuvant to standard gynecological care consisting of hormonal, analgesic or surgical treatment as necessary according to their symptoms during the study period. Environmental enrichment: The experimental group will participate in six modules that mimic and integrate the three hallmarks of EE: social interaction (more animals per cage = support group meetings, online support), novelty (toys and activities = exposure to new hands-on activities), and larger enclosures (larger cages = meetings in open environments). There will be 2 interventions per month, for three months, and a follow up 3 months after the end of the intervention |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Pain Perception | Mean level of maximum pain using the Visual Analog Scale (VAS), in which 1 is no pain and 10 is the worst pain imaginable. Categories: 1-4 low pain; 5-7 moderate pain; 8-10 severe pain. Therefore, the higher the score in the VAS the higher the pain level. | The total of participants is not equal to the total number of participants enrolled because not all participants completed this particular questionnaire of the several instruments they had to complete. | Posted | Mean | Standard Deviation | units on a scale | at baseline, at end of the intervention and 3 months after the end of intervention |
|
Six (6) months
Definition of adverse events is in accord with the clinical trials website guidelines.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Environmental Enrichment | Subjects randomized to the intervention condition will receive the EE intervention (social support, open spaces, novel stress relief activities) as an adjuvant to standard gynecological care consisting of hormonal, analgesic or surgical treatment as necessary according to their symptoms during the study period. Environmental enrichment: The experimental group will participate in six modules that mimic and integrate the three hallmarks of EE: social interaction (more animals per cage = support group meetings, online support), novelty (toys and activities = exposure to new hands-on activities), and larger enclosures (larger cages = meetings in open environments). There will be 2 interventions per month, for three months, and a follow up 3 months after the end of the intervention |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| skin reaction | Skin and subcutaneous tissue disorders | Non-systematic Assessment | A mild and transient irritation to an essential oil was reported by one participant during the aromatherapy session. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Idhaliz Flores | Ponce Research Institute, Ponce Health Sciences University | 787-840-2575 | 2206 | iflores@psm.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 15, 2019 | Aug 24, 2024 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jul 8, 2019 | Apr 14, 2025 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D004715 | Endometriosis |
| D017699 | Pelvic Pain |
| D000292 | Pelvic Inflammatory Disease |
| D007249 | Inflammation |
| ID | Term |
|---|---|
| D005831 | Genital Diseases, Female |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
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In this RCT study, subjects randomized to the intervention condition will receive the Environmental Enrichment (EE) intervention as an adjuvant to standard gynecological care consisting of hormonal, analgesic or surgical treatment as necessary according to their symptoms during the study period. Participants randomized to the control condition will receive only standard care as necessary according to their symptoms during the study period in addition to an online patient training online seminar.
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Investigators will not be blinded because the two arms are receiving different interventions. However, data will be coded such that data entry and initial analysis can be done in a blinded fashion as to intervention group until ad hoc analysis are conducted.
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| at baseline, at end of the intervention and 3 months after the end of intervention (for the intervention); at baseline and end of the intervention (for controls) |
| Depressive Symptomatology | The Patient Health Questionnaire-8 (PHQ-8) is a validated self-report tool used to assess the severity of depressive symptoms over the previous two weeks. The PHQ-8 includes 8 items, each scored on a 4-point scale: 0 = Not at all
Interpretation of total scores: 0-4: None to minimal depression 5-9: Mild depression 10-14: Moderate depression 15-19: Moderately severe depression 20-24: Severe depression The PHQ-8 was assessed at baseline, immediately post-intervention, and at 3-month follow-up for the intervention group, and at baseline and post-intervention for the control group. | at baseline, at end of the intervention and 3 months after the end of intervention; and at baseline and post-intervention for the control group. |
| Anxiety Symptomatology | General Anxiety Disorder 7 (GAD-7) survey assessed at baseline, end of intervention and 3 months from the end of intervention. The GAD-7 scores were also represented with clinical categorizations of anxiety levels as follows: GAD-7 score of 0-4 (none), 5-9 (mild), 10-14 (moderate), and 15-21 (severe). | at baseline, at end of the intervention and 3 months after the end of intervention (for the intervention group) and at baseline and end of the intervention (for the control group) |
| BG001 | Controls | Participants randomized to the control condition will receive only standard care as necessary according to their symptoms during the study period PLUS an online patient training module. They were visited by members of the study team twice at their homes or preset meeting place to obtain samples and surveys. |
| BG002 | Total | Total of all reporting groups |
| Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| pelvic pain | Count of Participants | Participants |
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| Dyspareunia | Count of Participants | Participants |
|
| Baseline pelvic pain levels | The Numerical Pain Scale (NRS) is a self-reported scale of pain ranging from 1 to 10, 1 being no pain, and 10 being the worst imaginable pain. Scale: 1-4 mild pain, 5-7 moderate pain, 8-10 severe pain | Mean | Standard Deviation | units on a scale |
|
| Perceived stress (PSS14) | Perceived Stress Scale 14 or PSS14: PSS-14 scores are obtained by reversing the scores on the seven positive items, e.g., 0=4, 1=3, 2=2, etc., and then summing across all 14 items. Items 4, 5, 6, 7, 9, 10, and 13 are the positively stated items. Individual scores on the PSS can range from 0 to 40 with higher scores indicating higher perceived • stress. ► Scores ranging from 0-13 would be considered low stress. ► Scores ranging from 14-26 would be considered moderate stress. ► Scores ranging from 27-40 would be considered high perceived stress. | Mean | Standard Deviation | units on a scale |
|
| OG001 | Controls | Participants randomized to the control condition will receive only standard care as necessary according to their symptoms during the study period PLUS an online patient training module. |
|
|
| Primary | Quality of Life (QoL) | QoL global impact scores measured using the Endometriosis Health Profile 30 (EHP-30), a disease-specific questionnaire to measure health related quality of life. The EHP-30 was developed by Jones et al., in 2001. Part 1 The first part contains 30 questions relevant to all women with endometriosis covering five areas: pain, emotional well-being, control and powerlessness, social support and self imaging scales. Each domain score is calculated by dividing the total scores of each item in the domain by the maximum possible score of all items in the domain multiplied by 100. Our outcome of interest is the global impact score, calculated as the mean of all completed subscale scores, with a range of 0 to 100. The global impact score ranges from 0 (indicating the best health status) to 100 (indicating the worst health status). No subscales are reported. | The total of participants is not equal to the total number of participants enrolled because not all participants completed this particular questionnaire out of the many instruments that they needed to complete; also not all completed the Follow up End of intervention questionnaire in the control group (16 out of 19 participants). | Posted | Mean | Standard Deviation | score on a scale | at baseline, at end of the intervention and 3 months after the end of intervention (for intervention); at baseline and end of intervention (for controls) |
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| Secondary | Perceived Stress Levels 14 | Perceived stress levels will be measured using the Perceived Stress Scale 14 at baseline, end of interventions and 3 months from the end of intervention for the intervention group, but only at baseline and end of the intervention for the control group. The survey asks the following 14 questions about stressful situations and helps determine what stress is to the participant and how stressful they feel their life to be. Higher scores indicate higher levels of stress. The 14 items are scored from 0 to 4. Total scores range from 0 to 56. Score categories are: Low Stress (scores 0 - 18) Moderate Stress (scores 19 - 37) High Stress (scores 38 - 56) | The total of participants is not equal to the total number of participants enrolled because not all participants completed this particular questionnaire out of the many instruments they were asked to complete. | Posted | Mean | Standard Deviation | score on a scale | at baseline, at end of the intervention and 3 months after the end of intervention (for the intervention); at baseline and end of the intervention (for controls) |
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|
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| Secondary | Depressive Symptomatology | The Patient Health Questionnaire-8 (PHQ-8) is a validated self-report tool used to assess the severity of depressive symptoms over the previous two weeks. The PHQ-8 includes 8 items, each scored on a 4-point scale: 0 = Not at all
Interpretation of total scores: 0-4: None to minimal depression 5-9: Mild depression 10-14: Moderate depression 15-19: Moderately severe depression 20-24: Severe depression The PHQ-8 was assessed at baseline, immediately post-intervention, and at 3-month follow-up for the intervention group, and at baseline and post-intervention for the control group. | The total of participants is not equal to the total number of participants enrolled because not all participants completed this particular questionnaire out of the many instruments they were asked to complete; also not all participants completed the follow up questionnaires at the end of the intervention or at 3 months after (only for the intervention group) | Posted | Mean | Standard Deviation | score on a scale | at baseline, at end of the intervention and 3 months after the end of intervention; and at baseline and post-intervention for the control group. |
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| Secondary | Anxiety Symptomatology | General Anxiety Disorder 7 (GAD-7) survey assessed at baseline, end of intervention and 3 months from the end of intervention. The GAD-7 scores were also represented with clinical categorizations of anxiety levels as follows: GAD-7 score of 0-4 (none), 5-9 (mild), 10-14 (moderate), and 15-21 (severe). | The total of participants is not equal to the total number of participants enrolled because not all participants completed this particular questionnaire out of many instruments they were asked to complete. | Posted | Mean | Standard Deviation | score on a scale | at baseline, at end of the intervention and 3 months after the end of intervention (for the intervention group) and at baseline and end of the intervention (for the control group) |
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| 0 |
| 29 |
| 0 |
| 29 |
| 1 |
| 29 |
| EG001 | Controls | Participants randomized to the control condition will receive only standard care as necessary according to their symptoms during the study period PLUS an online patient training module. | 0 | 27 | 0 | 27 | 0 | 27 |
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| D000091662 | Genital Diseases |
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D034161 | Pelvic Infection |
| D007239 | Infections |
| D000291 | Adnexal Diseases |
| D010335 | Pathologic Processes |
| End of intervention |
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| 3-months after |
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| End of intervention |
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| 3 months after |
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| End of intervention |
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| 3 months after |
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| End of intervention |
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| 3 months after |
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