Pain Reduction With an Immersive Digital Therapeutic Tool in Women Living With Endometriosis-Related Pelvic Pain: Randomized Controlled Trial

Background Chronic pelvic pain is a common and disabling condition in women living with endometriosis. Pharmacological and surgical treatments are not always effective at controlling pain and present important restrictions. Digital therapeutics (DTx) are emerging as major nonpharmacological alternatives that aim to extend the analgesic therapeutic arsenal of patients. Objective In this randomized controlled trial (RCT), we aimed to measure the immediate and 4-hour persisting effects of a single use 20-minute DTx (Endocare) on pain in women experiencing pelvic pain due to endometriosis. Methods A total of 45 women with endometriosis participated in a randomized controlled study comparing the analgesic effect of a single use of a virtual reality digital treatment named Endocare (n=23, 51%) to a 2D digital control (n=22, 49%). Perceived pain and pain relief were measured before the treatment and 15, 30, 45, 60, and 240 minutes after the end of the treatment. Results The clustered posttreatment pain was significantly reduced compared to the pretreatment for both Endocare and the control group (all P<.01). Endocare was significantly more effective than the control group (all P<.01). Endocare decreased the mean pain intensity from 6.0 (SD 1.31) before the treatment to 4.5 (SD 1.71) posttreatment, while the control only decreased it from 5.7 (SD 1.36) to 5.0 (SD 1.43). When comparing each posttreatment measures to the pretest, Endocare significantly reduced pain perception for all points in time up to 4 hours posttreatment. The differences did not reached significance for the control group. Moreover, Endocare was significantly superior to the control group 15, 30, and 45 minutes after the treatment (all P<.001). The mean perceived pain relief was significantly higher for Endocare at 28% (SD 2%) compared to the control, which was 15% (SD 1%) for all the posttreatment measurements (all P>.05). Conclusions Our study aimed to test the effects of a single use of a DTx treatment on reported pain at different time points in women diagnosed with endometriosis experiencing moderate-to-severe pelvic pain. Importantly, our results support that Endocare, a virtual reality immersive treatment, significantly reduce pain perception compared to a digital control in women living with endometriosis. Interestingly, we are the first to notice that the effect persisted up to 4 hours posttreatment. Trial Registration ClinicalTrials.gov NCT04650516; https://tinyurl.com/2a2eu9wv

Approx. Percentage of Users (starters) still using the app as recommended after 3 months yes: all primary outcomes were signi�cantly better in intervention group vs control partly: SOME primary outcomes were signi�cantly better in intervention group vs control no statistically signi�cant difference between control and intervention potentially harmful: control was signi�cantly better than intervention in one or more outcomes inconclusive: more research is needed Autre : not submitted yet -in early draft status not submitted yet -in late draft status, just before submission submitted to a journal but not reviewed yet submitted to a journal and after receiving initial reviewer comments submitted to a journal and accepted, but not published yet Manuscript tracking number * If this is a JMIR submission, please provide the manuscript tracking number under "other" (The ms tracking number can be found in the submission acknowledgement email, or when you login as author in JMIR. If the paper is already published in JMIR, then the ms tracking number is the four-digit number at the end of the DOI, to be found at the bottom of each published article in JMIR) 39531 1a) Does your paper address CONSORT item 1a? * I.e does the title contain the phrase "Randomized Controlled Trial"? (if not, explain the reason under "other") Identify the mode of delivery. Preferably use "web-based" and/or "mobile" and/or "electronic game" in the title. Avoid ambiguous terms like "online", "virtual", "interactive". Use "Internet-based" only if Intervention includes non-web-based Internet components (e.g. email), use "computer-based" or "electronic" only if o�ine products are used. Use "virtual" only in the context of "virtual reality" (3-D worlds). Use "online" only in the context of "online support groups". Complement or substitute product names with broader terms for the class of products (such as "mobile" or "smart phone" instead of "iphone"), especially if the application runs on different platforms.
Does your paper address subitem 1a-i? * Copy and paste relevant sections from manuscript title (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study "Immersive", "Digital Therapeutic"

1a-ii) Non-web-based components or important co-interventions in title
Mention non-web-based components or important co-interventions in title, if any (e.g., "with telephone support"). Does your paper address subitem 1a-ii?
Copy and paste relevant sections from manuscript title (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Votre réponse 1a-iii) Primary condition or target group in the title Mention primary condition or target group in the title, if any (e.g., "for children with Type I Diabetes") Example: A Web-based and Mobile Intervention with Telephone Support for Children with Type I Diabetes: Randomized Controlled Trial Does your paper address subitem 1a-iii? * Copy and paste relevant sections from manuscript title (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Mention key features/functionalities/components of the intervention and comparator in the abstract. If possible, also mention theories and principles used for designing the site. Keep in mind the needs of systematic reviewers and indexers by including important synonyms. (Note: Only report in the abstract what the main paper is reporting. If this information is missing from the main body of text, consider adding it) Does your paper address subitem 1b-i? * Copy and paste relevant sections from the manuscript abstract (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study "single use of a virtual reality digital treatment named Endocare", "to a 2D digital control" 1b-ii) Level of human involvement in the METHODS section of the ABSTRACT Clarify the level of human involvement in the abstract, e.g., use phrases like "fully automated" vs. "therapist/nurse/care provider/physician-assisted" (mention number and expertise of providers involved, if any). (Note: Only report in the abstract what the main paper is reporting. If this information is missing from the main body of text, consider adding it) 1 2 3 4 5 essential Does your paper address subitem 1b-ii?
Copy and paste relevant sections from the manuscript abstract (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Does your paper address subitem 1b-iii?
Copy and paste relevant sections from the manuscript abstract (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study 1 2 3 4 5 essential subitem not at all important 1 2 3 4 5 essential 1b-iv) RESULTS section in abstract must contain use data Report number of participants enrolled/assessed in each group, the use/uptake of the intervention (e.g., attrition/adherence metrics, use over time, number of logins etc.), in addition to primary/secondary outcomes. (Note: Only report in the abstract what the main paper is reporting. If this information is missing from the main body of text, consider adding it) Does your paper address subitem 1b-iv?
Copy and paste relevant sections from the manuscript abstract (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Does your paper address subitem 2a-ii? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study "Current management of endometriosis pain involves pharmacological (eg, hormonal therapy) and surgical treatments", "Hormonal therapies or surgeries are not adapted for women willing to get pregnant. Thereby, the development of nonpharmacological alternatives for the management of endometriosis pain is critical to extend the treatment arsenal for women with pelvic-perineal pain and endometriosis", "On these bases, a new digital therapeutic approach, Endocare, was created by combining various therapeutic procedures based on several modalities in a VR environment, individually known to reduce pain. Endocare therapeutic procedures comprise auditory (eg, alpha/theta binaural beats, nature-based sounds) and visual (eg, bilateral alternative stimulations) components associated with a 3D VR environment." METHODS 3a) Description of trial design (such as parallel, factorial) including allocation ratio 3b) Important changes to methods after trial commencement (such as eligibility criteria), with reasons Does your paper address CONSORT subitem 2b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study "In this randomized controlled trial, we hypothesized that a single use of the Endocare treatment would be able to significantly diminish the pain intensity in patients diagnosed with chronic pelvic pain associated with endometriosis." Does your paper address CONSORT subitem 3a? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study "This was a randomized, controlled, comparative, open-label, two-parallel-group interventional study." 1 2 3 4 5 essential 4a) Eligibility criteria for participants Does your paper address CONSORT subitem 3b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Non-applicable for our study.

3b-i) Bug fixes, Downtimes, Content Changes
Bug �xes, Downtimes, Content Changes: ehealth systems are often dynamic systems. A description of changes to methods therefore also includes important changes made on the intervention or comparator during the trial (e.g., major bug �xes or changes in the functionality or content) (5-iii) and other "unexpected events" that may have in�uenced study design such as staff changes, system failures/downtimes, etc. [2].
Does your paper address subitem 3b-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study 1 2 3 4 5 essential Does your paper address CONSORT subitem 4a? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study "The selection criteria were women over 18 years old with a magnetic resonance imagery (MRI) diagnosis of endometriosis who were willing to participate in the study and signed the informed consent form. All patients were recruited from a highly specialized center (ie, IFEMEndo). These patients experienced mostly severe pain related to their chronic pain condition and presented a long medical history concerning their endometriosis, which was often deep endometriosis.", "To be included in this study, the screened participants who met the selection criteria had to be living with moderate-to-severe endometriosis-related pain with a score ≥4 on 1-point numerical rating scale at the time of inclusion, a criterion shared among various studies."

4a-i) Computer / Internet literacy
Computer / Internet literacy is often an implicit "de facto" eligibility criterion -this should be explicitly clari�ed.
Does your paper address subitem 4a-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Votre réponse CONSORT-EHEALTH (V 1.6.1) -Submission/Publication Form https://docs.google.com/forms/d/e/1FAIpQLSfZBSUp1bwOc_OimqcS... essential 4a-ii) Open vs. closed, web-based vs. face-to-face assessments: Open vs. closed, web-based vs. face-to-face assessments: Mention how participants were recruited (online vs. o�ine), e.g., from an open access website or from a clinic, and clarify if this was a purely web-based trial, or there were face-to-face components (as part of the intervention or for assessment), i.e., to what degree got the study team to know the participant. In online-only trials, clarify if participants were quasi-anonymous and whether having multiple identities was possible or whether technical or logistical measures (e.g., cookies, email con�rmation, phone calls) were used to detect/prevent these.
Does your paper address subitem 4a-ii? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study "Recruitment was done when the patients came for their medical examination and were informed about this study. If the patients expressed interested in participating in this study, the research team offered them a new appointment at the clinic to receive the study treatment."

4a-iii) Information giving during recruitment
Information given during recruitment. Specify how participants were briefed for recruitment and in the informed consent procedures (e.g., publish the informed consent documentation as appendix, see also item X26), as this information may have an effect on user self-selection, user expectation and may also bias results.
4b) Settings and locations where the data were collected subitem not at all important 1 2 3 4 5 essential Does your paper address subitem 4a-iii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study

Votre réponse
Does your paper address CONSORT subitem 4b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study "This RCT was conducted between December 2020 and May 2021 at the Franco-European Multidisciplinary Endometriosis Institute (IFEMEndo), Clinic Tivoli-Ducos in Bordeaux, France."

4b-i) Report if outcomes were (self-)assessed through online questionnaires
Clearly report if outcomes were (self-)assessed through online questionnaires (as common in web-based trials) or otherwise. Does your paper address subitem 4b-i? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study "When patients returned to the clinic on the day of the inclusion visit, their pain level needed to be at least 4 on a 0-10 numeric pain rating scale to participate in this study.", "Once the treatment was completed, each participant was asked to rate on a paper questionnaire their pain perception on a 11-point NRS (0: no pain, 10: unbearable pain) and their perceived pain relief on a 5-point categorical scale 15 minutes (T15), 30 minutes (T30), 45 minutes (T45), and 60 minutes (T60) after administration of the allocated study treatment. During the first hour, participant remained under the direct supervision of the study site staff. After the first hour, and if cleared by the study site staff, participants were free to leave the study site and go home to complete next assessment 240 minutes (T240) after the end of the treatment."

4b-ii) Report how institutional affiliations are displayed
Report how institutional a�liations are displayed to potential participants [on ehealth media], as a�liations with prestigious hospitals or universities may affect volunteer rates, use, and reactions with regards to an intervention.(Not a required item -describe only if this may bias results)

Does your paper address subitem 4b-ii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Votre réponse CONSORT-EHEALTH (V 1.6.1) -Submission/Publication Form https://docs.google.com/forms/d/e/1FAIpQLSfZBSUp1bwOc_OimqcS...

5)
The interventions for each group with sufficient details to allow replication, including how and when they were actually administered subitem not at all important Mention names, credential, a�liations of the developers, sponsors, and owners [6] (if authors/evaluators are owners or developer of the software, this needs to be declared in a "Con�ict of interest" section or mentioned elsewhere in the manuscript).

Does your paper address subitem 5-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Votre réponse

5-ii) Describe the history/development process
Describe the history/development process of the application and previous formative evaluations (e.g., focus groups, usability testing), as these will have an impact on adoption/use rates and help with interpreting results. 1 2 3 4 5 essential Does your paper address subitem 5-ii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Votre réponse

5-iii) Revisions and updating
Revisions and updating. Clearly mention the date and/or version number of the application/intervention (and comparator, if applicable) evaluated, or describe whether the intervention underwent major changes during the evaluation process, or whether the development and/or content was "frozen" during the trial. Describe dynamic components such as news feeds or changing content which may have an impact on the replicability of the intervention (for unexpected events see item 3b).

Does your paper address subitem 5-iii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Votre réponse CONSORT-EHEALTH (V 1.6.1) -Submission/Publication Form https://docs.google.com/forms/d/e/1FAIpQLSfZBSUp1bwOc_OimqcS...

5-iv) Quality assurance methods
Provide information on quality assurance methods to ensure accuracy and quality of information provided [1], if applicable.
Does your paper address subitem 5-iv?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Votre réponse 5-v) Ensure replicability by publishing the source code, and/or providing screenshots/screen-capture video, and/or providing flowcharts of the algorithms used Ensure replicability by publishing the source code, and/or providing screenshots/screencapture video, and/or providing �owcharts of the algorithms used. Replicability (i.e., other researchers should in principle be able to replicate the study) is a hallmark of scienti�c reporting.
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Votre réponse

5-vi) Digital preservation
Digital preservation: Provide the URL of the application, but as the intervention is likely to change or disappear over the course of the years; also make sure the intervention is archived (Internet Archive, webcitation.org, and/or publishing the source code or screenshots/videos alongside the article). As pages behind login screens cannot be archived, consider creating demo pages which are accessible without login.
Does your paper address subitem 5-vi?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Votre réponse CONSORT-EHEALTH (V 1.6.1) -Submission/Publication Form https://docs.google.com/forms/d/e/1FAIpQLSfZBSUp1bwOc_OimqcS...

5-vii) Access
Access: Describe how participants accessed the application, in what setting/context, if they had to pay (or were paid) or not, whether they had to be a member of speci�c group. If known, describe how participants obtained "access to the platform and Internet" [1]. To ensure access for editors/reviewers/readers, consider to provide a "backdoor" login account or demo mode for reviewers/readers to explore the application (also important for archiving purposes, see vi).
Does your paper address subitem 5-vii? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study "The research team accompanied the patient to distinct isolated rooms and then handed them either the headset (ie, Endocare) or the tablet (ie, control). Patients were then guided orally by the investigator for up to 5 minutes until the beginning of the treatment (ie, Endocare or control Does your paper address subitem 5-viii? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study "Endocare was displayed through a VR headset (Oculus Quest) with high-quality headphones (APK K-240-MKII). Endocare is a standalone medical software device that is composed of an application stored in a VR headset, intended to mitigate pain for people prone to endometriosis. Endocare offers a 20-minute treatment consisting of a combination of auditory (eg, alpha/theta binaural beats, nature-based sounds) and visual (eg, bilateral alternative stimulations consisting of a sphere appearing and moving on a horizontal axis) therapeutic procedures integrated in a 3D VR environment.", "The digital control was also developed by Lucine specifically for this study (Figure 1). The digital control program was displayed through a tablet (Samsung Galaxy Tab A) with high-quality headphones similar to those used in the Endocare group (APK K-240-MKII). The digital comparator was a 20minute control with the same composition as the Endocare treatment (same context, environment, and duration) but without any immersive effects of the VR headset itself, nor the auditory (eg, alpha/theta binaural beats, nature-based sounds) and visual (eg, bilateral alternative stimulations) stimuli. A soundtrack composed of nature sounds related to the projected image." CONSORT-EHEALTH (V 1.6.1) -Submission/Publication Form https://docs.google.com/forms/d/e/1FAIpQLSfZBSUp1bwOc_OimqcS...

5-ix) Describe use parameters
Describe use parameters (e.g., intended "doses" and optimal timing for use). Clarify what instructions or recommendations were given to the user, e.g., regarding timing, frequency, heaviness of use, if any, or was the intervention used ad libitum.
Does your paper address subitem 5-ix?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Votre réponse

5-x) Clarify the level of human involvement
Clarify the level of human involvement (care providers or health professionals, also technical assistance) in the e-intervention or as co-intervention (detail number and expertise of professionals involved, if any, as well as "type of assistance offered, the timing and frequency of the support, how it is initiated, and the medium by which the assistance is delivered". It may be necessary to distinguish between the level of human involvement required for the trial, and the level of human involvement required for a routine application outside of a RCT setting (discuss under item 21 -generalizability).
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Votre réponse

5-xi) Report any prompts/reminders used
Report any prompts/reminders used: Clarify if there were prompts (letters, emails, phone calls, SMS) to use the application, what triggered them, frequency etc. It may be necessary to distinguish between the level of prompts/reminders required for the trial, and the level of prompts/reminders for a routine application outside of a RCT setting (discuss under item 21 -generalizability).
Does your paper address subitem 5-xi? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study There were no prompts nor reminders to use the application in our study because the technical team installed and set the devices.
CONSORT-EHEALTH (V 1.6.1) -Submission/Publication Form https://docs.google.com/forms/d/e/1FAIpQLSfZBSUp1bwOc_OimqcS... including how and when they were assessed 5-xii) Describe any co-interventions (incl. training/support) Describe any co-interventions (incl. training/support): Clearly state any interventions that are provided in addition to the targeted eHealth intervention, as ehealth intervention may not be designed as stand-alone intervention. This includes training sessions and support [1]. It may be necessary to distinguish between the level of training required for the trial, and the level of training for a routine application outside of a RCT setting (discuss under item 21 -generalizability. Does your paper address subitem 5-xii? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study There was no training to use the application in our study because the technical team installed and set the devices.
CONSORT-EHEALTH (V 1.6.1) -Submission/Publication essential Does your paper address CONSORT subitem 6b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Non-Applicable for our study.

7a-i) Describe whether and how expected attrition was taken into account when calculating the sample size
Describe whether and how expected attrition was taken into account when calculating the sample size.

Does your paper address subitem 7a-i?
Copy and paste relevant sections from manuscript title (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Votre réponse CONSORT-EHEALTH (V 1.6.1) -Submission/Publication Form https://docs.google.com/forms/d/e/1FAIpQLSfZBSUp1bwOc_OimqcS... 7b) When applicable, explanation of any interim analyses and stopping guidelines 8a) Method used to generate the random allocation sequence NPT: When applicable, how care providers were allocated to each trial group 8b) Type of randomisation; details of any restriction (such as blocking and block size) Does your paper address CONSORT subitem 7b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Non-Applicable in our study.
Does your paper address CONSORT subitem 8a? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study A statistician independent from the study has prepared the master list of randomization numbers for this study. The investigator has under no circumstances change the randomization number and the treatment arm allocated to the patient.
CONSORT-EHEALTH (V 1.6.1) -Submission/Publication Form https://docs.google.com/forms/d/e/1FAIpQLSfZBSUp1bwOc_OimqcS... 9) Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned 10) Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions Does your paper address CONSORT subitem 8b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study The randomisation has been produced in blocks, on a 1:1 balanced ratio.
Does your paper address CONSORT subitem 9? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study After eligibility has been confirmed, patients have been assigned a randomization number and to the associated treatment arm, in sequential order. Each subject has been treated with the treatment allocated to this randomization number.
CONSORT-EHEALTH (V 1.6.1) -Submission/Publication Form https://docs.google.com/forms/d/e/1FAIpQLSfZBSUp1bwOc_OimqcS... 11a) If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how NPT: Whether or not administering co-interventions were blinded to group assignment subitem not at all important 1 2 3 4 5 essential Does your paper address CONSORT subitem 10? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study A statistician independent from the study has prepared the master list of randomization numbers for this study. The investigator has enrolled participants and the clinical research associate has assigned participants to interventions.

11a-i) Specify who was blinded, and who wasn't
Specify who was blinded, and who wasn't. Usually, in web-based trials it is not possible to blind the participants [1, 3] (this should be clearly acknowledged), but it may be possible to blind outcome assessors, those doing data analysis or those administering cointerventions (if any).

Does your paper address subitem 11a-i? *
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study

Non-Applicable: our study is open labelled.
CONSORT-EHEALTH (V 1.6.1) -Submission/Publication Form https://docs.google.com/forms/d/e/1FAIpQLSfZBSUp1bwOc_OimqcS... 11a-ii) Discuss e.g., whether participants knew which intervention was the "intervention of interest" and which one was the "comparator" Informed consent procedures (4a-ii) can create biases and certain expectations -discuss e.g., whether participants knew which intervention was the "intervention of interest" and which one was the "comparator".

Does your paper address subitem 11a-ii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study

Votre réponse
Does your paper address CONSORT subitem 11b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Non-Relevant for our sutdy.
CONSORT-EHEALTH (V 1.6.1) -Submission/Publication Form https://docs.google.com/forms/d/e/1FAIpQLSfZBSUp1bwOc_OimqcS... 12a) Statistical methods used to compare groups for primary and secondary outcomes NPT: When applicable, details of whether and how the clustering by care providers or centers was addressed subitem not at all important 1 2 3 4 5 essential Does your paper address CONSORT subitem 12a? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study "A linear mixed-model framework was used for statistical analysis (SPSS 2020, International Business Machines Corporation). The selected covariance matrix of the repeated measurements that better fitted the data based on the Akaike Information Criterion was the first-order ante-dependence. There were 3 explanatory fixed factors: group (Endocare, control), time (T0, T15, T30, T45, T60, T240), and group*time, as well as a random effect on the intercept of each participant. In the first analysis, time (fixed effect) was parametrized as baseline (T0) versus all other times (T15 to T240). The analysis consisted of comparing T0 with the 5 posttreatment data clustered for both groups and looking at the interaction term (group*time). For pain relief, data were analyzed using R software (Free Software Foundation's GNU General Public License in source code form). Because data did not satisfy to normality when assessed with the Shapiro-Wilk normality test, Wilcoxon unilateral unpaired tests corrected for multiple comparisons with false discovery rate (FDR) were used."

12a-i) Imputation techniques to deal with attrition / missing values
Imputation techniques to deal with attrition / missing values: Not all participants will use the intervention/comparator as intended and attrition is typically high in ehealth trials. Specify how participants who did not use the application or dropped out from the trial were treated in the statistical analysis (a complete case analysis is strongly discouraged, and simple imputation techniques such as LOCF may also be problematic [4]). Does your paper address subitem 12a-i? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study As a general rule missing data will not be replaced.
Does your paper address CONSORT subitem 12b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study A contrast analysis was also performed to verify the difference between baseline (T0) and posttreatment times (clustered) in the 2 separate groups. In the second analysis, Time was parametrized as T0, T15, T30, T45, T60 and T240. A contrast analysis was also performed to test the difference between T0 and all other times (separated) in both groups separated. Bonferroni corrections were applied for multiple comparisons.

Does your paper address subitem X26-ii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Votre réponse

X26-iii) Safety and security procedures
Safety and security procedures, incl. privacy considerations, and any steps taken to reduce the likelihood or detection of harm (e.g., education and training, availability of a hotline)

RESULTS
13a) For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analysed for the primary outcome NPT: The number of care providers or centers performing the intervention in each group and the number of patients treated by each care provider in each center 13b) For each group, losses and exclusions after randomisation, together with reasons Does your paper address subitem X26-iii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study

Votre réponse
Does your paper address CONSORT subitem 13a? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study "Of the 45 women that participated in the study, 1 (2%) did not return the questionnaire. Among the patients included, 1 (2%) from the treatment group and 4 (9%) from the control group took rescue medication after T60 but before T240. Therefore, in accordance with the study design, no results at T240 were collected for these 5 patients. Participants from both groups were comparable in terms of age, height, and weight, as well as in pain intensity at T0." CONSORT-EHEALTH (V 1.6.1) -Submission/Publication Form https://docs.google.com/forms/d/e/1FAIpQLSfZBSUp1bwOc_OimqcS... * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study "Consequently, at least 40 women were planned to be included in the study. Finally, 46 participants were screened, of which 45 were included and randomized; 1 was a screen failure because she never went back for the study visit. A total of 44 (97.78%) participants completed the entire study."

13b-i) Attrition diagram
Strongly recommended: An attrition diagram (e.g., proportion of participants still logging in or using the intervention/comparator in each group plotted over time, similar to a survival curve) or other �gures or tables demonstrating usage/dose/engagement.

Does your paper address subitem 13b-i?
Copy and paste relevant sections from the manuscript or cite the �gure number if applicable (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study 1 2 3 4 5 essential 14b) Why the trial ended or was stopped (early) Does your paper address CONSORT subitem 14a? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study "This RCT was conducted between December 2020 and May 2021 at the Franco-European Multidisciplinary Endometriosis Institute (IFEMEndo), Clinic Tivoli-Ducos in Bordeaux, France." 14a-i) Indicate if critical "secular events" fell into the study period Indicate if critical "secular events" fell into the study period, e.g., signi�cant changes in Internet resources available or "changes in computer hardware or Internet delivery resources" Does your paper address subitem 14a-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study  CONSORT-EHEALTH (V 1.6.1) -Submission/Publication

15-i) Report demographics associated with digital divide issues
In ehealth trials it is particularly important to report demographics associated with digital divide issues, such as age, education, gender, social-economic status, computer/Internet /ehealth literacy of the participants, if known.

16) For each group, number of participants (denominator) included in each analysis
and whether the analysis was by original assigned groups subitem not at all important 16-i) Report multiple "denominators" and provide definitions Report multiple "denominators" and provide de�nitions: Report N's (and effect sizes) "across a range of study participation [and use] thresholds" [1], e.g., N exposed, N consented, N used more than x times, N used more than y weeks, N participants "used" the intervention/comparator at speci�c pre-de�ned time points of interest (in absolute and relative numbers per group). Always clearly de�ne "use" of the intervention.
Does your paper address subitem 16-i? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study 1 2 3 4 5 essential 17a) For each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence interval)

16-ii) Primary analysis should be intent-to-treat
Primary analysis should be intent-to-treat, secondary analyses could include comparing only "users", with the appropriate caveats that this is no longer a randomized sample (see 18-i).
Does your paper address subitem 16-ii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study

Votre réponse
Does your paper address CONSORT subitem 17a? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study "We first analyzed the differences between the baseline pain (T0) and the 5 clustered posttreatment measurements covering 15 minutes to 4 hours after the treatment (ie, T15, T30, T45, T60, and T240) in both groups using a linear mixed model. We did not observe any effect of the group (Endocare, control; F=.060, P=.807), but we did observe an effect of the time (T0, post-all; F=44.179, P<.001). Moreover, we found an interaction for group*time (F=7.343, P=.010), indicating that the mean reduction of pain through time (T0, post-all) was significantly different between each group (ie, Endocare, control)." 1 2 3 4 5 essential 17b) For binary outcomes, presentation of both absolute and relative effect sizes is recommended 17a-i) Presentation of process outcomes such as metrics of use and intensity of use In addition to primary/secondary (clinical) outcomes, the presentation of process outcomes such as metrics of use and intensity of use (dose, exposure) and their operational de�nitions is critical. This does not only refer to metrics of attrition (13-b) (often a binary variable), but also to more continuous exposure metrics such as "average session length". These must be accompanied by a technical description how a metric like a "session" is de�ned (e.g., timeout after idle time) [1] (report under item 6a).

Does your paper address subitem 17a-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study

Votre réponse
Does your paper address CONSORT subitem 17b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study 18) Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing pre-specified from exploratory Does your paper address CONSORT subitem 18? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study "Contrast analysis revealed that the mean reduction of pain was greater in the Endocare group (1.58; t=6.624, P<.001) than in the control group (0.38; t=2.781, P=.008).", "We then aimed to analyze the differences between the baseline (T0) and each of the 5 posttreatment measurements separately (ie, T15, T30, T45, T60, or T240) in both groups using a mixed model. We did not observe any effect of the group ( P=.114). This indicates that the mean reduction of pain through time was significantly different between each group (ie, Endocare, control) from T15 to T45, but it was not significantly different from T60 to T240. For the Endocare group, the pain perception reduction was significant in each of the 5 posttreatment measurements (all P<.05). For the control group, except for a tendency at T15 (P=.068), no significance was reached relative to the pain perception reduction in each of the 5 posttreatment measurements (all P>.05).", "At each posttreatment measurements, the partcipants were asked to measure their perceived pain relief on a 0 to 4 numerical scale from no relief to total relief. The mean pain relief reported for Endocare was 28% (SD 24.28) and 15% (SD 16.34)

18-i) Subgroup analysis of comparing only users
A subgroup analysis of comparing only users is not uncommon in ehealth trials, but if done, it must be stressed that this is a self-selected sample and no longer an unbiased sample from a randomized trial (see 16-iii).
Does your paper address subitem 18-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study

Votre réponse
Does your paper address CONSORT subitem 19? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study "Seven (15%) participants reported mild-to-moderate AEs, of which 4 (8%) were evaluated as probably unrelated and 3 (6%) as possibly related to the Endocare treatment. The 3 possibly related events were within the treatment group described as a mild headache and nausea related to motion sickness." CONSORT-EHEALTH (V 1.6.1) -Submission/Publication Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Votre réponse 22-i) Restate study questions and summarize the answers suggested by the data, starting with primary outcomes and process outcomes (use) Restate study questions and summarize the answers suggested by the data, starting with primary outcomes and process outcomes (use).
1 2 3 4 5 essential Does your paper address subitem 22-i? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study "In this RCT, we aimed to measure the immediate and 4 hours persisting effects of a single use of a 20-minute DTx (Endocare) on pain in women living with pelvic pain related to endometriosis. We showed that Endocare was able to significantly reduce the overall pain perception when comparing the pain at baseline (T0) with the combined 5 posttreatment measurements from 15 minutes (T15) to 4 hours (T240). We found that our digital control was also able to significantly reduce the overall pain perception but significantly less than the Endocare treatment. Next, we wanted to evaluate whether the pain reduction was significant at each posttreatment measurement (ie, T15, T30, T45, T60, and T240) compared to baseline (T0) in each group. We showed that this was the case for the Endocare group but not for the control group, thus confirming the analgesic effect of the Endocare treatment. To our knowledge, our study is the first to demonstrate an effect on pain reduction in women living with moderate-to-severe pelvic pain due to endometriosis by using a nonpharmacological treatment that combined VR with visual and auditory stimuli."

22-ii) Highlight unanswered new questions, suggest future research
Highlight unanswered new questions, suggest future research.

Does your paper address subitem 22-ii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Votre réponse

20-i) Typical limitations in ehealth trials
Typical limitations in ehealth trials: Participants in ehealth trials are rarely blinded. Ehealth trials often look at a multiplicity of outcomes, increasing risk for a Type I error. Discuss biases due to non-use of the intervention/usability issues, biases through informed consent procedures, unexpected events.
Does your paper address subitem 20-i? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study "One limitation of our study may be the population, as we decided to work with patients living with mostly severe pain related to a complex and chronic pain condition, which could represent a selection bias. We likely could have had slightly better treatment results with less severe pain conditions. However, to assess this potential selection bias and analyze wether the beneficial effect would be lessened in populations with complex pathologies related to endometriosis, we covariated for surgery and adenomyosis, two conditions with potentially more pain and less responses to the treatment. We found that the results were equivalent, suggesting a similar effect in all subpopulations, including those with a more complex pathophysiology. Nevertheless, an effect in the range of 30% for Endocare can ultimately be considered moderately significant according to the IMMPACT guidelines. This can be explained by the design of our study itself. Indeed, our relatively small sample size, or perhaps the unique use of the treatment, could have lessened the effect. Nevertheless, it is important to highlight the fact that we reached significance even with this design. Future studies should aim to confirm these results with a larger population size and repeated use of the treatment." 21) Generalisability (external validity, applicability) of the trial findings NPT: External validity of the trial �ndings according to the intervention, comparators, patients, and care providers or centers involved in the trial subitem not at all important

21-i) Generalizability to other populations
Generalizability to other populations: In particular, discuss generalizability to a general Internet population, outside of a RCT setting, and general patient population, including applicability of the study results for other organizations Does your paper address subitem 21-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Votre réponse 21-ii) Discuss if there were elements in the RCT that would be different in a routine application setting Discuss if there were elements in the RCT that would be different in a routine application setting (e.g., prompts/reminders, more human involvement, training sessions or other cointerventions) and what impact the omission of these elements could have on use, adoption, or outcomes if the intervention is applied outside of a RCT setting.

25)
Sources of funding and other support (such as supply of drugs), role of funders

X27) Conflicts of Interest (not a CONSORT item)
subitem not at all important 1 2 3 4 5 essential Does your paper address CONSORT subitem 25? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Private fundings from Lucine supported financially the entire study.

X27-i) State the relation of the study team towards the system being evaluated
In addition to the usual declaration of interests (�nancial or otherwise), also state the relation of the study team towards the system being evaluated, i.e., state if the authors/evaluators are distinct from or identical with the developers/sponsors of the intervention.
Does your paper address subitem X27-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or brie�y explain why the item is not applicable/relevant for your study Votre réponse As a result of using this checklist, did you make changes in your manuscript? * What were the most important changes you made as a result of using this checklist?

Votre réponse
How much time did you spend on going through the checklist INCLUDING making changes in your manuscript * We spent three hours going through the checklist.

yes no
Autre : STOP -Save this form as PDF before you click submit To generate a record that you �lled in this form, we recommend to generate a PDF of this page (on a Mac, simply select "print" and then select "print as PDF") before you submit it.
When you submit your (revised) paper to JMIR, please upload the PDF as supplementary �le.
Don't worry if some text in the textboxes is cut off, as we still have the complete information in our database. Thank you!