The Use of PulseNmore FC Device in Patients Undergoing IVF Treatment A Study to Evaluate the Safety and the Efficacy

Study Overview
=================
Brief Summary
-----------------
Medical equipment designed for self-use is emerging as an important and potentially widely used medical niche, enabling conducting simple diagnostic tests at home, while allowing the results to be shared with experts in the field of medicine (1, 2). Currently, devices for measurement of blood pressure, blood sugar are already widely used. In the area of pregnancy and childbirth, medical devices that exist for various uses during pregnancy can be used independently at home by the women - such as: blood pressure monitoring (3, 4), glucose monitoring by glucometers / sensors (5, 6) and monitoring of fetal heart rate with the use of Doppler (7-9). These home applications have been shown the potential to improve pregnancy outcomes, improve adherence to obstetric follow-up and care, save time for patients, preserve system resources, reduce mental stress and anxiety during pregnancy and increase patient satisfaction. The current practice in reproductive medicine, is to perform repeated vaginal sonographic exams along with serial blood test for hormone levels (Estradiol, LH and Progesterone), in order to monitor the follicles' size and endometrial thickness during ovarian stimulation. This is a single center, interventional, longitudinal prospective, of 100 women undergoing fertility treatment in the IVF unit of Belinson Hospital. The study will examine the performance of the video guided -transvaginal scan done with Pulsenmore FC device, performed by the patient independently and the clinician guided transvaginal scan done with Pulsenmore FC device, performed by the patient with remote guidance of a professional sonographer modes of the device separately, comparing them to the conventional ultrasound system in clinic scan (ground truth - GT). The study will have two arms. Patients will be randomized at 1:1 ratio to either to video guided procedure or to clinician guided procedure. Subjects will participate in the study for one IVF cycle, an estimated study period of 2 weeks, and scan schedule protocol will follow the standard of care scan schedule for IVF treatment. The last visit will be defined when the attending physician concludes that the follicle requitement potential of the cycle has been achieved and the patient is ready for oocyte aspiration. Informed Consent Criteria The consent form will be developed according to good clinical practice (GCP) and IRB requirements. A copy of the signed consent form will be provided to the patient. The main objectives of the study are: Demonstrate the safety of the device. Demonstrate the effectiveness of the device. The primary study endpoints address the safety of the device and its effectiveness. All endpoints' calculations will be performed separately for video guided and clinician guided modes. Determination of endpoints will be done by comparing video guided/clinician guided modes findings for each parameter to the ground truth (standard of care- the in-clinic visit) observations.

Detailed Description
-----------------
Medical equipment designed for self-use is emerging as an important and potentially widely used medical niche, enabling conducting simple diagnostic tests at home, while allowing the results to be shared with experts in the field of medicine (1, 2). In the area of pregnancy and childbirth, medical devices that exist for various uses during pregnancy can be used independently at home by the women - such as: blood pressure monitoring (3, 4), glucose monitoring by glucometers / sensors (5, 6) and monitoring of fetal heart rate with the use of Doppler (7-9). These home applications have been shown the potential to improve pregnancy outcomes, improve adherence to obstetric follow-up and care, save time for patients, preserve system resources, reduce mental stress and anxiety during pregnancy and increase patient satisfaction. The current practice in reproductive medicine, is to perform repeated vaginal sonographic exams along with serial blood test for hormone levels (Estradiol, LH and Progesterone), in order to monitor the follicles' size and endometrial thickness during ovarian stimulation. The diameter and quantity of the ovarian follicles, in combination with the blood levels of Estradiol, LH and Progesterone are used to monitor the follicular growth and to decide when and how to trigger oocyte maturation prior to the oocyte pick up (OPU). This is best achieved by the transvaginal approach, the sonograms performed by gynaecologists or certified ultrasound technician. Self-use of vaginal ultrasound probe for acquiring the images of stimulated ovaries may reduce women's stress, increase compliance, save travel and time for the patients as well as reduce medical system work-load. To date, there is only limited research in self-use sonography in IVF. It was shown to be accepted by both patients and reproductive endocrinologists, and to be a feasible part of routine infertility treatments protocols (10-13). A randomized controlled trial comparing self-use sonography with standard sonography performed by a professional, concluded that self-ultrasound is not inferior to traditional in-clinic sonographic assessment, and has the advantage of higher satisfaction rates and lower resource usage (12). A study published recently comparing self-administrated virtual transvaginal ultrasonography at home, guided by a remote certified ultrasound technologist to an in clinic transvaginal ultrasonography performed by another technician found the home guiding to be non-inferior to the in clinic in term of image quality and ovarian reserve assessment (16). Pulsenmore Ltd. has developed a small portable vaginal ultrasound device for personal use at home. The ultrasound device allows to scan and assess both the uterus and the ovaries. This ultrasound device connects to a smartphone and a user-friendly application simplifies its use. This ultrasound device is based on the company's 'Pulsenmore ES ultrasound system' which is a small abdominal ultrasound device for home and self-use by pregnant women. The device is an abdominal ultrasound probe that connects to a smartphone using a specially designed socket. The main difference between the devices is the different design of the ultrasound vaginal probe. Pulsenmore ES ultrasound system has CE and AMAR (Israeli Ministry of Health) approval . The device consists of 2 components: a cradle and an application (software). The cradle contains the electronic components and the ultrasound probe. 1. The primary safety endpoint for each study subject is whether there is severe device- or procedure- related adverse events observed during the study. The resulting event rates will be established separately for the video guided and clinician guided modes of the device. 2.Primary Effectiveness Endpoints. The study will examine the performance of the video guided and clinician guided modes of the device separately. This shall be utilizing various parameters in acquired images/clips utilizing the Pulsenmore FC system in the: Video guided mode- the transvaginal scan is performed by the patient independently. Clinician guided mode- the self-transvaginal scan is performed by the patient with the remote guidance of a professional sonographer. Comparing them to the conventional ultrasound system in clinical settings (ground truth - GT) in terms of visualization of the ovaries and uterus. The study will be considered successful for video guided and clinician guided separately, based on the concordance level of visualization of the ovaries and uterus when compared to GT in each visit and at the last visit. Study target population: 100 women ages 18-43 undergoing ovarian stimulation in the IVF unit of Belinson Hospital. Study Design Summary: This represents a single centre, longitudinal investigational prospective study, of 100 women undergoing fertility treatment in the IVF unit of Belinson Hospital. Approximately 120 women will be recruited to accommodate 20% drop out. A comparison between video guided scan and in clinic scan and, clinician guided scan and in clinic scan (ground truth - GT) will be performed in order to assess the safety, feasibility and efficacy of the Pulsenmore FC device in the two operation modes. The study will have two arms. Patients will be randomized at 1:1 ratio either to the clinician guided scan comparing the device output to the in clinic scan (ground truth) output or to the video guided scan comparing the device output to the in clinic scan (ground truth) output. Study subjects will each perform a total of 5-6 ultrasound sessions. The number of visits will be determined by the treating physician according to the IVF cycle progression. Each visit constituting of 2 different scans (video guided/clinician guided and in clinic scan). Subjects will participate in the study for one IVF cycle and scan schedule protocol will follow the standard of care scan schedule for IVF treatment. The last visit will be defined when the attending physician concludes that the follicle requitement potential of the cycle has been achieved and the patient is ready for oocyte aspiration. Before the enrolment of the 100 patients begins, a pilot study of 4 patients, 2 in each arm which will follow the same protocol will be enrolled. The purpose of the pilot is to streamline the procedure. They will be included in the safety outcome of the study but will not be part of the effectiveness determination of the product. The enrolment of the 100 patients will begin after the 4 initial patients were completed. Following informed consent screening and eligibility, female IVF patients between the ages of 18-43 will receive Pulsenmore FC device, a small transvaginal portable self-use ultrasound device that connects to a smartphone. Patients will be randomized to one of two study arms. The study technologists/ sonographers will undergo a proprietary patient guiding training program, including study materials, simulated exercises. Patients Device training will be developed by the company on the use of the device. Patients from both arms will go through the same training. The training will include an in clinic training and at home training. The in-clinic training will be done by a professional sonographer in a clinic private room. Once the training is completed, the patient's ability to operate the device will be tested, the patients will be asked to use the device independently and acquire images and clips of the ovaries and uterus. If the patient cannot operate the device, the training will be repeated one more time. However, if after the second training, the patient is still unable to operate the device, they will not be enrolled in the study. The patient will also receive an instruction brochure to take home. At the initiation of the cycle and during the ovarian stimulation, (see study visit schedule) the patients will have the following procedure performed on the same days set for ovarian measurement according to the standard practice: Video guided arm: Video guided scan which includes self-acquisition of ultrasound images of the ovaries/follicles and the endometrium performed initially independently by the patient (unassisted) guided by procedure's videos on Pulsenmore app, in a separate private room in the clinic. Later, on the same day, the patients will have an in-person clinic visit and will be scanned using a conventional sonographic equipment. The in-clinic scan serves as Ground truth (GT). The images from the video guided scan will be automatically uploaded to the cloud from the patient's device and interpreted by a physician. Clinician guided scan: an ultrasound scan during a telehealth session using Pulsenmore platform which will take place in a clinic private room, with a professional sonographer, who will instruct and guide the patient how to operate the ultrasound prob, to acquire the required images. Later, on the same day, the patients will have an in-person clinic visit and will be scanned using a conventional sonographic equipment. The in-clinic scan will serve as Ground truth (GT). The images from the clinician guided scan will be automatically uploaded to the cloud from the patient's device and interpret by a physician The scan interpretation will include but not limited to visualization of the uterus and ovaries, number and size of follicles and endometrial thickness. The in-person scans will be read and interpreted immediately after the procedure by a physician blinded to the previous video guided/clinician guided sessions. The images will be downloaded and stored for documentation. All results from the video guided scan/ clinician guided scan and in-person scans will be stored and compared. If any discordant data is found, additional 2 independent reviewers will read the scans in question. The in-person scan will be used as the gold standard. The independent reviewers should be blinded to the in-clinic scan and to the previous device output scans. Majority rule (two of three) will be used to establish the correct reading of any of the discordant parameters in the video guided and clinician guided modes. 2. Study procedures: Screening for eligibility and consent Women undergoing fertility treatments in the IVF unit of Beilenson are potentially eligible for screening. Patients who are interested in the study will sign a written informed consent to participate in the trial. Inclusion/exclusion criteria will be reviewed from the patient's chart. 120 women will be screened to accommodate 20% screening failure. Baseline Information: the following information will be obtained from a patient •Demographic information including patient age, ethnicity, BMI, highest level of education completed. •Medical background and medications.• Gravidity and parity. •Infertility diagnosis and type of protocol to be employed. Screening and enrolment: Eligible women, who are undergoing fertility IVF treatment in Beilinson IVF unit will receive an information about the study and if interested will be provide written informed consent. If eligibility is met, participant will be provided with device to be used during the study. All women will receive smartphone, ultrasound probe and base, probe covers, gel and wipes for probe cleaning. Baseline information will be collected. Randomization:Patients will be randomized at a 1:1 ratio to either video guided procedure or clinician guided procedure Training: Patient's Training and clinician training. Study visits: will include 5-6 visits during one IVF treatment cycle to match current practice. The number of visits and timing will be determined by the attending physician according to ovarian response to hormonal stimulation. The decision on the last visit is made when the attending physician concludes that the follicle requitement potential of the cycle has been achieved, and the patient is ready for oocyte aspiration. The first visit will be scheduled on day 2-3 of the beginning menstrual period, while the follicle size is less than 10 mm, and endometrial thickness is less than 6 mm. The last visit will be defined when the attending physician concludes that the follicle requitement potential of the cycle has been achieved. On the morning of each visit the patient will come to the clinic. All regular infertility clinic tests which include blood tests for Estradiol Progesterone and LH levels will be taken. Each visit will consist of: Video guided arm and Clinician guided arm 3.Statistical consideration a-Descriptive statistics 3.Statistical consideration a-Descriptive statistics b-Primary Safety Endpoints c-Primary Effectiveness Endpoints d-Secondary endpoints: 4.Data Collection and Documentation Source of Data Collection

Official Title
-----------------
The Use of PulseNmore FC Device in Patients Undergoing IVF Treatment A Study to Evaluate the Safety and the Efficacy

Conditions
-----------------
Women Undergoing Fertility Treatments

Intervention / Treatment
-----------------
* Device: PulseNmore FC


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women undergoing fertility treatments in the IVF unit of Belinson Hospital that require serial transvaginal ultrasound scans. Female age 18-43 Normal pelvic anatomy At least one completed IVF cycle Capable and willing to perform self vaginal ultrasound measurements Ability to understand and sign the informed consent Ability to read and understand instructions that are required for equipment use Ability to identify the uterus and ovaries on the device screen by the end of the training session Exclusion Criteria: Known uterine malformations. Known ovarian pathologies. Presence of hydrosalpinx. Intraabdominal adhesions. Previous lower abdominal surgery. BMI >40 Unable to use the trans-vaginal device. Subjects allergic to the ultrasound probe materials. Significant malposition of the ovaries.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 43 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Approximately 120 women will be recruited to accommodate 20% drop out. A comparison between video guided scan and in clinic scan and, clinician guided scan and in clinic scan (ground truth - GT) will be performed in order to assess the safety, feasibility and efficacy of the Pulsenmore FC device in the two operation modes. The study will have two arms. Patients will be randomized at 1:1 ratio either to the clinician guided scan comparing the device output to the in clinic scan (ground truth) output or to the video guided scan comparing the device output to the in clinic scan (ground truth) output.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: clinician guided scan comparing the device output to the in clinic scan (ground truth) output<br>2. Clinician guided scan: an ultrasound scan during a telehealth session using Pulsenmore platform which will take place in a clinic private room, with a professional sonographer, who will instruct and guide the patient how to operate the ultrasound prob, to acquire the required images. Later, on the same day, the patients will have an in-person clinic visit and will be scanned using a conventional sonographic equipment. The in-clinic scan will serve as Ground truth (GT). The images from the clinician guided scan will be automatically uploaded to the cloud from the patient's device and interpret by a physician The scan interpretation will include but not limited to visualization of the uterus and ovaries, number and size of follicles and endometrial thickness. The in-person scans will be read and interpreted immediately after the procedure by a physician blinded to the previous video guided/clinician guided sessions. The images will be downloaded and stored for documentation. | Device: PulseNmore FC<br>* Pulsenmore Ltd. has developed a small portable vaginal ultrasound device for personal use at home. The ultrasound device allows to scan and assess both the uterus and the ovaries. This ultrasound device connects to a smartphone and a user-friendly application simplifies its use. This ultrasound device is based on the company's 'Pulsenmore ES ultrasound system' which is a small abdominal ultrasound device for home and self-use by pregnant women. This (abdominal) ultrasound device allows scanning and detection of fetal pulse, count fetal movements, assess the amount of amniotic fluid and more. The device is an abdominal ultrasound probe that connects to a smartphone using a specially designed socket. The main difference between the devices is the different design of the ultrasound vaginal probe. The device consists of 2 components: a cradle and an application (software). The cradle contains the electronic components and the ultrasound probe.<br>|
| Experimental: video guided scan comparing the device output to the in clinic scan (ground truth) output.<br>1. Video guided arm: Video guided scan which includes self-acquisition of ultrasound images of the ovaries/follicles and the endometrium performed initially independently by the patient (unassisted) guided by procedure's videos on Pulsenmore app, in a separate private room in the clinic. Later, on the same day, the patients will have an in-person clinic visit and will be scanned using a conventional sonographic equipment. The in-clinic scan serves as Ground truth (GT). The images from the video guided scan will be automatically uploaded to the cloud from the patient's device and interpreted by a physician. | Device: PulseNmore FC<br>* Pulsenmore Ltd. has developed a small portable vaginal ultrasound device for personal use at home. The ultrasound device allows to scan and assess both the uterus and the ovaries. This ultrasound device connects to a smartphone and a user-friendly application simplifies its use. This ultrasound device is based on the company's 'Pulsenmore ES ultrasound system' which is a small abdominal ultrasound device for home and self-use by pregnant women. This (abdominal) ultrasound device allows scanning and detection of fetal pulse, count fetal movements, assess the amount of amniotic fluid and more. The device is an abdominal ultrasound probe that connects to a smartphone using a specially designed socket. The main difference between the devices is the different design of the ultrasound vaginal probe. The device consists of 2 components: a cradle and an application (software). The cradle contains the electronic components and the ultrasound probe.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incident of device related, or procedure related severe adverse events | The incidence of procedure related severe adverse events will be established, using reporting system for each individual subject enrolled in the study. The primary safety endpoint for each study subject is whether there is severe device- or procedure- related adverse events observed during the study. The resulting event rates will be established separately for the video guided and clinician guided modes of the device. | 24 months | 
| Comparison of device visualization of ovaries and uterus in a sagittal view to ground truth in each visit | The visualization of the ovaries and uterus in a sagittal view would be matched with the visualization of the ovaries and uterus derived by the ground truth (in-clinic ultrasound scan) | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of number of follicles >17 mm during the last IVF visit to ground truth | The number of ovarian follicles >17 mm at the last visit will be counted and matched with the number of ovarian follicles >17 mm at the last visit derived by the ground truth (in-clinic ultrasound scan) | 24 months | 
| Comparison of endometrium thickness during the last IVF visit to ground truth | The endometrium thickness at the last visit will be measured and matched with the endometrium thickness at the last visit derived by the ground truth (in-clinic ultrasound scan) | 24 months |