Delivering Transcutaneous Auricular Neurostimulation to Reduce Heavy Menstrual Bleeding in Von Willebrand Disease Patients

Background: Heavy menstrual bleeding (HMB) is defined as excessive blood loss that interferes with women's quality of life. HMB can be accompanied by other symptoms including dysmenorrhea, headache, fatigue, and anemia. About 10-15% of women with HMB have an underlying bleeding disorder, while 75-100% of women with von Willebrand Disease (VWD) experience HMB. While strategies including hormone therapy, desmopressin, recombinant factor, and hysterectomy demonstrate clinical benefit, HMB+VWD patients continue to experience poorer quality of life and greater healthcare resource utilization that general populations.

Transcutaneous auricular neurostimulation (tAN) is an FDA-cleared technology (Sparrow Ascent System, K230796) that stimulates branches of the vagus and trigeminal nerves on and around the ear. This technology leverages decades of clinical application of implantable cervical vagus nerve stimulation (VNS), which is an accepted therapy for the treatment of refractory epilepsy, depression and stroke. Studies show that cervical VNS also reduces bleeding times and shed blood volumes in animal models of soft tissue injury by rendering platelets more responsive to pro-coagulant stimuli. This approach was also effective in mice deficient in Factor VIII, suggesting that VNS may be a novel tool in the management of bleeding disorders. Transcutaneous auricular neurostimulation is an emerging non-invasive alternative to cervical VNS and has been applied for headache, migraine, heart failure, asthma, tinnitus, and other conditions . tAN stimulates the release of central nervous system endorphins, shifts circulating monocytes to an anti-inflammatory phenotype , inhibits pro-inflammatory cytokine release, and has sustained antinociceptive effects. tAN is currently being tested in a healthy human population to determine whether it can alter platelet phenotype.

Study design and Treatment: This open-label, decentralized pilot study will study whether tAN can reduce menstrual blood loss and improve health-related quality of life and menstrual symptoms in 10 VWD Type 1 participants with HMB when applied during menstruation. Participants will be enrolled in the study over the course of two consecutive menstrual cycles. During the Baseline Menstruation, no tAN treatment will be delivered, and Participants will estimate daily blood loss using a validated pictorial blood loss assessment chart (PBAC). Dysmenorrhea, quality of life, and duration of menstruation will be collected on the final day of the baseline menstruation using the Cox Menstrual Symptom Scale (CMSS), the Short Form (SF)-36, and the PBAC. During the Second Menstruation, participants will self-administer two daily 1-hour sessions of active tAN beginning Day 1 through the final day of Second Menstruation. Participants will estimate daily blood loss with the PBAC throughout the duration of their second menstruation, and the CMSS and SF-36 will be collected on the final day.

Eligibility Criteria: Inclusion criteria are regularly menstruating female participants between 18-45 years of age; diagnosis of VWD Type 1; history of menorrhagia as assessed by the Menorrhagia Screening Tool; on oral birth control (≥ 3 months) and willing to continue use throughout the study. Exclusion criteria are antifibrinolytic use within 30 days of enrollment; acquired bleeding disorder; use of anticoagulants including platelet inhibitors for 30 days prior to enrollment; known structural cause of HMB.

Statistical Methods: Mean total PBAC, CMSS and SF-36 scores will be compared between menstruations using the paired Student's T test. Average areas under the curve of daily PBAC scores will be computed for the baseline and treatment menstruations and compared with standard error and confidence intervals using Graphpad Prism.

Endpoints:

• Reduce menstrual blood loss.

• Improve perceived health-related quality of life through menstruation.

• Determine whether tAN can improve pain through menstruation.

At the time of abstract submission, three subjects have completed the study, and two are in process. Initial obstacles to recruitment were advertising to eligible subjects, given a high number of interested participants either did not meet the VWD diagnosis or were not on hormonal therapy. Enrollment is expected to conclude by October 2024.

Czura:Spark Biomedical Inc: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: Patents and applications: 10,695,568 B1, US 10,967,182 B2, US11,351,370 B2, AU2020313858A1, US20220305260A1, EP3996807A1, CN114423490A, WO 2005/092308 A3, US8729129, US10912712, US11260229B2, US20190321623A1. Benner:Spark Biomedical Inc: Current Employment. Le:Spark Biomedical Inc: Current Employment. Harada:Spark Biomedical Inc: Current Employment. McWade:Spark Biomedical Inc: Current Employment. Khodaparast:Spark Biomedical Inc: Current equity holder in private company, Current holder of stock options in a privately-held company, Patents & Royalties: Patents and applications: 10,695,568 B1, US 10,967,182 B2, US11,351,370 B2, AU2020313858A1, US20220305260A1, EP3996807A1, CN114423490A, WO 2005/092308 A3, US8729129, US10912712, US11260229B2, US20190321623A1. Covalin:Spark Biomedical: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company, Patents & Royalties: Patents and applications: 10,695,568 B1, US 10,967,182 B2, US11,351,370 B2, AU2020313858A1, US20220305260A1, EP3996807A1, CN114423490A, WO 2005/092308 A3, US8729129, US10912712, US11260229B2, US20190321623A1.