Clinical trial: Study of Efficacy, Cycle Control, and Safety of a NES-E2 Contraceptive Vaginal Ring (NCT03432416)

Eligibility criteria:
Inclusion Criteria:

          1. Good general overall health with no chronic medical conditions that result in periodic
             exacerbations requiring significant medical care.

          2. Age 18-35 years, inclusive, at the enrollment visit. (Note: subjects must be at least
             18 years of age to provide consent.)

          3. Have a regular menstrual cycle 21-35 days in duration when not using hormonal
             contraception

          4. Have an intact uterus and at least one ovary.

          5. Consistent use of effective contraception during the preceding cycle with no
             unprotected intercourse since last use (NOTE: women who use oral, transdermal,
             vaginal, or implantable hormonal contraceptives in the preceding cycle must have
             discontinued hormone use at least 4 days prior to start of treatment and must not have
             had unprotected intercourse since discontinuing the method. Copper IUD or
             Levonorgestrel releasing IUD users must have discontinued IUD use at least 4 days
             prior to start of treatment and have experienced a spontaneous menses following IUD
             removal.)

          6. No use of injectable contraceptives (e.g. depomedroxyprogesterone acetate) during the
             10 months prior to screening unless the subject has returned to normal menses (two
             consecutive menses) since last injection.

          7. Have a negative pregnancy test at the enrollment visit.

          8. Have a diastolic blood pressure (BP) <90 mm Hg and systolic BP <140 mm Hg after 5
             minutes rest in sitting position at the admission visit (below hypertension stage 2).
             (Note: History of hypertension stage 2 or higher, even if controlled with treatment,
             is exclusionary.)

          9. Willing to abstain from use of non-water based (including silicone based) vaginal
             lubricants during the study that could adversely affect the ring, causing it to
             expand.

         10. Understand and sign an IRB-approved informed consent form prior to screening
             activities (including fasting blood draws).

         11. BMI ≤ 35 kg/m2 and not having previously undergone bariatric surgery.

         12. Planning to have at least one act of heterosexual intercourse without the use of
             another contraceptive method each month during study participation until end of
             treatment and at risk for pregnancy.

        Exclusion Criteria:

          1. Planning pregnancy during study participation through the end of treatment visit.

          2. Within 30 days post-partum, currently breast-feeding, or has not had a spontaneous
             menses.

          3. Post-abortal and has not had a spontaneous menses.

          4. Abnormal genital bleeding.

          5. Participating in another clinical trial involving an investigational product within
             the last 30 days (prior to screening) or planning to participate in another clinical
             trial during this study.

          6. Not living in the catchment area of the study site.

          7. Known hypersensitivity to progestins or estrogens.

          8. Contraindications to combined estrogen-progestin contraceptive use including:

               1. Thrombophlebitis or thromboembolic disorders.

               2. Personal history of deep vein thrombophlebitis or thromboembolic disorders.

               3. History of venous thrombosis or embolism in a first-degree relative <55 years of
                  age suggesting a familial defect in the blood coagulation system.

               4. History of thrombosis or embolism OR any other personal or family history which
                  in the opinion of the investigator suggests increased risk.

               5. History of stroke.

               6. Known history of any of the following genetic mutations: Factor V Leiden
                  mutation, prothrombin mutation, antithrombin deficiency, or other clinically
                  significant thrombophilia.

               7. Known or suspected carcinoma of the breast.

               8. Carcinoma of the endometrium or other known or suspected estrogen-dependent
                  neoplasm.

               9. History of cholestatic jaundice of pregnancy or jaundice with prior hormonal
                  contraceptive use.

              10. History of hepatic adenomas or carcinomas.

              11. Known or suspected pregnancy.

              12. Smoking in women who are or will be 35 years during the course of the trial;
                  women <35 years who smoke 15 cigarettes or more per day must be evaluated by the
                  investigator for inclusion based on risk factors that would increase their risk
                  for cardiovascular disease (CVD) and thromboembolism, e.g. lipid levels, glucose
                  level, BP, BMI, family history of CVD at a young age. Individuals who use other
                  forms of tobacco should be evaluated similarly by the investigator for inclusion
                  based on the amount of tobacco use and their risk factors.

              13. History of retinal vascular lesions, unexplained partial or complete loss of
                  vision.

              14. History of headaches with focal neurological symptoms (e.g., migraines with
                  auras).

              15. Impaired mobility (e.g. wheelchair bound, bed-ridden) that, in the opinion of the
                  investigator, places the woman at increased risk of thrombosis.

          9. Unevaluated vaginal discharge or vaginal lesions. Subjects diagnosed at screening with
             a chlamydia or gonococcal infection may be included in the trial following treatment
             completion; partner treatment is also recommended. Subjects with yeast,
             trichomoniasis, or bacterial vaginosis infection requiring treatment may be enrolled
             after treatment completion. Investigators should determine if subjects are at an
             elevated risk for reinfection, e.g. multiple sex partners, untreated partner, and
             whether such subjects can be included. Women with a history of genital herpes can be
             included if outbreaks are infrequent.

         10. Have a known clinically significant Pap test abnormality, as managed by normal
             standard of care guidelines, that would require repeat evaluation or treatment during
             study participation based on the initial Pap findings.

         11. Known benign or malignant liver tumors, renal disease or active liver disease.

         12. Invasive cancer (past history of any carcinoma or sarcoma, except non-melanoma skin
             cancer).

         13. Current or past medically diagnosed severe depression, which, in the opinion of the
             investigator, could be exacerbated by use of a hormonal contraceptive.

         14. Known or suspected current alcohol dependence, chronic marijuana use, or any illicit
             drug use that may affect metabolism/transformation of study product and/or study
             treatment compliance. A chronic marijuana user is defined as someone who uses
             marijuana 4 or more times per week for study purposes.

         15. Elevated fasting clinical chemistry values or complete blood count (CBC) values
             designated clinically significant by the investigator or medically qualified
             sub-investigator.

         16. Uncontrolled thyroid disease.

         17. Known impaired hypothalamic-pituitary-adrenal axis.

         18. Known hypersensitivity to silicone rubber.

         19. History of toxic shock syndrome.

         20. Vaginal anatomic abnormality such as cystocele or rectocele that would preclude
             correct use of a vaginal ring.

         21. Planning major surgery during study participation.

         22. Severe current constipation.

         23. Use of liver enzyme inducers or inhibitors on a regular basis.

         24. Known HIV infection.

         25. Use of any medications, including antibiotics that can significantly interfere with
             the metabolism of hormonal contraceptives.

         26. Have an anticipated need for regular condom use, defined as use of at least one condom
             per month after enrollment.

         27. Have issues or concerns (in the judgment of the investigator) that may compromise the
             safety of the subject or confound the reliability of compliance and information
             acquired in this study.

         28. Any site staff member with delegated study responsibilities or a family member of a
             site staff member with delegated study responsibilities.
Female
Accepts Healthy Volunteers
Subject must be at least 18 Years old.
Subject must be at most 35 Years

Patient description (medical language): A 23-year-old female has prolonged oral bleeding immediately after a tooth extraction.  Despite several interventions, the bleeding persists for hours and stops only after desmopressin (DDAVP) administration.  The patient has heavy menstrual cycles each month.  She has no other medical problems and takes no medications.  Her mother and grandmother have also had excessive bleeding during menstrual period.  Review of systems is positive for mild bruising on his legs. Laboratory findings reveal a normal platelet count and an abnormal ristocetin cofactor assay, as well as CB <= 0.30 IU/mL and FVIII:C <= 0.40 IU/mL.

Patient description (patient's own words): I'm a 23 woman and I went to the ER because of non-stop bleeding after my tooth extraction. I tried to make the bleeding stop but it just kept going for hours and it finally stopped when I took some medication called DDAVP. I usually have heavy periods, just like my mom and grandma had. I don't have any other medical condition and I don't take any other medication. The doctor noticed the bruises on my legs. I had to do some lab tests. I had a normal platelet count but an abnormal ristocetin cofactor assay. I had low CB and FVIII:C levels.

Does the patient match the trial criteria? Entailment