Validation of Effectiveness on NaturalCycles Users (VENUS)

Background:

Natural Cycles (NC°) is a mobile-based application for contraception and fertility monitoring, cleared by the FDA and certified for contraceptive use in Europe, Brazil, Canada, Australia, Singapore, and South Korea. Based on user input of body temperature, menstruation dates, and optional urine luteinizing hormone tests, the application's algorithm estimates likely ovulation dates, fertile windows, and upcoming menstruation. In NC° Birth Control mode, potentially fertile days are flagged as "red" and labeled "Use protection", informing users to abstain or use barrier protection. Days not estimated to be fertile are shown as "green" and labeled "Not fertile".

Rationale:

This is a prospective, observational study designed to evaluate the contraceptive effectiveness of the Natural Cycles application under real-world conditions. While previous large-scale studies have established the effectiveness of NC°, they were largely observational analyses of passively logged user data. To meet evolving regulatory standards for contraceptive trials, particularly those mandated by the U.S. Food and Drug Administration (FDA), this prospective study has been designed to systematically capture intercourse and pregnancy outcomes on a cycle-by-cycle basis. This methodology overcomes the limitations of purely passive data collection and will yield a more complete and robust dataset for effectiveness calculations.

Study Design:

This is a prospective, single-arm, observational, direct-to-participant study conducted entirely remotely within the United States. Participants use the commercially available, regulated version of the NC° Birth Control application. Participation does not alter the core functionality or the contraceptive algorithm of the application. The study introduces structured data collection, active follow-up components, and a standardized exit procedure to ensure data integrity and completeness.

The study includes a pilot phase involving 20 participants who will be followed for two menstrual cycles. The primary purpose of this pilot study is to assess the feasibility and practical implementation of the study procedures, including participant adherence to the data logging requirements and the effectiveness of the automated reminders and manual contact protocols. Findings from the pilot phase will be used to refine study materials before full-scale recruitment begins. Data collected during the pilot study will be used for feasibility assessment only and will be excluded from the final efficacy analysis.

Study Procedures:

Upon registration with the NC° application, users are automatically screened against initial criteria. Those who appear eligible are invited via an in-app message to participate. The informed consent process is conducted entirely electronically.

Consenting participants then complete a comprehensive Onboarding Questionnaire to verify final eligibility criteria and collect baseline demographic data, contact information, and medical and reproductive history. At the first menstruation onset logged after completing the questionnaire, participants are invited to perform the entry urine pregnancy test and their participation can officially begin once they have confirmed its negative outcome.

During the active study period (up to one year), participants are required to log the occurrence and type of vaginal intercourse ("none," "protected," or "unprotected") every day. Menstruation, temperature, luteinising hormone test results, pregnancy test results and eventual emergency contraception should also be reported in the app. At the start of every menstrual cycle, participants will be requested to perform a urine pregnancy test, and log the outcome in the app.

Participation concludes for one of several pre-defined reasons, including completion of the 13-cycle duration, a reported pregnancy, desire to conceive, or discontinuation from either the study or product. Regardless of the reason for exit, all participants undergo a standardized study exit procedure, which consists of completing a detailed Exit Questionnaire and performing a final urine pregnancy test.

Quality Assurance Plan:

Data is entered directly by the participant into the NC° application, which serves as the electronic data capture system. This minimizes transcription errors. To ensure the accuracy of contemporaneously collected information, participants are only permitted to log or edit intercourse entries for up to five days after the event.

To promote adherence to daily intercourse logging, an automated push notification is sent each day to remind the participant to log intercourse data for the previous day. Bi-weekly, an in-app pop-up will prompt participants to complete any missing entries. If intercourse data is missing for ten consecutive days, authorized study staff will attempt to contact the participant by telephone. Similar reminders are set up to ensure the requested urine pregnancy test data is entered promptly.

All study data is pseudonymized. Direct identifiers (e.g., name, email address) are separated from health data and replaced with a unique participant code. A strict, role-based access protocol is enforced: the study management team has secure access to contact information for operational tasks (e.g., follow-up calls), while the data analysis team only has access to the pseudonymized dataset.

Statistical Analysis Plan:

The contraceptive efficacy will be evaluated using Kaplan-Meier (KM) survival analysis, which is the current standard for contraceptive research as it appropriately handles censored data (e.g., participants who withdraw or are lost to follow-up). The primary outcome is the 13-cycle cumulative contraceptive failure rate, calculated as 1 minus the cumulative survival probability at cycle 13, presented with 95% confidence intervals. As a secondary measure for historical comparison, the Pearl Index will also be calculated.

Analyses will be performed on two key populations: the Intent-to-Treat (ITT) Population and Per-Protocol (PP) Population. The ITT population corresponds to typical use and includes all eligible cycles from all enrolled participants, reflecting real-world effectiveness. The PP Population corresponds to perfect use and includes only cycles where the participant logged intercourse data for all fertile days and adhered strictly to the instructions for use (i.e., abstention or barrier protection on all fertile days).

One-year study and product continuation rates will also be estimated using KM survival analysis.