Validation of Effectiveness on NaturalCycles Users (VENUS)

A Prospective Observational Study on the Contraceptive Effectiveness of the Natural Cycles Application (The VENUS Study)

The goal of this observational study is to measure the effectiveness of the Natural Cycles digital birth control application at preventing pregnancy in sexually active women aged 18 to 35 with no known history of infertility. The main questions it aims to answer are:

• What is the pregnancy rate of the application over one year, for all users?
• What is the pregnancy rate of the application over one year, for users who follow the application's instructions perfectly?

Participants will:

• Use the Natural Cycles application for birth control for up to one year.
• Log information about daily sexual activity in the app.
• Complete a questionnaire at the beginning and end of their participation.
• Perform urine pregnancy tests (provided by mail) upon entry to the study, at the start of every cycle during the study, and upon exit from the study.

Study Overview

• Status: Recruiting
• Conditions: Contraception
• Intervention / Treatment: Behavioral: Log daily intercourse information; Device: Natural Cycles application

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 2000

Contacts and Locations

• Study Contact: Name: Agathe van Lamsweerde, MSc; Phone Number: 201-431-6036; Email: venus_study@naturalcycles.com

Study Locations

• United States
  • New York
    • New York, New York, United States, 10036
      • Recruiting
      • Natural Cycles USA Corp
      • Contact: Megan Callanan; Phone Number: 201-431-6036; Email: venus_study@naturalcycles.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

New Natural Cycles application users living in the United States

Description

Inclusion Criteria:

• Wants to avoid pregnancy for 13 cycles.
• Is willing to rely solely on Natural Cycles as their sole contraception method for 13 cycles.
• Is not currently using permanent contraceptive methods, such as sterilization (of either the user or their partner), or hormonal methods, such as the hormonal contraceptive implant or IUD.
• Has an intact uterus, both ovaries and both fallopian tubes to the best of their knowledge.
• Has an average cycle length between 21 and 35 days. The user anticipates heterosexual intercourse at least once a month in the next year.
• Is willing to enter data on a daily basis and perform pregnancy tests as requested by protocol.
• Is willing to complete a satisfaction survey at the end of her study participation.

Exclusion Criteria:

• Has EU-citizenship
• Has had a Depo-Provera injection in the last 10 months or has had less than three consecutive, spontaneous menstrual cycles since their last injection.
• Has had less than three consecutive, spontaneous menstrual cycles after removing a hormonal implant.
• Has had less than three consecutive, spontaneous menstrual cycles after the end of a pregnancy.
• Has had less than three consecutive, spontaneous menstrual cycles since she last breastfed.
• Has (or partner has) known fertility issues, such as infertility and sterilization, or have been advised by a healthcare professional that they may have difficulty conceiving for any reason.
• Has a medical condition possibly impacting fertility, i.e. endometriosis, a history of Pelvic Inflammatory Disease (PID), significant uterine fibroids or adenomyosis, or another diagnosed medical condition that they have been told affects fertility.
• Is regularly taking one of the following prescribed pharmaceutical medications known to be teratogenic (i.e., a medication that can cause birth defects):

Isotretinoin (like Accutane, Absorica, Claravis, or Myorisan) for severe acne Valproic acid or divalproex sodium (like Depakote, Depakene, or Topamax) for seizures (epilepsy), migraines, or bipolar disorder Methotrexate (Trexall, Rheumatrex) or leflunomide (Arava) for autoimmune conditions ACE Inhibitors (like Lisinopril, Enalapril) or Angiotensin II Receptor Blockers (ARBs) (like Losartan, Valsartan) for high blood pressure or heart conditions Warfarin (Coumadin, Jantoven) for blood clot prevention

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

NC° Users Participating in Study; An individual who has recently registered to the Natural Cycles app will be screened based on the information routinely collected at registration and invited to the study if they meet specific screening criteria. After informed consent, the onboarding survey will explicitly verify further inclusion and exclusion criteria with participants.

Behavioral: Log daily intercourse information; For the duration of their participation in the study, participants will use the contraceptive app as usual but will be prompted to diligently log daily intercourse information and to regularly test for pregnancy. Upon exiting the study for any reason, all participants will complete a urine pregnancy test and an online Exit Questionnaire.; Device: Natural Cycles application; Users will receive daily fertility status from Natural Cycles application

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
13-Cycles Cumulative Contraceptive Failure Rate	The cumulative contraceptive failure rate in Typical Use and Perfect Use will be calculated using Kaplan-Meier survival analysis. This represents the probability of becoming pregnant within the first year of typical or perfect use of the Natural Cycles app. A confirmed pregnancy, identified through a positive urine pregnancy test, will be considered an event.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pearl Index (PI)	The traditional Pearl Index (number of pregnancies per 100 woman-years of exposure) for Typical Use and Perfect Use. This will allow for comparison with historical contraceptive studies.	1 year
One-year study continuation rate	The rate at which participants continue their active involvement in the research study, calculated using Kaplan-Meier survival analysis. Discontinuation from the study for any reason is an event.	1 year
One-year product continuation rate	The rate at which participants continue using the Natural Cycles app as their primary contraceptive method, independent of study exit, calculated using Kaplan-Meier survival analysis. Discontinuation of product use as contraception (e.g., switching to "Plan Pregnancy" mode, becoming inactive in the app) is an event.	1 year
Participant satisfaction ratings	Assessment of participants' satisfaction with the Natural Cycles Birth Control method, collected through an online Exit Questionnaire. This includes qualitative feedback on user experience.	At study exit, at most 1 year after entry to study.

Collaborators and Investigators

• Sponsor: Natural Cycles
• Investigators: Principal Investigator: Eleonora Benhar, PhD, Natural Cycles Nordic AB; Principal Investigator: Kristina Gemzell-Danielsson, PhD, Karolinska Institutet

Study record dates

Study Major Dates

• Study Start (Actual): April 28, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: November 18, 2025
• First Submitted That Met QC Criteria: April 28, 2026
• First Posted (Actual): May 5, 2026

Study Record Updates

• Last Update Posted (Actual): May 8, 2026
• Last Update Submitted That Met QC Criteria: May 7, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: RES-2025-001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No