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International Active Surveillance Study - Folate in Oral Contraceptives Utilization Study

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Trial Information

International Active Surveillance Study - Folate in Oral Contraceptives Utilization Study

New oral contraceptives (OCs) containing drospirenone (DRSP) or dienogest
(DNG)/ethinylestradiol (EE) plus levomefolate calcium (metafolin) have been recently
introduced and will be introduced in a number of countries in the near future. Although the
safety of OCs has improved over the last 50 years with reductions in the estrogen and
progestogen dose, special attention regarding oral contraceptive safety amongst women with
risk factors for venous and arterial thromboembolism as well as cancer is necessary. Folic
acid supplementation has been implicated in both the prevention and the promotion of several
cancers, including colorectal cancer (CRC). Chronic folate deficiency seems to be associated
with colorectal carcinogenesis, while high folic acid levels may have a tumor-promoting
effect. On balance an oral contraceptive containing folate may be advantageous for several
reasons. It may increase baseline folate levels with potential for protecting against some
malignancies and concurrently decrease the risk of neural tube defects in women who become
pregnant due to OC-failure, incorrect OC-use or after stopping the OC for a planned
pregnancy. Although unexpected, it is unclear whether combined oral contraceptives plus
metafolin in general and specifically DRSP/EE plus metafolin and DNG/EE plus metafolin will
alter the risk profile of established oral contraceptives.

This study investigates the safety of these new oral contraceptives with regard to
cardiovascular outcomes and colorectal cancer.

INAS-FOCUS is a prospective, controlled, non-interventional cohort study with three study
arms: users of DRSP/EE/metafolin, users of DNG/EE/metafolin and users of OCs containing
other estrogen/progestogen combinations. The users will be grouped to starters (first-ever
users), switchers (women switching OC without a pill intake break) and restarters (women
with a pill intake break). Users of an OC are accrued by a network of prescribing
physicians. Baseline and follow-up information is collected via a self-administered
questionnaire. Data analysis will be based on life-table methods comparing the cohorts.

Inclusion Criteria:

- Women starting OC use ("starters")

- Women switching OC use without a pill intake break ("switchers")

- Women restarting OC use after a pill intake break ("restarters")

- Women willing to participate in the active surveillance

Exclusion Criteria:

- Long-term users

- Women who do not agree to participate

- Women with a language barrier

Type of Study:


Study Design:

Observational Model: Cohort, Time Perspective: Prospective

Outcome Measure:

Cardiovascular events

Outcome Time Frame:

Within 6 years

Safety Issue:


Principal Investigator

Juergen C Dinger, PhD, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Center for Epidemiology and Health Research


United States: Food and Drug Administration

Study ID:




Start Date:

October 2010

Completion Date:

December 2025

Related Keywords:

  • Contraception
  • Drospirenone
  • Dienogest
  • Metafolin
  • Folic acid
  • Safety