Clinical trial NCT01266408: INAS-FOCUS (International Active Surveillance Study - Folate in Oral Contraceptives Utilization Study)
Official title: International Active Surveillance Study - Folate in Oral Contraceptives Utilization Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Contraception
Keywords: Drospirenone
Dienogest
Metafolin
Folic acid
Safety
Lead sponsor: Center for Epidemiology and Health Research, Germany
Sponsor class: OTHER
Collaborators: name: Bayer
First posted: 2010-12-24
Enrollment: 82921
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Women using oral contraceptives

Brief summary: The study compares the risks of short- and long-term use of contraceptives containing drospirenone (DRSP) or dienogest (DNG)/ethinylestradiol (EE) plus levomefolate calcium (metafolin) with the risks of short- and long-term use of other established oral contraceptives (OCs).

Detailed description: 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.

Amendment, approved by the Safety Monitoring and Advisory Council on 13th May 2018:

During study recruitment, only one combined oral contraceptive was launched containing metafolin (DRSP/EE+) and the planned third cohort arm (users of DNG/EE+) was rendered obsolete.

In addition, early recruitment rates and exposure figures in INAS-FOCUS suggested that the study would be inadequately powered to accurately assess the risk of colorectal cancer at 15 years. Interim reports were presented to the Safety Monitoring and Advisory Council (SMAC) and in consultation with the funder, a decision made to discontinue INAS-FOCUS following analysis of cardiovascular events (Part 1 of study). The current protocol reflects the developments discussed above. The original three cohorts have been reduced to two (DRSP/EE+ and other OCs containing estrogen/progestogen) and Part II (long-term assessment of risk of colorectal cancer) has been removed from the protocol. Colorectal cancer outcomes will be analyzed as a secondary outcome for signal detection purposes only.

For historical accuracy and context, the introduction and background sections of the protocol have been left unchanged.

Eligibility criteria: 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

Primary outcomes:
measure: Absolute risk of Venous Thromboembolic Events
timeFrame: Within 6 years
measure: Absolute risk of Acute Myocardial Infarction
timeFrame: Within 6 years
measure: Absolute risk of Cerebrovascular Accidents
timeFrame: Within 6 years
Secondary outcomes:
measure: Colorectal cancer
timeFrame: Within 6 years
measure: Other cancer entities
timeFrame: Within 6 years
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Center for Epidemiology and Health Research
Study officials:
affiliation: Center for Epidemiology and Health Research
name: Juergen C Dinger, PhD, MD
role: PRINCIPAL_INVESTIGATOR
References: