Long-term Active Surveillance Study for Oral Contraceptives (LASS)

• Sponsor: Center for Epidemiology and Health Research, Germany (Other)
• Overall Status: Completed
• CT.gov ID: NCT00676065
• Collaborator: Bayer (Industry)
• Enrollment: 58,303
• Location: 1
• Duration (Months): 129.9
• Patients Per Site Per Month: 448.7

Study Details

Study Description

Brief Summary

The objective of this study is to characterize and compare the risks of long-term use of oral contraceptives containing drospirenone and of other established oral contraceptives.

Condition or Disease	Intervention/Treatment	Phase
Arterial Thromboembolism; Venous Thromboembolism; Breast Cancer

Detailed Description

The LASS Study is a large, multinational, prospective, controlled, non-interventional, long-term cohort study that follows a series of cohorts. The cohorts consist of new users (first-ever users, switchers and restarters) of three different groups of oral contraceptives (OCs): OCs containing drospirenone (DRSP), OCs containing levonorgestrel (LNG) and OCs containing other progestogens. A "non-interference" approach is used to provide standardized, comprehensive, reliable information on these groups of OCs under routine medical conditions.

The main clinical outcomes of interest for the long-term follow-up are arterial and venous thromboembolism as well as breast cancer. Regular, active contacts with the cohort members (=active surveillance) provide all necessary information on health-related events or changes in health status.

The study is based on the existing long-term EURAS cohorts who are still in follow-up. LASS succeeds EURAS and prolongs the follow-up period for another five years. Total follow-up time of members of the long-term cohorts will be between 6 and 10 years. By means of annual contacts almost all relevant clinical outcomes will be captured. This will be accomplished by contacting the relevant physicians and by reviewing relevant source documents in the case of relevant clinical outcomes.

Study Design

• Study Type: Observational
• Actual Enrollment: 58303 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Long-term Active Surveillance Study for Oral Contraceptives (LASS)
• Study Start Date: Feb 1, 2001
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Dec 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
1 Women who take oral contraceptives containing drospirenone
2 Women who take oral contraceptives containing levonorgestrel
3 Women who take oral contraceptives containing other progestogens

Outcome Measures

Primary Outcome Measures

1. Arterial Thromboembolism [Within 10 years]

   Arterial thromboembolism associated with the use of oral contraceptives containing drospirenone or levonorgestrel or other progestogens.

2. Venous Thromboembolism [Within 10 years]

   Venous thromboembolism associated with the use of oral contraceptives containing drospirenone or levonorgestrel or other progestogens.

3. Breast Cancer [Within 10 years]

   Breast cancer associated with the use of hormonal contraceptives either containing both drospirenone (DRSP) and ethinylestradiol (EE), levonorgestrel (LNG) or any other hormonal contraceptive without DRSP.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Women who are prescribed an oral contraceptive and who are new users (first-ever users, switchers or restarters) of the formulation

Exclusion Criteria:

• Women who do not consent to participate in the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Center for Epidemiology and Health Research	Berlin		Germany

Sponsors and Collaborators

• Center for Epidemiology and Health Research, Germany
• Bayer

Investigators

• Principal Investigator: Juergen Dinger, MD, PhD, Center for Epidemiology and Health Research Berlin, Germany

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Juergen Dinger, MD, PhD, Principal Investigator, Center for Epidemiology and Health Research, Germany
• ClinicalTrials.gov Identifier: NCT00676065
• Other Study ID Numbers: ZEG2006_03
• First Posted: May 12, 2008
• Last Update Posted: Nov 19, 2014
• Last Verified: Nov 1, 2014

• Keywords provided by Juergen Dinger, MD, PhD, Principal Investigator, Center for Epidemiology and Health Research, Germany: Contraception; Thromboembolism; Breast Cancer
• Additional relevant MeSH terms: Thromboembolism; Venous Thromboembolism

Study Results

Participant Flow

Recruitment Details	In the LASS study, 59,510 women were recruited overall. Of these, 836 participants were excluded due to protocol violation (e.g. patient did not start OC use). Furthermore, 371 patients started treatment with non-oral contraceptives. These patients were followed-up but were not part of the per protocol Population (58,303 patients).

Arm/Group Title	Yasmin	OC-LNG	OC-other
Arm/Group Description	Users of oral contraceptives containing 3 mg DRSP and 30 mcg ethinylestradiol	Users of oral contraceptives containing levonorgestrel	Users of oral contraceptives containing other progestogens
Period Title: Overall Study
STARTED	16534	15428	26341
COMPLETED	16534	15428	26341
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	DRSP/EE	OC-LNG	OC-other	Total
Arm/Group Description	Users of oral contraceptives containing 3 mg DRSP and 30 mcg ethinylestradiol	Users of oral contraceptives containing levonorgestrel	Users of oral contraceptives containing other progestogens	Total of all reporting groups
Overall Participants	16534	15428	26341	58303
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25.9 (8.1)	25.1 (8.7)	24.8 (7.8)	25.2 (8.2)
Sex: Female, Male (Count of Participants)
Female	16534 100%	15428 100%	26341 100%	58303 100%
Male	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Europe	16534 100%	15428 100%	26341 100%	58303 100%

Outcome Measures

1. Primary Outcome

Title	Arterial Thromboembolism
Description	Arterial thromboembolism associated with the use of oral contraceptives containing drospirenone or levonorgestrel or other progestogens.
Time Frame	Within 10 years

Outcome Measure Data

Analysis Population Description

The number of participants refers to the ITT study population. During the course od the study, women could for example stop use of oral contraception at any point of time. Therefore, the woman-years of exposure for each group are provided in addition.

Arm/Group Title	DRSP/EE	OC-LNG	OC-other
Arm/Group Description	Users of oral contraceptives containing 3 mg DRSP and 30 mcg ethinylestradiol	Users of oral contraceptives containing levonorgestrel	Users of oral contraceptives containing other progestogens
Measure Participants	16534	15428	26341
Measure Woman-years, AT-population	52278	57539	106221
Number [participants]	7 0%	22 0.1%	34 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DRSP/EE, OC-LNG
	Comments	Tested null hypotheses: the ATE hazard ratio for DRSP/E2 vs. OCs containing LNG is higher or equal to 2.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The LASS study was designed to analyse rare events (incidence rate <1 per 1,000 woman-years and ≥ 1 per 10,000 WY). 300,000 WY of observation would be sufficient to exclude a two-fold risk of rare events in users of DRSP compared to other oral contraceptives with a power (1-β) of 0.80 and an one-sided α of 0.05.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95%; 0.2 to 0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was adjusted for age, BMI, smoking, hypertension and family history

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DRSP/EE, OC-other
	Comments	Tested null hypotheses: the ATE hazard ratio for DRSP/E2 vs. OCs containing other progestogens is higher or equal to 2.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The LASS study was designed to analyse rare events (incidence rate <1 per 1,000 woman-years and ≥ 1 per 10,000 WY). 300,000 WY of observation would be sufficient to exclude a two-fold risk of rare events in users of DRSP compared to other oral contraceptives with a power (1-β) of 0.80 and an one-sided α of 0.05.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95%; 0.2 to 0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was adjusted for age, BMI, smoking, hypertension and family history

2. Primary Outcome

Title	Venous Thromboembolism
Description	Venous thromboembolism associated with the use of oral contraceptives containing drospirenone or levonorgestrel or other progestogens.
Time Frame	Within 10 years

Outcome Measure Data

Analysis Population Description

The number of participants refers to the ITT study population. During the course od the study, women could for example stop use of oral contraception at any point of time. Therefore, the woman-years of exposure for each group are provided in addition.

Arm/Group Title	DRSP/EE	OC-LNG	OC-other
Arm/Group Description	Users of oral contraceptives containing 3 mg DRSP and 30 mcg ethinylestradiol	Users of oral contraceptives containing levonorgestrel	Users of oral contraceptives containing other progestogens
Measure Participants	16534	15428	26341
Measure Woman-years, AT population	52278	57539	106221
Number [participants]	56 0.3%	53 0.3%	144 0.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DRSP/EE, OC-LNG
	Comments	Tested null hypotheses: the VTE hazard ratio for DRSP/E2 vs. OCs containing LNG is higher or equal to 2.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The LASS study was designed to analyse rare events (incidence rate <1 per 1,000 woman-years and ≥ 1 per 10,000 WY). 300,000 WY of observation would be sufficient to exclude a two-fold risk of rare events in users of DRSP compared to other oral contraceptives with a power (1-β) of 0.80 and an one-sided α of 0.05.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95%; 0.8 to 1.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was adjusted for age, BMI, current duration of use, and family history of VTE.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DRSP/EE, OC-other
	Comments	Tested null hypotheses: the VTE hazard ratio for DRSP/E2 vs. OCs containing other progestogens is higher or equal to 2.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The LASS study was designed to analyse rare events (incidence rate <1 per 1,000 woman-years and ≥ 1 per 10,000 WY). 300,000 WY of observation would be sufficient to exclude a two-fold risk of rare events in users of DRSP compared to other oral contraceptives with a power (1-β) of 0.80 and an one-sided α of 0.05.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95%; 0.5 to 1.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was adjusted for age, BMI, current duration of use, and family history of VTE.

3. Primary Outcome

Title	Breast Cancer
Description	Breast cancer associated with the use of hormonal contraceptives either containing both drospirenone (DRSP) and ethinylestradiol (EE), levonorgestrel (LNG) or any other hormonal contraceptive without DRSP.
Time Frame	Within 10 years

Outcome Measure Data

Analysis Population Description

The number of participants refers to the ITT study population. During the course od the study, women could for example stop use of oral contraception at any point of time. Therefore, the woman-years of exposure for each group are provided in addition.

Arm/Group Title	DRSP/EE	OC-LNG	OC-other
Arm/Group Description	Users of oral contraceptives containing 3 mg DRSP and 30 mcg ethinylestradiol	Users of oral contraceptives containing levonorgestrel	Users of oral contraceptives containing other progestogens
Measure Participants	16534	15428	26341
Measure Woman-years	52278	57539	106221
Number [participants]	27 0.2%	31 0.2%	45 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DRSP/EE, OC-LNG
	Comments	Tested null hypotheses: the breast cancer hazard ratio for DRSP/E2 vs. OCs containing LNG is higher or equal to 2.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The LASS study was designed to analyse rare events (incidence rate <1 per 1,000 woman-years and ≥ 1 per 10,000 WY). 300,000 WY of observation would be sufficient to exclude a two-fold risk of rare events in users of DRSP compared to other oral contraceptives with a power (1-β) of 0.80 and an one-sided α of 0.05.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 95%; 0.5 to 1.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was adjusted for age, BMI, smoking, educational level and age at menarche.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DRSP/EE, OC-other
	Comments	Tested null hypotheses: the breast cancer hazard ratio for DRSP/E2 vs. OCs containing other progestogens is higher or equal to 2.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The LASS study was designed to analyse rare events (incidence rate <1 per 1,000 woman-years and ≥ 1 per 10,000 WY). 300,000 WY of observation would be sufficient to exclude a two-fold risk of rare events in users of DRSP compared to other oral contraceptives with a power (1-β) of 0.80 and an one-sided α of 0.05.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; 0.6 to 1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was adjusted for age, BMI, smoking, educational level and age at menarche.

Adverse Events

Time Frame	Information on adverse events was collected over a time period of 10 years.
Adverse Event Reporting Description	ITT population. All study participants were asked for adverse events at each follow-up.
Arm/Group Title	DRSP/EE		OC-LNG		OC-other
Arm/Group Description	Users of oral contraceptives containing 3 mg DRSP and 30 mcg ethinylestradiol		Users of oral contraceptives containing levonorgestrel		Users of oral contraceptives containing other progestogens
All Cause Mortality
	DRSP/EE		OC-LNG		OC-other
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	DRSP/EE		OC-LNG		OC-other
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1912/16534 (11.6%)		2121/15428 (13.7%)		3936/26341 (14.9%)
Blood and lymphatic system disorders
Diseases of the blood and the bloodforming organs	7/16534 (0%)		9/15428 (0.1%)		18/26341 (0.1%)
Cardiac disorders
Cardiovascular system	198/16534 (1.2%)		226/15428 (1.5%)		425/26341 (1.6%)
Ear and labyrinth disorders
Ear	24/16534 (0.1%)		28/15428 (0.2%)		53/26341 (0.2%)
Endocrine disorders
Endocrine diseases	50/16534 (0.3%)		74/15428 (0.5%)		96/26341 (0.4%)
Eye disorders
Eye	19/16534 (0.1%)		24/15428 (0.2%)		40/26341 (0.2%)
Gastrointestinal disorders
Digestive system	248/16534 (1.5%)		265/15428 (1.7%)		503/26341 (1.9%)
Infections and infestations
Infectious diseases	86/16534 (0.5%)		86/15428 (0.6%)		171/26341 (0.6%)
Injury, poisoning and procedural complications
Injury, poisoning, accidents, etc.	337/16534 (2%)		358/15428 (2.3%)		651/26341 (2.5%)
Musculoskeletal and connective tissue disorders
Muscoskeletal system & connective tissue	206/16534 (1.2%)		233/15428 (1.5%)		403/26341 (1.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms, malignant	59/16534 (0.4%)		72/15428 (0.5%)		124/26341 (0.5%)
Neoplasms, benign	96/16534 (0.6%)		97/15428 (0.6%)		179/26341 (0.7%)
Pregnancy, puerperium and perinatal conditions
Pregnancy, delivery & puerperium	51/16534 (0.3%)		62/15428 (0.4%)		99/26341 (0.4%)
Psychiatric disorders
Psychiatric & neurological disorders	114/16534 (0.7%)		136/15428 (0.9%)		274/26341 (1%)
Reproductive system and breast disorders
Genitourinary system	279/16534 (1.7%)		290/15428 (1.9%)		572/26341 (2.2%)
Respiratory, thoracic and mediastinal disorders
Respiratory system	56/16534 (0.3%)		64/15428 (0.4%)		128/26341 (0.5%)
Skin and subcutaneous tissue disorders
Skin	82/16534 (0.5%)		97/15428 (0.6%)		200/26341 (0.8%)
Other (Not Including Serious) Adverse Events
	DRSP/EE		OC-LNG		OC-other
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16534 (0%)		0/15428 (0%)		0/26341 (0%)

Limitations/Caveats

In non-experimental studies the possibility of bias and residual confounding can never be entirely eliminated. The findings may exclude large, but not small relative risks.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.