Transatlantic Active Surveillance on Cardiovascular Safety of NuvaRing (TASC) (TASC)

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ClinicalTrials.gov Identifier: NCT00524771

Recruitment Status : Completed

First Posted : September 5, 2007

Results First Posted : April 9, 2014

Last Update Posted : April 9, 2014

Sponsor:

Collaborator:

Organon

Information provided by (Responsible Party):

Juergen Dinger, MD, PhD, Center for Epidemiology and Health Research, Germany

Study Type	Observational
Study Design	Observational Model: Cohort; Time Perspective: Prospective
Condition	Contraception
Enrollment	34100

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	NuvaRing	Combined Oral Contraceptives (COC)
Arm/Group Description	Users of an etonogestrel-containing...	Users of combined oral contraceptiv...
Arm/Group Description	Users of an etonogestrel-containing and ethinylestradiol-containing vaginal ring	Users of combined oral contraceptive pills
Period Title: Overall Study
Started	17084	17016
Completed	16864 ^[1]	16431 ^[1]
Not Completed	220	585
Reason Not Completed
Protocol Violation	220	585
[1] Numbers completed refer to first follow-up. Individual follow-up ranged between 0.5 and 4.0 years.

Baseline Characteristics

Arm/Group Title		NuvaRing	Combined Oral Contraceptives (COC)	Total
Arm/Group Description		Users of an etonogestrel-containing...	Users of combined oral contraceptiv...	Total of all reporting groups
Arm/Group Description		Users of an etonogestrel-containing and ethinylestradiol-containing vaginal ring	Users of combined oral contraceptive pills	Total of all reporting groups
Overall Number of Baseline Participants		16864	16431	33295
Baseline Analysis Population Description		...
Baseline Analysis Population Description		All study participants that were not excluded due to protocol violations.
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	16864 participants	16431 participants	33295 participants
		28.0 (7.3)	26.9 (7.6)	27.4 (7.5)
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	16864 participants	16431 participants	33295 participants
	<=18 years	127 0.8%	406 2.5%	533 1.6%
	Between 18 and 65 years	16737 99.2%	16025 97.5%	32762 98.4%
	>=65 years	0 0.0%	0 0.0%	0 0.0%
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	16864 participants	16431 participants	33295 participants
	Female	16864 100.0%	16431 100.0%	33295 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment Measure Type: Number Unit of measure: Participants	Number Analyzed	16864 participants	16431 participants	33295 participants
Europe		8215	7699	15914
United States		8649	8732	17381

Outcome Measures

1.Primary Outcome


Title	Number of Participants With Venous Thromboembolism (VTE)
Description	Venous thromboembolism (VTE) associated with the use of hormonal contr...
Description	Venous thromboembolism (VTE) associated with the use of hormonal contraceptives that contain both an estrogen and progestin.
Time Frame	Time to event analysis within 48 months

Outcome Measure Data

Analysis Population Description

Study participants that were not excluded due to protocol violations.


Arm/Group Title	NuvaRing	Combined Oral Contraceptives (COC)	COC2
Arm/Group Description:	Users of an etonogestrel-containing...	Users of combined oral contraceptiv...	A priori defined subgroup of users ...
Arm/Group Description:	Users of an etonogestrel-containing and ethinylestradiol-containing vaginal ring	Users of combined oral contraceptive pills	A priori defined subgroup of users of combined oral contraceptive pills without desogestrel or gestodene
Overall Number of Participants Analyzed	16864	16431	13811
Measure Type: Number Unit of Measure: participants
	19	26	21

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NuvaRing, Combined Oral Contraceptives (COC)
	Comments	Tested null hypothesis: VTE hazard ratio for NuvaRing vs. COCs is higher or equal to 2. This analysis represents the a priori defined primary statistical analysis.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Sample size calculations were based on a non-inferiority test of two exponential survival curves . These calculations are based on the following assumptions: 1) one-sided α of 0.025; 2) power (1-β) of 0.80; VTE incidence rate of 9.1 VTE/10.000 WY and 4) non-inferiority limit on hazard ratio of 2.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 95% 0.5 to 1.5
	Estimation Comments	Hazard ratio was adjusted age, BMI, duration of current use and family history of VTE.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NuvaRing, COC2
	Comments	Tested null hypothesis: VTE hazard ratio for NuvaRing vs. COC2 is higher or equal to 2.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Sample size calculations were based on the primary statistical analysis (see above).

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95% 0.4 to 1.7
	Estimation Comments	Hazard ratio was adjusted age, BMI, duration of current use and family history of VTE.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	NuvaRing, Combined Oral Contraceptives (COC)
	Comments	Like analysis 1 (see above) but restricted to exposure period of less than 6 months.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Sample size calculations were based on the primary statistical analysis (see above).

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95% 0.3 to 2.2
	Estimation Comments	Hazard ratio was adjusted age, BMI, duration of current use and family history of VTE.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	NuvaRing, Combined Oral Contraceptives (COC)
	Comments	Like analysis 1 (see above) but restricted to exposure period of 6 - 12 months.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Sample size calculations were based on the primary statistical analysis (see above).

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 95% 0.3 to 2.6
	Estimation Comments	Hazard ratio was adjusted age, BMI, duration of current use and family history of VTE.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	NuvaRing, Combined Oral Contraceptives (COC)
	Comments	Like analysis 1 (see above) but restricted to exposure period of > 12 months.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Sample size calculations were based on the primary statistical analysis (see above).

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95% 0.3 to 2.3
	Estimation Comments	Hazard ratio was adjusted age, BMI, duration of current use and family history of VTE.

2.Primary Outcome


Title	Number of Participants With Arterial Thromboembolism (ATE)
Description	Arterial Thromboembolism (ATE) associated with the use of hormonal con...
Description	Arterial Thromboembolism (ATE) associated with the use of hormonal contraceptives that contain both an estrogen and progestin.
Time Frame	Time to event analysis within 48 months

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	NuvaRing	Combined Oral Contraceptives (COC)	COC2
Arm/Group Description:	Users of an etonogestrel-containing...	Users of combined oral contraceptiv...	A priori defined subgroup of users ...
Arm/Group Description:	Users of an etonogestrel-containing and ethinylestradiol-containing vaginal ring	Users of combined oral contraceptive pills	A priori defined subgroup of users of combined oral contraceptive pills without desogestrel or gestodene
Overall Number of Participants Analyzed	16864	16431	13811
Measure Type: Number Unit of Measure: participants
	5	8	6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NuvaRing, Combined Oral Contraceptives (COC)
	Comments	[Not Specified]
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Sample size calculations were based on the primary statistical analysis (see above).

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95% 0.2 to 2.3
	Estimation Comments	The hazard ratio was adjusted for age, BMI, Smoking, and treated hypertension.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NuvaRing, COC2
	Comments	[Not Specified]
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Sample size calculations were based on the primary statistical analysis (see above).

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95% 0.2 to 2.6
	Estimation Comments	Hazard ratio was adjusted for age, BMI, smoking, and treated hypertension.

Adverse Events

Time Frame	Information on adverse events was collected over a period of 4 years.
Adverse Event Reporting Description	All study participants were asked for adverse events at each follow-up.

Arm/Group Title	NuvaRing	Combined Oral Contraceptives (COC)
Arm/Group Description	Users of an etonogestrel-containing...	Users of combined oral contraceptiv...
Arm/Group Description	Users of an etonogestrel-containing and ethinylestradiol-containing vaginal ring	Users of combined oral contraceptive pills
All-Cause Mortality
	NuvaRing	Combined Oral Contraceptives (COC)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events Serious Adverse Events
	NuvaRing	Combined Oral Contraceptives (COC)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	577/17084 (3.38%)	751/17016 (4.41%)
Blood and lymphatic system disorders
Diseases of the blood and blood-forming organs ^† 1	3/17084 (0.02%)	3/17016 (0.02%)
Cardiac disorders
Cardiovascular system ^† 1	53/17084 (0.31%)	75/17016 (0.44%)
Ear and labyrinth disorders
Ear ^† 1	8/17084 (0.05%)	9/17016 (0.05%)
Endocrine disorders
Endocrine diseases ^† 1	7/17084 (0.04%)	8/17016 (0.05%)
Eye disorders
Eye ^† 1	3/17084 (0.02%)	5/17016 (0.03%)
Gastrointestinal disorders
Digestive system ^† 1	126/17084 (0.74%)	169/17016 (0.99%)
Infections and infestations
Infectious diseases ^† 1	20/17084 (0.12%)	30/17016 (0.18%)
Injury, poisoning and procedural complications
Injury, poisening, accidents, etc ^† 1	102/17084 (0.60%)	125/17016 (0.73%)
Musculoskeletal and connective tissue disorders
Muscosceletal system & connective tissue ^† 1	19/17084 (0.11%)	26/17016 (0.15%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms, malignant ^† 1	14/17084 (0.08%)	19/17016 (0.11%)
Neoplasms, benign ^† 1	9/17084 (0.05%)	10/17016 (0.06%)
Psychiatric disorders
Psychiatric & neurological disorders ^† 1	42/17084 (0.25%)	52/17016 (0.31%)
Reproductive system and breast disorders
Genitourinary system ^† 1	112/17084 (0.66%)	144/17016 (0.85%)
Respiratory, thoracic and mediastinal disorders
Respiratory system ^† 1	40/17084 (0.23%)	54/17016 (0.32%)
Skin and subcutaneous tissue disorders
Skin ^† 1	19/17084 (0.11%)	22/17016 (0.13%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, ICD 10
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	NuvaRing	Combined Oral Contraceptives (COC)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/16864 (0.00%)	0/16431 (0.00%)

Limitations and 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.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Dr. Juergen Dinger
Organization:	Center for Epidemiology and Health Research, Germany
Phone:	0049 (0)30 945 101 20
EMail:	dinger@zeg-berlin.de

Publications of Results:

Dinger J, Möhner S, Heinemann K. Cardiovascular risk associated with the use of an etonogestrel-containing vaginal ring. Obstet Gynecol. 2013 Oct;122(4):800-808. doi: 10.1097/AOG.0b013e3182a5ec6b.

Layout table for additonal information

Responsible Party:	Juergen Dinger, MD, PhD, Center for Epidemiology and Health Research, Germany
ClinicalTrials.gov Identifier:	NCT00524771
Other Study ID Numbers:	ZEG2007_03
First Submitted:	September 4, 2007
First Posted:	September 5, 2007
Results First Submitted:	March 3, 2014
Results First Posted:	April 9, 2014
Last Update Posted:	April 9, 2014

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