Drug-drug Interaction of BI 201335 and Microgynon

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01570244
• Collaborator: (none)
• Enrollment: 16
• Location: 1
• Arms: 2
• Duration (Months): 4
• Patients Per Site Per Month: 4

Study Details

Study Description

Brief Summary

This study will investigate possible effect of multiple oral doses of BI 201335 on the steady state pharmacokinetics of ethinylestradiol and levonogestrel

Condition or Disease	Intervention/Treatment	Phase
Hepatitis C, Chronic	Drug: levonorgestrel; Drug: Ethinylestradiol; Drug: levonorgestrel; Drug: BI 201335; Drug: Ethinylestradiol	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Two-period, Fixed-sequence, Phase I Trial to Evaluate the Effect of Multiple Doses of 240 mg BI 201335 QD on the Multiple-dose Pharmacokinetics of a Combination of Ethinylestradiol and Levonorgestrel in Healthy Premenopausal Female Volunteers
• Study Start Date: Apr 1, 2012
• Actual Primary Completion Date: Aug 1, 2012
• Actual Study Completion Date: Aug 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Reference multiple doses of Microgynon	Drug: levonorgestrel; multiple doses; Drug: Ethinylestradiol; multiple doses
Active Comparator: Test multiple doses of Microgynon + BI 201335	Drug: levonorgestrel; multiple doses; Drug: Ethinylestradiol; multiple doses; Drug: BI 201335; multiple doses

Outcome Measures

Primary Outcome Measures

1. AUCt,ss of Ethinylestradiol [on day 13 of first period and on day 8 of second period 0:00, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 hours (h) after drug administration]

   Area under the curve over the dosing interval t under steady state conditions of ethinylestradiol

2. Cmax,ss of Ethinylestradiol [on day 13 of first period and on day 8 of second period 0:00, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 h after drug administration]

   maximum measured concentration over the uniform dosing interval under steady state conditions of ethinylestradiol

3. C24,ss of Ethinylestradiol [on day 13 of first period and on day 8 of second period 0:00, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 h after drug administration]

   measured concentration of the analyte at the end of dosing interval under steady state conditions of ethinylestradiol

4. AUCτ,ss of Levonorgestrel [on day 13 of first period and on day 8 of second period 0:00, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 h after drug administration]

   Area under the curve over the dosing interval τ under steady state conditions of levonorgestrel

5. Cmax,ss of Levonorgestrel [on day 13 of first period and on day 8 of second period 0:00, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 h after drug administration]

   maximum measured concentration over the uniform dosing interval under steady state conditions of levonorgestrel

6. C24,ss of Levonorgestrel [on day 13 of first period and on day 8 of second period 0:00, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 h after drug administration]

   measured concentration of the analyte at the end of dosing interval under steady state conditions of levonorgestrel

Secondary Outcome Measures

1. Clinical Relevant Abnormalities for Vital Signs, Physical Examination, Blood Chemistry, Haematology, Urinanalysis and ECG. [from drug administration up to 14 days]

   Clinical relevant abnormalities for Vital Signs, Physical Examination, Blood Chemistry, Haematology, Urinanalysis and ECG. New abnormal findings or worsening of baseline conditions were reported as Adverse Events.

2. Number of Participants With Drug Related Adverse Events [from drug administration up to 14 days]

   number of participants with investigator-defined drug related adverse events

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 35 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion criteria:

1. Healthy female subjects

Exclusion criteria:

1. Any relevant deviation from healthy conditions

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1220.56.1 Boehringer Ingelheim Investigational Site	Biberach		Germany

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01570244
• Other Study ID Numbers: 1220.56; 2011-006061-17
• First Posted: Apr 4, 2012
• Last Update Posted: Aug 3, 2015
• Last Verified: Jul 1, 2015

• Additional relevant MeSH terms: Hepatitis C; Hepatitis C, Chronic; Levonorgestrel; Ethinyl Estradiol

Study Results

Participant Flow

Arm/Group Title	All Subjects
Arm/Group Description	The trial was a nonrandomised, noncontrolled, open-label, 2-period fixed-sequence trial to evaluate the possible effect of multiple doses of faldaprevir on the multiple-dose pharmacokinetics of a combination of ethinylestradiol and levonorgestrel. The trial was to be performed in 16 healthy female volunteers. Period 1: Microgynon (150 μg Ethinylestradiol+30 μg Levonorgestrel) tablets. Period 2: Microgynon tablets and Faldaprevir.
Period Title: Microgynon
STARTED	16
COMPLETED	16
NOT COMPLETED	0
Period Title: Microgynon
STARTED	16
COMPLETED	15
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	All Subjects
Arm/Group Description	The trial was a nonrandomised, noncontrolled, open-label, 2-period fixed-sequence trial to evaluate the possible effect of multiple doses of faldaprevir on the multiple-dose pharmacokinetics of a combination of ethinylestradiol and levonorgestrel. The trial was to be performed in 16 healthy female volunteers.
Overall Participants	16
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28.4 (5.1)
Sex: Female, Male (Count of Participants)
Female	16 100%
Male	0 0%

Outcome Measures

1. Primary Outcome

Title	AUCt,ss of Ethinylestradiol
Description	Area under the curve over the dosing interval t under steady state conditions of ethinylestradiol
Time Frame	on day 13 of first period and on day 8 of second period 0:00, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 hours (h) after drug administration

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: all subjects in the treated set who provided at least 1 observation for at least 1 primary pharmacokinetic endpoint, who did not have important protocol violations relevant to the evaluation of PK endpoints, and who did not have vomiting until 2·median tmax,ss of ethinylestradiol or levonorgestrel on Day 13 or on Day 8.

Arm/Group Title	Microgynon	Microgynon + Faldaprevir
Arm/Group Description	Multiple doses of Microgynon (150 µg Ethinylestradiol+30 µg Levonorgestrel) tablets once daily in the morning.	Multiple doses of Microgynon (150 µg Ethinylestradiol+30 µg Levonorgestrel) tablets once daily in the morning. Faldaprevir: loading dose of 480 mg (morning and evening doses of 240 mg on Day 1 of Period 2), on subsequent days 240 mg once daily in the morning.
Measure Participants	16	15
Geometric Mean (Geometric Coefficient of Variation) [pg*h/mL]	1010 (23.5)	1450 (27.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Microgynon, Microgynon + Faldaprevir
	Comments	relative bioavailability comparison (Microgynon + Faldaprevir : Microgynon) of Ethinylestradiol
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	investigation of relative bioavailability (no formal testing)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	140.96
	Confidence Interval	(2-Sided) 90%; 133.84 to 148.47
	Parameter Dispersion	Type: Standard Deviation; Value: 8.1
	Estimation Comments	the standard deviation is actually the geometric coefficient of variation

2. Primary Outcome

Title	Cmax,ss of Ethinylestradiol
Description	maximum measured concentration over the uniform dosing interval under steady state conditions of ethinylestradiol
Time Frame	on day 13 of first period and on day 8 of second period 0:00, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 h after drug administration

Outcome Measure Data

Analysis Population Description

PK set

Arm/Group Title	Microgynon	Microgynon + Faldaprevir
Arm/Group Description	Multiple doses of Microgynon (150 µg Ethinylestradiol+30 µg Levonorgestrel) tablets once daily in the morning.	Multiple doses of Microgynon (150 µg Ethinylestradiol+30 µg Levonorgestrel) tablets once daily in the morning. Faldaprevir: loading dose of 480 mg (morning and evening doses of 240 mg on Day 1 of Period 2), on subsequent days 240 mg once daily in the morning.
Measure Participants	16	15
Geometric Mean (Geometric Coefficient of Variation) [pg/mL]	108 (23.6)	127 (25.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Microgynon, Microgynon + Faldaprevir
	Comments	relative bioavailability comparison (Microgynon + Faldaprevir : Microgynon) of Ethinylestradiol
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	investigation of relative bioavailability (no formal testing)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	114.82
	Confidence Interval	(2-Sided) 90%; 105.49 to 124.97
	Parameter Dispersion	Type: Standard Deviation; Value: 13.2
	Estimation Comments	the standard deviation is actually the geometric coefficient of variation

3. Primary Outcome

Title	C24,ss of Ethinylestradiol
Description	measured concentration of the analyte at the end of dosing interval under steady state conditions of ethinylestradiol
Time Frame	on day 13 of first period and on day 8 of second period 0:00, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 h after drug administration

Outcome Measure Data

Analysis Population Description

PK set

Arm/Group Title	Microgynon	Microgynon + Faldaprevir
Arm/Group Description	Multiple doses of Microgynon (150 µg Ethinylestradiol+30 µg Levonorgestrel) tablets once daily in the morning.	Multiple doses of Microgynon (150 µg Ethinylestradiol+30 µg Levonorgestrel) tablets once daily in the morning. Faldaprevir: loading dose of 480 mg (morning and evening doses of 240 mg on Day 1 of Period 2), on subsequent days 240 mg once daily in the morning.
Measure Participants	16	15
Geometric Mean (Geometric Coefficient of Variation) [pg/mL]	19.1 (32.9)	33.2 (42.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Microgynon, Microgynon + Faldaprevir
	Comments	relative bioavailability comparison (Microgynon + Faldaprevir : Microgynon) of Ethinylestradiol
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	investigation of relative bioavailability (no formal testing)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	171.37
	Confidence Interval	(2-Sided) 90%; 160.20 to 183.33
	Parameter Dispersion	Type: Standard Deviation; Value: 10.5
	Estimation Comments	the standard deviation is actually the geometric coefficient of variation

4. Secondary Outcome

Title	Clinical Relevant Abnormalities for Vital Signs, Physical Examination, Blood Chemistry, Haematology, Urinanalysis and ECG.
Description	Clinical relevant abnormalities for Vital Signs, Physical Examination, Blood Chemistry, Haematology, Urinanalysis and ECG. New abnormal findings or worsening of baseline conditions were reported as Adverse Events.
Time Frame	from drug administration up to 14 days

Outcome Measure Data

Analysis Population Description

Treated set: This subject set included all 16 subjects who were administered trial medication and were documented to have taken at least 1 dose of investigational treatment.

Arm/Group Title	Microgynon	Microgynon + Faldaprevir
Arm/Group Description	Multiple doses of Microgynon (150 µg Ethinylestradiol+30 µg Levonorgestrel) tablets once daily in the morning.	Multiple doses of Microgynon (150 µg Ethinylestradiol+30 µg Levonorgestrel) tablets once daily in the morning. Faldaprevir: loading dose of 480 mg (morning and evening doses of 240 mg on Day 1 of Period 2), on subsequent days 240 mg once daily in the morning.
Measure Participants	16	16
Number [participants]	0 0%	0 NaN

5. Secondary Outcome

Title	Number of Participants With Drug Related Adverse Events
Description	number of participants with investigator-defined drug related adverse events
Time Frame	from drug administration up to 14 days

Outcome Measure Data

Analysis Population Description

treated set

Arm/Group Title	Microgynon	Microgynon + Faldaprevir
Arm/Group Description	Multiple doses of Microgynon (150 µg Ethinylestradiol+30 µg Levonorgestrel) tablets once daily in the morning.	Multiple doses of Microgynon (150 µg Ethinylestradiol+30 µg Levonorgestrel) tablets once daily in the morning. Faldaprevir: loading dose of 480 mg (morning and evening doses of 240 mg on Day 1 of Period 2), on subsequent days 240 mg once daily in the morning.
Measure Participants	16	16
Number [participants]	2 12.5%	15 NaN

6. Primary Outcome

Title	AUCτ,ss of Levonorgestrel
Description	Area under the curve over the dosing interval τ under steady state conditions of levonorgestrel
Time Frame	on day 13 of first period and on day 8 of second period 0:00, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 h after drug administration

Outcome Measure Data

Analysis Population Description

PK set

Arm/Group Title	Microgynon	Microgynon + Faldaprevir
Arm/Group Description	Multiple doses of Microgynon (150 µg Ethinylestradiol+30 µg Levonorgestrel) tablets once daily in the morning.	Multiple doses of Microgynon (150 µg Ethinylestradiol+30 µg Levonorgestrel) tablets once daily in the morning. Faldaprevir: loading dose of 480 mg (morning and evening doses of 240 mg on Day 1 of Period 2), on subsequent days 240 mg once daily in the morning.
Measure Participants	16	15
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	83.3 (42.0)	120 (40.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Microgynon, Microgynon + Faldaprevir
	Comments	relative bioavailability comparison (Microgynon + Faldaprevir : Microgynon) of Levonorgestrel
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	investigation of relative bioavailability (no formal testing)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	140.53
	Confidence Interval	(2-Sided) 90%; 136.40 to 144.78
	Parameter Dispersion	Type: Standard Deviation; Value: 4.6
	Estimation Comments	the standard deviation is actually the geometric coefficient of variation

7. Primary Outcome

Title	Cmax,ss of Levonorgestrel
Description	maximum measured concentration over the uniform dosing interval under steady state conditions of levonorgestrel
Time Frame	on day 13 of first period and on day 8 of second period 0:00, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 h after drug administration

Outcome Measure Data

Analysis Population Description

PK set

Arm/Group Title	Microgynon	Microgynon + Faldaprevir
Arm/Group Description	Multiple doses of Microgynon (150 µg Ethinylestradiol+30 µg Levonorgestrel) tablets once daily in the morning.	Multiple doses of Microgynon (150 µg Ethinylestradiol+30 µg Levonorgestrel) tablets once daily in the morning. Faldaprevir: loading dose of 480 mg (morning and evening doses of 240 mg on Day 1 of Period 2), on subsequent days 240 mg once daily in the morning.
Measure Participants	16	15
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	7.57 (34.9)	8.95 (33.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Microgynon, Microgynon + Faldaprevir
	Comments	relative bioavailability comparison (Microgynon + Faldaprevir : Microgynon) of Levonorgestrel
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	investigation of relative bioavailability (no formal testing)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	115.28
	Confidence Interval	(2-Sided) 90%; 110.81 to 119.92
	Parameter Dispersion	Type: Standard Deviation; Value: 6.1
	Estimation Comments	the standard deviation is actually the geometric coefficient of variation

8. Primary Outcome

Title	C24,ss of Levonorgestrel
Description	measured concentration of the analyte at the end of dosing interval under steady state conditions of levonorgestrel
Time Frame	on day 13 of first period and on day 8 of second period 0:00, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 h after drug administration

Outcome Measure Data

Analysis Population Description

PK set

Arm/Group Title	Microgynon	Microgynon + Faldaprevir
Arm/Group Description	Multiple doses of Microgynon (150 µg Ethinylestradiol+30 µg Levonorgestrel) tablets once daily in the morning.	Multiple doses of Microgynon (150 µg Ethinylestradiol+30 µg Levonorgestrel) tablets once daily in the morning. Faldaprevir: loading dose of 480 mg (morning and evening doses of 240 mg on Day 1 of Period 2), on subsequent days 240 mg once daily in the morning.
Measure Participants	16	15
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	2.43 (49.4)	3.85 (47.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Microgynon, Microgynon + Faldaprevir
	Comments	relative bioavailability comparison (Microgynon + Faldaprevir : Microgynon) of Levonorgestrel
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	investigation of relative bioavailability (no formal testing)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	153.85
	Confidence Interval	(2-Sided) 90%; 145.99 to 162.14
	Parameter Dispersion	Type: Standard Deviation; Value: 8.2
	Estimation Comments	the standard deviation is actually the geometric coefficient of variation

Adverse Events

Time Frame	from the time the subject signed the informed consent (56 to 28 days before drug administration) through the observational phase until the end-of-study examination (6 to 14 days after the end of period 2)
Adverse Event Reporting Description	During the run-in-period, the volunteers were to be contacted at least twice and asked to report adverse events and concomitant medication. In addition, each volunteer was to be assessed regularly by the medical staff throughout the clinical trial as well as at the end of observation and whenever necessary as deemed by the investigator.
Arm/Group Title	Microgynon		Microgynon + BI 201335
Arm/Group Description	Multiple doses of Microgynon (150 µg Ethinylestradiol+30 µg Levonorgestrel) tablets once daily in the morning.		Multiple doses of Microgynon (150 µg Ethinylestradiol+30 µg Levonorgestrel) tablets once daily in the morning. Faldaprevir: loading dose of 480 mg (morning and evening doses of 240 mg on Day 1 of Period 2), on subsequent days 240 mg once daily in the morning.
All Cause Mortality
	Microgynon		Microgynon + BI 201335
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Microgynon		Microgynon + BI 201335
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	Microgynon		Microgynon + BI 201335
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/16 (75%)		14/16 (87.5%)
Cardiac disorders
Tachycardia	0/16 (0%)		1/16 (6.3%)
Eye disorders
Ocular icterus	0/16 (0%)		6/16 (37.5%)
Gastrointestinal disorders
Abdominal discomfort	0/16 (0%)		4/16 (25%)
Abdominal pain upper	0/16 (0%)		1/16 (6.3%)
Diarrhoea	0/16 (0%)		2/16 (12.5%)
Flatulence	0/16 (0%)		1/16 (6.3%)
Haemorrhoids	1/16 (6.3%)		0/16 (0%)
Nausea	0/16 (0%)		8/16 (50%)
Stomatitis	0/16 (0%)		1/16 (6.3%)
Vomiting	1/16 (6.3%)		4/16 (25%)
General disorders
Asthenia	0/16 (0%)		1/16 (6.3%)
Fatigue	0/16 (0%)		1/16 (6.3%)
Oedema peripheral	0/16 (0%)		1/16 (6.3%)
Pain	0/16 (0%)		1/16 (6.3%)
Swelling	1/16 (6.3%)		0/16 (0%)
Infections and infestations
Oral herpes	2/16 (12.5%)		0/16 (0%)
Injury, poisoning and procedural complications
Arthropod bite	0/16 (0%)		1/16 (6.3%)
Metabolism and nutrition disorders
Decreased appetite	0/16 (0%)		7/16 (43.8%)
Increased appetite	0/16 (0%)		2/16 (12.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/16 (6.3%)		0/16 (0%)
Bone pain	1/16 (6.3%)		1/16 (6.3%)
Muscle tightness	0/16 (0%)		1/16 (6.3%)
Myalgia	0/16 (0%)		1/16 (6.3%)
Nervous system disorders
Dizziness	1/16 (6.3%)		3/16 (18.8%)
Dysgeusia	0/16 (0%)		1/16 (6.3%)
Headache	5/16 (31.3%)		6/16 (37.5%)
Orthostatic intolerance	1/16 (6.3%)		0/16 (0%)
Paraesthesia	0/16 (0%)		1/16 (6.3%)
Psychiatric disorders
Apathy	0/16 (0%)		2/16 (12.5%)
Renal and urinary disorders
Pollakiuria	0/16 (0%)		1/16 (6.3%)
Reproductive system and breast disorders
Metrorrhagia	1/16 (6.3%)		0/16 (0%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	1/16 (6.3%)		1/16 (6.3%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	0/16 (0%)		1/16 (6.3%)
Pruritus	0/16 (0%)		1/16 (6.3%)
Rash	0/16 (0%)		1/16 (6.3%)
Rash papular	0/16 (0%)		1/16 (6.3%)
Vascular disorders
Haematoma	0/16 (0%)		1/16 (6.3%)
Hot flush	0/16 (0%)		3/16 (18.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.