Pharmacokinetics and Safety in Healthy Volunteers

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02045979
• Collaborator: (none)
• Enrollment: 327
• Locations: 3
• Arms: 3
• Actual Duration (Months): 4.6
• Patients Per Site: 109
• Patients Per Site Per Month: 23.7

Study Details

Study Description

Brief Summary

Investigate the pharmacokinetics, safety and tolerability of BI695501 and to establish pharmacokinetic similarity of BI 695501 to adalimumab.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: BI 695501; Drug: adalimumab-EU source; Drug: adalimumab-US source	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 327 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: Pharmacokinetics and Safety of BI 695501 in Healthy Subjects: a Randomized, Double-blind, Single Dose, Parallel-arm, Active Comparator Clinical Phase I Study
• Actual Study Start Date: Jan 31, 2014
• Actual Primary Completion Date: Jun 20, 2014
• Actual Study Completion Date: Jun 20, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BI 695501 Subject to receive one subcutaneous (s.c.) injection from a prefilled syringe containing BI 695501	Drug: BI 695501; BI 695501 single s.c. injection
Active Comparator: adalimumab-EU source Subject to receive one subcutaneous (s.c.) injection from a prefilled syringe containing adalimumab-EU source	Drug: adalimumab-EU source; adalimumab-EU source single s.c. injection
Active Comparator: adalimumab-US source Subject to receive one subcutaneous (s.c.) injection from a prefilled syringe containing adalimumab-US source	Drug: adalimumab-US source; adalimumab-US source single s.c. injection.

Outcome Measures

Primary Outcome Measures

1. Area Under the Concentration Time Curve (AUC) From Time Zero to Infinity (AUC 0-∞) of BI 695501, US-licensed Humira® or EU-approved Humira® [at -1 hour (h) (pre dosing) and 1h, 4, 8, 12, 24, 48, 72, 84, 96, 108, 120, 132, 144, 168, 192, 240, 312, 480, 648, 1032, 1320 h post dosing and on day 71 post dosing.]

   Area under the concentration time curve (AUC) from time zero to infinity (AUC 0-∞) of BI 695501, US-licensed Humira® or EU-approved Humira®. Abbreviation used: Pharmacokinetics (PK).

2. Area Under the Concentration Time Curve From Time Zero to Last Measurable Concentration (AUC0-tz) of BI 695501, US-licensed Humira® or EU-approved Humira® [at -1 hour (h) (pre dosing) and 1h, 4, 8, 12, 24, 48, 72, 84, 96, 108, 120, 132, 144, 168, 192, 240, 312, 480, 648, 1032, 1320 h post dosing and on day 71 post dosing.]

   Area under the concentration time curve from time zero to last measurable concentration (AUC0-tz) of BI 695501, US-licensed Humira® or EU-approved Humira®.

3. Maximum Concentration (Cmax) of BI 695501, US-licensed Humira® or EU-approved Humira® [at -1 hour (h) (pre dosing) and 1h, 4, 8, 12, 24, 48, 72, 84, 96, 108, 120, 132, 144, 168, 192, 240, 312, 480, 648, 1032, 1320 h post dosing and on day 71 post dosing.]

   Maximum concentration (Cmax) of BI 695501, US-licensed Humira® or EU-approved Humira®.

Secondary Outcome Measures

1. AUC (0-168) of BI 695501, US-licensed Humira® or EU-approved Humira® [at -1 hour (h) (pre dosing) and 1h, 4, 8, 12, 24, 48, 72, 84, 96, 108, 120, 132, 144, 168 hours post dosing]

   Area under the concentration time curve (AUC) from time zero to 168 hours post dose (AUC 0-168) of BI 695501, US-licensed Humira® or EU-approved Humira®. PK is the abbreviation for Pharmacokinetic(s).

2. AUC (0-312) of BI 695501, US-licensed Humira® or EU-approved Humira® [at -1 hour (h) (pre dosing) and 1h, 4, 8, 12, 24, 48, 72, 84, 96, 108, 120, 132, 144, 168, 192, 240, 312 hours post dosing]

   Area under the concentration time curve (AUC) from time zero to 312 hours post dose (AUC 0-312) of BI 695501, US-licensed Humira® or EU-approved Humira®. PK is the abbreviation for Pharmacokinetic(s).

3. AUC (0-480) of BI 695501, US-licensed Humira® or EU-approved Humira® [at -1 hour (h) (pre dosing) and 1h, 4, 8, 12, 24, 48, 72, 84, 96, 108, 120, 132, 144, 168, 192, 240, 312, 480 hours post dosing]

   Area under the concentration time curve (AUC) from time zero to 480 hours post dose (AUC 0-480) of BI 695501, US-licensed Humira® or EU-approved Humira®. PK is the abbreviation for Pharmacokinetic(s).

4. AUC (0-648) of BI 695501, US-licensed Humira® or EU-approved Humira® [at -1 hour (h) (pre dosing) and 1h, 4, 8, 12, 24, 48, 72, 84, 96, 108, 120, 132, 144, 168, 192, 240, 312, 480, 648 hours post dosing]

   Area under the concentration time curve (AUC) from time zero to 648 hours post dose (AUC 0-648) of BI 695501, US-licensed Humira® or EU-approved Humira®. PK is the abbreviation for Pharmacokinetic(s).

5. AUC (0-1032) of BI 695501, US-licensed Humira® or EU-approved Humira® [at -1 hour (h) (pre dosing) and 1h, 4, 8, 12, 24, 48, 72, 84, 96, 108, 120, 132, 144, 168, 192, 240, 312, 480, 648, 1032 hours post dosing]

   Area under the concentration time curve (AUC) from time zero to 1032 hours post dose (AUC 0-1032) of BI 695501, US-licensed Humira® or EU-approved Humira® PK is the abbreviation for Pharmacokinetic(s).

6. AUC 0-∞,Obs of BI 695501, US-licensed Humira® or EU-approved Humira® [at -1 hour (h) (pre dosing) and 1h, 4, 8, 12, 24, 48, 72, 84, 96, 108, 120, 132, 144, 168, 192, 240, 312, 480, 648, 1032, 1320 h post dosing and on day 71 post dosing.]

   Area under the concentration time curve (AUC) from time zero to infinity (AUC 0-∞) based on the last observed concentration at time of last measureable concentration (tz) of BI 695501, US-licensed Humira® or EU-approved Humira®. PK is the abbreviation of Pharmacokinetic(s).

7. Number (Proportion) of Subjects With Drug Related Adverse Events [Day 1 through Day 71]

   All events with an onset after the first administration of the trial medication up to a period of 70 days after the last administration of the trial medication (i.e., end of the REP) was assigned to the treatment phase for evaluation and was defined as a treatment-emergent AE (TEAE). A treatment-related AE was defined as any TEAE assessed by the investigator as related to the trial medication. All safety data were displayed and analyzed using descriptive statistical methods. No formal inferential analyses were planned for safety comparisons. Tabulations of frequencies and proportions, as appropriate were used for the evaluation of categorical (qualitative) data, and tabulations of descriptive statistics were used to analyze continuous (quantitative) data.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Inclusion criteria:

Healthy males according to the following criteria:

1. Based upon a complete medical history, including the physical examination, vital signs (blood pressure [BP] and pulse rate [PR]), 12-lead electrocardiogram (ECG), and clinical laboratory tests;

2. Age-greater than or equal to 18 years and less than or equal to 55 years;

3. Body mass index (BMI) =18.5 to =29.9 kg/m2; and

4. Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice and the local legislation.

Exclusion criteria:

1. Any clinically relevant abnormal finding of the medical examination (including blood pressure (BP), pulse rate (PR), and electrocardiogram (ECG) deviating from normal and of clinical relevance;

2. Any evidence of a clinically relevant previous or concomitant disease as judged by the investigator including gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, hormonal disorders, or diseases of the central nervous system (such as epilepsy), psychiatric disorders, or neurological disorders;

3. History of relevant orthostatic hypotension, fainting spells, or blackouts;

4. Chronic or relevant acute infections. A negative result for human immunodeficiency virus (HIV), Hepatitis B (Hep B), and hepatitis C (Hep C) is required for participation;

5. History of relevant allergy/hypersensitivity (including allergy to drug or its excipients);

6. Intake of prescribed or over-the-counter drugs with a long half-life (greater than 24 hours) within at least one month or at least 5 half-lives of the respective drug (whichever is longer) prior to administration or during the trial;

7. Previous exposure of a biologic drug;

8. Use of drugs which might reasonably influence the results of the trial prior to dosing and at any time during the trial;

9. Intake of an investigational drug in another trial within two months prior to intake of study medication in this trial or intake of an investigational drug during the course of this trial;

10. Smoker (greater than 10 cigarettes or greater than 3 cigars or greater than 3 pipes/day);

11. Inability to refrain from smoking during days of confinement at the trial site;

12. History of alcohol abuse (estimated average more than 4 units/day);

13. Unwillingness/inability to refrain from intake of alcoholic beverages from 48 hours prior to the study medication administration and until Day 7 post study medication administration;

14. Unwillingness/inability to limit alcohol intake to a maximum of three units per day until e.o.s.;

15. Current drug abuse;

16. Blood donation (more than 100 mL within four weeks prior to administration of the study medication or during the trial);

17. Vigorous exercise 72 hours prior to dosing. Unwilling to avoid vigorous exercise for 7 days post dosing. Contact sport should be avoided during the entire study;

18. Any out-of-range laboratory values considered clinically significant by the investigator; subjects with creatine kinase (CK) values three times the upper limit of normal (ULN) at Day -1 are excluded from participation;

19. Subjects considered unsuitable for inclusion by the investigator (e.g., inability to understand and comply with the study requirements or presence of any condition which, in the opinion of the investigator, would not allow safe participation in the study); or

20. Inability to comply with dietary regimen of trial site.

21. Subjects with known Human immunodeficiency virus (HIV), Acquired Immunodeficiency Syndrome, other clinically significant immunological disorders, or auto-immune disorders, (e.g., Rheumatoid arthritis (RA), lupus erythematosus, scleroderma, etc.);

22. Subject has received a live or attenuated vaccine within 12 weeks prior to enrolling in the trial; or

23. Positive finding in Interferon-gamma-release assay testing (IGRA-T). In cases where at the screening visit the IGRA result is indeterminate, the subject will have a PPD skin test performed, provided that the screening period timeframe can be maintained. If not, the subject will not be enrolled in this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1297.8.1001 Boehringer Ingelheim Investigational Site	Antwerpen		Belgium
2	1297.8.2001 Boehringer Ingelheim Investigational Site	Auckland		New Zealand
3	1297.8.2002 Boehringer Ingelheim Investigational Site	Christchurch		New Zealand

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: NCT02045979
• Other Study ID Numbers: 1297.8; 2013-003722-84
• First Posted: Jan 27, 2014
• Last Update Posted: Jun 20, 2018
• Last Verified: Sep 1, 2017

• Additional relevant MeSH terms: Adalimumab

Study Results

Participant Flow

Recruitment Details	In this trial 324 healthy subjects were randomized into 3 arms.
Pre-assignment Detail	All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that they (the subject) met all strictly implemented inclusion/exclusion criteria. Subjects were not randomised to trial treatment if any one of the specific entry criteria were violated.

Arm/Group Title	BI 695501	US-licensed Humira®	EU-approved Humira®
Arm/Group Description	Subject to receive a single subcutaneous (s.c.) injection from a prefilled syringe containing 40 milligram (mg)/0.8 millilitre (mL) BI 695501 solution.	Subject to receive a single subcutaneous (s.c.) injection from a prefilled syringe containing 40 mg/0.8 mL US-licensed Humira®	Subject to receive a single subcutaneous (s.c.) injection from a prefilled syringe containing 40 mg/0.8 mL European Union (EU)-approved Humira®.
Period Title: Overall Study
STARTED	108	108	108
COMPLETED	106	107	107
NOT COMPLETED	2	1	1

Baseline Characteristics

Arm/Group Title	BI 695501	US-licensed Humira®	EU-approved Humira®	Total
Arm/Group Description	single s.c. injection 40 mg/0.8 mL BI 695501 solution.	single s.c. injection 40 mg/0.8 mL US-licensed Humira®	single s.c. injection 40 mg/0.8 mL EU-approved Humira®	Total of all reporting groups
Overall Participants	108	108	108	324
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	30 (11)	31 (11)	30 (12)	31 (11)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%
Male	108 100%	108 100%	108 100%	324 100%

Outcome Measures

1. Primary Outcome

Title	Area Under the Concentration Time Curve (AUC) From Time Zero to Infinity (AUC 0-∞) of BI 695501, US-licensed Humira® or EU-approved Humira®
Description	Area under the concentration time curve (AUC) from time zero to infinity (AUC 0-∞) of BI 695501, US-licensed Humira® or EU-approved Humira®. Abbreviation used: Pharmacokinetics (PK).
Time Frame	at -1 hour (h) (pre dosing) and 1h, 4, 8, 12, 24, 48, 72, 84, 96, 108, 120, 132, 144, 168, 192, 240, 312, 480, 648, 1032, 1320 h post dosing and on day 71 post dosing.

Outcome Measure Data

Analysis Population Description

PK analysis set consisted of all randomized subjects who received the single dose of trial medication (BI 695501, US-licensed - or EU-approved Humira®), had at least one evaluable primary PK endpoint and were without important protocol deviations or violations thought to significantly affect the PK of BI 695501, US-licensed - or EU-approved Humira®

Arm/Group Title	BI 695501	US-licensed Humira®	EU-approved Humira®
Arm/Group Description	single s.c. injection 40 mg/0.8 mL BI 695501 solution.	single s.c. injection 40 mg/0.8 mL US-licensed Humira®	single s.c. injection 40 mg/0.8 mL EU-approved Humira®
Measure Participants	106	105	105
Geometric Mean (Geometric Coefficient of Variation) [microgram (µg)*hour (h)/millilitre (mL)]	2630 (52.4)	2470 (51.2)	2650 (38.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695501, US-licensed Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	PK similarity of the two treatments was to be concluded if the 90% CI for the ratio of adjusted geometric means was within 80.00 - 125.00 percent (%).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	108.62
	Confidence Interval	(2-Sided) 90%; 98.50 to 119.79
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 695501, EU-approved Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	PK similarity of the two treatments was to be concluded if the 90% CI for the ratio of adjusted geometric means was within 80.00 - 125.00 %.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	101.27
	Confidence Interval	(2-Sided) 90%; 92.45 to 110.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	US-licensed Humira®, EU-approved Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	PK similarity of the two treatments was to be concluded if the 90% CI for the ratio of adjusted geometric means was within 80.00 - 125.00 %.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	94.02
	Confidence Interval	(2-Sided) 90%; 86.01 to 102.78
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

2. Primary Outcome

Title	Area Under the Concentration Time Curve From Time Zero to Last Measurable Concentration (AUC0-tz) of BI 695501, US-licensed Humira® or EU-approved Humira®
Description	Area under the concentration time curve from time zero to last measurable concentration (AUC0-tz) of BI 695501, US-licensed Humira® or EU-approved Humira®.
Time Frame	at -1 hour (h) (pre dosing) and 1h, 4, 8, 12, 24, 48, 72, 84, 96, 108, 120, 132, 144, 168, 192, 240, 312, 480, 648, 1032, 1320 h post dosing and on day 71 post dosing.

Outcome Measure Data

Analysis Population Description

The PK analysis set.

Arm/Group Title	BI 695501	US-licensed Humira®	EU-approved Humira®
Arm/Group Description	single s.c. injection 40 mg/0.8 mL BI 695501 solution.	single s.c. injection 40 mg/0.8 mL US-licensed Humira®	single s.c. injection 40 mg/0.8 mL EU-approved Humira®
Measure Participants	106	107	106
Geometric Mean (Geometric Coefficient of Variation) [µg*h/mL]	2440 (47.8)	2300 (45.1)	2480 (33.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695501, US-licensed Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	PK similarity of the two treatments was to be concluded if the 90% CI for the ratio of adjusted geometric means was within 80.00 - 125.00 %.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	107.32
	Confidence Interval	(2-Sided) 90%; 98.49 to 116.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 695501, EU-approved Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	PK similarity of the two treatments was to be concluded if the 90% CI for the ratio of adjusted geometric means was within 80.00 - 125.00 %.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	99.93
	Confidence Interval	(2-Sided) 90%; 92.15 to 108.37
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	US-licensed Humira®, EU-approved Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	PK similarity of the two treatments was to be concluded if the 90% CI for the ratio of adjusted geometric means was within 80.00 - 125.00 %.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	93.66
	Confidence Interval	(2-Sided) 90%; 86.76 to 101.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

3. Primary Outcome

Title	Maximum Concentration (Cmax) of BI 695501, US-licensed Humira® or EU-approved Humira®
Description	Maximum concentration (Cmax) of BI 695501, US-licensed Humira® or EU-approved Humira®.
Time Frame	at -1 hour (h) (pre dosing) and 1h, 4, 8, 12, 24, 48, 72, 84, 96, 108, 120, 132, 144, 168, 192, 240, 312, 480, 648, 1032, 1320 h post dosing and on day 71 post dosing.

Outcome Measure Data

Analysis Population Description

The PK analysis set.

Arm/Group Title	BI 695501	US-licensed Humira®	EU-approved Humira®
Arm/Group Description	single s.c. injection 40 mg/0.8 mL BI 695501 solution.	single s.c. injection 40 mg/0.8 mL US-licensed Humira®	single s.c. injection 40 mg/0.8 mL EU-approved Humira®
Measure Participants	107	108	107
Geometric Mean (Geometric Coefficient of Variation) [µg/mL]	3.907 (34.1)	3.900 (34.5)	4.140 (30.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695501, US-licensed Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	PK similarity of the two treatments was to be concluded if the 90% CI for the ratio of adjusted geometric means was within 80.00 - 125.00 %.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	100.85
	Confidence Interval	(2-Sided) 90%; 95.15 to 106.88
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 695501, EU-approved Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	PK similarity of the two treatments was to be concluded if the 90% CI for the ratio of adjusted geometric means was within 80.00 - 125.00 %.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	96.39
	Confidence Interval	(2-Sided) 90%; 91.06 to 102.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	US-licensed Humira®, EU-approved Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	PK similarity of the two treatments was to be concluded if the 90% CI for the ratio of adjusted geometric means was within 80.00 - 125.00 %.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	95.93
	Confidence Interval	(2-Sided) 90%; 90.83 to 101.33
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

4. Secondary Outcome

Title	AUC (0-168) of BI 695501, US-licensed Humira® or EU-approved Humira®
Description	Area under the concentration time curve (AUC) from time zero to 168 hours post dose (AUC 0-168) of BI 695501, US-licensed Humira® or EU-approved Humira®. PK is the abbreviation for Pharmacokinetic(s).
Time Frame	at -1 hour (h) (pre dosing) and 1h, 4, 8, 12, 24, 48, 72, 84, 96, 108, 120, 132, 144, 168 hours post dosing

Outcome Measure Data

Analysis Population Description

The PK analysis set.

Arm/Group Title	BI 695501	US-licensed Humira®	EU-approved Humira®
Arm/Group Description	single s.c. injection 40 mg/0.8 mL BI 695501 solution.	single s.c. injection 40 mg/0.8 mL US-licensed Humira®	single s.c. injection 40 mg/0.8 mL EU-approved Humira®
Measure Participants	107	108	107
Geometric Mean (Geometric Coefficient of Variation) [µg*h/mL]	480 (41.1)	493 (40.7)	513 (39.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695501, US-licensed Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing; two-sided 90% Confidence Interval (CI) for the ratio of adjusted geometric means was calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	98.30
	Confidence Interval	(2-Sided) 90%; 91.54 to 105.55
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 695501, EU-approved Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing; two-sided 90% CI for the ratio of adjusted geometric means was calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	96.05
	Confidence Interval	(2-Sided) 90%; 89.27 to 103.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	US-licensed Humira®, EU-approved Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing; two-sided 90% CI for the ratio of adjusted geometric means was calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	98.11
	Confidence Interval	(2-Sided) 90%; 91.42 to 105.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

5. Secondary Outcome

Title	AUC (0-312) of BI 695501, US-licensed Humira® or EU-approved Humira®
Description	Area under the concentration time curve (AUC) from time zero to 312 hours post dose (AUC 0-312) of BI 695501, US-licensed Humira® or EU-approved Humira®. PK is the abbreviation for Pharmacokinetic(s).
Time Frame	at -1 hour (h) (pre dosing) and 1h, 4, 8, 12, 24, 48, 72, 84, 96, 108, 120, 132, 144, 168, 192, 240, 312 hours post dosing

Outcome Measure Data

Analysis Population Description

The PK analysis set.

Arm/Group Title	BI 695501	US-licensed Humira®	EU-approved Humira®
Arm/Group Description	single s.c. injection 40 mg/0.8 mL BI 695501 solution.	single s.c. injection 40 mg/0.8 mL US-licensed Humira®	single s.c. injection 40 mg/0.8 mL EU-approved Humira®
Measure Participants	107	108	107
Geometric Mean (Geometric Coefficient of Variation) [µg*h/mL]	957 (36.5)	967 (34.9)	1010 (31.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695501, US-licensed Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing; two-sided 90% CI for the ratio of adjusted geometric means was calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	99.61
	Confidence Interval	(2-Sided) 90%; 93.66 to 105.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 695501, EU-approved Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing; two-sided 90% CI for the ratio of adjusted geometric means was calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	97.19
	Confidence Interval	(2-Sided) 90%; 91.39 to 103.35
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	US-licensed Humira®, EU-approved Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing; two-sided 90% CI for the ratio of adjusted geometric means was calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	97.97
	Confidence Interval	(2-Sided) 90%; 92.58 to 103.68
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

6. Secondary Outcome

Title	AUC (0-480) of BI 695501, US-licensed Humira® or EU-approved Humira®
Description	Area under the concentration time curve (AUC) from time zero to 480 hours post dose (AUC 0-480) of BI 695501, US-licensed Humira® or EU-approved Humira®. PK is the abbreviation for Pharmacokinetic(s).
Time Frame	at -1 hour (h) (pre dosing) and 1h, 4, 8, 12, 24, 48, 72, 84, 96, 108, 120, 132, 144, 168, 192, 240, 312, 480 hours post dosing

Outcome Measure Data

Analysis Population Description

The PK analysis set.

Arm/Group Title	BI 695501	US-licensed Humira®	EU-approved Humira®
Arm/Group Description	single s.c. injection 40 mg/0.8 mL BI 695501 solution.	single s.c. injection 40 mg/0.8 mL US-licensed Humira®	single s.c. injection 40 mg/0.8 mL EU-approved Humira®
Measure Participants	107	108	107
Geometric Mean (Geometric Coefficient of Variation) [µg*h/mL]	1400 (35.8)	1390 (32.2)	1440 (28.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695501, US-licensed Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing; two-sided 90% CI for the ratio of adjusted geometric means was calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	101.23
	Confidence Interval	(2-Sided) 90%; 95.45 to 107.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 695501, EU-approved Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing; two-sided 90% CI for the ratio of adjusted geometric means was calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	98.83
	Confidence Interval	(2-Sided) 90%; 93.27 to 104.72
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	US-licensed Humira®, EU-approved Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing; two-sided 90% CI for the ratio of adjusted geometric means was calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	98.01
	Confidence Interval	(2-Sided) 90%; 93.15 to 103.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

7. Secondary Outcome

Title	AUC (0-648) of BI 695501, US-licensed Humira® or EU-approved Humira®
Description	Area under the concentration time curve (AUC) from time zero to 648 hours post dose (AUC 0-648) of BI 695501, US-licensed Humira® or EU-approved Humira®. PK is the abbreviation for Pharmacokinetic(s).
Time Frame	at -1 hour (h) (pre dosing) and 1h, 4, 8, 12, 24, 48, 72, 84, 96, 108, 120, 132, 144, 168, 192, 240, 312, 480, 648 hours post dosing

Outcome Measure Data

Analysis Population Description

The PK analysis set.

Arm/Group Title	BI 695501	US-licensed Humira®	EU-approved Humira®
Arm/Group Description	single s.c. injection 40 mg/0.8 mL BI 695501 solution.	single s.c. injection 40 mg/0.8 mL US-licensed Humira®	single s.c. injection 40 mg/0.8 mL EU-approved Humira®
Measure Participants	107	108	107
Geometric Mean (Geometric Coefficient of Variation) [µg*h/mL]	1730 (37.0)	1680 (33.2)	1760 (27.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695501, US-licensed Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing; two-sided 90% CI for the ratio of adjusted geometric means was calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	103.68
	Confidence Interval	(2-Sided) 90%; 97.47 to 110.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 695501, EU-approved Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing; two-sided 90% CI for the ratio of adjusted geometric means was calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	100.16
	Confidence Interval	(2-Sided) 90%; 94.37 to 106.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	US-licensed Humira®, EU-approved Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing; two-sided 90% CI for the ratio of adjusted geometric means was calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	97.02
	Confidence Interval	(2-Sided) 90%; 92.07 to 102.24
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

8. Secondary Outcome

Title	AUC (0-1032) of BI 695501, US-licensed Humira® or EU-approved Humira®
Description	Area under the concentration time curve (AUC) from time zero to 1032 hours post dose (AUC 0-1032) of BI 695501, US-licensed Humira® or EU-approved Humira® PK is the abbreviation for Pharmacokinetic(s).
Time Frame	at -1 hour (h) (pre dosing) and 1h, 4, 8, 12, 24, 48, 72, 84, 96, 108, 120, 132, 144, 168, 192, 240, 312, 480, 648, 1032 hours post dosing

Outcome Measure Data

Analysis Population Description

The PK analysis set.

Arm/Group Title	BI 695501	US-licensed Humira®	EU-approved Humira®
Arm/Group Description	single s.c. injection 40 mg/0.8 mL BI 695501 solution.	single s.c. injection 40 mg/0.8 mL US-licensed Humira®	single s.c. injection 40 mg/0.8 mL EU-approved Humira®
Measure Participants	107	106	106
Geometric Mean (Geometric Coefficient of Variation) [µg*h/mL]	2190 (41.4)	2080 (38.5)	2210 (29.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695501, US-licensed Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing; two-sided 90% CI for the ratio of adjusted geometric means was calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	106.57
	Confidence Interval	(2-Sided) 90%; 99.07 to 114.63
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 695501, EU-approved Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing; two-sided 90% CI for the ratio of adjusted geometric means was calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	100.94
	Confidence Interval	(2-Sided) 90%; 94.24 to 108.12
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	US-licensed Humira®, EU-approved Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing; two-sided 90% CI for the ratio of adjusted geometric means was calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	95.37
	Confidence Interval	(2-Sided) 90%; 89.53 to 101.60
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

9. Secondary Outcome

Title	AUC 0-∞,Obs of BI 695501, US-licensed Humira® or EU-approved Humira®
Description	Area under the concentration time curve (AUC) from time zero to infinity (AUC 0-∞) based on the last observed concentration at time of last measureable concentration (tz) of BI 695501, US-licensed Humira® or EU-approved Humira®. PK is the abbreviation of Pharmacokinetic(s).
Time Frame	at -1 hour (h) (pre dosing) and 1h, 4, 8, 12, 24, 48, 72, 84, 96, 108, 120, 132, 144, 168, 192, 240, 312, 480, 648, 1032, 1320 h post dosing and on day 71 post dosing.

Outcome Measure Data

Analysis Population Description

The PK analysis set.

Arm/Group Title	BI 695501	US-licensed Humira®	EU-approved Humira®
Arm/Group Description	single s.c. injection 40 mg/0.8 mL BI 695501 solution.	single s.c. injection 40 mg/0.8 mL US-licensed Humira®	single s.c. injection 40 mg/0.8 mL EU-approved Humira®
Measure Participants	106	105	105
Geometric Mean (Geometric Coefficient of Variation) [µg*h/mL]	2630 (52.6)	2470 (51.3)	2640 (38.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695501, US-licensed Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing; two-sided 90% CI for the ratio of adjusted geometric means was calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	108.70
	Confidence Interval	(2-Sided) 90%; 98.54 to 119.90
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 695501, EU-approved Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing; two-sided 90% CI for the ratio of adjusted geometric means was calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	101.36
	Confidence Interval	(2-Sided) 90%; 92.51 to 111.05
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	US-licensed Humira®, EU-approved Humira®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing; two-sided 90% CI for the ratio of adjusted geometric means was calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	94.04
	Confidence Interval	(2-Sided) 90%; 86.01 to 102.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	An analysis of covariance (ANCOVA) model on the logarithmic scale with fixed effects for treatment and trial site as well as age (as recorded at the time of informed consent) and body weight (as recorded at baseline) as continuous covariates.

10. Secondary Outcome

Title	Number (Proportion) of Subjects With Drug Related Adverse Events
Description	All events with an onset after the first administration of the trial medication up to a period of 70 days after the last administration of the trial medication (i.e., end of the REP) was assigned to the treatment phase for evaluation and was defined as a treatment-emergent AE (TEAE). A treatment-related AE was defined as any TEAE assessed by the investigator as related to the trial medication. All safety data were displayed and analyzed using descriptive statistical methods. No formal inferential analyses were planned for safety comparisons. Tabulations of frequencies and proportions, as appropriate were used for the evaluation of categorical (qualitative) data, and tabulations of descriptive statistics were used to analyze continuous (quantitative) data.
Time Frame	Day 1 through Day 71

Outcome Measure Data

Analysis Population Description

The safety analysis set consisted of all subjects who received the single dose of trial medication (BI 695501, US-licensed Humira® or EU-approved Humira®).

Arm/Group Title	BI 695501	US-licensed Humira®	EU-approved Humira®
Arm/Group Description	single s.c. injection 40 mg/0.8 mL BI 695501 solution.	single s.c. injection 40 mg/0.8 mL US-licensed Humira®	single s.c. injection 40 mg/0.8 mL EU-approved Humira®
Measure Participants	108	108	108
Number [participants]	21 19.4%	29 26.9%	28 25.9%

Adverse Events

Time Frame	Day 1 (first administration of trial medication) until day 71
Arm/Group Title	BI 695501		US-licensed Humira®		EU-approved Humira®
Arm/Group Description	single s.c. injection 40 mg/0.8 mL BI 695501 solution.		single s.c. injection 40 mg/0.8 mL US-licensed Humira®		single s.c. injection 40 mg/0.8 mL EU-approved Humira®
All Cause Mortality
	BI 695501		US-licensed Humira®		EU-approved Humira®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	BI 695501		US-licensed Humira®		EU-approved Humira®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/108 (2.8%)		3/108 (2.8%)		2/108 (1.9%)
Gastrointestinal disorders
Abdominal pain	1/108 (0.9%)		0/108 (0%)		1/108 (0.9%)
Infections and infestations
Appendicitis	0/108 (0%)		2/108 (1.9%)		0/108 (0%)
Injury, poisoning and procedural complications
Ankle fracture	1/108 (0.9%)		0/108 (0%)		0/108 (0%)
Concussion	1/108 (0.9%)		0/108 (0%)		0/108 (0%)
Hand fracture	1/108 (0.9%)		0/108 (0%)		0/108 (0%)
Laceration	0/108 (0%)		1/108 (0.9%)		0/108 (0%)
Renal and urinary disorders
Nephrolithiasis	0/108 (0%)		0/108 (0%)		1/108 (0.9%)
Other (Not Including Serious) Adverse Events
	BI 695501		US-licensed Humira®		EU-approved Humira®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	51/108 (47.2%)		52/108 (48.1%)		51/108 (47.2%)
Gastrointestinal disorders
Abdominal pain	2/108 (1.9%)		7/108 (6.5%)		1/108 (0.9%)
Diarrhoea	4/108 (3.7%)		7/108 (6.5%)		0/108 (0%)
Nausea	6/108 (5.6%)		2/108 (1.9%)		3/108 (2.8%)
Infections and infestations
Upper respiratory tract infection	19/108 (17.6%)		17/108 (15.7%)		22/108 (20.4%)
Nervous system disorders
Headache	25/108 (23.1%)		25/108 (23.1%)		28/108 (25.9%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	6/108 (5.6%)		2/108 (1.9%)		4/108 (3.7%)
Rhinorrhoea	3/108 (2.8%)		4/108 (3.7%)		6/108 (5.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Other - 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.