Pharmacokinetics and Safety in Healthy Volunteers - Study Results

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double; Primary Purpose: Treatment
Condition	Healthy
Interventions	Drug: BI 695501 Drug: adalimumab-EU source Drug: adalimumab-US source
Enrollment	327

Participant Flow

Recruitment Details	In this trial 324 healthy subjects were randomized into 3 arms.
Pre-assignment Details	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 subcuta...	Subject to receive a single subcuta...	Subject to receive a single subcuta...
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 ^[1]	108 ^[2]	108 ^[1]
Completed	106	107	107
Not Completed	2	1	1
Reason Not Completed
Informed Consent Withdrawn	2	0	1
not specified above	0	1	0
[1] 1 subject (not included to the 108) was randomized but did never take any study medication. [2] 1 subject (not included to the 108) was randomized but did never take any study medication..

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 ...	single s.c. injection 40 mg/0.8 mL ...	single s.c. injection 40 mg/0.8 mL ...	Total of all reporting groups
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 Number of Baseline Participants		108	108	108	324
Baseline Analysis Population Description		...
Baseline Analysis Population Description		The safety analysis set consisted of all subjects who received the single dose of trial medication.
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	108 participants	108 participants	108 participants	324 participants
		30 (11)	31 (11)	30 (12)	31 (11)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	108 participants	108 participants	108 participants	324 participants
	Female	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Male	108 100.0%	108 100.0%	108 100.0%	324 100.0%

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 infini...
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 ...	single s.c. injection 40 mg/0.8 mL ...	single s.c. injection 40 mg/0.8 mL ...
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®
Overall Number of Participants Analyzed	106	105	105
Geometric Mean (Geometric Coefficient of Variation) Unit of Measure: 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	[Not Specified]
	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 (%).

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	108.62
	Confidence Interval	(2-Sided) 90% 98.50 to 119.79
	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	[Not Specified]
	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 %.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	101.27
	Confidence Interval	(2-Sided) 90% 92.45 to 110.94
	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	[Not Specified]
	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 %.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	94.02
	Confidence Interval	(2-Sided) 90% 86.01 to 102.78
	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 measura...
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 ...	single s.c. injection 40 mg/0.8 mL ...	single s.c. injection 40 mg/0.8 mL ...
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®
Overall Number of Participants Analyzed	106	107	106
Geometric Mean (Geometric Coefficient of Variation) Unit of Measure: 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	[Not Specified]
	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 %.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	107.32
	Confidence Interval	(2-Sided) 90% 98.49 to 116.94
	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	[Not Specified]
	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 %.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	99.93
	Confidence Interval	(2-Sided) 90% 92.15 to 108.37
	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	[Not Specified]
	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 %.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	93.66
	Confidence Interval	(2-Sided) 90% 86.76 to 101.11
	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...
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 ...	single s.c. injection 40 mg/0.8 mL ...	single s.c. injection 40 mg/0.8 mL ...
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®
Overall Number of Participants Analyzed	107	108	107
Geometric Mean (Geometric Coefficient of Variation) Unit of Measure: 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	[Not Specified]
	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 %.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	100.85
	Confidence Interval	(2-Sided) 90% 95.15 to 106.88
	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	[Not Specified]
	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 %.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	96.39
	Confidence Interval	(2-Sided) 90% 91.06 to 102.03
	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	[Not Specified]
	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 %.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	95.93
	Confidence Interval	(2-Sided) 90% 90.83 to 101.33
	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 ho...
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 ...	single s.c. injection 40 mg/0.8 mL ...	single s.c. injection 40 mg/0.8 mL ...
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®
Overall Number of Participants Analyzed	107	108	107
Geometric Mean (Geometric Coefficient of Variation) Unit of Measure: 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	[Not Specified]
	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.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	98.30
	Confidence Interval	(2-Sided) 90% 91.54 to 105.55
	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	[Not Specified]
	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.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	96.05
	Confidence Interval	(2-Sided) 90% 89.27 to 103.36
	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	[Not Specified]
	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.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	98.11
	Confidence Interval	(2-Sided) 90% 91.42 to 105.27
	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 ho...
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 ...	single s.c. injection 40 mg/0.8 mL ...	single s.c. injection 40 mg/0.8 mL ...
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®
Overall Number of Participants Analyzed	107	108	107
Geometric Mean (Geometric Coefficient of Variation) Unit of Measure: 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	[Not Specified]
	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.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	99.61
	Confidence Interval	(2-Sided) 90% 93.66 to 105.94
	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	[Not Specified]
	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.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	97.19
	Confidence Interval	(2-Sided) 90% 91.39 to 103.35
	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	[Not Specified]
	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.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	97.97
	Confidence Interval	(2-Sided) 90% 92.58 to 103.68
	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 ho...
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 ...	single s.c. injection 40 mg/0.8 mL ...	single s.c. injection 40 mg/0.8 mL ...
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®
Overall Number of Participants Analyzed	107	108	107
Geometric Mean (Geometric Coefficient of Variation) Unit of Measure: 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	[Not Specified]
	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.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	101.23
	Confidence Interval	(2-Sided) 90% 95.45 to 107.36
	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	[Not Specified]
	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.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	98.83
	Confidence Interval	(2-Sided) 90% 93.27 to 104.72
	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	[Not Specified]
	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.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	98.01
	Confidence Interval	(2-Sided) 90% 93.15 to 103.11
	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 ho...
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 ...	single s.c. injection 40 mg/0.8 mL ...	single s.c. injection 40 mg/0.8 mL ...
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®
Overall Number of Participants Analyzed	107	108	107
Geometric Mean (Geometric Coefficient of Variation) Unit of Measure: 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	[Not Specified]
	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.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	103.68
	Confidence Interval	(2-Sided) 90% 97.47 to 110.29
	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	[Not Specified]
	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.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	100.16
	Confidence Interval	(2-Sided) 90% 94.37 to 106.29
	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	[Not Specified]
	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.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	97.02
	Confidence Interval	(2-Sided) 90% 92.07 to 102.24
	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 h...
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 ...	single s.c. injection 40 mg/0.8 mL ...	single s.c. injection 40 mg/0.8 mL ...
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®
Overall Number of Participants Analyzed	107	106	106
Geometric Mean (Geometric Coefficient of Variation) Unit of Measure: 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	[Not Specified]
	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.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	106.57
	Confidence Interval	(2-Sided) 90% 99.07 to 114.63
	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	[Not Specified]
	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.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	100.94
	Confidence Interval	(2-Sided) 90% 94.24 to 108.12
	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	[Not Specified]
	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.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	95.37
	Confidence Interval	(2-Sided) 90% 89.53 to 101.60
	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 infini...
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 ...	single s.c. injection 40 mg/0.8 mL ...	single s.c. injection 40 mg/0.8 mL ...
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®
Overall Number of Participants Analyzed	106	105	105
Geometric Mean (Geometric Coefficient of Variation) Unit of Measure: 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	[Not Specified]
	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.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	108.70
	Confidence Interval	(2-Sided) 90% 98.54 to 119.90
	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	[Not Specified]
	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.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	101.36
	Confidence Interval	(2-Sided) 90% 92.51 to 111.05
	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	[Not Specified]
	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.

Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	94.04
	Confidence Interval	(2-Sided) 90% 86.01 to 102.82
	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 m...
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 ...	single s.c. injection 40 mg/0.8 mL ...	single s.c. injection 40 mg/0.8 mL ...
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®
Overall Number of Participants Analyzed	108	108	108
Measure Type: Number Unit of Measure: participants
	21	29	28

Adverse Events

Time Frame	Day 1 (first administration of trial medication) until day 71
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	BI 695501	US-licensed Humira®	EU-approved Humira®
Arm/Group Description	single s.c. injection 40 mg/0.8 mL ...	single s.c. injection 40 mg/0.8 mL ...	single s.c. injection 40 mg/0.8 mL ...
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 (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events Serious Adverse Events
	BI 695501	US-licensed Humira®	EU-approved Humira®
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	3/108 (2.78%)	3/108 (2.78%)	2/108 (1.85%)
Gastrointestinal disorders
Abdominal pain ^† 1	1/108 (0.93%)	0/108 (0.00%)	1/108 (0.93%)
Infections and infestations
Appendicitis ^† 1	0/108 (0.00%)	2/108 (1.85%)	0/108 (0.00%)
Injury, poisoning and procedural complications
Ankle fracture ^† 1	1/108 (0.93%)	0/108 (0.00%)	0/108 (0.00%)
Concussion ^† 1	1/108 (0.93%)	0/108 (0.00%)	0/108 (0.00%)
Hand fracture ^† 1	1/108 (0.93%)	0/108 (0.00%)	0/108 (0.00%)
Laceration ^† 1	0/108 (0.00%)	1/108 (0.93%)	0/108 (0.00%)
Renal and urinary disorders
Nephrolithiasis ^† 1	0/108 (0.00%)	0/108 (0.00%)	1/108 (0.93%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MEDDRA 17.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	BI 695501	US-licensed Humira®	EU-approved Humira®
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	51/108 (47.22%)	52/108 (48.15%)	51/108 (47.22%)
Gastrointestinal disorders
Abdominal pain ^† 1	2/108 (1.85%)	7/108 (6.48%)	1/108 (0.93%)
Diarrhoea ^† 1	4/108 (3.70%)	7/108 (6.48%)	0/108 (0.00%)
Nausea ^† 1	6/108 (5.56%)	2/108 (1.85%)	3/108 (2.78%)
Infections and infestations
Upper respiratory tract infection ^† 1	19/108 (17.59%)	17/108 (15.74%)	22/108 (20.37%)
Nervous system disorders
Headache ^† 1	25/108 (23.15%)	25/108 (23.15%)	28/108 (25.93%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain ^† 1	6/108 (5.56%)	2/108 (1.85%)	4/108 (3.70%)
Rhinorrhoea ^† 1	3/108 (2.78%)	4/108 (3.70%)	6/108 (5.56%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MEDDRA 17.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS 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.

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.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Boehringer Ingelheim Call Center
Organization:	Boehringer Ingelheim
Phone:	1-800-243-0127
EMail:	clintriage.rdg@boehringer-ingelheim.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Huizinga TWJ, Torii Y, Muniz R. Adalimumab Biosimilars in the Treatment of Rheumatoid Arthritis: A Systematic Review of the Evidence for Biosimilarity. Rheumatol Ther. 2021 Mar;8(1):41-61. doi: 10.1007/s40744-020-00259-8. Epub 2020 Dec 1.

Kang J, Eudy-Byrne RJ, Mondick J, Knebel W, Jayadeva G, Liesenfeld KH. Population pharmacokinetics of adalimumab biosimilar adalimumab-adbm and reference product in healthy subjects and patients with rheumatoid arthritis to assess pharmacokinetic similarity. Br J Clin Pharmacol. 2020 Nov;86(11):2274-2285. doi: 10.1111/bcp.14330. Epub 2020 Jun 11.

Wynne C, Altendorfer M, Sonderegger I, Gheyle L, Ellis-Pegler R, Buschke S, Lang B, Assudani D, Athalye S, Czeloth N. Bioequivalence, safety and immunogenicity of BI 695501, an adalimumab biosimilar candidate, compared with the reference biologic in a randomized, double-blind, active comparator phase I clinical study (VOLTAIRE(R)-PK) in healthy subjects. Expert Opin Investig Drugs. 2016 Dec;25(12):1361-1370. doi: 10.1080/13543784.2016.1255724.

Layout table for additonal information

Responsible Party:	Boehringer Ingelheim
ClinicalTrials.gov Identifier:	NCT02045979
Other Study ID Numbers:	1297.8 2013-003722-84 ( EudraCT Number: EudraCT )
First Submitted:	January 23, 2014
First Posted:	January 27, 2014
Results First Submitted:	September 11, 2017
Results First Posted:	June 20, 2018
Last Update Posted:	June 20, 2018