Pharmacokinetics and Safety of BI 695501

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02899338
• Collaborator: (none)
• Enrollment: 162
• Locations: 2
• Arms: 2
• Actual Duration (Months): 5.1
• Patients Per Site: 81
• Patients Per Site Per Month: 15.9

Study Details

Study Description

Brief Summary

To characterize and compare the pharmacokinetics and to assess the safety of BI 695501 after single injection using either auto injector or prefilled syringe.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: BI695501 Prefilled syringe; Drug: BI695501Autoinjector	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 162 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized, Single-dose, Parallel-arm, Open-label Phase I Trial to Compare the Pharmacokinetics, Safety and Tolerability of BI 695501 Administered Subcutaneously Via Prefilled Syringe or Autoinjector
• Actual Study Start Date: Sep 21, 2016
• Actual Primary Completion Date: Feb 9, 2017
• Actual Study Completion Date: Feb 23, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BI695501 Autoinjector	Drug: BI695501Autoinjector
Active Comparator: BI695501 Prefilled syringe	Drug: BI695501 Prefilled syringe

Outcome Measures

Primary Outcome Measures

1. Area Under the Concentration-time Curve of BI 695501 in Plasma Over the Time Interval From 0 to 1368 Hours (AUC0-1368) After Administration Via PFS and AI. [From 0 to 1368 hours post-dose. Samples were collected pre-dose and 1, 4, 8, 12, 24, 48, 60, 72, 84, 96, 108, 120, 132, 144, 168, 216, 336, 504, 672, 840, 1032, and 1368 hours post-dose.]

   The AUC0-1368 of 40 mg BI 695501 administered via PFS and AI was measured. Plasma concentrations were measured using a validated enzyme-linked immunosorbent assay (ELISA). Only concentration values within the validated concentration range of 0.025 to 2.0 micrograms per millilitre (µg/mL) and actual sampling times were used.

2. The Maximum Measured Concentration of BI 695501 in Plasma (Cmax) After Administration Via PFS and AI [From 0 to 1368 hours post-dose. Samples were collected pre-dose and 1, 4, 8, 12, 24, 48, 60, 72, 84, 96, 108, 120, 132, 144, 168, 216, 336, 504, 672, 840, 1032, and 1368 hours post-dose.]

   The Cmax of 40 mg BI 695501 administered via PFS and AI. Plasma concentrations were measured using a validated ELISA. Only concentration values within the validated concentration range of 0.025 to 2.0 µg/mL and actual sampling times were used.

3. Area Under the Concentration-time Curve of BI 695501 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) After Administration Via PFS and AI. [Samples were collected pre-dose and 1, 4, 8, 12, 24, 48, 60, 72, 84, 96, 108, 120, 132, 144, 168, 216, 336, 504, 672, 840, 1032, and 1368 hours post-dose.]

   The AUC0-∞ of 40 mg BI 695501 administered via PFS and AI. Plasma concentrations were measured using a validated ELISA. Only concentration values within the validated concentration range of 0.025 to 2.0 µg/mL and actual sampling times were used.

Secondary Outcome Measures

1. The Percentage of Subjects With Drug-related Treatment-emergent Adverse Events (TEAEs) From Day 1 to Day 70. [From Day 1 to Day 70]

   A treatment-related TEAE was defined as any TEAE assessed by the Investigator as related to the trial medication. A TEAE was defined as an adverse event (AE) that started or worsened in severity on or after the single dose of trial medication up to 10 weeks (70 days) post-dose.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion criteria:

• Age between 18 and 65 years (inclusive)

• BMI of >17.5 to <35.0 kg/m2

• Healthy male or female subjects, according to the investigator´s assessment, based on a complete medical history including a physical examination, vital signs (blood pressure [BP], pulse rate [PR]), 12-lead ECG, and clinical laboratory tests.

• Subjects who meet any of the following criteria:

• Surgically sterilized (confirmed 6 month prior to enrollment)

• Have surgically sterilized sexual partner (confirmed 6 month prior to enrollment)

• Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous levels of follicle-stimulating hormone (FSH) above 40 U/L and estradiol below 30 ng/L is confirmatory)

• Subjects agree to use an adequate contraception, starting from the begin of the trial and until 6 months after the dose of the trial drug: e.g. any of the following methods plus condom: implants, injectables, combined oral or vaginal contraceptives, intrauterine device

• Signed and dated written informed consent in accordance with Good Clinical Practice (GCP) and local legislation prior to admission to the trial

Exclusion criteria:

• Previous exposure to adalimumab or proposed adalimumab biosimilar drugs.

• Any finding in the medical examination (including blood pressure (BP), pulse rate (PR) or electrocardiogram (ECG)) that deviates from normal and judged as clinically relevant by the investigator.

• Any evidence of a concomitant disease judged as clinically relevant by the investigator including gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, hormonal disorders or diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders.

• History of relevant orthostatic hypotension, fainting spells, or blackouts.

• Chronic or relevant acute infections.

• Positive result for HIV, hepatitis B virus (HBV), and hepatitis C (Hep C) at screening.

• History of relevant allergy or hypersensitivity including allergy to the trial medication, its excipients or device materials (e.g. natural rubber or latex).

• Within 10 days prior to administration of trial medication, use of drugs that might reasonably influence the results of the trial.

• Intake of an investigational drug in another trial within 2 months or 5 half-lives (whichever longer) prior to planned administration of the trial medication in this trial or intake of an investigational drug during the course of this trial.

• Alcohol abuse (consumption of more than 28 units/week).

• Unwillingness/inability to refrain from intake of alcoholic beverages from 48 hours prior to the trial medication administration and until Day 14 post trial medication administration; and/or to limit alcohol intake to a maximum of 3 units per day until e.o.t.

• Drug abuse or positive drug screening.

• Blood donation of more than 500 mL within 30 days prior to administration of trial medication or intended donation during the trial.

• Intention to perform excessive physical activities within 4days prior to administration of trial medication or contact sport during the entire trial and unwilling to avoid vigorous exercise for 14 days post dosing.

• Inability to comply with dietary regimen of trial site.

• Any out-of-range laboratory values considered clinically significant by the investigator; (subjects with creatine kinase (CK) values 2 times the upper limit of normal (ULN) at Day -1 are to be excluded from participation).

• Subject is assessed as unsuitable for inclusion by the investigator, for instance, because he is considered not able to understand and comply with trial requirements, or has a condition that would not allow safe participation in the trial.

• Subjects with any immunological disorders or auto-immune disorders, (e.g., Rheumatoid arthritis (RA), lupus erythematosus, scleroderma, etc.).

• Subject has received a live vaccine within 12 weeks prior to enrolling in the trial.

• History of tuberculosis (TB) or positive finding in Interferon-gamma release assay (IGRA).

• Evidence of skin irritation or infection at the planned injection place.

• Currently enrolled in another investigational device or drug study

• Any condition that, in the investigator´s opinion, makes them an unreliable study subject or unlikely to complete the trial

• Women who are pregnant, nursing, or who plan to become pregnant while in the trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	SGS Life Sciences Services	Antwerpen		Belgium	2060
2	PRA Health Sciences Onderzoekscentrum Martini	Groningen		Netherlands	9728 NZ

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

• Study Protocol - Aug 23, 2016
• Statistical Analysis Plan - Jan 9, 2017

More Information

Additional Information:

• Synopsis Link

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02899338
• Other Study ID Numbers: 1297.13; 2016-003158-34
• First Posted: Sep 14, 2016
• Last Update Posted: Oct 11, 2018
• Last Verified: Oct 1, 2018

Study Results

Participant Flow

Pre-assignment Detail	Subjects were randomized in 1:1 ratio to receive BI 695501 (autoinjector) or BI 695501 (prefilled syringe).

Arm/Group Title	BI695501 Prefilled Syringe	BI695501 Autoinjector
Arm/Group Description	Patients were administered a single subcutaneous dose of 40 milligram (mg)/0.8 milliliter (mL) BI 695501 (solution for injection) using a prefilled syringe (PFS).	Patients were administered a single subcutaneous dose of 40 milligram (mg)/0.8 milliliter (mL) BI 695501 (solution for injection) using an autoinjector (AI).
Period Title: Overall Study
STARTED	81	81
COMPLETED	78	79
NOT COMPLETED	3	2

Baseline Characteristics

Arm/Group Title	BI695501 Prefilled Syringe	BI695501 Autoinjector	Total
Arm/Group Description	Patients were administered a single subcutaneous dose of 40 milligram (mg)/0.8 milliliter (mL) BI 695501 (solution for injection) using a prefilled syringe (PFS).	Patients were administered a single subcutaneous dose of 40 milligram (mg)/0.8 milliliter (mL) BI 695501 (solution for injection) using an autoinjector (AI).	Total of all reporting groups
Overall Participants	81	81	162
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	44.5 (14.74)	41.5 (14.44)	43.0 (14.62)
Sex: Female, Male (Count of Participants)
Female	44 54.3%	43 53.1%	87 53.7%
Male	37 45.7%	38 46.9%	75 46.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	81 100%	81 100%	162 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	2 2.5%	2 1.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 3.7%	1 1.2%	4 2.5%
White	78 96.3%	77 95.1%	155 95.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 1.2%	1 0.6%
Body weight at baseline (Kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kilogram (kg)]	74.84 (15.421)	75.25 (14.909)	75.04 (15.122)

Outcome Measures

1. Primary Outcome

Title	Area Under the Concentration-time Curve of BI 695501 in Plasma Over the Time Interval From 0 to 1368 Hours (AUC0-1368) After Administration Via PFS and AI.
Description	The AUC0-1368 of 40 mg BI 695501 administered via PFS and AI was measured. Plasma concentrations were measured using a validated enzyme-linked immunosorbent assay (ELISA). Only concentration values within the validated concentration range of 0.025 to 2.0 micrograms per millilitre (µg/mL) and actual sampling times were used.
Time Frame	From 0 to 1368 hours post-dose. Samples were collected pre-dose and 1, 4, 8, 12, 24, 48, 60, 72, 84, 96, 108, 120, 132, 144, 168, 216, 336, 504, 672, 840, 1032, and 1368 hours post-dose.

Outcome Measure Data

Analysis Population Description

PKS: The pharmacokinetic set (PKS) consisted of all randomized subjects who received the single dose of trial medication (BI 695501 administered via PFS or AI), had at least 1 evaluable primary PK parameter, and were without important protocol deviations or violations thought to significantly affect the PK of BI 695501.

Arm/Group Title	BI695501 Prefilled Syringe	BI695501 Autoinjector
Arm/Group Description	Patients were administered a single subcutaneous dose of 40 milligram (mg)/0.8 milliliter (mL) BI 695501 (solution for injection) using a prefilled syringe (PFS).	Patients were administered a single subcutaneous dose of 40 milligram (mg)/0.8 milliliter (mL) BI 695501 (solution for injection) using an autoinjector (AI).
Measure Participants	76	79
Geometric Mean (Geometric Coefficient of Variation) [microgram hour per milliliter (μg*h/mL)]	2100 (43.9)	2150 (45.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI695501 Prefilled Syringe, BI695501 Autoinjector
	Comments	Comparison AI versus PFS
	Type of Statistical Test	Equivalence
	Comments	The relative bioavailability of BI 695501 using AI (A) compared with BI 695501 using PFS (B) was estimated, in an exploratory manner, by the ratios of the geometric means (A/B) using the analysis of variance (ANOVA)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio
	Estimated Value	101.71
	Confidence Interval	(2-Sided) 90%; 91.31 to 113.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 42.28
	Estimation Comments	Standard error of the mean is actually the Inter-individual geometric coefficient of variation (gCV)

2. Primary Outcome

Title	The Maximum Measured Concentration of BI 695501 in Plasma (Cmax) After Administration Via PFS and AI
Description	The Cmax of 40 mg BI 695501 administered via PFS and AI. Plasma concentrations were measured using a validated ELISA. Only concentration values within the validated concentration range of 0.025 to 2.0 µg/mL and actual sampling times were used.
Time Frame	From 0 to 1368 hours post-dose. Samples were collected pre-dose and 1, 4, 8, 12, 24, 48, 60, 72, 84, 96, 108, 120, 132, 144, 168, 216, 336, 504, 672, 840, 1032, and 1368 hours post-dose.

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	BI695501 Prefilled Syringe	BI695501 Autoinjector
Arm/Group Description	Patients were administered a single subcutaneous dose of 40 milligram (mg)/0.8 milliliter (mL) BI 695501 (solution for injection) using a prefilled syringe (PFS).	Patients were administered a single subcutaneous dose of 40 milligram (mg)/0.8 milliliter (mL) BI 695501 (solution for injection) using an autoinjector (AI).
Measure Participants	79	81
Geometric Mean (Geometric Coefficient of Variation) [µg/mL]	3.86 (27.8)	3.86 (23.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI695501 Prefilled Syringe, BI695501 Autoinjector
	Comments	Comparison AI versus PFS
	Type of Statistical Test	Equivalence
	Comments	The relative bioavailability of BI 695501 using AI (A) compared with BI 695501 using PFS (B) was estimated, in an exploratory manner, by the ratios of the geometric means (A/B) using ANOVA
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio
	Estimated Value	100.11
	Confidence Interval	(2-Sided) 90%; 94.17 to 106.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 23.72
	Estimation Comments	Standard error of the mean is actually the Inter-individual gCV

3. Primary Outcome

Title	Area Under the Concentration-time Curve of BI 695501 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) After Administration Via PFS and AI.
Description	The AUC0-∞ of 40 mg BI 695501 administered via PFS and AI. Plasma concentrations were measured using a validated ELISA. Only concentration values within the validated concentration range of 0.025 to 2.0 µg/mL and actual sampling times were used.
Time Frame	Samples were collected pre-dose and 1, 4, 8, 12, 24, 48, 60, 72, 84, 96, 108, 120, 132, 144, 168, 216, 336, 504, 672, 840, 1032, and 1368 hours post-dose.

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	BI695501 Prefilled Syringe	BI695501 Autoinjector
Arm/Group Description	Patients were administered a single subcutaneous dose of 40 milligram (mg)/0.8 milliliter (mL) BI 695501 (solution for injection) using a prefilled syringe (PFS).	Patients were administered a single subcutaneous dose of 40 milligram (mg)/0.8 milliliter (mL) BI 695501 (solution for injection) using an autoinjector (AI).
Measure Participants	76	79
Geometric Mean (Geometric Coefficient of Variation) [μg*h/mL]	2250 (50.3)	2330 (50.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI695501 Prefilled Syringe, BI695501 Autoinjector
	Comments	Comparison AI versus PFS
	Type of Statistical Test	Equivalence
	Comments	The relative bioavailability of BI 695501 using AI (A) compared with BI 695501 using PFS (B) was estimated, in an exploratory manner, by the ratios of the geometric means (A/B) using ANOVA
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio
	Estimated Value	103.19
	Confidence Interval	(2-Sided) 90%; 91.38 to 116.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 48.21
	Estimation Comments	Standard error of the mean is actually the Inter-individual gCV

4. Secondary Outcome

Title	The Percentage of Subjects With Drug-related Treatment-emergent Adverse Events (TEAEs) From Day 1 to Day 70.
Description	A treatment-related TEAE was defined as any TEAE assessed by the Investigator as related to the trial medication. A TEAE was defined as an adverse event (AE) that started or worsened in severity on or after the single dose of trial medication up to 10 weeks (70 days) post-dose.
Time Frame	From Day 1 to Day 70

Outcome Measure Data

Analysis Population Description

All treated subjects (i.e. all subjects who received 1 dose of trial medication) were included in the safety analysis set (SAF).

Arm/Group Title	BI695501 Prefilled Syringe	BI695501 Autoinjector
Arm/Group Description	Patients were administered a single subcutaneous dose of 40 milligram (mg)/0.8 milliliter (mL) BI 695501 (solution for injection) using a prefilled syringe (PFS).	Patients were administered a single subcutaneous dose of 40 milligram (mg)/0.8 milliliter (mL) BI 695501 (solution for injection) using an autoinjector (AI).
Measure Participants	81	81
Number [Percentage of participants]	37.0 45.7%	38.3 47.3%

Adverse Events

Time Frame	From single dose administration till 10 weeks; up to 70 days
Adverse Event Reporting Description	All events with an onset after the single dose of trial medication up to a period of 10 weeks (70 days) were assigned to the treatment phase for evaluation and were considered to be TEAEs. The SAF population was used which consisted of all subjects that received a single dose of trial medication.
Arm/Group Title	BI695501 Autoinjector		BI695501 Prefilled Syringe
Arm/Group Description	Patients were administered a single subcutaneous dose of 40 milligram (mg)/0.8 milliliter (mL) BI 695501 (solution for injection) using an autoinjector (AI).		Patients were administered a single subcutaneous dose of 40 milligram (mg)/0.8 milliliter (mL) BI 695501 (solution for injection) using a prefilled syringe (PFS).
All Cause Mortality
	BI695501 Autoinjector		BI695501 Prefilled Syringe
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/81 (0%)		0/81 (0%)
Serious Adverse Events
	BI695501 Autoinjector		BI695501 Prefilled Syringe
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/81 (2.5%)		1/81 (1.2%)
Injury, poisoning and procedural complications
Ligament rupture	1/81 (1.2%)		0/81 (0%)
Wrist fracture	0/81 (0%)		1/81 (1.2%)
Nervous system disorders
Seizure	1/81 (1.2%)		0/81 (0%)
Other (Not Including Serious) Adverse Events
	BI695501 Autoinjector		BI695501 Prefilled Syringe
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	47/81 (58%)		41/81 (50.6%)
Gastrointestinal disorders
Abdominal discomfort	8/81 (9.9%)		9/81 (11.1%)
Diarrhoea	3/81 (3.7%)		5/81 (6.2%)
Nausea	8/81 (9.9%)		4/81 (4.9%)
General disorders
Influenza like illness	5/81 (6.2%)		5/81 (6.2%)
Injection site erythema	14/81 (17.3%)		7/81 (8.6%)
Injection site haematoma	6/81 (7.4%)		0/81 (0%)
Injection site induration	4/81 (4.9%)		5/81 (6.2%)
Injection site pain	5/81 (6.2%)		4/81 (4.9%)
Injection site swelling	6/81 (7.4%)		5/81 (6.2%)
Infections and infestations
Nasopharyngitis	11/81 (13.6%)		9/81 (11.1%)
Musculoskeletal and connective tissue disorders
Back pain	5/81 (6.2%)		8/81 (9.9%)
Nervous system disorders
Headache	16/81 (19.8%)		11/81 (13.6%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	2/81 (2.5%)		9/81 (11.1%)

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.