Comparison of Methotrexate (MTX) and the VIBEX™ MTX Device

• Sponsor: Antares Pharma Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01618968
• Collaborator: (none)
• Enrollment: 49
• Location: 1
• Arms: 4
• Duration (Months): 3
• Patients Per Site Per Month: 16.2

Study Details

Study Description

Brief Summary

Relative Bioavailability Comparison study

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis (RA)	Drug: MTX	Phase 2

Detailed Description

A Phase 2, Open-Label, Randomized, 3-Way Crossover Study to Compare the Relative Bioavailability of Oral Methotrexate and the VIBEX™ MTX Device in Adult Subjects With Rheumatoid Arthritis

Study Design

• Study Type: Interventional
• Actual Enrollment: 49 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Exposure, Safety and Local Tolerance Study Comparing the Relative Bioavailability of Oral Methotrexate and the VIBEX™ MTX Device in Adult Subjects With Rheumatoid Arthritis
• Study Start Date: May 1, 2012
• Actual Primary Completion Date: Aug 1, 2012
• Actual Study Completion Date: Aug 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 10 mg Methotrexate (MTX) MTX dose group was assigned based on the subject's current therapeutic regimen of MTX and rheumatoid arthritis disease status. The sequence of treatments A, B and C was randomly assigned.	Drug: MTX; Treatment A - 1 dose (4, 6, 8 or 10 tablets respectively to make up 10 mg, 15 mg, 20 mg or 25 mg MTX - per subject's dose group) Treatment B - SC injection using VIBEX MTX device into abdomen (VIBEX MTX device pre-filled with 10 mg, 15 mg, 20 mg or 25 mg MTX) Treatment C - SC injection using VIBEX MTX device into thigh (VIBEX MTX device pre-filled with 10 mg, 15 mg, 20 mg or 25 mg MTX); Other Names: Commercially available 2.5 mg MTX oral tablets VIBEX MTX
Experimental: 15 mg MTX MTX dose group was assigned based on the subject's current therapeutic regimen of MTX and rheumatoid arthritis disease status. The sequence of treatments A, B and C was randomly assigned.	Drug: MTX; Treatment A - 1 dose (4, 6, 8 or 10 tablets respectively to make up 10 mg, 15 mg, 20 mg or 25 mg MTX - per subject's dose group) Treatment B - SC injection using VIBEX MTX device into abdomen (VIBEX MTX device pre-filled with 10 mg, 15 mg, 20 mg or 25 mg MTX) Treatment C - SC injection using VIBEX MTX device into thigh (VIBEX MTX device pre-filled with 10 mg, 15 mg, 20 mg or 25 mg MTX); Other Names: Commercially available 2.5 mg MTX oral tablets VIBEX MTX
Experimental: 20 mg MTX MTX dose group was assigned based on the subject's current therapeutic regimen of MTX and rheumatoid arthritis disease status. The sequence of treatments A, B and C was randomly assigned.	Drug: MTX; Treatment A - 1 dose (4, 6, 8 or 10 tablets respectively to make up 10 mg, 15 mg, 20 mg or 25 mg MTX - per subject's dose group) Treatment B - SC injection using VIBEX MTX device into abdomen (VIBEX MTX device pre-filled with 10 mg, 15 mg, 20 mg or 25 mg MTX) Treatment C - SC injection using VIBEX MTX device into thigh (VIBEX MTX device pre-filled with 10 mg, 15 mg, 20 mg or 25 mg MTX); Other Names: Commercially available 2.5 mg MTX oral tablets VIBEX MTX
Experimental: 25 mg MTX MTX dose group was assigned based on the subject's current therapeutic regimen of MTX and rheumatoid arthritis disease status. The sequence of treatments A, B and C was randomly assigned.	Drug: MTX; Treatment A - 1 dose (4, 6, 8 or 10 tablets respectively to make up 10 mg, 15 mg, 20 mg or 25 mg MTX - per subject's dose group) Treatment B - SC injection using VIBEX MTX device into abdomen (VIBEX MTX device pre-filled with 10 mg, 15 mg, 20 mg or 25 mg MTX) Treatment C - SC injection using VIBEX MTX device into thigh (VIBEX MTX device pre-filled with 10 mg, 15 mg, 20 mg or 25 mg MTX); Other Names: Commercially available 2.5 mg MTX oral tablets VIBEX MTX

Outcome Measures

Primary Outcome Measures

1. Dose-Normalized AUC[0-Inf] for MTX [24 Hour period]

   Dose-normalized area under the curve from time zero to infinity (AUC[0-inf]/Dose) for each treatment

2. Dose-Normalized AUC[0-24] for MTX [24 Hour period]

   Dose-normalized area under the curve from time zero to 24 hours (AUC[0-24]/Dose) for each treatment

3. Dose-Normalized Cmax for MTX [24 Hour period]

   Dose-normalized maximum observed concentration (Cmax) for each treatment

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female patients ≥18 years of age, diagnosed with Rheumatoid Arthritis

Exclusion Criteria:

• Pregnant females

• Any other clinically significant disease or disorder which, in the opinion of the investigator might put the subject at risk

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Altoona Center for Clinical Research	Duncansville	Pennsylvania	United States	16635

Sponsors and Collaborators

• Antares Pharma Inc.

Investigators

• Principal Investigator: Alan J Kivitz, MD;CPI, Altoona Center for Clinical Research

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Antares Pharma Inc.
• ClinicalTrials.gov Identifier: NCT01618968
• Other Study ID Numbers: MTX-11-003
• First Posted: Jun 14, 2012
• Last Update Posted: May 19, 2014
• Last Verified: May 1, 2014

• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid

Study Results

Participant Flow

Recruitment Details	Subjects were screened and enrolled at 4 sites in the US. Approximately equal number of subjects on 10 mg, 15 mg, 20 mg and 25 mg doses were recruited. The dose group was determined by the Investigator based on subject's current therapeutic regimen of MTX and disease status. The subject's dose was the same for the entire study
Pre-assignment Detail	MTX was administered via randomized sequence and crossover of Treatment A, Treatment B and Treatment C within the same dose group. Treatments were administered at a 7 day interval (On study days 1, 8 and 15)

Arm/Group Title	10mg MTX	15mg MTX	20mg MTX	25mg MTX
Arm/Group Description	[administered via randomized sequence and crossover of Treatment A - Oral Methotrexate (MTX) Tablets, Treatment B - SC injection of Vibex MTX into the Abdomen and Treatment C - SC injection of Vibex MTX into the Thigh]	[administered via randomized sequence and crossover of Treatment A - Oral Methotrexate (MTX) Tablets, Treatment B - SC injection of Vibex MTX into the Abdomen and Treatment C - SC injection of Vibex MTX into the Thigh]	[administered via randomized sequence and crossover of Treatment A - Oral Methotrexate (MTX) Tablets, Treatment B - SC injection of Vibex MTX into the Abdomen and Treatment C - SC injection of Vibex MTX into the Thigh]	[administered via randomized sequence and crossover of Treatment A - Oral Methotrexate (MTX) Tablets, Treatment B - SC injection of Vibex MTX into the Abdomen and Treatment C - SC injection of Vibex MTX into the Thigh]
Period Title: Overall Study
STARTED	13	12	12	12
Received Treatment A	12	12	12	11
Received Treatment B	13	12	12	12
Received Treatment C	12	12	12	11
COMPLETED	12	12	12	11
NOT COMPLETED	1	0	0	1

Baseline Characteristics

Arm/Group Title	10mg MTX	15mg MTX	20mg MTX	25mg MTX	Total
Arm/Group Description	[administered via randomized sequence and crossover of Treatment A - Oral Methotrexate (MTX) Tablets, Treatment B - SC injection of Vibex MTX into the Abdomen and Treatment C - SC injection of Vibex MTX into the Thigh]	[administered via randomized sequence and crossover of Treatment A - Oral Methotrexate (MTX) Tablets, Treatment B - SC injection of Vibex MTX into the Abdomen and Treatment C - SC injection of Vibex MTX into the Thigh]	[administered via randomized sequence and crossover of Treatment A - Oral Methotrexate (MTX) Tablets, Treatment B - SC injection of Vibex MTX into the Abdomen and Treatment C - SC injection of Vibex MTX into the Thigh]	[administered via randomized sequence and crossover of Treatment A - Oral Methotrexate (MTX) Tablets, Treatment B - SC injection of Vibex MTX into the Abdomen and Treatment C - SC injection of Vibex MTX into the Thigh]	Total of all reporting groups
Overall Participants	13	12	12	12	49
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.9 (12.51)	63.4 (7.49)	60.0 (10.40)	59.0 (11.53)	61.4 (10.53)
Sex: Female, Male (Count of Participants)
Female	11 84.6%	5 41.7%	8 66.7%	7 58.3%	31 63.3%
Male	2 15.4%	7 58.3%	4 33.3%	5 41.7%	18 36.7%
Race/Ethnicity, Customized (participants) [Number]
White	12 92.3%	11 91.7%	10 83.3%	11 91.7%	44 89.8%
African American	1 7.7%	1 8.3%	2 16.7%	1 8.3%	5 10.2%
Region of Enrollment (participants) [Number]
United States	13 100%	12 100%	12 100%	12 100%	49 100%

Outcome Measures

1. Primary Outcome

Title	Dose-Normalized AUC[0-Inf] for MTX
Description	Dose-normalized area under the curve from time zero to infinity (AUC[0-inf]/Dose) for each treatment
Time Frame	24 Hour period

Outcome Measure Data

Analysis Population Description

The Population was defined as all randomized subjects who received at least 1 dose of study drug and who had at least 1 valid post-dose plasma concentration value.

Arm/Group Title	Treatment A	Treatment B	Treatment C
Arm/Group Description	Oral Methotrexate (MTX) Tablets	SC injection of Vibex MTX into the Abdomen	SC injection of Vibex MTX into the Thigh
Measure Participants	47	49	47
Mean (Standard Deviation) [ng*hr/mL/mg]	109.47 (39.19)	140.84 (46.66)	136.45 (46.675)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	To compare the relative bioavailability of methotrexate (MTX) following oral administration to that obtained after subcutaneous (SC) injection into the abdomen using the VIBEX MTX device by measuring the area under the curve from time zero to the last measurable concentration AUC(0-inf).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioavailability comparisons were performed at each dose level.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Test / Reference Ratio
	Estimated Value	127.99
	Confidence Interval	(2-Sided) 90%; 121.61 to 134.70
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	To compare the relative bioavailability of MTX following oral administration to that obtained after SC injection into the thigh using the VIBEX MTX device by measuring the AUC(0-Inf).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioavailability comparisons were performed at each dose level.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Test / Reference Ratio
	Estimated Value	125.48
	Confidence Interval	(2-Sided) 90%; 119.43 to 131.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	To compare the relative bioavailability of MTX following SC injection into the abdomen to that obtained after SC injection into the thigh using the VIBEX MTX device by measuring the AUC(0-inf)
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Test of bioequivalence was performed at each dose level.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Test / Reference ratio
	Estimated Value	101.85
	Confidence Interval	(2-Sided) 90%; 99.41 to 104.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Dose-Normalized AUC[0-24] for MTX
Description	Dose-normalized area under the curve from time zero to 24 hours (AUC[0-24]/Dose) for each treatment
Time Frame	24 Hour period

Outcome Measure Data

Analysis Population Description

The Population was defined as all randomized subjects who received at least 1 dose of study drug and who had at least 1 valid post-dose plasma concentration value.

Arm/Group Title	Treatment A	Treatment B	Treatment C
Arm/Group Description	Oral Methotrexate (MTX) Tablets	SC injection of Vibex MTX into the Abdomen	SC injection of Vibex MTX into the Thigh
Measure Participants	47	49	47
Mean (Standard Deviation) [ng*hr/mL/mg]	107.64 (37.732)	137.88 (44.513)	133.78 (44.406)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	To compare the relative bioavailability of methotrexate (MTX) following oral administration to that obtained after subcutaneous (SC) injection into the abdomen using the VIBEX MTX device by measuring the area under the curve from time zero to the 24 hour concentration AUC(0-24)
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioavailability comparisons were performed at each dose level.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Test / Reference Ratio
	Estimated Value	127.65
	Confidence Interval	(2-Sided) 90%; 121.28 to 134.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	To compare the relative bioavailability of methotrexate (MTX) following oral administration to that obtained after subcutaneous (SC) injection into the thigh using the VIBEX MTX device by measuring the area under the curve from time zero to the 24 hour concentration AUC(0-24)
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioavailability comparisons were performed at each dose level.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Test / Reference ratio
	Estimated Value	125.20
	Confidence Interval	(2-Sided) 90%; 119.16 to 131.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	To compare the relative bioavailability of MTX following SC injection into the abdomen to that obtained after SC injection into the thigh using the VIBEX MTX device by measuring the area under the curve from time zero to the 24 hour concentration AUC(0-24)
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Test of bioequivalence was performed at each dose level.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Test / Reference Ratio
	Estimated Value	101.82
	Confidence Interval	(2-Sided) 90%; 99.39 to 104.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Dose-Normalized Cmax for MTX
Description	Dose-normalized maximum observed concentration (Cmax) for each treatment
Time Frame	24 Hour period

Outcome Measure Data

Analysis Population Description

The Population was defined as all randomized subjects who received at least 1 dose of study drug and who had at least 1 valid post-dose plasma concentration value.

Arm/Group Title	Treatment A	Treatment B	Treatment C
Arm/Group Description	Oral Methotrexate (MTX) Tablets	SC injection of Vibex MTX into the Abdomen	SC injection of Vibex MTX into the Thigh
Measure Participants	47	49	47
Mean (Standard Deviation) [ng/mL/mg]	22.697 (7.496)	21.935 (8.243)	18.436 (5.321)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	To compare the relative bioavailability of methotrexate (MTX) following oral administration to that obtained after subcutaneous (SC) injection into the abdomen using the VIBEX MTX device by measuring the maximum observed concentration (Cmax)
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioavailability comparisons were performed at each dose level.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Test / Reference ratio
	Estimated Value	94.83
	Confidence Interval	(2-Sided) 90%; 86.42 to 104.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	To compare the relative bioavailability of methotrexate (MTX) following oral administration to that obtained after subcutaneous (SC) injection into the thigh using the VIBEX MTX device by measuring the maximum observed concentration (Cmax)
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioavailability comparisons were performed at each dose level.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Test / Reference Ratio
	Estimated Value	82.12
	Confidence Interval	(2-Sided) 90%; 76.16 to 88.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	To compare the relative bioavailability of MTX following SC injection into the abdomen to that obtained after SC injection into the thigh using the VIBEX MTX device by measuring the maximum observed concentration (Cmax)
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Test of bioequivalence was performed at each dose level.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Test / Reference Ratio
	Estimated Value	115.63
	Confidence Interval	(2-Sided) 90%; 108.83 to 122.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	The Safety Population was defined as all randomized subjects who received at least 1 dose of study drug. The Safety Population included 49 subjects.
Adverse Event Reporting Description	Adverse events were classified by treatment at onset. Any adverse event that occurred on Day 1 (after check-in) for a given treatment period was assigned to the treatment for that period.
Arm/Group Title	10mg MTX		15mg MTX		20mg MTX		25mg MTX
Arm/Group Description	[administered via randomized sequence and crossover of Treatment A - Oral Methotrexate (MTX) Tablets, Treatment B - SC injection of Vibex MTX into the Abdomen and Treatment C - SC injection of Vibex MTX into the Thigh]		[administered via randomized sequence and crossover of Treatment A - Oral Methotrexate (MTX) Tablets, Treatment B - SC injection of Vibex MTX into the Abdomen and Treatment C - SC injection of Vibex MTX into the Thigh]		[administered via randomized sequence and crossover of Treatment A - Oral Methotrexate (MTX) Tablets, Treatment B - SC injection of Vibex MTX into the Abdomen and Treatment C - SC injection of Vibex MTX into the Thigh]		[administered via randomized sequence and crossover of Treatment A - Oral Methotrexate (MTX) Tablets, Treatment B - SC injection of Vibex MTX into the Abdomen and Treatment C - SC injection of Vibex MTX into the Thigh]
All Cause Mortality
	10mg MTX		15mg MTX		20mg MTX		25mg MTX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	10mg MTX		15mg MTX		20mg MTX		25mg MTX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		1/12 (8.3%)		0/12 (0%)		1/12 (8.3%)
Cardiac disorders
Sick Sinus Syndrome (15 mg Vibex MTX SC Thigh)	0/13 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0
Myocardial Infarction (25 mg Vibex MTX SC Abdomen)	0/13 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1
Other (Not Including Serious) Adverse Events
	10mg MTX		15mg MTX		20mg MTX		25mg MTX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/13 (15.4%)		0/12 (0%)		1/12 (8.3%)		0/12 (0%)
Gastrointestinal disorders
Nausea (20 mg MTX Oral)	0/13 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0
General disorders
Fatigue (10 mg Vibex MTX SC Thigh)	1/13 (7.7%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0
Musculoskeletal and connective tissue disorders
Rheumatoid Arthritis (10 mg Vibex MTX SC Abdomen)	1/13 (7.7%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.