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Exposure Study Comparing 3 Routes of Methotrexate (MTX) Administration

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ClinicalTrials.gov Identifier: NCT01737944
Recruitment Status : Completed
First Posted : November 30, 2012
Results First Posted : February 25, 2014
Last Update Posted : February 25, 2014
Sponsor:
Information provided by (Responsible Party):
Antares Pharma Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Rheumatoid Arthritis
Intervention Drug: Methotrexate (MTX)
Enrollment 38
Recruitment Details Subjects were screened and enrolled at 2 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 patient's dose was the same for the entire study.
Pre-assignment Details The order of Methotrexate (MTX) treatment arms (A-SC injection with Vibex-MTX device, B-SC injection without device and C-IM Injection) were randomly assigned and dosing was separated by interval of atleast 7 days to allow for washout before the next treatment was administered.
Arm/Group Title 10mg MTX Group 15mg MTX Group 20mg MTX Group 25mg MTX Group
Hide Arm/Group Description [administered via randomized sequence and crossover of Treatment Arm A -SC injection with Vibex MTX device, Treatment Arm B -SC injection without device and Treatment Arm C -IM Injection] [administered via randomized sequence and crossover of Treatment Arm A -SC injection with Vibex MTX device, Treatment Arm B -SC injection without device and Treatment Arm C -IM Injection] [administered via randomized sequence and crossover of Treatment Arm A -SC injection with Vibex MTX device, Treatment Arm B -SC injection without device and Treatment Arm C -IM Injection] [administered via randomized sequence and crossover of Treatment Arm A -SC injection with Vibex MTX device, Treatment Arm B -SC injection without device and Treatment Arm C -IM Injection]
Period Title: Overall Study
Started 9 9 9 [1] 9 [1]
Completed 9 9 9 9
Not Completed 0 0 0 0
[1]
10 patients randomized, one patient discontinued before first study drug dose
Arm/Group Title 10mg MTX Group 15mg MTX Group 20mg MTX Group 25mg MTX Group Total
Hide Arm/Group Description [Administered via randomized sequence and crossover of Treatment Arm A, Treatment Arm B and Treatment Arm C] [Administered via randomized sequence and crossover of Treatment Arm A, Treatment Arm B and Treatment Arm C] [Administered via randomized sequence and crossover of Treatment Arm A, Treatment Arm B and Treatment Arm C] [Administered via randomized sequence and crossover of Treatment Arm A, Treatment Arm B and Treatment Arm C] Total of all reporting groups
Overall Number of Baseline Participants 9 9 9 9 36
Hide Baseline Analysis Population Description
38 subjects were randomized to a treatment sequence. Two subjects discontinued prior to receiving the first study drug dose. Safety Population = 36 subjects who received study drug and completed all study visits. All 36 subjects were included in Pharmacokinetic Population. No discontinuations after first study drug dose.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 9 participants 9 participants 9 participants 36 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
7
  77.8%
6
  66.7%
7
  77.8%
7
  77.8%
27
  75.0%
>=65 years
2
  22.2%
3
  33.3%
2
  22.2%
2
  22.2%
9
  25.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 9 participants 9 participants 9 participants 9 participants 36 participants
61.2  (10.97) 63.4  (7.26) 60.8  (6.18) 63.0  (6.80) 62.1  (7.76)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 9 participants 9 participants 9 participants 36 participants
Female
7
  77.8%
5
  55.6%
6
  66.7%
7
  77.8%
25
  69.4%
Male
2
  22.2%
4
  44.4%
3
  33.3%
2
  22.2%
11
  30.6%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 9 participants 9 participants 9 participants 9 participants 36 participants
9 9 9 9 36
1.Primary Outcome
Title Bioequivalence Based Upon Dose-Normalized AUC[0-Inf] for MTX
Hide Description Dose-normalized area under the curve from time zero to infinity (AUC[0-inf]/Dose) for each treatment
Time Frame 24 Hour period
Hide Outcome Measure Data
Hide 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 Arm A Treatment Arm B Treatment Arm C
Hide Arm/Group Description:
Subcutaneous (SC) injection with the Vibex MTX device
SC injection of MTX without the device
Intramuscular (IM) injection of MTX
Overall Number of Participants Analyzed 36 36 36
Mean (Standard Deviation)
Unit of Measure: ng*hr/mL/mg
118.14  (42.300) 122.63  (40.648) 116.71  (41.394)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Treatment Arm A, Treatment Arm B
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The bioequivalence of Methotrexate following Treatment A - SC injection with the Vibex MTX device and Treatment B - SC injection without the device was established if the 90% CI for the geometric LS Mean ratios of AUC(0-inf)/Dose were within the range of 80% to 125%.
Method of Estimation Estimation Parameter Test / Reference Ratio
Estimated Value 96.24
Confidence Interval (2-Sided) 90%
92.33 to 100.31
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Treatment Arm A, Treatment Arm C
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The bioequivalence of Methotrexate following Treatment A-SC injection with the Vibex MTX device and Treatment C-IM injection was established if the 90% CI for the geometric LS Mean ratios of AUC(0-inf)/Dose were within the range of 80% to 125%.
Method of Estimation Estimation Parameter Test / Reference Ratio
Estimated Value 101.28
Confidence Interval (2-Sided) 90%
97.17 to 105.56
Estimation Comments [Not Specified]
2.Primary Outcome
Title Bioequivalence Based Upon Dose-Normalized AUC[0-24] for MTX
Hide Description Dose-normalized area under the curve from time zero to 24 hours post-dose (AUC[0-24]/Dose) for each treatment
Time Frame 24 Hour period
Hide Outcome Measure Data
Hide Analysis Population Description
Dose-normalized MTX PK parameter AUC(0-24)/Dose used for comparison
Arm/Group Title Treatment Arm A Treatment Arm B Treatment Arm C
Hide Arm/Group Description:
Subcutaneous (SC) injection with the Vibex MTX device
SC injection of MTX without the device
Intramuscular (IM) injection of MTX
Overall Number of Participants Analyzed 36 36 36
Mean (Standard Deviation)
Unit of Measure: ng*hr/mL/mg
116.60  (40.963) 121.08  (39.405) 122.63  (40.648)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Treatment Arm A, Treatment Arm B
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The bioequivalence of Methotrexate following Treatment A-SC injection with the Vibex MTX device and Treatment B-SC injection was established if the 90% CI for the geometric LS Mean ratios of AUC(0-24)/Dose were within the range of 80% to 125%.
Method of Estimation Estimation Parameter Test / Reference Ratio
Estimated Value 96.22
Confidence Interval (2-Sided) 90%
92.32 to 100.28
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Treatment Arm A, Treatment Arm C
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The bioequivalence of Methotrexate following Treatment A-SC injection with the Vibex MTX device and Treatment C-IM injection was established if the 90% CI for the geometric LS Mean ratios of AUC(0-24)/Dose were within the range of 80% to 125%.
Method of Estimation Estimation Parameter Test / Reference Ratio
Estimated Value 101.14
Confidence Interval (2-Sided) 90%
97.06 to 105.40
Estimation Comments [Not Specified]
3.Primary Outcome
Title Bioequivalence Based Upon Dose-Normalized Cmax for MTX
Hide Description Dose-normalized maximum observed concentration for each treatment
Time Frame 24 Hour period
Hide Outcome Measure Data
Hide 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 Arm A Treatment Arm B Treatment Arm C
Hide Arm/Group Description:
Subcutaneous (SC) injection with the Vibex MTX device
SC injection of MTX without the device
Intramuscular (IM) injection of MTX
Overall Number of Participants Analyzed 36 36 36
Mean (Standard Deviation)
Unit of Measure: ng/mL/mg
21.43  (8.310) 22.38  (10.263) 23.37  (7.188)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Treatment Arm A, Treatment Arm B
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The bioequivalence of Methotrexate following Treatment A-SC injection with the Vibex MTX device and Treatment B-SC injection without the device was established if the 90% CI for the geometric LS Mean ratios of Cmax/Dose were within the range of 80% to 125%.
Method of Estimation Estimation Parameter Test / Reference Ratio
Estimated Value 96.76
Confidence Interval (2-Sided) 90%
87.93 to 106.47
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Treatment Arm A, Treatment Arm C
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The bioequivalence of Methotrexate following Treatment A-SC injection with the Vibex MTX device and Treatment C-IM injection was established if the 90% CI for the geometric LS Mean ratios of Cmax/Dose were within the range of 80% to 125%.
Method of Estimation Estimation Parameter Test / Reference Ratio
Estimated Value 89.79
Confidence Interval (2-Sided) 90%
81.61 to 98.78
Estimation Comments [Not Specified]
Time Frame The Safety Population was defined as all randomized subjects who received at least 1 dose of study drug. The Safety Population included 36 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
Hide Arm/Group Description [Administered via randomized sequence and crossover of Treatment A, Treatment B and Treatment C] [Administered via randomized sequence and crossover of Treatment A, Treatment B and Treatment C] [Administered via randomized sequence and crossover of Treatment A, Treatment B and Treatment C] [Administered via randomized sequence and crossover of Treatment A, Treatment B and Treatment C]
All-Cause Mortality
10mg MTX 15mg MTX 20mg MTX 25mg MTX
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide 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   0/9 (0.00%)      0/9 (0.00%)      0/9 (0.00%)      0/9 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2.8%
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   1/9 (11.11%)      0/9 (0.00%)      2/9 (22.22%)      1/9 (11.11%)    
General disorders         
Injection site erythema  1 [1]  0/9 (0.00%)  0 0/9 (0.00%)  0 1/9 (11.11%)  1 0/9 (0.00%)  0
Infections and infestations         
Nasopharyngitis  1 [2]  0/9 (0.00%)  0 0/9 (0.00%)  0 1/9 (11.11%)  1 0/9 (0.00%)  0
Skin and subcutaneous tissue disorders         
Maculopapular rash  1 [2]  1/9 (11.11%)  2 0/9 (0.00%)  0 0/9 (0.00%)  0 0/9 (0.00%)  0
Vascular disorders         
Hypertension  1 [1]  0/9 (0.00%)  0 0/9 (0.00%)  0 0/9 (0.00%)  0 1/9 (11.11%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.1
[1]
AE Occurred During Treatment B
[2]
AE Occurred During Treatment A
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Jonathan Jaffe, MD; Vice President Clinical Development
Organization: Antares Pharma
Phone: 1-609-359-3020 ext 324
EMail: jjaffe@antarespharma.com
Layout table for additonal information
Responsible Party: Antares Pharma Inc.
ClinicalTrials.gov Identifier: NCT01737944     History of Changes
Other Study ID Numbers: MTX-10-001
First Submitted: November 27, 2012
First Posted: November 30, 2012
Results First Submitted: January 25, 2013
Results First Posted: February 25, 2014
Last Update Posted: February 25, 2014