Rheumatoid Arthritis
Conditions
Brief summary
The purpose of the study is to evaluate the effect of LX3305 on methotrexate (MTX) pharmacokinetics and to evaluate the safety and tolerability of LX3305 given over 14 days in subjects with stable rheumatoid arthritis that are receiving stable doses of MTX.
Interventions
DRUGLX3305
Daily oral intake of LX3305 for 14 days.
DRUGLX3305 Placebo
Matching placebo dosing with daily oral intake for 14 days.
DRUGMethotrexate
Once weekly stable-dose methotrexate.
Sponsors
Lexicon Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males and females ≥ 18 years old * Must be willing to practice 2 adequate methods of contraception for the duration of the study * Rheumatoid arthritis present for at least 3 months; functional class I, II, or III as defined by ACR criteria * Treatment with methotrexate (7.5 to 25 mg per week) for at least the last 3 months, and currently receiving stable dose methotrexate for at least one month prior to the start of the study * Ability to provide written informed consent
Exclusion criteria
* Women who are pregnant or nursing * History of other current inflammatory arthritis * History of opportunistic infection * History of recurrent infections or current infection 2 weeks prior to start of study * Presence of significant, uncontrolled medical problems * Treatment with any disease-modifying anti-rheumatoid drugs other than methotrexate within 4 weeks prior to start of study * Use of chondroitin sulfate, glucosamine sulfate, minocycline, or matrix metalloproteinase inhibitors, H-2 blockers, proton pump inhibitors, or misoprostol within 4 weeks prior to study start * Receipt of live vaccine within 8 weeks prior to study start * Rheumatoid arthritis, functional class IV as defined by ACR criteria
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Amount of 7-OH-MTX Excreted in the Urine | Day 15 | — |
| Half-life of Methotrexate in Plasma | Day 15 | — |
| Amount of Methotrexate Excreted in the Urine | Day 15 | — |
| 7-Hydroxymethotrexate (7-OH-MTX) Maximum Plasma Concentration | Day 15 | 7-OH-MTX is the primary metabolite of methotrexate. |
| Time to Reach Maximum Plasma Concentration of 7-OH-MTX | Day 15 | — |
| Methotrexate Maximum Plasma Concentration | Day 15 | — |
| Time to Reach Maximum Plasma Concentration of Methotrexate | Day 15 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Maximum Plasma Concentration of LX3305 in the Presence of MTX | Day 15 | — |
| Half-life of LX3305 in Plasma in the Presence of MTX | Day 15 | — |
| Percentage of Change From Baseline in Absolute Total Lymphocyte Count at Day 15 | Day 15 | Baseline was defined as pre-dose on Day 1. |
| Maximum Plasma Concentration of LX3305 in the Presence of MTX | Day 15 | — |
Countries
United States
Participant flow
Recruitment details
This study was performed at one center in Dallas, TX. Recruitment began in January 2009 and the last subject completed the study in March 2009.
Pre-assignment details
One subject did not complete the study due to an adverse event of uveitis on Day 1 and was not dosed with study drug. This subject was not included in any population analyses. Therefore, the participant flow includes 15 subjects, 12 receiving active drug and 3 receiving placebo.
Participants by arm
| Arm | Count |
|---|---|
| LX3305 + Methotrexate Daily oral intake of 100 mg LX3305 for 14 days. | 12 |
| Methotrexate Matching placebo dosing with daily oral intake for 14 days. | 3 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | LX3305 + Methotrexate | Methotrexate | Total |
|---|---|---|---|
| Age Continuous | 59.8 years STANDARD_DEVIATION 10.25 | 58.7 years STANDARD_DEVIATION 14.74 | 59.5 years STANDARD_DEVIATION 10.67 |
| Region of Enrollment United States | 12 participants | 3 participants | 15 participants |
| Sex: Female, Male Female | 12 Participants | 3 Participants | 15 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 12 | 3 / 3 |
| serious Total, serious adverse events | 0 / 12 | 0 / 3 |
Outcome results
Primary
7-Hydroxymethotrexate (7-OH-MTX) Maximum Plasma Concentration
7-OH-MTX is the primary metabolite of methotrexate.
Time frame: Day 15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LX3305 + Methotrexate | 7-Hydroxymethotrexate (7-OH-MTX) Maximum Plasma Concentration | 25.5 ng/mL | Standard Deviation 12.8 |
| Methotrexate | 7-Hydroxymethotrexate (7-OH-MTX) Maximum Plasma Concentration | 25.5 ng/mL | Standard Deviation 15.4 |
Primary
Amount of 7-OH-MTX Excreted in the Urine
Time frame: Day 15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LX3305 + Methotrexate | Amount of 7-OH-MTX Excreted in the Urine | 285 µg | Standard Deviation 106 |
| Methotrexate | Amount of 7-OH-MTX Excreted in the Urine | 281 µg | Standard Deviation 109 |
Primary
Amount of Methotrexate Excreted in the Urine
Time frame: Day 15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LX3305 + Methotrexate | Amount of Methotrexate Excreted in the Urine | 3861 µg | Standard Deviation 1720 |
| Methotrexate | Amount of Methotrexate Excreted in the Urine | 4022 µg | Standard Deviation 1218 |
Primary
Half-life of Methotrexate in Plasma
Time frame: Day 15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LX3305 + Methotrexate | Half-life of Methotrexate in Plasma | 3.80 hours | Standard Deviation 0.52 |
| Methotrexate | Half-life of Methotrexate in Plasma | 3.80 hours | Standard Deviation 0.693 |
Primary
Methotrexate Maximum Plasma Concentration
Time frame: Day 15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LX3305 + Methotrexate | Methotrexate Maximum Plasma Concentration | 215 ng/mL | Standard Deviation 71.4 |
| Methotrexate | Methotrexate Maximum Plasma Concentration | 177 ng/mL | Standard Deviation 72.1 |
Primary
Time to Reach Maximum Plasma Concentration of 7-OH-MTX
Time frame: Day 15
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LX3305 + Methotrexate | Time to Reach Maximum Plasma Concentration of 7-OH-MTX | 6.01 hours |
| Methotrexate | Time to Reach Maximum Plasma Concentration of 7-OH-MTX | 8.00 hours |
Primary
Time to Reach Maximum Plasma Concentration of Methotrexate
Time frame: Day 15
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LX3305 + Methotrexate | Time to Reach Maximum Plasma Concentration of Methotrexate | 0.98 hours |
| Methotrexate | Time to Reach Maximum Plasma Concentration of Methotrexate | 1.25 hours |
Secondary
Half-life of LX3305 in Plasma in the Presence of MTX
Time frame: Day 15
Population: This outcome was not measured in the Methotrexate + LX3305 placebo subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LX3305 + Methotrexate | Half-life of LX3305 in Plasma in the Presence of MTX | 5.89 hours | Standard Deviation 1.54 |
Secondary
Maximum Plasma Concentration of LX3305 in the Presence of MTX
Time frame: Day 15
Population: This outcome was not measured in the Methotrexate + LX3305 placebo subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LX3305 + Methotrexate | Maximum Plasma Concentration of LX3305 in the Presence of MTX | 588 ng/mL | Standard Deviation 233 |
Secondary
Percentage of Change From Baseline in Absolute Total Lymphocyte Count at Day 15
Baseline was defined as pre-dose on Day 1.
Time frame: Day 15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LX3305 + Methotrexate | Percentage of Change From Baseline in Absolute Total Lymphocyte Count at Day 15 | -14.049 Percent | Standard Deviation 29.1505 |
| Methotrexate | Percentage of Change From Baseline in Absolute Total Lymphocyte Count at Day 15 | -6.152 Percent | Standard Deviation 15.0143 |
Secondary
Time to Maximum Plasma Concentration of LX3305 in the Presence of MTX
Time frame: Day 15
Population: This outcome was not measured in the Methotrexate + LX3305 placebo subjects.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LX3305 + Methotrexate | Time to Maximum Plasma Concentration of LX3305 in the Presence of MTX | 2.25 hours |