Study Evaluating the Analgesic Efficacy and Safety of ADL5859 in Participants With Rheumatoid Arthritis

Rheumatoid Arthritis Clinical Trial

Official title:

A Phase 2a Randomized, Placebo- and Active-Controlled, Single-Dose, 3-Period, Crossover Study Followed by a Randomized, Placebo-Controlled, 14-Day, Parallel-Group Study Evaluating the Analgesic Efficacy and Safety of ADL5859 in Subjects With Rheumatoid Arthritis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00626275
• Other study ID #: 33CL232
• Status: Completed
• Phase: Phase 2
• First received: February 22, 2008
• Last updated: June 4, 2015
• Start date: October 2007
• Est. completion date: September 2008

Study information

• Verified date: June 2015
• Source: Cubist Pharmaceuticals LLC
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the effectiveness of ADL5859 in relieving pain associated with rheumatoid arthritis (RA) compared with placebo and naproxen (similar to Aleve®). A second objective is to see whether the effect of ADL5859 differs after a single dose compared with multiple doses.

Description:

This Phase 2a study was conducted in 2 parts. Part A was a randomized, single-dose, double-blind, placebo- and active-controlled, 3-way crossover phase during which participants were administered study medication in the clinical facility. Part B was a 14-day, randomized, double-blind, placebo-controlled, parallel-group, multiple-dose phase in which participants self-administered study medication at home.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 46
• Est. completion date: September 2008
• Est. primary completion date: September 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Male and female participants between 18 and 75 years of age, inclusive

• Have a documented history of rheumatoid arthritis (diagnosed according to American College of Rheumatology criteria)

• Have painful rheumatoid arthritis with pain predominantly in the lower extremities (that is, hip, knees, ankles, and/or feet)

• Have an evoked lower extremity pain intensity (ELEPI) score of 5 or higher on a numeric pain rating scale (NPRS) completed on Day 1 of Part A before dosing (after resting for 45 minutes and then walking for at least 10 minutes on a treadmill) and then have a minimum ELEPI score of 4 on other visits during Part A

• If receiving disease modifying antirheumatic drugs, have a stable dose regimen for at least 30 days before study entry (90 days before study entry for biologic therapy)

• If biologic therapy has been recently discontinued, Enbrel™ or Orencia™ must have been discontinued at least 30 days before study entry, and Humira™, Remicade™, and Rituxan™ must have been discontinued at least 60 days before study entry

• For male participants, be surgically sterile or agree to use an appropriate method of contraception

• For female participants of child bearing potential, be surgically sterile or using an insertable, injectable, transdermal, or combination oral contraceptive deemed highly effective by the US Food and Drug Administration (FDA) through the completion of the study and have negative findings on a urine pregnancy test before administration of study medication (women who are postmenopausal [no menses for at least 2 years] are also eligible to participate)

• Have a body weight of at least 45 kilograms (kg)

• Be able to understand and comply with the protocol requirements (such as repeated treadmill walking and diary completion via the interactive voice response system), instructions, and protocol-specified restrictions.

Exclusion Criteria:

• Have an overall pain intensity (OPI) score equal to 10 at screening or before the first dose of study medication in Part A

• Have a pain intensity score for the upper body (that is, back, neck, fingers, wrists, elbows, and/or shoulders) above 7 on a numeric pain rating scale (NPRS) before study medication administration

• Have a history of headache requiring prescription treatment within 6 months of study entry

• Have significant renal disease (as indicated by blood urea nitrogen or serum creatinine = 2 times the upper limit of normal) or have significant hepatic disease (as indicated by liver function test results = 2 times the upper limit of normal)

• Have evidence of symptomatic orthostatic hypotension

• Have a history of a seizure disorder, including febrile seizures

• Have, as determined by the investigator or the sponsor's medical monitor, a history or clinical manifestations of significant renal, hepatic, cardiovascular, metabolic, neurologic, psychiatric, or other conditions that would affect study participation

• Are taking cytochrome P450 (CYP) 3A4/5 or P glycoprotein (P gp) transporter inhibitors

• Have taken oral steroids within 30 days of study entry or intra articular steroids within 60 days of study entry (inhaled or topical steroids or stable oral dose = 10 mg is permitted)

• Have a history or presence of allergy or intolerance to nonsteroidal anti-inflammatory drugs or acetaminophen, or have a history of drug or other allergy that, in the opinion of the investigator, contraindicates participation in the study

• Have a history of alcoholism or drug addiction or abuse within 5 years before the scheduled administration of study medication

• Have participated in a trial of any investigational medication within 30 days before study drug administration

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• ADL5859

• Naproxen

• Placebo

• ADL5859

• Placebo

Locations

Country	Name	City	State
United States	University Hospitals Case Medical Center, Division of Rheumatology, Rheumatology Clinical Research Unit	Beachwood	Ohio
United States	Covance Clinical Research Unit Inc.	Daytona Beach	Florida
United States	Altoona Center for Clinical Research	Duncansville	Pennsylvania
United States	Advanced Biomedical Research of America	Las Vegas	Nevada
United States	Winthrop University Hospital, Clinical Trials Center	Mineola	New York
United States	Heartland Clinical Research, Inc.	Omaha	Nebraska
United States	New England Research Associates	Trumbull	Connecticut
United States	The Center for Rheumatology and Bone Research	Wheaton	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
Cubist Pharmaceuticals LLC

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part A: Average Difference Between Baseline and Post Dose Evoked (by Treadmill Walking) Lower-Extremity Pain Intensity Scores (AELEPID) Over the 6 Hours After Dosing	Approximately 1 hour before baseline and again approximately 45 minutes before the 2-, 4-, and 6-hour time points, participants rested for 45 minutes, then they started the treadmill walk at 15 minutes before baseline and at the 2-, 4-, and 6-hour time points. After the treadmill walk, participants were asked to rate their lower extremity pain on an 11 point Numeric Pain Rating Scale (NPRS), with 0 indicating No Pain and 10 indicating Worst Possible Pain. The average difference between baseline and 6 hours post dose evoked lower-extremity pain intensity scores (AELEPID-6) is presented for each treatment group. Difference = predose (baseline) NPRS score - NPRS score 6 hours post dose.; Least square (LS) means and standard errors (SE) were calculated from an analysis-of-covariance (ANCOVA) model with fixed effects for sequence, treatment, period, predose evoked lower extremity pain intensity as a covariate, and a random effect for participant nested within sequence.	Baseline through 6 hours post dose	No
Primary	Part B: The Mean of Daily Average "Now" Lower Extremity Pain Intensity (LEPI) Score During the 2-Week Period	Participants assessed their "Now" LEPI 3 times each day (morning, midday, and evening at approximately 10 AM, 2 PM, and 8 PM) and before taking any rescue medication. At each time point, participants were asked to rate their lower extremity pain on an 11-point Numeric Pain Rating Scale (NPRS), with 0 indicating No Pain and 10 indicating Worst Possible Pain. If a scheduled pain assessment was taken within 4 hours of rescue medication, the observed pain score was replaced by the pain score obtained right before the rescue medication was taken.; LS means and SE were calculated from an analysis-of-covariance model with effect for treatment and baseline "Now" LEPI (before dosing for Treatment Period 1 of Part A) as a covariate. Participants with no postbaseline assessments were excluded from the baseline summary.	Baseline through 2 Weeks	No
Secondary	Part A: Pain Intensity Score (NPRS Score) for Overall Pain, for Lower Extremity Pain, and for Evoked (by Treadmill Walking) Lower Extremity Pain	Overall Pain Intensity (OPI), "Now" Lower Extremity Pain Intensity (LEPI), and Evoked Lower Extremity Pain Intensity (ELEPI) were assessed using the 11-point Numeric Pain Rating Scale (NPRS), with 0 indicating No Pain and 10 indicating Worst Possible Pain. OPI was assessed at 15 minutes before dosing for baseline and at 6 and 12 hours (hr) after dosing. At 15 minutes before dosing, during Period 1 only, participants were also asked to assess their average LEPI over the last 24 hours as a baseline measurement. "Now" LEPI was assessed at 15 minutes before dosing for baseline and at the 1-, 2-, 3-, 4-, 5-, 6-, and 12-hour time points. Approximately 1 hour before dosing and approximately 45 minutes before the 2-, 4-, and 6-hour time points, the participant rested for 45 minutes, then (after the "Now" LEPI assessment) he or she started a treadmill walk at 15 minutes before dosing for baseline and at the 2-, 4-, and 6-hour time points, and then assessed ELEPI.	Baseline up to 12 hours post dose	No
Secondary	Part B: Mean Daily LEPI Scores for Weeks 1 and 2	Participants assessed their "Now" LEPI 3 times each day (morning, midday, and evening at approximately 10 AM, 2 PM, and 8 PM) and before taking any rescue medication. At each time point, participants were asked to rate their lower extremity pain on an 11 point Numeric Pain Rating Scale (NPRS), with 0 indicating No Pain and 10 indicating Worst Possible Pain. If a scheduled pain assessment was taken within 4 hours of rescue medication, the observed pain score was replaced by the pain score obtained right before the rescue medication was taken.	Baseline through Week 1 and Week 1 through Week 2	No
Secondary	Part A: Pain Intensity Difference Between Baseline and the Value at Each Scheduled Time Point for Overall Pain	Overall Pain Intensity (OPI) was assessed by the participant using the 11-point Numeric Pain Rating Scale (NPRS), with 0 indicating No Pain and 10 indicating Worst Possible Pain. OPI was assessed at 15 minutes before dosing for baseline and at 6 and 12 hours after dosing. Difference = predose (baseline) OPI score - OPI score 6 and 12 hours post dose.	Baseline, 6 and 12 hours post dose	No
Secondary	Part A: Average Difference Between Baseline and Postdose Evoked Lower Extremity Pain Over the 4 Hours After Dosing	Evoked Lower Extremity Pain Intensity (ELEPI) was assessed using the 11-point Numeric Pain Rating Scale (NPRS), with 0 indicating No Pain and 10 indicating Worst Possible Pain. Approximately 1 hour before dosing and approximately 45 minutes before the 2-, 4-, and 6-hour time points, the participant rested for 45 minutes, then he or she started a treadmill walk at 15 minutes before dosing for baseline and at the 2-, 4-, and 6-hour time points, and then assessed ELEPI. Difference = predose (baseline) ELEPI score - ELEPI score 4 hours post dose.	Baseline, 4 hours post dose	No
Secondary	Part A: Mean Peak Difference in ELEPI According to the NPRS Scale	Evoked Lower Extremity Pain Intensity (ELEPI) was assessed using the 11-point NPRS. Participants were asked to rate their lower extremity pain on an 11 point NPRS, with 0 indicating No Pain and 10 indicating Worst Possible Pain. If a scheduled pain assessment was taken within 4 hours of rescue medication, the observed pain score was replaced by the pain score obtained right before the rescue medication was taken. Approximately 1 hour before dosing and approximately 45 minutes before the 2-, 4-, and 6-hour time points, the participant rested for 45 minutes, then he or she started a treadmill walk at 15 minutes before dosing for baseline and at the 2-, 4-, and 6-hour time points, and then assessed ELEPI. Peak ELEPID was defined as the maximum of ELEPIDs recorded at 2, 4, and 6 hours post dose. Difference = predose (baseline) NPRS score - peak NPRS score up to 6 hours post dose.	Baseline, Up to 6 hours post dose	No
Secondary	Part A: Percentage of Participants in Each Treatment Group Achieving a 25%, 50%, or 75% Reduction From Baseline in Evoked Lower Extremity Pain Intensity Scores	Percentage was measured by identifying the number of participants who achieved the desired percentage Reduction From Baseline in ELEPI Score at either 2, 4, and 6 hours post dose and was divided the by the number of total participants in the given group and then multiplied by 100 to equate to a percentage.	Up to 2, 4, and 6 hours post dosing	No
Secondary	Part B: Participants' Global Evaluation of Study Medication	For Part B, each participant's global evaluation (overall impression) of study medication was obtained at each weekly visit. Scores were recorded on the Case Report Form (CRF) on a 5 point scale ranging from "excellent" to "poor". Participant counts per score were reported at Week 1 (Day 7) and Week 2 (Day 14).	Up to Week 1 and Week 2	No
Secondary	Part B: Mean Daily Average LEPI Scores Over the Last 24 Hours at Week 1 and Week 2	Each day during Part B, participants rated their Lower Extremity Pain Intensity over the last 24 hours on an 11-point NPRS, with 0 indicating No Pain and 10 indicating Worst Possible Pain	Week 1 and Week 2	No
Secondary	Part B: Mean Daily Average Overall Pain Intensity Scores Over Week 1, Over Week 2, and Over a 2-Week Period	During Part B, participants returned to the clinic for 2 additional visits at approximately weekly intervals for assessments of Overall Pain Index (OPI). Participants rated their OPI on an 11-point Numeric Pain Rating Scale (NPRS) with 0 indicating No Pain and 10 indicating Worst possible pain	Baseline through Week 1, Week 1 through Week 2, and Baseline through Week 2	No
Secondary	Part B: Percentage of Participants Using Rescue Medication	The percentage of participants who took at least 1 dose of rescue medication during 2-week treatment period of Part B is presented.	Baseline through Week 2	No
Secondary	Part A: Participant's Global Evaluation of Study Medication	For each treatment period during Part A, each participant's global evaluation (overall impression) of study medication was obtained 6 hours after dosing. Scores were recorded on the Case Report Form (CRF) on a 5 point scale ranging from "excellent" to "poor". Participant counts per score were reported once in Part A.	6 hours post dose during Treatment Periods 1, 2, and 3 of Part A	No