MPC-004 for the Treatment of an Acute Gout Flare (AGREE)

A Multicenter, Randomized, Double Blind, Placebo Controlled, Parallel Group, 1 Week, Dose Comparison Study to Evaluate the Efficacy, Safety, and Tolerability of MPC-004 in Patients With an Acute Gout Flare

This study is a multicenter, randomized, double-blind, placebo-controlled, parallel group, dose-comparison to determine the efficacy and safety of a standard-dose of colchicine (4.8 mg) versus low-dose colchicine (1.8 mg) or placebo for acute gout flares.

Study Overview

• Status: Completed
• Conditions: Gout
• Intervention / Treatment: Drug: High Dose Colchicine (4.8 mg total dose); Drug: Low Dose Colchicine (1.8mg total dose); Other: Placebo Control

Detailed Description

This study is a multi-center, randomized, double-blind, placebo-controlled, parallel group trial to compare the efficacy and safety of standard-dose colchicine (STD)(total dose = 4.8 mg) versus low-dose colchicine (total dose 1.8 mg) or placebo for the treatment of acute gout flares. Eight hundred and thirteen patients with a confirmed diagnosis of gout were screened. 238 of the screened patients failed screening; 235(98.7%) failed because they did not meet inclusion/exclusion criteria. The 575 eligible patients were randomly assigned (1:1:1) to one of three treatment groups . At the randomization visit the investigator dispensed a blister card containing eight identical looking capsules (in a combination of active drug and placebo capsules) in a double blind fashion for use during their next gout flare. Patients were instructed to self-initiate treatment with the study medication within 12 hours of a gout flare onset. Gout flares were determined by calling a Gout Flare Call Center established for this purpose. At Investigator discretion, rescue medication could also be provided, but patients were encouraged not to use rescue medication within the first 24 hours after starting treatment with study drug. Of the 575 study participants, 185 had a qualifying gout flare and 390 did not. Patients used a diary to record study drug administration, pain score, the presence or absence of gastrointestinal adverse events (nausea, vomiting, diarrhea, and abdominal pain) and the timing of any rescue medication use prior to beginning treatment and 1, 2, 3, 4, 5, 6, 7, 8, 16, 24, 32, 40, 48, 56, 64, and 72 hours after the start of dosing.

The pain score was based on a scale of 1 - 10 where 1 was no pain and 10 was the worst pain imaginable. Efficacy was defined as a 50% reduction in pain score in the target joint at 24 hours in patients who did not use rescue medicine. The primary efficacy analysis was to be based on an Intent-to-Treat (ITT) population, defined as all patients who were randomized, contacted the Call Center, and were instructed to begin taking study drug. An otherwise qualified patient was excluded from the ITT population only if the patient returned a study drug blister pack completely unused.

Secondary outcome measures compared the efficacy of STD dose colchicine to a low dose regimen and placebo using the same criteria for efficacy as for the primary outcome measure.

Additional secondary outcome measures were time to 50% and 90% reduction in pain in the target joint analyzed by treatment group using Kaplan-Meier methods, and the change in mean pain intensity from 0 to 72 hours plotted by time point for each treatment group.

All safety analyses were carried out using the safety population defined as all patients who received at least one dose of study medication regardless of authorization by the Call Center To determine the safety of colchicine when administered via two different dose regimens all patients who had a gout flare were seen by the investigator as soon as possible after onset and evaluated until the flare and any adverse events resolved. All adverse effects, whether recorded by the patient in the diary or obtained by systematic evaluation by the investigator were recorded and reported in tabular form. Treatment-emergent adverse events (TEAE) were summarized by MedDRA System Organ Class and preferred terms and tabulated according treatment arm, overall incidence, severity and relationship to study medication. Multiple events within a patient were counted once and at greatest severity and closest relationship to study medication.

• Study Type: Interventional
• Enrollment (Actual): 185
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States
    • Birmingham, Alabama, United States, 35205
      • Innovative Clinical Trials
    • Columbiana, Alabama, United States, 35051
      • Tomac, Inc.
    • Huntsville, Alabama, United States, 35801
      • Rheumatology Associates of North Alabama
  • Arizona
    • Tucson, Arizona, United States
    • Tucson, Arizona, United States, 85741
      • Genova Clinical Research
  • Arkansas
    • Jonesboro, Arkansas, United States, 72401
      • NEA Clinic
    • Little Rock, Arkansas, United States, 72204
      • Arkansas Primary Care Clinic
  • California
    • Irvine, California, United States, 92618
      • Irvine Center for Clinical Research
    • La Jolla, California, United States
    • Paramount, California, United States
    • Rancho Cucamonga, California, United States, 91730
      • Rancho Cucamonga Clinical Trials
    • San Diego, California, United States
    • West Covina, California, United States
  • Florida
    • Clearwater, Florida, United States, 33755
      • Florida Medical Center
    • Crystal River, Florida, United States, 34429
      • Nature Coast Clinical Research
    • Gainesville, Florida, United States, 32607
      • Southeastern Integrated Medical
    • Green Cove Springs, Florida, United States, 32043
      • George E. Platt, MD
    • Jacksonville, Florida, United States, 32216
      • Jacksonville Center for Clinical Research
    • Jupiter, Florida, United States, 33458
      • Health Awareness, Inc.
    • Lake Mary, Florida, United States
    • Lake Worth, Florida, United States, 33461
      • Medical Research Trust
    • Orange City, Florida, United States, 32763
      • Hillcrest Medical Center
    • Ormond Beach, Florida, United States, 32174
      • Farmer MD, PA
    • Port Orange, Florida, United States, 32127
      • Coastal Medical Research, Inc.
    • Tampa, Florida, United States, 33609
      • Southwest Florida Clinical Research Center
    • Vero Beach, Florida, United States, 32960
      • Geodessey Research, LLC
    • Winter Haven, Florida, United States, 33880
      • Bond Clinic
  • Georgia
    • Calhoun, Georgia, United States, 30701
      • Global Research Partners & Consultants, Inc.
    • Decatur, Georgia, United States
    • Lawrenceville, Georgia, United States, 30045
      • North Georgia Rheumatology Group, PC
    • Tifton, Georgia, United States, 31794
      • Arthritis & Osteoporosis Center of South Georgia
  • Idaho
    • Boise, Idaho, United States
    • Meridian, Idaho, United States, 83642
      • Idaho Arthritis & Osteoporosis Center
  • Illinois
    • Libertyville, Illinois, United States, 60048
      • Lake County Research Associates
    • Moline, Illinois, United States
  • Iowa
    • Cedar Rapids, Iowa, United States, 52401
      • Physicians Clinic of Iowa
  • Kentucky
    • Elizabethtown, Kentucky, United States, 42701
      • The Center for Arthritis & Osteoporosis
    • Louisville, Kentucky, United States, 40202
      • David H. Neustadt PSCq
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70808
      • Gulf Coast Research
  • Maryland
    • Frederick, Maryland, United States, 21702
      • Arthritis and Osteoporosis Center of Maryland
    • Rockville, Maryland, United States
    • Wheaton, Maryland, United States, 20902
      • The Center for Rheumatology & Bone Research
  • Massachusetts
    • Springfield, Massachusetts, United States, 01103
      • Future Care Studies
    • Worcester, Massachusetts, United States, 01610
      • Clinical Pharmacology Study Group
  • Michigan
    • Lansing, Michigan, United States, 48910
      • Justus Fiechtner, Md, Mph
  • Mississippi
    • Hattiesburg, Mississippi, United States, 39402
      • Arthritis Associates
  • Missouri
    • Florissant, Missouri, United States, 63031
      • Medical Center Healthcare Research
    • Saint Louis, Missouri, United States, 63117
      • Medex Healthcare
  • Nevada
    • Las Vegas, Nevada, United States
    • Reno, Nevada, United States, 89502
      • Arthritis Center of Reno
  • New Jersey
    • Manalapan, New Jersey, United States, 07726
      • Arthritis & Osteoporisis Associates
    • Medford, New Jersey, United States, 08055
      • Rheumatology and Arthritis Associates
    • Voorhees, New Jersey, United States
  • New York
    • Albany, New York, United States
    • Brewster, New York, United States, 10509
      • Southwest Medical Associates
    • New York, New York, United States
      • Concorde Medical Group
    • Rochester, New York, United States
    • Syracuse, New York, United States
    • Williamsville, New York, United States
  • North Carolina
    • Belmont, North Carolina, United States, 28012
      • Arthritis Consultants of the Carolinas
    • Charlotte, North Carolina, United States, 28207
      • Arthritis & Osteoporosis Consultants Of The Carolinas
  • Ohio
    • Dayton, Ohio, United States
    • Mayfield Village, Ohio, United States
    • Middleburg Heights, Ohio, United States
  • Pennsylvania
    • Duncansville, Pennsylvania, United States
    • Harleysville, Pennsylvania, United States
    • Philadelphia, Pennsylvania, United States
  • South Carolina
    • Orangeburg, South Carolina, United States
  • Tennessee
    • Milan, Tennessee, United States
    • New Tazewell, Tennessee, United States
  • Texas
    • Arlington, Texas, United States
    • Austin, Texas, United States
    • Carrollton, Texas, United States
    • Fort Worth, Texas, United States
    • Houston, Texas, United States
    • Irving, Texas, United States
    • San Antonio, Texas, United States
    • Sugarland, Texas, United States
  • Virginia
    • Ettrick, Virginia, United States
    • Portsmouth, Virginia, United States
    • Reston, Virginia, United States
    • Suffolk, Virginia, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients of either gender and of any race ≥18 years of age.
2. If female, patients must be postmenopausal as evidenced by lack of menses for ≥12 consecutive months.
3. Patients must present with a confirmed diagnosis of gout.
4. Patients must have experienced ≥2 acute gouty arthritic attacks in the 12 months prior to randomization.
5. Patients on urate lowering therapy must be on a stable dose and schedule with no changes in therapy for 4 weeks prior to randomization and expected to remain on a stable regimen during study participation.
6. Patients must be willing to adhere to the study schedule and the protocol requirements.
7. Patients must be willing and able to give written informed consent. A HIPAA and/or state privacy consent must also be signed.

Exclusion Criteria:

1. Patients with acute polyarticular gout (>4 joints).
2. Patients who have experienced >2 acute gouty arthritic attacks per month, or >12 attacks overall, in the 6 months prior to randomization.
3. Patients with arthritis due to any cause other than gout that may confound any study assessments per Investigator discretion.
4. Patients with a history of myocardial infarction, unstable angina, cerebrovascular events, or coronary artery bypass grafting within the previous 6 months prior to screening.
5. Patients with active myeloid leukemia, obstructive gastrointestinal cancer, or metastatic cancer.
6. Patients with chronic renal dysfunction (creatinine clearance <60 mL/min as estimated with the Cockcroft Gault formula).
7. Patients with chronic hepatic dysfunction.
8. Patients with a history of alcohol or substance abuse within the 12 months prior to randomization.
9. Patients who have any concomitant illness or other finding that, in the opinion of the Investigator, would confound the study data or place the patient at unacceptable risk if the patient were to participate in the study, or that would require frequent adjustments in concomitant medications during the course of the study.
10. Patients using systemic corticosteroid, cyclosporine, adalimumab, etanercept, infliximab, anakinra, abatacept, mycophenolate, azathioprine, anticoagulants (warfarin, heparin, low molecular weight heparin [LMWH], antithrombin agents, thrombin inhibitors, or selective Factor Xa inhibitors [note, use of aspirin ≤325 mg/day is allowed]), or chronic use of non steroidal anti inflammatory drugs (NSAIDs), acetaminophen, tramadol, and other analgesics such as opiates at screening
11. Use of any investigational drug within 30 days prior to randomization.
12. Patients currently participating in another research study or anticipated to enroll in such during participation in this study.
13. Patients for whom informed consent cannot be obtained.
14. Patients who have previously been randomized into this study and begun ingestion of study drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo Control; At randomization, patients were given an identical looking blister pack containing (8) placebo capsules identical in appearance to the study drug. Patients were instructed to take 2 capsules initially followed by an additional capsule every hour for a total of six additional doses beginning within 12 hours of onset of a qualifying gout flare as confirmed by calling the gout flare call center.; Other Names: Placebo capsule
Experimental: High Dose Colchicine; After confirmation of a gout flare, patients were to begin standard dosing of colchicine 4.8mg (two capsules (1.8mg) initially followed by additional one capsule doses (0.6mg) every hour for an additional 6 doses).	Drug: High Dose Colchicine (4.8 mg total dose); At randomization, patients were given an identical looking blister pack containing (8) over encapsulated colchicine 0.6 mg tablets identical in appearance to placebo capsules. Patients were instructed to take 2 capsules initially (1.2 mg) followed by an additional capsule (0.6 mg) every hour for a total of six additional doses (total colchicine dose 4.8 mg) beginning within 12 hours of onset of a qualifying gout flare as confirmed by calling the gout flare call center.; Other Names: Colcrys TM, Colchicine 0.6 mg
Experimental: Low Dose Colchicine; Within 12 hours of a confirmed gout flare, patients were to begin the low dose colchicine regimen consisting of a total dose of 1.8 mg - two colchicine capsules initially (1.2 mg)followed an hour later by a single additional capsule of active drug(0.6 mg)then by 5 additional hourly doses of an identical looking placebo capsules	Drug: Low Dose Colchicine (1.8mg total dose); At randomization, patients were given an identical looking blister pack containing (3) over encapsulated colchicine 0.6 mg tablets identical in appearance to placebo capsules and five placebo capsules. Patients were instructed to take 2 capsules initially (0.6 mg x 2) followed by an additional capsule every hour for a total of six additional doses (one active (0.6 mg) and 5 placebo capsules), a total colchicine dose = 1.8 mg) beginning within 12 hours of onset of a qualifying gout flare as confirmed by calling the gout flare call center; Other Names: Colcrys TM, Colchicine 0.6 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Responders	Responders were defined as patients who achieved a ≥ 50% reduction in target joint pain score from baseline at 24 hours without using rescue drug, using an 11 point scale from 0 to 10, with 10 being the worst pain imaginable after beginning therapy.	24 hours after baseline

Collaborators and Investigators

• Sponsor: Takeda
• Investigators: Study Chair: Matthew W Davis, MD, RPh, AR Scientific, Inc.

Publications and helpful links

General Publications

• Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW. High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum. 2010 Apr;62(4):1060-8. doi: 10.1002/art.27327.

Study record dates

Study Major Dates

• Study Start: April 1, 2007
• Primary Completion (Actual): October 1, 2007
• Study Completion (Actual): October 1, 2007

Study Registration Dates

• First Submitted: July 23, 2007
• First Submitted That Met QC Criteria: July 24, 2007
• First Posted (Estimate): July 25, 2007

Study Record Updates

• Last Update Posted (Estimate): November 1, 2012
• Last Update Submitted That Met QC Criteria: October 30, 2012
• Last Verified: October 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Metabolism, Inborn Errors; Crystal Arthropathies; Purine-Pyrimidine Metabolism, Inborn Errors; Gout; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Gout Suppressants; Colchicine
• Other Study ID Numbers: MPC 004-06-3001