Gout
Conditions
Brief summary
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.
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.
Interventions
DRUGHigh 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.
DRUGLow 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
OTHERPlacebo 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.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Responders | 24 hours after baseline | 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. |
Countries
United States
Participant flow
Recruitment details
In 2007 between 4 April and 3 December 813 patients were screened at 74 US treatment centers. 72 centers randomized a total 575 patients. 185 patients at 54 centers had a qualifying gout flare and 184 are included in the ITT population. The remaining, 390 patients had no flare or had a flare that failed to qualify for study medication use
Pre-assignment details
813 patients with confirmed diagnosis of gout based on American College of Rheumatology criteria were screened. 575 patients qualified and were randomized within 28 days of screening. 238 patients failed screening. The vast majority, 235 (98.7%) failed to meet inclusion/exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| High Dose Colchicine(MPC-004) Standard Dose Colchicine - 4.8 mg (total dose): 1.2 mg of oral colchicine (2 x 0.6 mg tablets) at onset of confirmed gout flare followed by 0.6 mg oral colchicine (1 x 0.6 mg tablet) every hour for 6 hours. All doses were over encapsulated to mimic the appearance of the placebo. | 52 |
| Low Dose Colchicine(MPC-004) Low Dose Colchicine - 1.8 mg (total dose): 1.2 mg of oral colchicine (2 x 0.6 mg tablets) at onset of confirmed gout flare followed by 0.6 mg oral colchicine (1 x 0.6 mg tablet) after 1 hours followed by placebo every hour thereafter hourly for 5 additional hours. All active doses were over encapsulated to mimic the appearance of the placebo. | 74 |
| Placebo Two oral placebo capsules at onset of a confirmed gout flare followed by 1 oral placebo capsule every hour for an additional 6 hours. | 59 |
| Total | 185 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 0 | 1 | 1 |
| Overall Study | Lost to Follow-up | 1 | 1 | 1 |
| Overall Study | Other | 5 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | High Dose Colchicine(MPC-004) | Low Dose Colchicine(MPC-004) | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 6 Participants | 13 Participants | 6 Participants | 25 Participants |
| Age, Categorical Between 18 and 65 years | 46 Participants | 61 Participants | 53 Participants | 160 Participants |
| Age Continuous | 51.9 years STANDARD_DEVIATION 10.02 | 51.4 years STANDARD_DEVIATION 11.79 | 51.2 years STANDARD_DEVIATION 11.36 | 51.5 years STANDARD_DEVIATION 11.12 |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Male | 49 Participants | 72 Participants | 55 Participants | 176 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 40 / 52 | 27 / 74 | 16 / 59 |
| serious Total, serious adverse events | 0 / 52 | 0 / 74 | 0 / 59 |
Outcome results
Primary
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.
Time frame: 24 hours after baseline
Population: The Intent-to-Treat (ITT) population(N=184) was used. The ITT group is defined as all patients who were randomized,and had a qualifying gout flare based on contact with the Gout Flare Call Center, who were instructed to begin taking and took at least one dose of the study drug study drug. One patient had a flare, but
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose Colchicine(MPC-004) | Responders | 17 Participants |
| Low Dose Colchicine(MPC-004) | Responders | 28 Participants |
| Placebo | Responders | 9 Participants |