Pharmacokinetic and Exploratory Electrocardiogram (ECG) Study
Study Details
Study Description
Brief Summary
This study will characterize the pharmacokinetics of colchicine after an oral dosing regimen of 4.8 mg over 6 hours. In addition it will compare the electrocardiogram (ECG) changes, if any, from this dosing regimen to that of a single dose of moxifloxacin 400 mg, a positive control for the corrected QT interval (QTc) prolongation.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Detailed Description
This study will characterize the pharmacokinetics of colchicine after an oral dosing regimen of 4.8 mg over 6 hours. In addition, it will determine whether or not there is a trend toward effect of this high dose regimen on the electrocardiogram (ECG), mainly the corrected QT interval (QTc), via comparison to a 400 mg dose of moxifloxacin, a positive control for QTc prolongation. Eighteen healthy, non-smoking, non-obese, non-pregnant adults between the ages of 18 to 55 years of age will be randomized in a double blind fashion to either the colchicine or moxifloxacin treatment groups. On the day prior to the study (Day -1), subjects will receive colchicine and moxifloxacin placebos according to the same schedule and conditions as will be present during the study, and baseline ECG's will be determined by 24 hour 12-lead Holter monitoring. On Day 1, after a minimum 10 hour overnight fast, subjects enrolled in the colchicine treatment group (N=15) will receive two 0.6 mg capsules (plus one dose moxifloxacin placebo) followed by an additional 0.6 mg colchicine dose (plus one dose moxifloxacin placebo) every hour for 6 additional doses; subjects in the moxifloxacin treatment group will receive placebo doses matching the colchicine treatment group over the first 5 hours, then 400 mg moxifloxacin (plus one dose colchicine placebo) at the 6 hour point. Fasting will continue for 4 hours after the first dose at which time a standardized meal will be served. Blood will be drawn from all participants at times sufficient to adequately define the pharmacokinetics of colchicine. During the study, continuous 24-hour ECG monitoring via 12-lead Holter monitor will be performed. Triplicate ECG records will be extracted from 5 minute observation periods throughout the 24 hours post dose. Finally, all study subjects will be monitored for adverse effects throughout the entire study period.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Colchicine
|
Drug: Colchicine
two 0.6 mg capsules (1.2 mg dose) followed by an additional 0.6mg capsule every hour for 6 additional doses
Other Names:
|
| Active Comparator: Moxifloxacin
|
Drug: Moxifloxacin
400 mg capsule at the 6 hour point
|
Outcome Measures
Primary Outcome Measures
- Maximum Plasma Concentration (Cmax) [serial pharmacokinetic blood samples collected pre-dose and 1 (prior to second dose), 3 (prior to fourth dose), 6 (prior to final dose), 6.17, 6.33, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 10, 12, 23, 36, 48, 72 and 96 hours post-dose]
The maximum or peak concentration that colchicine reaches in the plasma.
- Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] [serial pharmacokinetic blood samples collected pre-dose and 1 (prior to second dose), 3 (prior to fourth dose), 6 (prior to final dose), 6.17, 6.33, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 10, 12, 23, 36, 48, 72 and 96 hours post-dose]
The area under the plasma concentration versus time curve, from time 0 to the time of the last measurable concentration (t), as calculated by the linear trapezoidal rule.
- Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] [serial pharmacokinetic blood samples collected pre-dose and 1 (prior to second dose), 3 (prior to fourth dose), 6 (prior to final dose), 6.17, 6.33, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 10, 12, 23, 36, 48, 72 and 96 hours post-dose]
The area under the plasma concentration versus time curve from time 0 to infinity. AUC(0-∞) was calculated as the sum of AUC(0-t) plus the ratio of the last measurable plasma concentration to the elimination rate constant.
Secondary Outcome Measures
- Electrocardiogram (ECG) Evaluation of the QTcF Interval (Colchicine) [24 hours - measured 0.5 hr prior to first dose (baseline), then 1, 3, 6, 7, 8, 10, 12, and 23 hours after first dose]
The QT interval assesses cardiac repolarization and risk for arrhythmias. It is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. It is dependent on heart rate and is corrected (c) to aid interpretation via Fridericia's adjustment (F), and is reported as QTcF.
- Electrocardiogram (ECG) Evaluation of the QTcF Interval (Moxifloxacin) [24 hours - measured 0.5 hr prior to dose (baseline), then 1, 3, 6, 7, 8, 10, 12, and 23 hours after dose]
The QT interval assesses cardiac repolarization and risk for arrhythmias. It is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. It is dependent on heart rate and is corrected (c) to aid interpretation via Fridericia's adjustment (F), and is reported as QTcF.
Eligibility Criteria
Criteria
Inclusion Criteria:
- Healthy adults 18-55 years of age, non smoking and non-pregnant, weighing at least 55kg and within 15% of ideal body weight, with no significant EKG changes
Exclusion Criteria:
-
Pregnant or lactating
-
Test positive at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HbsAg), or hepatitis C virus (HCV)
-
Recent (2-year) history or evidence of alcoholism or drug abuse
-
History or presence of significant cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric disease
-
History or family history of congenital long QT syndrome (LQTS) or sudden death possibly related to LQTS
-
Subjects who have used any drugs or substances known to inhibit or induce cytochrome (CYP) P450 enzymes and/or P-glycoprotein (P-gp) within 30 days prior to the first dose and throughout the study
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | PRACS Institute, Ltd. - Cetero Research | Fargo | North Dakota | United States | 58104 |
Sponsors and Collaborators
- Mutual Pharmaceutical Company, Inc.
Investigators
- Principal Investigator: Anthony R Godfrey, Pharm.D., PRACS Institiute, Ltd.
Study Documents (Full-Text)
None provided.More Information
Additional Information:
- Recalls, Market Withdrawals and Safety Alerts
- Daily Med - Posting of Recently Submitted Labeling to the FDA
Publications
None provided.- MPC-004-07-1002
Study Results
Participant Flow
| Recruitment Details | Eighteen (18) healthy, non-smoking, adult male and female volunteers, consisting of university students and members of the community at large, were to be enrolled. |
|---|---|
| Pre-assignment Detail | 50 subjects screened, 28 were screen failures, 4 were alternates |
| Arm/Group Title | Colchicine | Moxifloxacin |
|---|---|---|
| Arm/Group Description | 1.2mg initially (two 0.6 mg capsules) followed by an additional 0.6mg capsule every hour for 6 additional doses [4.8mg over 6 hours] | 400 mg capsule at the 6 hour point |
| Period Title: Overall Study | ||
| STARTED | 15 | 3 |
| COMPLETED | 15 | 3 |
| NOT COMPLETED | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Colchicine | Moxifloxacin | Total |
|---|---|---|---|
| Arm/Group Description | 1.2mg initially (two 0.6 mg capsules) followed by an additional 0.6mg capsule every hour for 6 additional doses [4.8mg over 6 hours] | 400 mg capsule at the 6 hour point | Total of all reporting groups |
| Overall Participants | 15 | 3 | 18 |
| Age (Count of Participants) | |||
| <=18 years |
0
0%
|
0
0%
|
0.0
0%
|
| Between 18 and 65 years |
15
100%
|
3
100%
|
18.0
100%
|
| >=65 years |
0
0%
|
0
0%
|
0.0
0%
|
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
30.1
(10.4)
|
21.3
(0.6)
|
28.7
(10.0)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
7
46.7%
|
1
33.3%
|
8.0
44.4%
|
| Male |
8
53.3%
|
2
66.7%
|
10.0
55.6%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
1
6.7%
|
0
0%
|
1.0
5.6%
|
| Asian |
0
0%
|
0
0%
|
0.0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0.0
0%
|
| Black or African American |
1
6.7%
|
0
0%
|
1.0
5.6%
|
| White |
13
86.7%
|
3
100%
|
16.0
88.9%
|
| More than one race |
0
0%
|
0
0%
|
0.0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0.0
0%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
15
100%
|
3
100%
|
18.0
100%
|
Outcome Measures
| Title | Maximum Plasma Concentration (Cmax) |
|---|---|
| Description | The maximum or peak concentration that colchicine reaches in the plasma. |
| Time Frame | serial pharmacokinetic blood samples collected pre-dose and 1 (prior to second dose), 3 (prior to fourth dose), 6 (prior to final dose), 6.17, 6.33, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 10, 12, 23, 36, 48, 72 and 96 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Colchicine |
|---|---|
| Arm/Group Description | 1.2mg initially (two 0.6 mg capsules) followed by an additional 0.6mg capsule every hour for 6 additional doses [4.8mg over 6 hours] |
| Measure Participants | 15 |
| Mean (Standard Deviation) [ng/mL] |
6.84
(1.30)
|
| Title | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] |
|---|---|
| Description | The area under the plasma concentration versus time curve, from time 0 to the time of the last measurable concentration (t), as calculated by the linear trapezoidal rule. |
| Time Frame | serial pharmacokinetic blood samples collected pre-dose and 1 (prior to second dose), 3 (prior to fourth dose), 6 (prior to final dose), 6.17, 6.33, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 10, 12, 23, 36, 48, 72 and 96 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Colchicine |
|---|---|
| Arm/Group Description | 1.2mg initially (two 0.6 mg capsules) followed by an additional 0.6mg capsule every hour for 6 additional doses [4.8mg over 6 hours] |
| Measure Participants | 15 |
| Mean (Standard Deviation) [ng-hr/mL] |
104.95
(24.61)
|
| Title | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] |
|---|---|
| Description | The area under the plasma concentration versus time curve from time 0 to infinity. AUC(0-∞) was calculated as the sum of AUC(0-t) plus the ratio of the last measurable plasma concentration to the elimination rate constant. |
| Time Frame | serial pharmacokinetic blood samples collected pre-dose and 1 (prior to second dose), 3 (prior to fourth dose), 6 (prior to final dose), 6.17, 6.33, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 10, 12, 23, 36, 48, 72 and 96 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Colchicine |
|---|---|
| Arm/Group Description | 1.2mg initially (two 0.6 mg capsules) followed by an additional 0.6mg capsule every hour for 6 additional doses [4.8mg over 6 hours] |
| Measure Participants | 15 |
| Mean (Standard Deviation) [ng-hr/mL] |
118.20
(26.01)
|
| Title | Electrocardiogram (ECG) Evaluation of the QTcF Interval (Colchicine) |
|---|---|
| Description | The QT interval assesses cardiac repolarization and risk for arrhythmias. It is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. It is dependent on heart rate and is corrected (c) to aid interpretation via Fridericia's adjustment (F), and is reported as QTcF. |
| Time Frame | 24 hours - measured 0.5 hr prior to first dose (baseline), then 1, 3, 6, 7, 8, 10, 12, and 23 hours after first dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Baseline | Hour 1 | Hour 3 | Hour 6 | Hour 7 | Hour 8 | Hour 10 | Hour 12 | Hour 23 |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | measured 0.5 hr prior to initial colchicine dose | measured 1 hour after initial colchicine dose | measured 3 hours after initial colchicine dose | measured 6 hours after initial colchicine dose | measured 7 hours after initial colchicine dose | measured 8 hours after initial colchicine dose | measured 10 hours after initial colchicine dose | measured 12 hours after initial colchicine dose | measured 23 hours after initial colchicine dose |
| Measure Participants | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 |
| Mean (Standard Deviation) [milliseconds] |
401.62
(20.18)
|
397.80
(19.63)
|
401.76
(20.04)
|
394.73
(10.72)
|
388.84
(15.57)
|
393.93
(16.30)
|
396.02
(16.15)
|
396.89
(11.85)
|
399.36
(17.38)
|
| Title | Electrocardiogram (ECG) Evaluation of the QTcF Interval (Moxifloxacin) |
|---|---|
| Description | The QT interval assesses cardiac repolarization and risk for arrhythmias. It is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. It is dependent on heart rate and is corrected (c) to aid interpretation via Fridericia's adjustment (F), and is reported as QTcF. |
| Time Frame | 24 hours - measured 0.5 hr prior to dose (baseline), then 1, 3, 6, 7, 8, 10, 12, and 23 hours after dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Baseline | Hour 1 | Hour 3 | Hour 6 | Hour 7 | Hour 8 | Hour 10 | Hour 12 | Hour 23 |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | measured 0.5 hour prior to moxifloxacin dose | measured 1 hour after moxifloxacin dose | measured 3 hours after moxifloxacin dose | measured 6 hours after moxifloxacin dose | measured 7 hours after moxifloxacin dose | measured 8 hours after moxifloxacin dose | measured 10 hours after moxifloxacin dose | measured 12 hours after moxifloxacin dose | measured 23 hours after moxifloxacin dose |
| Measure Participants | 3 | 3 | 3 | 3 | 3 | 3 | 3 | 3 | 3 |
| Mean (Standard Deviation) [milliseconds] |
402.11
(12.04)
|
398.89
(1.65)
|
403.67
(17.91)
|
397.00
(8.46)
|
397.89
(8.31)
|
397.44
(2.59)
|
402.67
(13.23)
|
405.22
(17.64)
|
416.00
(13.68)
|
Adverse Events
| Time Frame | ||||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Colchicine | Moxifloxacin | ||
| Arm/Group Description | 1.2mg initially (two 0.6 mg capsules) followed by an additional 0.6mg capsule every hour for 6 additional doses [4.8mg over 6 hours] | 400 mg capsule at the 6 hour point | ||
All Cause Mortality |
||||
| Colchicine | Moxifloxacin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Colchicine | Moxifloxacin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/15 (0%) | 0/3 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Colchicine | Moxifloxacin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 15/15 (100%) | 0/3 (0%) | ||
| Gastrointestinal disorders | ||||
| diarrhoea | 15/15 (100%) | 15 | 0/3 (0%) | 0 |
| flatulence | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 |
| nausea | 7/15 (46.7%) | 7 | 0/3 (0%) | 0 |
| vomiting | 6/15 (40%) | 8 | 0/3 (0%) | 0 |
| General disorders | ||||
| vessel puncture site pain | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 |
| Nervous system disorders | ||||
| dizziness | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 |
| headache | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||
| nasal congestion | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 |
| nasopharyngitis | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 |
| pharyngolaryngeal pain | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
| Name/Title | Medical Director |
|---|---|
| Organization | Mutual Pharmaceutical Company, Inc. |
| Phone | 215-697-1743 |
| clinicaltrials@urlmutual.com |
- MPC-004-07-1002