Healthy, No Evidence of Disease
Conditions
Keywords
Healthy, No Evidence of Disease
Brief summary
RATIONALE: Garlic supplements may alter the pharmacokinetics of oxycodone, thereby affecting its effectiveness as an opioid analgesic for the relief of moderate or severe pain. PURPOSE: This randomized phase 4 trial is studying how garlic supplements may change the pharmacokinetics of oxycodone and its analgesic and side effects in healthy volunteers.
Detailed description
OBJECTIVES: * To determine whether CYP3A (Cytochrome P450 3A) and/or P-glycoprotein mediated interactions exist between garlic supplements and oxycodone (a commonly used oral opioid analgesic) in healthy volunteers. OUTLINE: This is a single-blind, randomized, crossover study. Participants are randomized to 1 of 2 arms. Each arm entails two 30-day treatment periods, with a washout of at least 4 weeks in between. * Arm I: In Period 1, participants receive oral garlic powder twice daily on days 1-28 and oral oxycodone on day 28. In Period 2, participants receive oral placebo twice daily on days 1-28 and oral oxycodone on day 28. * Arm II: In Period 1, participants receive oral placebo twice daily on days 1-28 and oral oxycodone on days 28. In Period 2, participants receive oral garlic powder twice daily on days 1-28 and oral oxycodone on day 28. In both periods of each arm, participants receive a combination of oral midazolam and oral digoxin for CYP3A and P-glycoprotein phenotyping on day 29. Blood samples are collected periodically and analyzed by liquid chromatography-mass spectrometry (LC-MS). Blood and urine samples are collected after receiving oxycodone for pharmacokinetic characterization. Plasma concentrations of oxycodone and its metabolites are measured by LC-MS. Response to experimentally induced pain by the Cold Pressor Test (CPT) is assessed at baseline and periodically after oxycodone treatment. Subjective ratings of opioid side effects are assessed by validated questionnaires for somatic side effects and cognitive function impairments.
Interventions
DIETARY_SUPPLEMENTgarlic powder tablets
Each Garlicin tablet has a claimed allicin content of 3,200 microgram per tablet
DRUGoxycodone
Single administration of three 5-mg oxycodone tablets or a 15-mg dose
Sponsors
National Cancer Institute (NCI)
Fred Hutchinson Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
21 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy volunteer * Body mass index 20-32
Exclusion criteria
* Not pregnant * No history of cardiopulmonary, liver, renal, endocrine, neurologic, or psychiatric disease * No anemia * No known adverse reactions to opioids, benzodiazepines, cardiac glycosides, or garlic supplements * No known allergy or hypersensitivity to sulfur-containing food or drugs * No significant gastrointestinal intolerance to lactose in dairy products * No recent history of alcohol or substance abuse * No history of or concurrent heavy daily consumption of allium vegetables (i.e., garlic, shallots, leeks, and chives) * No handicaps due to visual and hearing impairments * No resting heart rate \< 50 beats per minutes * No abnormal cardiac rhythm by EKG * No unusually sensitive response or resistance to pain stimulation (Cold Pressor Test) * Must be right handed * No color blindness * No history of learning disabilities or dyslexia * Must be literate and proficient in English * Must be a nonsmoker * No concurrent medication except oral contraceptives * No concurrent grapefruit or grapefruit juice * No other concurrent over-the-counter herbal products or herbal tea
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Oxycodone Oral Clearance | Serial blood sampling over 24 hours after a 15-mg oral dose of oxycodone | Oxycodone oral clearance is computed by Dose/AUC, where AUC is the area under the plasma oxycodone concentration-time curve from time zero to infinity. Oral clearance is a measure of the rate at which oxycodone is cleared from the body via metabolism. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cold Pressor Tolerance AUC | Repeated testing for tolerance to Cold Pressor Test just before and at 45, 90, 150 and 300 min after a single 15-mg oral dose of oxycodone | Cold Pressor Test measures response to experimentally induced pain, in this case by immersion of a subject's hand in icy-cold water. Tolerance is the duration of time a subject is able to keep his/her hand immersed in the cold water. A prolongation in tolerance time indicates analgesic response to oxycodone treatment. Cold Pressor Tolerance AUC is the area under the tolerance versus time curve over a 300-min period after a test dose of oxycodone. Because of non-normality in sample distribution, log transformed AUC estimates were analyzed by Generalized Linear Model. |
| Somatic Side Effects Total Score | SSE scores at 150 min after a single 15-mg oral dose of oxycodone | Subjects rated the bodily side effects they experienced at 90, 150 and 300 min after oxycodone administration on a 35-item Somatic Side Effects (SSE) questionnaire. Total score (i.e., average of the scores for all 35 items) ranges on a numerical scale from 0 (no somatic side effects) to a maximum of 4 (extreme somatic aide effects). Only the peak SSE scores at 150 min are reported herein. |
| Cognitive-Affective Side Effects Total Score | CASE scores at 150 min after a single 15-mg oral dose of oxycodone | Subjects rated the mental side effects they experienced at 90, 150 and 300 min after oxycodone administration on a 36-item Cognitive-Affective Side Effects (CASE) questionnaire. Total score (i.e., average of the scores for all 36 items) ranges on a numerical scale from 0 (no somatic side effects) to a maximum of 4 (extreme somatic aide effects). Only the peak CASE scores at 150 min are reported herein. |
| Oral Midazolam Test | Serial blood sampling over 6 hours after a 5-mg oral test dose of midazolam | Midazolam when given orally is a probe substrate for the in vivo intestinal and hepatic activity of CYP3A (Cytochrome P450 3A) enzymes. The phenotype index in this case is the area under the plasma midazolam concentration from time zero to 360 min after a 5-mg oral test dose. A decrease in oral midazolam AUC indicates enhanced activity of CYP3A enzymes, possibly as a result of enzyme induction. |
| Oral Digoxin Test | Serial blood sampling over 4 hours after a 0.5-mg oral test dose of digoxin | Digoxin when given orally is a probe substrate for the efflux activity of P-glycoprotein in the small intestine. The phenotype index in this case is the area under the plasma digoxin concentration from time zero to 240 min after a 0.5-mg oral test dose. A decrease in oral digoxin AUC indicates an enhanced activity of P-glycoprotein, possibly as a result of transporter upregulation. |
Countries
United States
Participant flow
Recruitment details
Recruitment period was between November 2006 and August 2008. Healthy subjects were recruited from the University of Washington and Fred Hutchinson Cancer Research Center campuses through public notices.
Participants by arm
| Arm | Count |
|---|---|
| Garlic First, Then Placebo Two 30-day treatment periods separated by a washout of at least 4 weeks. In Period 1, participants receive oral garlic powder (Nature's Way Garlicin tablet) twice daily on days 1-30, and undergo testings with oxycodone on day 28 and a combination of oral midazolam and digoxin on day 29. In Period 2, participants receive oral placebo tablet twice daily on days 1-30, and undergo testings with oxycodone on day 28 and a combination of oral midazolam and digoxin on day 29. | 6 |
| Placebo First, Then Garlic Two 30-day treatment periods separated by a washout of at least 4 weeks. In Period 1, participants receive oral placebo tablet twice daily on days 1-30, and undergo testings with oxycodone on day 28 and a combination of oral midazolam and digoxin on day 29. In Period 2, participants receive oral garlic powder (Nature's Way Garlicin tablet) twice daily on days 1-30, and undergo testings with oxycodone on day 28 and a combination of oral midazolam and digoxin on day 29. | 6 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Intervention 1 (30 Days) | Fainting upon Blood Draw | 1 | 0 |
| Intervention 1 (30 Days) | Withdrawal by Subject | 1 | 0 |
| Intervention 2 (30 Days) | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Garlic First, Then Placebo | Total | Placebo First, Then Garlic |
|---|---|---|---|
| Age, Continuous | 28.3 years STANDARD_DEVIATION 5.2 | 29.9 years STANDARD_DEVIATION 5.8 | 30.5 years STANDARD_DEVIATION 6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 11 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 11 Participants | 5 Participants |
| Region of Enrollment United States | 6 Participants | 12 Participants | 6 Participants |
| Sex: Female, Male Female | 3 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 0 / 15 | 0 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 |
Outcome results
Primary
Oxycodone Oral Clearance
Oxycodone oral clearance is computed by Dose/AUC, where AUC is the area under the plasma oxycodone concentration-time curve from time zero to infinity. Oral clearance is a measure of the rate at which oxycodone is cleared from the body via metabolism.
Time frame: Serial blood sampling over 24 hours after a 15-mg oral dose of oxycodone
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Garlic | Oxycodone Oral Clearance | 1.82 L/min | Standard Deviation 0.4 |
| Placebo | Oxycodone Oral Clearance | 2.04 L/min | Standard Deviation 0.51 |
p-value: >0.05Generalized Estimating Equations
Secondary
Cognitive-Affective Side Effects Total Score
Subjects rated the mental side effects they experienced at 90, 150 and 300 min after oxycodone administration on a 36-item Cognitive-Affective Side Effects (CASE) questionnaire. Total score (i.e., average of the scores for all 36 items) ranges on a numerical scale from 0 (no somatic side effects) to a maximum of 4 (extreme somatic aide effects). Only the peak CASE scores at 150 min are reported herein.
Time frame: CASE scores at 150 min after a single 15-mg oral dose of oxycodone
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Garlic | Cognitive-Affective Side Effects Total Score | 1.884 units on a scale | Standard Deviation 0.118 |
| Placebo | Cognitive-Affective Side Effects Total Score | 1.714 units on a scale | Standard Deviation 0.147 |
p-value: >0.05Generalized Estimating Equations
Secondary
Cold Pressor Tolerance AUC
Cold Pressor Test measures response to experimentally induced pain, in this case by immersion of a subject's hand in icy-cold water. Tolerance is the duration of time a subject is able to keep his/her hand immersed in the cold water. A prolongation in tolerance time indicates analgesic response to oxycodone treatment. Cold Pressor Tolerance AUC is the area under the tolerance versus time curve over a 300-min period after a test dose of oxycodone. Because of non-normality in sample distribution, log transformed AUC estimates were analyzed by Generalized Linear Model.
Time frame: Repeated testing for tolerance to Cold Pressor Test just before and at 45, 90, 150 and 300 min after a single 15-mg oral dose of oxycodone
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Garlic | Cold Pressor Tolerance AUC | 3.513 log (sec*min) | Standard Deviation 0.904 |
| Placebo | Cold Pressor Tolerance AUC | 3.715 log (sec*min) | Standard Deviation 0.604 |
p-value: >0.05Generalized Estimating Equations
Secondary
Oral Digoxin Test
Digoxin when given orally is a probe substrate for the efflux activity of P-glycoprotein in the small intestine. The phenotype index in this case is the area under the plasma digoxin concentration from time zero to 240 min after a 0.5-mg oral test dose. A decrease in oral digoxin AUC indicates an enhanced activity of P-glycoprotein, possibly as a result of transporter upregulation.
Time frame: Serial blood sampling over 4 hours after a 0.5-mg oral test dose of digoxin
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Garlic | Oral Digoxin Test | 231 (ng/mL)*min | Standard Deviation 50 |
| Placebo | Oral Digoxin Test | 226 (ng/mL)*min | Standard Deviation 58 |
p-value: >0.05t-test, 1 sided
Secondary
Oral Midazolam Test
Midazolam when given orally is a probe substrate for the in vivo intestinal and hepatic activity of CYP3A (Cytochrome P450 3A) enzymes. The phenotype index in this case is the area under the plasma midazolam concentration from time zero to 360 min after a 5-mg oral test dose. A decrease in oral midazolam AUC indicates enhanced activity of CYP3A enzymes, possibly as a result of enzyme induction.
Time frame: Serial blood sampling over 6 hours after a 5-mg oral test dose of midazolam
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Garlic | Oral Midazolam Test | 2491 (ng/mL)*min | Standard Deviation 789 |
| Placebo | Oral Midazolam Test | 2495 (ng/mL)*min | Standard Deviation 825 |
Comparison: The secondary hypothesis being tested is that garlic powder induces CYP3A-mediated metabolism resulting in a lower oral midazolam AUC.p-value: >0.05t-test, 1 sided
Secondary
Somatic Side Effects Total Score
Subjects rated the bodily side effects they experienced at 90, 150 and 300 min after oxycodone administration on a 35-item Somatic Side Effects (SSE) questionnaire. Total score (i.e., average of the scores for all 35 items) ranges on a numerical scale from 0 (no somatic side effects) to a maximum of 4 (extreme somatic aide effects). Only the peak SSE scores at 150 min are reported herein.
Time frame: SSE scores at 150 min after a single 15-mg oral dose of oxycodone
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Garlic | Somatic Side Effects Total Score | 0.560 units on a scale | Standard Deviation 0.14 |
| Placebo | Somatic Side Effects Total Score | 0.711 units on a scale | Standard Deviation 0.184 |
p-value: >0.05Generalized Estimating Equations