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Human experimental pain models are useful in understanding the mechanisms underlying clinical pain conditions and can be used to test the analgesic efficacy of drugs used in the management of pain. Once established these models can be used as mechanism biomarkers in early development clinical studies to establish proof of mechanism for novel compounds. The cold pain model is a mechanistic pain biomarker with potential application in proof of mechanism studies. In this study we aim to set up this cold pain model at a Clinical Research Unit and demonstrate we can effectively screen subjects for this model and examine the effect of morphine, diphenhydramine, and gabapentin in the cold pain model.
Cold pain methodology development
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Gabapentin 1200mg | Active Comparator |
| |
| Diphenhydramine 50 mg | Active Comparator |
| |
| Morphine 10 mg | Active Comparator |
| |
| Placebo formulations | Placebo Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Gabapentin | Drug | Capsule, single 1200mg dose |
| |
| Diphenhydramine |
| Measure | Description | Time Frame |
|---|---|---|
| Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | Area under the cold pain test Visual Analog Scale (VAS) time curve (AUCcpt 0 to 120 seconds [sec]) averaged over the 120 sec for each time point assessed. Participant adjusted 100 millimeter (mm) electronic VAS with range of "no pain" (0) to "maximum pain" (100) at the anchor endpoints of the scale and "moderate pain" at the midpoint. Pain reported while non-dominant hand was placed in thermostatically controlled water bath at 2±1°C for a maximum of 120 sec. | Pre-dose, 1, 1.5, 2, 4, and 8 hours post-dose |
| Interpolated Average Pain (0-8 Hours) | Interpolated average pain (0 to 8 hours): area under the curve (AUC) of average pain (0 to 120 seconds) recorded at each of the time points taken over 8 hour time period divided by 8. | Pre-dose to 8 hours post-dose |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Clinically Significant Findings in Vital Signs | Supine blood pressure measured to nearest millimeter of mercury (mmHg), pulse rate measured with automated device or manually in the brachial/radial artery for at least 30 seconds. | Predose, Day 1, Day 2 each treatment period, follow-up visit (at least 7 days after last dosing) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Pfizer CT.gov Call Center | Pfizer | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Pfizer Investigational Site | Brussels | 1070 | Belgium |
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| Label | URL |
|---|---|
| To obtain contact information for a study center near you, click here. | View source |
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Prior to entering the treatment phases of the study, participants were required to successfully pass cold pain screening tests. Twenty participants were randomized and 19 participants received treatment consisting of a crossover sequence of 4 study drugs administered in sequence I, II, III or IV.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo, Morphine, Diphenhydramine, Gabapentin | Placebo (capsules, tablet and intravenous (IV) first, then morphine 10 mg IV, then diphenhydramine 50 mg tablet, then gabapentin 1200 mg capsule. |
| FG001 | Morphine, Gabapentin, Placebo, Diphenhydramine | Morphine 10 mg intravenous (IV) first, then gabapentin 1200 mg capsule, placebo (capsules, tablet and IV), then diphenhydramine 50 mg tablet. |
| FG002 | Gabapentin, Diphenhydramine, Morphine, Placebo | Gabapentin 1200 mg capsule first, then diphenhydramine 50 mg tablet, then morphine 10 mg intravenous (IV), then placebo (capsules, tablet and IV). |
| FG003 | Diphenhydramine, Placebo, Gabapentin, Morphine | Diphenhydramine 50 mg tablet first, then placebo (capsules, tablet and intravenous (IV), then gabapentin 1200 mg capsule, then morphine 10 mg IV. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Entire Study Population | Includes all participants who initiated in any treatment sequence |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | Area under the cold pain test Visual Analog Scale (VAS) time curve (AUCcpt 0 to 120 seconds [sec]) averaged over the 120 sec for each time point assessed. Participant adjusted 100 millimeter (mm) electronic VAS with range of "no pain" (0) to "maximum pain" (100) at the anchor endpoints of the scale and "moderate pain" at the midpoint. Pain reported while non-dominant hand was placed in thermostatically controlled water bath at 2±1°C for a maximum of 120 sec. | Participants for analysis = participants who completed all of the four treatment periods. | Posted | Mean | Standard Deviation | mm | Pre-dose, 1, 1.5, 2, 4, and 8 hours post-dose |
|
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Safety population: all subjects who received at least 1 dose of study medication. An Adverse Event (AE) term may be reported as both a serious and non-serious AE, but are distinct events. AE may = serious for 1 subject and = non-serious for another subject or subject may have experienced both a serious and non-serious episode of the same event.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Gabapentin | Gabapentin single oral 1200 mg dose |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vision blurred | Eye disorders | MedDRA 10.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Pfizer ClinicalTrials.gov Call Center | Pfizer, Inc. | 1-800-718-1021 | ClinicalTrials.gov_Inquiries@pfizer.com |
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| ID | Term |
|---|---|
| D000077206 | Gabapentin |
| D004155 | Diphenhydramine |
| D009020 | Morphine |
| ID | Term |
|---|---|
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D005680 | gamma-Aminobutyric Acid |
| D000613 | Aminobutyrates |
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| Drug |
Tablet, single 50mg dose |
|
| Morphine | Drug | IV, single 10mg dose |
|
| Placebo | Drug | Placebo formulations (Capsule, tablet, IV to match the active treatments and to be administered in a double-dummy fashion). |
|
| Number of Participants With Clinically Significant Abnormal Findings on Physical Examination | Full physical examination consisting of an examination of the abdomen, cardiovascular systems, lungs, lymph nodes, mouth, musculoskeletal and neurological systems, skin, extremities, head, ears, eyes, nose, throat and thyroid gland. | Pre-dose and follow-up visit (at least 7 days after last dosing) |
| Number of Participants With Abnormal Findings on Electrocardiogram (ECG) | Standard 12-lead ECG performed after subject had rested quietly for at least 10 minutes in a supine position. | Pre-dose and follow-up visit (at least 7 days after last dosing) |
| Number of Participants With Abnormal Haematology, Clinical Chemistry, Urinalysis Results | Standard haematology, clinical chemistry, and urinalysis safety laboratory tests. | Pre-dose, follow-up visit (at least 7 days after last dosing) |
| Number of Participants With Abnormal Cardiac Monitoring Results | Continuous cardiac monitoring during intervenous (IV) infusion dosing (morphine or placebo). | Pre-dose through duration of IV infusion dosing |
| Number of Participants With Abnormal Pulse Oxymetry Results | Pulse oxymetry to monitor percentage of hemoglobin saturated with oxygen during intervenous (IV) infusion dosing (morphine or placebo). | Predose through duration of IV infusion dosing |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Morphine |
Morphine single IV 10 mg dose |
| OG002 | Diphenhydramine | Diphenhydramine single oral 50 mg dose |
| OG003 | Placebo | Oral and IV doses to match active treatments |
|
|
|
| Primary | Interpolated Average Pain (0-8 Hours) | Interpolated average pain (0 to 8 hours): area under the curve (AUC) of average pain (0 to 120 seconds) recorded at each of the time points taken over 8 hour time period divided by 8. | Participants for analysis = participants who completed all of the four treatment periods. | Posted | Least Squares Mean | Standard Error | hours | Pre-dose to 8 hours post-dose |
|
|
|
|
| Secondary | Number of Participants With Clinically Significant Findings in Vital Signs | Supine blood pressure measured to nearest millimeter of mercury (mmHg), pulse rate measured with automated device or manually in the brachial/radial artery for at least 30 seconds. | Safety population: all subjects who received at least 1 dose of study medication. Although individual listing data for vital signs were collected, summary statistics were not generated for this outcome measure. | Posted | Number | participants | Predose, Day 1, Day 2 each treatment period, follow-up visit (at least 7 days after last dosing) |
|
|
| Secondary | Number of Participants With Clinically Significant Abnormal Findings on Physical Examination | Full physical examination consisting of an examination of the abdomen, cardiovascular systems, lungs, lymph nodes, mouth, musculoskeletal and neurological systems, skin, extremities, head, ears, eyes, nose, throat and thyroid gland. | Safety population: all subjects who received at least 1 dose of study medication. Although individual subject data were collected, results were not captured for inclusion in the study database. | Posted | Number | participants | Pre-dose and follow-up visit (at least 7 days after last dosing) |
|
|
| Secondary | Number of Participants With Abnormal Findings on Electrocardiogram (ECG) | Standard 12-lead ECG performed after subject had rested quietly for at least 10 minutes in a supine position. | Safety population: all subjects who received at least 1 dose of study medication. Although individual subject data were collected and monitored, summary statistics were not generated for this outcome measure. | Posted | Number | participants | Pre-dose and follow-up visit (at least 7 days after last dosing) |
|
|
| Secondary | Number of Participants With Abnormal Haematology, Clinical Chemistry, Urinalysis Results | Standard haematology, clinical chemistry, and urinalysis safety laboratory tests. | Safety population: all subjects who received at least 1 dose of study medication. Although individual subject data were collected and monitored, summary statistics were not generated for this outcome measure. | Posted | Number | particpants | Pre-dose, follow-up visit (at least 7 days after last dosing) |
|
|
| Secondary | Number of Participants With Abnormal Cardiac Monitoring Results | Continuous cardiac monitoring during intervenous (IV) infusion dosing (morphine or placebo). | Safety population: all subjects who received at least 1 dose of study medication. Although continuous cardiac monitoring was performed throughout IV dosing, results were not captured for inclusion in the study database. | Posted | Number | participants | Pre-dose through duration of IV infusion dosing |
|
|
| Secondary | Number of Participants With Abnormal Pulse Oxymetry Results | Pulse oxymetry to monitor percentage of hemoglobin saturated with oxygen during intervenous (IV) infusion dosing (morphine or placebo). | Safety population: all subjects who received at least 1 dose of study medication. Although pulse oxymetry was performed throughout IV dosing, results were not captured for inclusion in the study database. | Posted | Number | participants | Predose through duration of IV infusion dosing |
|
|
| 0 |
| 19 |
| 9 |
| 19 |
| EG001 | Morphine | Morphine single IV 10 mg dose | 0 | 19 | 18 | 19 |
| EG002 | Diphenhydramine | Diphenhydramine single oral 50 mg dose | 0 | 19 | 5 | 19 |
| EG003 | Placebo | Oral and IV doses to match active treatments | 0 | 19 | 3 | 19 |
| Dry mouth | Gastrointestinal disorders | MedDRA 10.1 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 10.1 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 10.1 | Systematic Assessment |
|
| Asthenia | General disorders | MedDRA 10.1 | Systematic Assessment |
|
| Chest pain | General disorders | MedDRA 10.1 | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA 10.1 | Systematic Assessment |
|
| Feeling abnormal | General disorders | MedDRA 10.1 | Systematic Assessment |
|
| Feeling drunk | General disorders | MedDRA 10.1 | Systematic Assessment |
|
| Oral herpes | Infections and infestations | MedDRA 10.1 | Systematic Assessment |
|
| Musculoskeletal stiffness | Musculoskeletal and connective tissue disorders | MedDRA 10.1 | Systematic Assessment |
|
| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA 10.1 | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA 10.1 | Systematic Assessment |
|
| Head discomfort | Nervous system disorders | MedDRA 10.1 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 10.1 | Systematic Assessment |
|
| Paraesthesia | Nervous system disorders | MedDRA 10.1 | Systematic Assessment |
|
| Somnolence | Nervous system disorders | MedDRA 10.1 | Systematic Assessment |
|
| Speech disorder | Nervous system disorders | MedDRA 10.1 | Systematic Assessment |
|
| Stress | Psychiatric disorders | MedDRA 10.1 | Systematic Assessment |
|
| Hyperhidrosis | Skin and subcutaneous tissue disorders | MedDRA 10.1 | Systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA 10.1 | Systematic Assessment |
|
| Hot flush | Vascular disorders | MedDRA 10.1 | Systematic Assessment |
|
Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
| D002087 |
| Butyrates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D003509 | Cyclohexanecarboxylic Acids |
| D000146 | Acids, Carbocyclic |
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D005021 | Ethylamines |
| D001559 | Benzhydryl Compounds |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D009022 | Morphine Derivatives |
| D009019 | Morphinans |
| D053610 | Opiate Alkaloids |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
| D006572 | Heterocyclic Compounds, Bridged-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D010616 | Phenanthrenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D011083 | Polycyclic Compounds |
| Mean Difference (Final Values) |
| -9.43 |
| Standard Error of the Mean |
| 2.17 |
| 2-Sided |
| 90 |
| -13.07 |
| -5.79 |
| No |
| Superiority or Other |
| Mixed Models Analysis | Mean Difference (Final Values) | 0.84 | Standard Error of the Mean | 2.17 | 2-Sided | 90 | -2.80 | 4.48 | No | Superiority or Other |