Clinical Neuropharmacology of Pain in Spinal Cord Injury- Dextromethorphan Dose Response Clinical Trial
Study Details
Study Description
Brief Summary
This randomized, placebo-controlled, double-blind 4x4 crossover clinical trial was part of a larger NIH-funded study to evaluate the analgesic efficacy of three doses of chronic oral (PO) dextromethorphan compared to placebo in central neuropathic pain following spinal cord injury. Subjects' maximally tolerated doses (MTD) were first determined to establish individual dose-analgesic response relationships in a run-in period; following a washout period, subjects were then randomized to receive an order of four doses of dextromethorphan (including placebo) in a 4x4 Latin square cross-over design.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 2 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Placebo Comparator: 0% MTD Dex 0% MTD Dextromethorphan |
Drug: Dextromethorphan
0, 25, 50 and 100% of maximum tolerated dose, each administered over a 4 week period
|
Experimental: 25% MTD Dex 25% MTD Dextromethorphan |
Drug: Dextromethorphan
0, 25, 50 and 100% of maximum tolerated dose, each administered over a 4 week period
|
Experimental: 50% MTD Dex 50% MTD Dextromethorphan |
Drug: Dextromethorphan
0, 25, 50 and 100% of maximum tolerated dose, each administered over a 4 week period
|
Experimental: 100% MTD Dex 100% MTD Dextromethorphan |
Drug: Dextromethorphan
0, 25, 50 and 100% of maximum tolerated dose, each administered over a 4 week period
|
Outcome Measures
Primary Outcome Measures
- Mean Pain Intensity (Percent Change From Baseline) [1st week of maintenance period (week prior to hospital admission for nested study; subjects traveled to Boston on days 6-7 of the maintenance period)]
Primary outcome was percent change from baseline in mean pain intensity (transformed Gracely Scale; 0-35). Baseline was defined as the week prior to randomization. The greater the percent change, the bigger the reduction in pain intensity.
Secondary Outcome Measures
- Satisfaction [Last week prior to admission (end of 1-week maintenance period)]
Satisfaction with study treatment assessed over the 7 days prior to admission (5-point categorical scale)
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Healthy male or female adults, age 18 to 70 with central neuropathic pain for a minimum of 3 months following SCI as confirmed by neurologic evaluation, with an average pain intensity score of at least moderate over at least 50% of the day for the 7 days prior to the screening visit and over the 7 days prior to starting study medication.
-
Subjects used no medication or a stabilized medication regimen for chronic and well-controlled medical conditions
-
Serum laboratory examination obtained at study entry:
-
Liver function tests (albumin within 20% of normal, SGOT/SGPT within 50% of normal).
-
For women of childbearing age: negative serum beta HCG.
-
Postmenopausal women, or be physically incapable of childbearing, or be practicing an acceptable method of birth control.
-
Normal cognitive function.
-
Normal communicative ability (English).
-
Ability to demonstrate competence in recording five times daily in pain diary for 1 week (with 100% compliance), and in completing required questionnaires.
-
Signed informed consent.
Exclusion Criteria:
-
Pregnancy or breast-feeding.
-
Renal or hepatic dysfunction.
-
Significant cardiac disease (e.g. MI within 1 year).
-
Signs or symptoms of central neurological disorder, excluding SCI.
-
Severe psychological disorder requiring treatment.
-
Concurrent use of monoamine oxidase inhibitors within 2 weeks prior to study entry.
-
Use of known CYP2D6 (but not CYP3A4) inhibitors or inducers.
-
History of hypersensitivity or intolerance to dextromethorphan or lidocaine.
-
Chronic substance abuse, including alcohol.
-
Participation in a study of an investigational drug or device within 30 days prior to screening for this study.
-
Poor metabolizer of P450 2D6 substrates.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Translational Pain Research, Brigham and Women's Hospital | Boston | Massachusetts | United States | 02115 |
Sponsors and Collaborators
- Brigham and Women's Hospital
- National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
- Principal Investigator: Christine N. Sang, MD, MPH, Translational Pain Research, Brigham and Women's Hospital (Disclosure: Patent)
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- R01NS041503
Study Results
Participant Flow
Recruitment Details | Subjects were recruited nationally from referring physicians, through advertisements, and through existing databases. |
---|---|
Pre-assignment Detail | During the screening visit, P450 2D6 phenotype status was determined for each subject to identify drug-metabolizing capacity; those who were P450 2D6 poor-metabolizers were excluded. Following screen, each subject entered a dose escalation period to determine his/her maximum tolerated dose (MTD), prior to randomization. |
Arm/Group Title | Dextromethorphan Dose Response (DDR) Clinical Trial |
---|---|
Arm/Group Description | Each subject received four doses of dextromethorphan; 0% (placebo), 25%, 50%, and 100% of the maximum tolerated dose in a balanced randomized order. Each dose was administered for a period of 28 days; on day 21 of each phase, subjects traveled to the study site to undergo study procedures in a nested clinical trial (not described here). |
Period Title: Overall Study | |
STARTED | 26 |
0% MTD | 25 |
25% MTD | 26 |
50% MTD | 25 |
100% MTD | 25 |
COMPLETED | 25 |
NOT COMPLETED | 1 |
Baseline Characteristics
Arm/Group Title | Dextromethorphan Dose Response Clinical Trial |
---|---|
Arm/Group Description | Each subject received four doses of dextromethorphan; 0% (placebo), 25%, 50%, and 100% of the maximum tolerated dose in a balanced randomized order. Each dose was administered for a period of 28 days; on day 21 of each phase, subjects traveled to the study site to undergo study procedures in a nested clinical trial (not described here). |
Overall Participants | 26 |
Age (Count of Participants) | |
<=18 years |
0
0%
|
Between 18 and 65 years |
25
96.2%
|
>=65 years |
1
3.8%
|
Age (years) [Mean (Standard Deviation) ] | |
Mean (Standard Deviation) [years] |
46.84
(11.32)
|
Sex: Female, Male (Count of Participants) | |
Female |
14
53.8%
|
Male |
12
46.2%
|
Region of Enrollment (participants) [Number] | |
North America |
26
100%
|
Outcome Measures
Title | Mean Pain Intensity (Percent Change From Baseline) |
---|---|
Description | Primary outcome was percent change from baseline in mean pain intensity (transformed Gracely Scale; 0-35). Baseline was defined as the week prior to randomization. The greater the percent change, the bigger the reduction in pain intensity. |
Time Frame | 1st week of maintenance period (week prior to hospital admission for nested study; subjects traveled to Boston on days 6-7 of the maintenance period) |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | 0% MTD Dex | 25% MTD Dex | 50% MTD Dex | 100% MTD Dex |
---|---|---|---|---|
Arm/Group Description | 0% (placebo) of maximum tolerated dose of dextromethorphan; dose was administered for a period of 28 days, and on day 21, subjects traveled to the study site to undergo additional study procedures. | 25% of maximum tolerated dose of dextromethorphan; dose was administered for a period of 28 days, and on day 21, subjects traveled to the study site to undergo additional study procedures. | 50% of maximum tolerated dose of dextromethorphan; dose was administered for a period of 28 days, and on day 21, subjects traveled to the study site to undergo additional study procedures. | 100% of maximum tolerated dose of dextromethorphan; dose was administered for a period of 28 days, and on day 21, subjects traveled to the study site to undergo additional study procedures. |
Measure Participants | 25 | 26 | 25 | 25 |
Mean (Standard Error) [Percent change from baseline] |
-0.006
(0.01)
|
-0.018
(0.005)
|
-0.073
(0.01)
|
-0.24
(0.01)
|
Title | Satisfaction |
---|---|
Description | Satisfaction with study treatment assessed over the 7 days prior to admission (5-point categorical scale) |
Time Frame | Last week prior to admission (end of 1-week maintenance period) |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | 0% MTD Dex | 25% MTD Dex | 50% MTD Dex | 100% MTD Dex |
---|---|---|---|---|
Arm/Group Description | 0% (placebo) of maximum tolerated dose of dextromethorphan; dose was administered for a period of 28 days, and on day 21, subjects traveled to the study site to undergo additional study procedures. | 25% of maximum tolerated dose of dextromethorphan; dose was administered for a period of 28 days, and on day 21, subjects traveled to the study site to undergo additional study procedures. | 50% of maximum tolerated dose of dextromethorphan; dose was administered for a period of 28 days, and on day 21, subjects traveled to the study site to undergo additional study procedures. | 100% of maximum tolerated dose of dextromethorphan; dose was administered for a period of 28 days, and on day 21, subjects traveled to the study site to undergo additional study procedures. |
Measure Participants | 25 | 26 | 25 | 25 |
Not Satisfied |
20
76.9%
|
18
NaN
|
16
NaN
|
9
NaN
|
Fairly Satisfied |
2
7.7%
|
5
NaN
|
7
NaN
|
8
NaN
|
Satisfied |
3
11.5%
|
2
NaN
|
0
NaN
|
5
NaN
|
Very/Extremely Satisfied |
0
0%
|
1
NaN
|
2
NaN
|
3
NaN
|
Adverse Events
Time Frame | Adverse event data were collected post-dose through the end of treatment in each arm. | |||||||
---|---|---|---|---|---|---|---|---|
Adverse Event Reporting Description | All anticipated and unanticipated post-dose adverse events that were possibly, probably, or definitely related to the study drug are reported. | |||||||
Arm/Group Title | 0% MTD Dex | 25% MTD Dex | 50% MTD Dex | 100% MTD Dex | ||||
Arm/Group Description | 0% (placebo) of maximum tolerated dose of dextromethorphan; dose was administered for a period of 28 days, and on day 21, subjects traveled to the study site to undergo additional study procedures. | 25% of maximum tolerated dose of dextromethorphan; dose was administered for a period of 28 days, and on day 21, subjects traveled to the study site to undergo additional study procedures. | 50% of maximum tolerated dose of dextromethorphan; dose was administered for a period of 28 days, and on day 21, subjects traveled to the study site to undergo additional study procedures. | 100% of maximum tolerated dose of dextromethorphan; dose was administered for a period of 28 days, and on day 21, subjects traveled to the study site to undergo additional study procedures. | ||||
All Cause Mortality |
||||||||
0% MTD Dex | 25% MTD Dex | 50% MTD Dex | 100% MTD Dex | |||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | / (NaN) | / (NaN) | / (NaN) | / (NaN) | ||||
Serious Adverse Events |
||||||||
0% MTD Dex | 25% MTD Dex | 50% MTD Dex | 100% MTD Dex | |||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/25 (0%) | 0/26 (0%) | 0/25 (0%) | 0/25 (0%) | ||||
Other (Not Including Serious) Adverse Events |
||||||||
0% MTD Dex | 25% MTD Dex | 50% MTD Dex | 100% MTD Dex | |||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 2/25 (8%) | 3/26 (11.5%) | 2/25 (8%) | 16/25 (64%) | ||||
Ear and labyrinth disorders | ||||||||
Tinnitis | 0/25 (0%) | 0 | 0/26 (0%) | 0 | 2/25 (8%) | 2 | 0/25 (0%) | 0 |
Nervous system disorders | ||||||||
Sedation | 0/25 (0%) | 0 | 0/26 (0%) | 0 | 0/25 (0%) | 0 | 8/25 (32%) | 8 |
Blurry Vision | 0/25 (0%) | 0 | 0/26 (0%) | 0 | 0/25 (0%) | 0 | 3/25 (12%) | 3 |
Interference with Alertness | 2/25 (8%) | 2 | 3/26 (11.5%) | 3 | 0/25 (0%) | 0 | 3/25 (12%) | 3 |
Interference with Ability to Drive | 0/25 (0%) | 0 | 0/26 (0%) | 0 | 0/25 (0%) | 0 | 2/25 (8%) | 2 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Christine N. Sang, MD, MPH |
---|---|
Organization | Translational Pain Research, Brigham and Women's Hospital |
Phone | 617-525-7246 |
paintrials@partners.org |
- R01NS041503