Multiple Sclerosis
Conditions
Keywords
Multiple Sclerosis, Duloxetine, Pain
Brief summary
Many patients with Multiple Sclerosis experience pain that is caused by the effects of MS on the nervous system. The purpose of this study is to see if an investigational drug (Duloxetine) will reduce pain in subjects with MS. The US Food and Drug administration (FDA) has approved this drug for use with depression or pain from diabetes.However, it is considered investigational for this study because it has not been approved for patients with MS. This study will recruit patients with MS who have central pain which is 4 or greater on a scale of 1-10. Patients must have experienced pain for 2 months or longer prior to begining the study.The study will last 10 weeks, patients will be randomized either Duloxetine or placebo and will be carefully monitored throughout the study. Patients will keep pain/sleep diaries during the study period and will be provided Ibuprofen for pain control.
Detailed description
Between 350,000 and 400,000 Americans have Multiple Sclerosis, a chronic neurological disease characterized by demyelination and axonal degeneration. Pain is an important symptom of MS, reported in 44% to 80% of patients. Duloxetine is FDA apprBetween 350,000 and 400,000 Americans have Multiple Sclerosis, a chronic neurological disease characterized by demyelination and axonal degeneration. Pain is an important symptom of MS, reported in 44% to 80% of patients. Duloxetine is FDA approved for use in treatment of diabetic painful neuropathy and depression. Since the analgesic mechanism of action of Duloxetine is believed to occur in the Central Nervous System, there is reason to believe that it may also be effective in central pain conditions, such as MS. Our study design includes a 1:1 randomization of Duloxetine to placebo. We hypothesize that the Duloxetine group will experience reductions in the weekly 24 hour average and worst pain scores that exceed 1.5 and that are significantly greater than reductions achieved in the placebo group. We also hypothesize that Duloxetine will be well tolerated with no significant group differences in adverse effects, sleep and quality of life as measured by the SF-36 approved for use in treatment of diabetic painful neuropathy and depression. Since the analgesic mechanism of action of Duloxetine is believed to occur in the Central Nervous System, there is reason to believe that it may also be effective in central pain conditions, such as MS. Our study design includes a 1:1 randomization of Duloxetine to placebo. We hypothesize that the Duloxetine group will experience reductions in the weekly 24 hour average and worst pain scores that exceed 1.5 and that are significantly greater than reductions achieved in the placebo group. We also hypothesize that Duloxetine will be well tolerated with no significant group differences in adverse effects, sleep and quality of life as measured by the SF-36.
Interventions
DRUGDuloxetine
Patients will be randomly assigned to Duloxetine 30mg/d for 1 week, 60mg/d for 5 weeks and 30mg/d for 1 week or placebo for 7 weeks under double-blind conditions.
DRUGPlacebo
Subjects are randomized to either Duloxetine or Placebo
Sponsors
Eli Lilly and Company
Brown, Theodore R., M.D., MPH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of MS made at least 3 months prior based on McDonald or Proser criteria. * Age over 17. * Clinical stability defined as no MS exacerbation or change in disease modifying therapy for 90 days prior to screening. * Daily pain attributed to MS, present for a minimum of 2 months prior to screening. * Minimum baseline score of 4 on the 24-h Worst Pain Score rated on an 11 point (0-10) point Likert Scale within the identified region of central pain.
Exclusion criteria
* Pain that could not clearly be differentiated from causes other than Multiple Sclerosis, such as diabetic neuropathy, PVD, arthritis or other musculoskeletal condition, chronic headache, visceral pain. * Transient pains such as dysesthetic L'Hermittes sign alone. * Current or historical diagnosis of mania, bipolar disorder or psychosis. * Concomitant use of monoamine oxidase inhibitors (MAOI) or thioridazine.(MAOI drug must be discontinued 14 days prior to enrollment. At least 5 days must have passed after study drug discontinuation before MAOI drug may be started.) * Concomitant use of a serotonin reuptake inhibitor or venlafaxine or duloxetine within 4 weeks of baseline. * Use of any analgesic medication except ibuprofen for neurogenic pain 7 days prior to the baseline visit and until study termination. * Use of an opioid, marijuana or dronabinol within 7 days of baseline. * Narrow angle glaucoma. * Depression with suicidality. * Substantial alcohol use. Because it is possible that Duloxetine and alcohol interact to cause liver injury, duloxetine should not be prescribed to patients with substantial alcohol use. Potential subjects will be asked how much alcohol they drink. If the answer is over 2 drinks a day this will generally constitute an exclusion. * History of chronic hepatic insufficiency or ALT or AST\> twice the upper limit of normal. Because it is possible thast Duloxetine may aggravate pre exisitng liver disease, duloxetine should not be prescribed to patients with chronic liver disease. * Renal insufficiency (Creatinine Clearance , 30mL/minor serum creatinine \> 1.9). Duloxetine is not recommended for patients with end stage renal disease (requiring dialysis) or severe renal impairment. Population PK analyses suggest that mild to moderate degrees of renal dysfunction (estimated CrCl 30-80ml/min)have no significant effect on Duloxetine clearance. We will calculate creatinine clearance using the Cockcroft-Gault calculation. This is the most common calculation used in FDA producy labeling: Males=(140-age)(wt in kg)(serum creatinine)(72). Females= malesx 0.85. * Uncontrolled hypertention (SBP\>180, DBP\>105) * Females who are breast feeding, pregnant, or have potential to become pregnant during the course of the study.(fertile and unwilling/unable to use effective contraceptive measures) * Any other serious and/or unstable medical condition. * Allergy to ibuprofen or any other non steroidal anti inflammatory drug (NSAID) * Any history of peptic ulcer disease within 2 years or lifetime history of NSAID-associated gastritis or other toxicity. * Patients taking low dose aspirin will be instructed to contact their primary physicianto ask whether they may safely discontinue aspirin while participating in this study. If the recommendation is to continue aspirin or if use of aspirin is for secondary prevention of arteriosclerotic disease, then they will be excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Worst Pain Score | at week 6 | Weekly mean of 24 hour Worst Pain Score, percent change from baseline. Range is 0-10 with 0= no pain and 10= worst possible pain. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Average Pain Score. | at week 6 | Percent change in Weekly mean of 24 hour Average pain Score, Week 6 vs. baseline. Range is 0-10 with 0= no pain and 10= worst possible pain. |
| Global Impression of Change | Week 6 vs baseline | global impression: How do you feel about the effects of the medication over the past 7 days? 7 point scale, 7 = delighted, 1= terrible |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Duloxetine subjects will be randomized to study drug (Duloxetine) or Placebo. Subjects will take 30 mg (10 capsules) titrate up to 60 mg( 40 capsules) and titrate back down to 30 mg.
Placebo: Patients will be randomly assigned to Duloxetine 30mg/d for 1 week, 60mg/d for 5 weeks and 30mg/d for 1 week or placebo for 7 weeks under double-blind conditions.
Placebo: Subjects are randomized to either Duloxetine or Placebo | 18 |
| Placebo subjects will be randomized to study drug (Duloxetine) or Placebo. Subjects will take 30 mg (10 capsules) titrate up to 60 mg( 40 capsules) and titrate back down to 30 mg.
Placebo: Patients will be randomly assigned to Duloxetine 30mg/d for 1 week, 60mg/d for 5 weeks and 30mg/d for 1 week or placebo for 7 weeks under double-blind conditions.
Placebo: Subjects are randomized to either Duloxetine or Placebo | 20 |
| Total | 38 |
Baseline characteristics
| Characteristic | Duloxetine | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 54.71 years STANDARD_DEVIATION 9.97 | 56.33 years STANDARD_DEVIATION 11.23 | 56.3 years STANDARD_DEVIATION 9.97 |
| Sex: Female, Male Female | 11 Participants | 13 Participants | 24 Participants |
| Sex: Female, Male Male | 7 Participants | 7 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 18 | 2 / 20 |
| serious Total, serious adverse events | 0 / 18 | 0 / 20 |
Outcome results
Primary
Percent Change in Worst Pain Score
Weekly mean of 24 hour Worst Pain Score, percent change from baseline. Range is 0-10 with 0= no pain and 10= worst possible pain.
Time frame: at week 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine | Percent Change in Worst Pain Score | -29.1 percent reduction on 0-10 analog scale | Standard Deviation 20.4 |
| Placebo | Percent Change in Worst Pain Score | -11.5 percent reduction on 0-10 analog scale | Standard Deviation 18.2 |
p-value: 0.016t-test, 2 sided
Secondary
Global Impression of Change
global impression: How do you feel about the effects of the medication over the past 7 days? 7 point scale, 7 = delighted, 1= terrible
Time frame: Week 6 vs baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine | Global Impression of Change | 4.77 units on a scale | Standard Deviation 1.3 |
| Placebo | Global Impression of Change | 3.94 units on a scale | Standard Deviation 1.16 |
p-value: 0.074t-test, 2 sided
Secondary
Percent Change in Average Pain Score.
Percent change in Weekly mean of 24 hour Average pain Score, Week 6 vs. baseline. Range is 0-10 with 0= no pain and 10= worst possible pain.
Time frame: at week 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine | Percent Change in Average Pain Score. | -38.5 percent reduction on 0-10 analog scale | Standard Deviation 29.1 |
| Placebo | Percent Change in Average Pain Score. | -10.4 percent reduction on 0-10 analog scale | Standard Deviation 18.85 |
p-value: 0.002t-test, 2 sided