HIV Infections, Peripheral Neuropathy
Conditions
Keywords
HIV Infections, Neuropathy, Pain
Brief summary
Neuropathy results from damage to the nerves in the feet and legs. It is usually experienced as pain, tingling or numbness. In HIV-infected people, neuropathy can result from the infection itself or be a side effect of antiretroviral treatment. The purpose of this study is to determine whether two different drugs, methadone and duloxetine, reduce neuropathy-associated pain in HIV-infected people. This study will also examine whether utilization of both of these drugs is more effective than treatment with only one.
Detailed description
Peripheral neuropathy is now recognized as the most common neurological complication of HIV disease and its treatment. Before highly active antiretroviral therapy (HAART) was introduced, the prevalence of HIV-associated distal sensory polyneuropathy (DSP) was already estimated to be 35%, mostly contained to populations with moderate to advanced immunosuppression. Now, since the advent of HAART, the prevalence of HIV-associated neuropathy has increased to 52%, possibly due to a combination of antiretroviral toxic neuropathy (ATN), decreased mortality, and accumulated medical comorbidities. Successful treatment of neuropathic pain is inherently difficult, and treatment of HIV-associated neuropathic pain is particularly complicated. To date, evidence supporting effective therapies for neuropathic HIV-associated pain is lacking, despite several types and classes of drugs having been evaluated in clinical trials. This study will evaluate the safety and efficacy of duloxetine, methadone, and the combination of duloxetine and methadone in painful HIV-associated neuropathy. Both of these drugs are approved by the Food and Drug Administration (FDA) but for purposes unrelated to HIV-associated neuropathy, and no previous studies have utilized these two treatments for this purpose. For this study, 120 participants with painful HIV-associated neuropathy will be recruited. The trial will last for approximately 23 weeks. Each participant will receive a total of 4 study treatments. The following treatment pairings will be given in a sequence determined by randomization: 1. duloxetine and methadone placebo 2. methadone and duloxetine placebo 3. duloxetine and methadone 4. duloxetine placebo and methadone placebo Each treatment period will last 4 weeks and will be followed by a 1-week combined taper and washout. People wishing to enroll in this study will have a screening visit that will last about 3 hours. During this visit, participants will have an HIV test, physical exam, neurologic exam, blood drawn, electrocardiogram (EKG), and a pregnancy test, if applicable. Participants will also be asked about their current health and any medications they may be taking. They will also be asked about their mood and be given the results of tests performed at the screening visit. If screening qualifies participants for the study, they will return for a pre-entry visit lasting 2 hours. During this visit, participants will have a limited physical exam and be asked about changes in their health or medicines since screening. Participants will also be given a pain diary with instructions to record neuropathy pain every day for each of the 7 days before beginning the study and throughout the study. After beginning the study, participants will return to the clinic for another 8 visits. These visits are at the end of each 4-week treatment period and at the end of each 1-week crossover period. At each visit, there will be a limited physical exam and participants will answer questions about their health and medications. Participants will also be told the results of routine lab tests and pregnancy tests performed during the study.
Interventions
DRUGDuloxetine
During each treatment period, participants will take duloxetine in the following doses. On Days 1 to 5, participants will take one 30-mg capsule orally, once daily. On Days 6 to 28, participants will take two 30-mg capsules orally, once daily. During days 29 to 31 dosage will be reduced to one capsule daily and then discontinued on Day 32.
During each treatment period, participants will take duloxetine placebo in the following doses. On Days 1 to 5, participants will take one 30-mg capsule orally, once daily. On Days 6 to 28, participants will take two 30-mg capsules orally, once daily. During days 29 to 31 dosage will be reduced to one capsule daily and then discontinued on Day 32.
DRUGMethadone
During each treatment period, participants will take methadone in the following doses. On Days 1 to 5, participants will take one 5-mg capsule orally, twice daily. On Days 6 to 10, participants will take one 5-mg capsule orally, three times daily. On Days 11 to 28, participants will take two 5-mg capsules orally, three times daily. On Days 29 to 31, dosage will be one 5-mg capsule orally, three times daily. On Days 32 to 34, dosage will be decreased to one 5-mg capsule, twice daily and ultimately discontinued on Day 35.
During each treatment period, participants will take methadone placebo in the following doses. On Days 1 to 5, participants will take one 5-mg capsule orally, twice daily. On Days 6 to 10, participants will take one 5-mg capsule orally, three times daily. On Days 11 to 28, participants will take two 5-mg capsules orally, three times daily. On Days 29 to 31, dosage will be one 5-mg capsule orally, three times daily. On Days 32 to 34, dosage will be decreased to one 5-mg capsule, twice daily and ultimately discontinued on Day 35.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HIV infected * HIV-associated neuropathy * Able and willing to provide informed consent * Successful completion of a daily baseline pain diary over 1 week immediately prior to entry with a mean pain intensity of 4 or more on an 11-point Likert scale * Karnofsky performance score of 60 or more within 45 days prior to entry * Required laboratory values. More information on this criterion can be found in the study protocol. * Willing to comply with protocol requirements for the duration of the study, to include daily completion of the pain diary as instructed, attendance at all study visits, and avoidance of prohibited medications * On stable or no antiretroviral therapy for 30 days prior to entry. Participants on ARV therapy should plan to remain on the same regimen and drug dose for the duration of the study. Participants not on ARV therapy should have no plans to initiate therapy during study enrollment. * Not pregnant
Exclusion criteria
* Conditions that confound a diagnosis of HIV-associated neuropathy or preclude accurate assessment of neuropathy symptoms, at the discretion of the site investigator. More information on this criterion can be found in the study protocol. * Potential for unstable neuropathy symptoms during study participation due tthe following: (1) discontinuation of dideoxynucleoside nucleoside reverse transcriptase inhibitor (NRTI) within 16 weeks prior to entry, (2)treatment within 120 days prior to entry with any drug that the site investigator considers may contribute to sensory neuropathy * Current history of significant depression on antidepressant therapy precluding withdrawal from antidepressants, upon impression of site investigator with input from the participant's mental health provider where available * History of active substance abuse or dependence identified through medical chart review or self-report such that, in the opinion of the site investigator, participation poses undue risk for the participant * History of alcohol-related complications within 6 months prior to entry that include but are not restricted to alcohol withdrawal seizures, alcoholic hallucinosis, delirium tremens, or being in an alcohol detoxification program - Treatment with tricyclic antidepressants, selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors (SNRIs), bupropion, or tramadol that, upon judgment of the site investigator, cannot be tapered and discontinued prior to the pre-entry visit * Treatment with an analgesic opioid regimen of more than 60 mg oral morphine equivalent per day within 45 days prior to entry * Cognitive impairment that, in the opinion of the site investigator and based on clinical impression, might impact the ability to comply with the study protocol * Use of an investigational agent within 45 days prior to entry except for expanded-access drugs or drugs used in an ACTG protocol for HIV treatment or for HIV-associated complications, if the drug is not prohibited by this protocol * Acute active AIDS-defining opportunistic infection (OI) within 30 days prior to entry. Participants with no evidence of active disease and receiving maintenance therapy of AIDS-related OIs will be eligible * Serious illness requiring systemic treatment and/or hospitalization within 45 days prior to entry * End-stage renal dialysis requiring hemodialysis * History of known or suspected hepatic cirrhosis diagnosed by signs and symptoms, radiography, or prior liver biopsy with Metavir score of more than 2 * Prolonged QTc interval (more than 0.45 seconds) within 90 days prior to entry * Felt to be at high risk of opioid-induced respiratory compromise. More information on this criterion can be found in the study protocol. * Diagnosis of a new seizure disorder or seizure within 90 days prior to entry * History of acute angle-closure glaucoma, at the discretion of the site investigator * Known allergy/sensitivity or any hypersensitivity to duloxetine, methadone, acetaminophen, or their ingredients * Breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Weekly Mean Pain Score Derived From Self-reported Average Daily Pain Intensity on an 11-point Likert Scale | During the fourth treatment week of each treatment period | Pain was measured on an 11-point Likert numerical rating scale, ranging from 0=''No pain to 10=''Pain as bad as you can imagine. Participants were given pain diaries at weeks 0, 5, 10, and 15. They started the diary 7 days prior to their clinic visits at weeks 0, 4, 9, 14, and 19. During the 7 days, each morning, they recorded their pain level due to neuropathy by circling the number that best described their neuropathy pain on average over the past 24 hours. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With 30% or More Improvement in Mean Pain Score on an 11-point Likert Scale | At Baseline and over the fourth treatment week of each treatment period | Pain was measured on an 11-point Likert numerical rating scale, ranging from 0=''No pain to 10=''Pain as bad as you can imagine at baseline and over the fourth treatment week of each treatment period. The % of improvement was calculated as (x-y)/x,where x was the MPI score at baseline, and y was the MPI score at the end of each treatment stage. |
| Number of Participants With 50% or More Improvement in Mean Pain Score on an 11-point Likert Scale | At Baseline and over the fourth treatment week of each treatment period | Pain was measured on an 11-point Likert numerical rating scale, ranging from 0=''No pain to 10=''Pain as bad as you can imagine at baseline and over the fourth treatment week of each treatment period. The % of improvement was calculated as (x-y)/x,where x was the MPI score at baseline, and y was the MPI score at the end of each treatment stage. |
| Mean Nighttime Pain Measure on an 11-point Likert Scale | Over the fourth treatment week of each treatment period | Pain was measured on an 11-point Likert numerical rating scale, ranging from 0=''No pain to 10=''Pain as bad as you can imagine. Participants were given pain diaries at weeks 0, 5, 10, and 15. They started the diary 7 days prior to their clinic visits at weeks 0, 4, 9, 14, and 19. During the 7 days, each morning, they recorded their pain level due to neuropathy by circling the number that best described their neuropathy pain on average during the night time. |
| Pain-related Interference Measured by the Brief Pain Inventory (BPI) Interference Items | At the fourth week of each treatment period | The BPI interference scale measured level of interference with the following seven items: 1. General activity 2. Mood 3. Walking ability 4. Normal work 5. Relations with other people 6. Sleep 7. Enjoyment of life Interference scales range from 0='Does not interfere' to 10='Completely interferes'. The overall BPI score is the mean of seven item with the minimum and maximal scores of 0 and 70, respectively. |
| Quality of Life Measured by SF-36 Healthy Survey (SF-36) | At the fourth treatment week of each treatment period | The data for this outcome are not available for the analysis due to an issue with a company which provides software to calculate SF-36. |
| Maximum Tolerated Dose of Duloxetine and Methadone | During each treatment period | — |
| Number of Participants With Treatment-emergent Grade 2 to 4 Adverse Events | From study entry to end of study at week 20 or premature study discontinuation | The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 was used (see the link to the grading table in Protocol Section) |
| Emotional Functioning as Measured by the Center for Epidemiologic Studies Depression Scale (CES-D) | At the fourth treatment week of each treatment period | The CES-D is a 20-item self-report rating inventory measuring characteristic attitudes and symptoms of depression. Participants were asked to score each item: (0) Rarely, (1) Occasionally, (2) Sometimes, and (3) Most of time. Some items are multiplied by -1 to change direction. The overall CES-D score is simply the sum of 20 items. The highest possible total CES-D score is 48, and the lowest possible score is -12. The total CES-D score is considered missing if more than 4 items are not answered. |
| Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | At the fourth treatment week of each treatment period | The GIC scale is a validated instrument that consists of seven verbal descriptors on a 7-point scale: 1. Very much improved 2. Much improved 3. Minimally improved 4. No change 5. Minimally worse 6. Much worse 7. Very much worse Participants were carefully instructed to consider the impact of study treatments on their level of neuropathic pain intensity during the baseline phase of the study. |
| Use of Rescue Medication (Acetaminophen) | During each treatment period and the subsequent cross-over (or final study week) period | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Sensory and Affective Qualities of Pain Measured by the McGill Pain Questionnaire - Short Form (MPQ-SF) | At the fourth treatment week of each treatment period | This was one of the exploratory objectives and was not analyzed as the study was terminated. We do not have any plan to analyze this endpoint in the future. |
| Methadone Trough Level and Weekly Mean Pain Scores | During the fourth week of each treatment period | This was one of the exploratory objectives and was not analyzed as the study was terminated. We do not have any plan to analyze this endpoint. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited across 8 of 15 study sites in the AIDS Clinical Trials Group system between August 2009 and October 2010. The sites were: Harbor-UCLA Medical Center, Harvard MGH, Houston AIDS Research Team, Metrohealth Medical Center in Cleveland, Northwestern University, UC San Diego Medical Center, Washington Univ., Univ. of Colorado.
Participants by arm
| Arm | Count |
|---|---|
| D + MTD-P, Then D-P + MTD, Then D+MTD, Then D-P + MTD-P Participants will receive treatment in the following order: (Period 1, Weeks 1 to 4) duloxetine(D) and methadone placebo (MTD-P), (Period 2, Weeks 6 to 9) duloxetine placebo(D-P) and methadone(MTD), (Period 3, Weeks 11 to 14) duloxetine(D) and methadone(MTD), (Period 4, Weeks 16 to 19) duloxetine placebo(D-P) and methadone placebo(MTD-P)
Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6,and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6. Each treatment period lasted four weeks and was followed by a 1-week combined taper and washout. Flexible dosing allowed participants to receive either the target ceiling dose or the maximum tolerated dose of study treatments. | 4 |
| D-P + MTD, Then D-P + MTD-P, Then D + MTD-P, Then D + MTD Participants will receive treatment in the following order: (Period 1, Weeks 1 to 4) duloxetine placebo and methadone, (Period 2,Weeks6 to9)duloxetine placebo and methadone placebo, (Period 3, Weeks 11 to 14)duloxetine and methadone placebo, (Period 4, Weeks 16 to 19) duloxetine and methadone
Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6. Each treatment period lasted four weeks and was followed by a 1-week combined taper and washout. Flexible dosing allowed participants to receive either the target ceiling dose or the maximum tolerated dose of study treatments. | 4 |
| D + MTD, Then D + MTD-P, Then D-P + MTD-P, Then D-P + MTD Participants will receive treatment in the following order: (Period 1, Weeks 1 to 4) duloxetine and methadone, (Period 2, Weeks 6 to 9) duloxetine and methadone placebo, (Period 3, Weeks 11 to 14) duloxetine placebo and methadone placebo, (Period 4, Weeks 16 to 19) duloxetine placebo and methadone
Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6, and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6. Each treatment period lasted four weeks and was followed by a 1-week combined taper and washout. Flexible dosing allowed participants to receive either the target ceiling dose or the maximum tolerated dose of study treatments. | 3 |
| D-P + MTD-P, Then D + MTD, Then D-P + MTD, Then D + MTD-P Participants will receive treatment in the following order: (Period 1, Weeks 1 to 4) duloxetine placebo and methadone placebo, (Period 2, Weeks 6 to 9) duloxetine and methadone, (Period 3, Weeks 11 to 14) duloxetine placebo and methadone, (Period 4, Weeks 16 to 19) duloxetine and methadone placebo
Methadone and matching placebo were initiated at 5mg twice daily (BID), titrated to 5mg three times daily (TID) on Day 6,and thereafter titrated to target dose of 10mg TID by Day 11. Duloxetine and matching placebo were initiated at 30mg daily for 5 days and thereafter titrated to a target dose of 60mg daily at Day 6. Each treatment period lasted four weeks and was followed by a 1-week combined taper and washout. Flexible dosing allowed participants to receive either the target ceiling dose or the maximum tolerated dose of study treatments. | 4 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Milestones Period 1 (Weeks 0-5) | Adverse Event | 1 | 1 | 0 | 1 |
| Milestones Period 1 (Weeks 0-5) | Physician Decision | 0 | 1 | 0 | 0 |
| Period 2 (Weeks 6-10) | Adverse Event | 0 | 1 | 1 | 0 |
| Period 2 (Weeks 6-10) | Physician Decision | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | D + MTD-P, Then D-P + MTD, Then D+MTD, Then D-P + MTD-P | D-P + MTD, Then D-P + MTD-P, Then D + MTD-P, Then D + MTD | D + MTD, Then D + MTD-P, Then D-P + MTD-P, Then D-P + MTD | D-P + MTD-P, Then D + MTD, Then D-P + MTD, Then D + MTD-P | Total |
|---|---|---|---|---|---|
| Age, Customized 20-29 | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Age, Customized 30-39 | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Age, Customized 40-49 | 0 participants | 0 participants | 1 participants | 1 participants | 2 participants |
| Age, Customized 50-59 | 3 participants | 2 participants | 1 participants | 2 participants | 8 participants |
| Age, Customized >= 60 | 1 participants | 1 participants | 1 participants | 0 participants | 3 participants |
| Baseline Brief Pain Inventory (BPI) Interference Scores | 5.6 Scores on a scale STANDARD_DEVIATION 1.1 | 4.1 Scores on a scale STANDARD_DEVIATION 0.5 | 4.5 Scores on a scale STANDARD_DEVIATION 2.8 | 6.1 Scores on a scale STANDARD_DEVIATION 3.7 | 5.1 Scores on a scale STANDARD_DEVIATION 2.3 |
| Baseline CD4 Counts | 400 cells/µL STANDARD_DEVIATION 278 | 522 cells/µL STANDARD_DEVIATION 328 | 867 cells/µL STANDARD_DEVIATION 162 | 249 cells/µL STANDARD_DEVIATION 173 | 486 cells/µL STANDARD_DEVIATION 315 |
| Baseline CD8 Counts | 970 cells/µL STANDARD_DEVIATION 639 | 490 cells/µL STANDARD_DEVIATION 205 | 1042.33 cells/µL STANDARD_DEVIATION 1110 | 794.75 cells/µL STANDARD_DEVIATION 534 | 809.73 cells/µL STANDARD_DEVIATION 618 |
| Baseline Center for Epidemiologic Studies Depression (CES-D) Scores | 13 Scores on a scale STANDARD_DEVIATION 10 | 11 Scores on a scale STANDARD_DEVIATION 8 | 9 Scores on a scale STANDARD_DEVIATION 9 | 16 Scores on a scale STANDARD_DEVIATION 22 | 12 Scores on a scale STANDARD_DEVIATION 13 |
| Baseline Daily Mean Pain Intensity (MPI) Scores | 7.8 Scores on a scale STANDARD_DEVIATION 0.5 | 6.5 Scores on a scale STANDARD_DEVIATION 1.3 | 6 Scores on a scale STANDARD_DEVIATION 1 | 7.3 Scores on a scale STANDARD_DEVIATION 2.2 | 6.9 Scores on a scale STANDARD_DEVIATION 1.4 |
| Baseline Log10(HIV RNA Viral Load) in copies/mL <= 1.70 | 2 participants | 3 participants | 3 participants | 2 participants | 10 participants |
| Baseline Log10(HIV RNA Viral Load) in copies/mL =1.71 | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Baseline Log10(HIV RNA Viral Load) in copies/mL =2.19 | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Baseline Log10(HIV RNA Viral Load) in copies/mL =2.34 | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Baseline Log10(HIV RNA Viral Load) in copies/mL =4.61 | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Baseline Log10(HIV RNA Viral Load) in copies/mL =5.90 | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Baseline Night Time Mean Pain Intensity (MPI) Scores | 7.3 Scores on a scale STANDARD_DEVIATION 1 | 6.8 Scores on a scale STANDARD_DEVIATION 1 | 7.3 Scores on a scale STANDARD_DEVIATION 1.2 | 8 Scores on a scale STANDARD_DEVIATION 1.4 | 7.3 Scores on a scale STANDARD_DEVIATION 1.1 |
| Race/Ethnicity, Customized Black/African American | 2 participants | 1 participants | 1 participants | 1 participants | 5 participants |
| Race/Ethnicity, Customized Hispanic/Latino | 1 participants | 0 participants | 1 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized White/Caucasian | 1 participants | 3 participants | 1 participants | 2 participants | 7 participants |
| Region of Enrollment United States | 4 participants | 4 participants | 3 participants | 4 participants | 15 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 1 Participants | 4 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 11 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 5 / 10 | 4 / 11 | 6 / 10 | 5 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 11 | 0 / 10 | 0 / 10 |
Outcome results
Primary
Weekly Mean Pain Score Derived From Self-reported Average Daily Pain Intensity on an 11-point Likert Scale
Pain was measured on an 11-point Likert numerical rating scale, ranging from 0=''No pain to 10=''Pain as bad as you can imagine. Participants were given pain diaries at weeks 0, 5, 10, and 15. They started the diary 7 days prior to their clinic visits at weeks 0, 4, 9, 14, and 19. During the 7 days, each morning, they recorded their pain level due to neuropathy by circling the number that best described their neuropathy pain on average over the past 24 hours.
Time frame: During the fourth treatment week of each treatment period
Population: The analysis was per protocol. Since this is a cross-over trial, the number of participants analyzed do not match with the ones in the flow chart.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine and Methadone | Weekly Mean Pain Score Derived From Self-reported Average Daily Pain Intensity on an 11-point Likert Scale | 5.20 Scores on a scale | Standard Deviation 2.44 |
| Duloxetine and Methadone Placebo | Weekly Mean Pain Score Derived From Self-reported Average Daily Pain Intensity on an 11-point Likert Scale | 5.91 Scores on a scale | Standard Deviation 2.47 |
| Duloxetine Placebo and Methadone | Weekly Mean Pain Score Derived From Self-reported Average Daily Pain Intensity on an 11-point Likert Scale | 6.20 Scores on a scale | Standard Deviation 2.35 |
| Duloxetine Placebo and Methadone Placebo | Weekly Mean Pain Score Derived From Self-reported Average Daily Pain Intensity on an 11-point Likert Scale | 5.70 Scores on a scale | Standard Deviation 2.16 |
Secondary
Emotional Functioning as Measured by the Center for Epidemiologic Studies Depression Scale (CES-D)
The CES-D is a 20-item self-report rating inventory measuring characteristic attitudes and symptoms of depression. Participants were asked to score each item: (0) Rarely, (1) Occasionally, (2) Sometimes, and (3) Most of time. Some items are multiplied by -1 to change direction. The overall CES-D score is simply the sum of 20 items. The highest possible total CES-D score is 48, and the lowest possible score is -12. The total CES-D score is considered missing if more than 4 items are not answered.
Time frame: At the fourth treatment week of each treatment period
Population: The analysis was per protocol. Since this is a cross-over trial, the number of participants analyzed do not match with the ones in the flow chart.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine and Methadone | Emotional Functioning as Measured by the Center for Epidemiologic Studies Depression Scale (CES-D) | 13.8 Scores on a scale | Standard Deviation 10.9 |
| Duloxetine and Methadone Placebo | Emotional Functioning as Measured by the Center for Epidemiologic Studies Depression Scale (CES-D) | 13.8 Scores on a scale | Standard Deviation 14.5 |
| Duloxetine Placebo and Methadone | Emotional Functioning as Measured by the Center for Epidemiologic Studies Depression Scale (CES-D) | 13.3 Scores on a scale | Standard Deviation 10.8 |
| Duloxetine Placebo and Methadone Placebo | Emotional Functioning as Measured by the Center for Epidemiologic Studies Depression Scale (CES-D) | 13.3 Scores on a scale | Standard Deviation 13.2 |
Secondary
Maximum Tolerated Dose of Duloxetine and Methadone
Time frame: During each treatment period
Population: The number below is the highest tolerated daily dose in mg based on n=12 for Methadone and n=10 for Duloxetine.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Duloxetine and Methadone | Maximum Tolerated Dose of Duloxetine and Methadone | 30 mg |
| Duloxetine and Methadone Placebo | Maximum Tolerated Dose of Duloxetine and Methadone | 60 mg |
Secondary
Mean Nighttime Pain Measure on an 11-point Likert Scale
Pain was measured on an 11-point Likert numerical rating scale, ranging from 0=''No pain to 10=''Pain as bad as you can imagine. Participants were given pain diaries at weeks 0, 5, 10, and 15. They started the diary 7 days prior to their clinic visits at weeks 0, 4, 9, 14, and 19. During the 7 days, each morning, they recorded their pain level due to neuropathy by circling the number that best described their neuropathy pain on average during the night time.
Time frame: Over the fourth treatment week of each treatment period
Population: The analysis was per protocol. Since this is a cross-over trial, the number of participants analyzed do not match with the ones in the flow chart.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine and Methadone | Mean Nighttime Pain Measure on an 11-point Likert Scale | 5.20 Scores on a scale | Standard Error 2.35 |
| Duloxetine and Methadone Placebo | Mean Nighttime Pain Measure on an 11-point Likert Scale | 5.82 Scores on a scale | Standard Error 2.27 |
| Duloxetine Placebo and Methadone | Mean Nighttime Pain Measure on an 11-point Likert Scale | 5.90 Scores on a scale | Standard Error 2.33 |
| Duloxetine Placebo and Methadone Placebo | Mean Nighttime Pain Measure on an 11-point Likert Scale | 6.10 Scores on a scale | Standard Error 2.47 |
Secondary
Number of Participants With 30% or More Improvement in Mean Pain Score on an 11-point Likert Scale
Pain was measured on an 11-point Likert numerical rating scale, ranging from 0=''No pain to 10=''Pain as bad as you can imagine at baseline and over the fourth treatment week of each treatment period. The % of improvement was calculated as (x-y)/x,where x was the MPI score at baseline, and y was the MPI score at the end of each treatment stage.
Time frame: At Baseline and over the fourth treatment week of each treatment period
Population: The analysis was per protocol. Since this is a cross-over trial, the number of participants analyzed do not match with the ones in the flow chart.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Duloxetine and Methadone | Number of Participants With 30% or More Improvement in Mean Pain Score on an 11-point Likert Scale | 2 participants |
| Duloxetine and Methadone Placebo | Number of Participants With 30% or More Improvement in Mean Pain Score on an 11-point Likert Scale | 2 participants |
| Duloxetine Placebo and Methadone | Number of Participants With 30% or More Improvement in Mean Pain Score on an 11-point Likert Scale | 2 participants |
| Duloxetine Placebo and Methadone Placebo | Number of Participants With 30% or More Improvement in Mean Pain Score on an 11-point Likert Scale | 2 participants |
Secondary
Number of Participants With 50% or More Improvement in Mean Pain Score on an 11-point Likert Scale
Pain was measured on an 11-point Likert numerical rating scale, ranging from 0=''No pain to 10=''Pain as bad as you can imagine at baseline and over the fourth treatment week of each treatment period. The % of improvement was calculated as (x-y)/x,where x was the MPI score at baseline, and y was the MPI score at the end of each treatment stage.
Time frame: At Baseline and over the fourth treatment week of each treatment period
Population: The analysis was per protocol. Since this is a cross-over trial, the number of participants analyzed do not match with the ones in the flow chart.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Duloxetine and Methadone | Number of Participants With 50% or More Improvement in Mean Pain Score on an 11-point Likert Scale | 2 participants |
| Duloxetine and Methadone Placebo | Number of Participants With 50% or More Improvement in Mean Pain Score on an 11-point Likert Scale | 2 participants |
| Duloxetine Placebo and Methadone | Number of Participants With 50% or More Improvement in Mean Pain Score on an 11-point Likert Scale | 1 participants |
| Duloxetine Placebo and Methadone Placebo | Number of Participants With 50% or More Improvement in Mean Pain Score on an 11-point Likert Scale | 2 participants |
Secondary
Number of Participants With Treatment-emergent Grade 2 to 4 Adverse Events
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 was used (see the link to the grading table in Protocol Section)
Time frame: From study entry to end of study at week 20 or premature study discontinuation
Population: The analysis was per protocol. Since this is a cross-over trial, the number of participants analyzed do not match with the ones in the flow chart.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Duloxetine and Methadone | Number of Participants With Treatment-emergent Grade 2 to 4 Adverse Events | 5 Participants |
| Duloxetine and Methadone Placebo | Number of Participants With Treatment-emergent Grade 2 to 4 Adverse Events | 4 Participants |
| Duloxetine Placebo and Methadone | Number of Participants With Treatment-emergent Grade 2 to 4 Adverse Events | 6 Participants |
| Duloxetine Placebo and Methadone Placebo | Number of Participants With Treatment-emergent Grade 2 to 4 Adverse Events | 5 Participants |
Secondary
Pain-related Interference Measured by the Brief Pain Inventory (BPI) Interference Items
The BPI interference scale measured level of interference with the following seven items: 1. General activity 2. Mood 3. Walking ability 4. Normal work 5. Relations with other people 6. Sleep 7. Enjoyment of life Interference scales range from 0='Does not interfere' to 10='Completely interferes'. The overall BPI score is the mean of seven item with the minimum and maximal scores of 0 and 70, respectively.
Time frame: At the fourth week of each treatment period
Population: The analysis was per protocol. Since this is a cross-over trial, the number of participants analyzed do not match with the ones in the flow chart.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Duloxetine and Methadone | Pain-related Interference Measured by the Brief Pain Inventory (BPI) Interference Items | 3.14 Scores on a scale |
| Duloxetine and Methadone Placebo | Pain-related Interference Measured by the Brief Pain Inventory (BPI) Interference Items | 4.14 Scores on a scale |
| Duloxetine Placebo and Methadone | Pain-related Interference Measured by the Brief Pain Inventory (BPI) Interference Items | 3.64 Scores on a scale |
| Duloxetine Placebo and Methadone Placebo | Pain-related Interference Measured by the Brief Pain Inventory (BPI) Interference Items | 3.14 Scores on a scale |
Secondary
Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale
The GIC scale is a validated instrument that consists of seven verbal descriptors on a 7-point scale: 1. Very much improved 2. Much improved 3. Minimally improved 4. No change 5. Minimally worse 6. Much worse 7. Very much worse Participants were carefully instructed to consider the impact of study treatments on their level of neuropathic pain intensity during the baseline phase of the study.
Time frame: At the fourth treatment week of each treatment period
Population: The analysis was per protocol. Since this is a cross-over trial, the number of participants analyzed do not match with the ones in the flow chart.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Duloxetine and Methadone | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | CGIC - No change | 4 participants |
| Duloxetine and Methadone | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | PGIC - Very much improved | 1 participants |
| Duloxetine and Methadone | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | PGIC - Much worse | 0 participants |
| Duloxetine and Methadone | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | CGIC - Minimally improved | 1 participants |
| Duloxetine and Methadone | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | PGIC - No change | 3 participants |
| Duloxetine and Methadone | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | CGIC - Much worse | 0 participants |
| Duloxetine and Methadone | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | PGIC - Minimally improved | 2 participants |
| Duloxetine and Methadone | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | CGIC - Much improved | 4 participants |
| Duloxetine and Methadone | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | CGIC - Very much improved | 1 participants |
| Duloxetine and Methadone | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | PGIC - Much improved | 4 participants |
| Duloxetine and Methadone Placebo | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | PGIC - Much worse | 0 participants |
| Duloxetine and Methadone Placebo | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | PGIC - No change | 6 participants |
| Duloxetine and Methadone Placebo | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | PGIC - Very much improved | 0 participants |
| Duloxetine and Methadone Placebo | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | PGIC - Much improved | 1 participants |
| Duloxetine and Methadone Placebo | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | PGIC - Minimally improved | 4 participants |
| Duloxetine and Methadone Placebo | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | CGIC - Very much improved | 1 participants |
| Duloxetine and Methadone Placebo | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | CGIC - Much improved | 1 participants |
| Duloxetine and Methadone Placebo | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | CGIC - Minimally improved | 1 participants |
| Duloxetine and Methadone Placebo | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | CGIC - No change | 8 participants |
| Duloxetine and Methadone Placebo | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | CGIC - Much worse | 0 participants |
| Duloxetine Placebo and Methadone | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | PGIC - Very much improved | 1 participants |
| Duloxetine Placebo and Methadone | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | CGIC - Minimally improved | 3 participants |
| Duloxetine Placebo and Methadone | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | CGIC - Very much improved | 1 participants |
| Duloxetine Placebo and Methadone | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | PGIC - Much worse | 1 participants |
| Duloxetine Placebo and Methadone | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | CGIC - Much worse | 0 participants |
| Duloxetine Placebo and Methadone | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | CGIC - Much improved | 3 participants |
| Duloxetine Placebo and Methadone | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | PGIC - Minimally improved | 4 participants |
| Duloxetine Placebo and Methadone | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | PGIC - No change | 2 participants |
| Duloxetine Placebo and Methadone | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | CGIC - No change | 3 participants |
| Duloxetine Placebo and Methadone | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | PGIC - Much improved | 2 participants |
| Duloxetine Placebo and Methadone Placebo | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | PGIC - Much improved | 1 participants |
| Duloxetine Placebo and Methadone Placebo | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | PGIC - Much worse | 0 participants |
| Duloxetine Placebo and Methadone Placebo | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | PGIC - Very much improved | 1 participants |
| Duloxetine Placebo and Methadone Placebo | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | CGIC - Very much improved | 1 participants |
| Duloxetine Placebo and Methadone Placebo | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | CGIC - No change | 4 participants |
| Duloxetine Placebo and Methadone Placebo | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | CGIC - Much improved | 1 participants |
| Duloxetine Placebo and Methadone Placebo | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | CGIC - Much worse | 1 participants |
| Duloxetine Placebo and Methadone Placebo | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | CGIC - Minimally improved | 3 participants |
| Duloxetine Placebo and Methadone Placebo | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | PGIC - Minimally improved | 4 participants |
| Duloxetine Placebo and Methadone Placebo | Patient and Clinician Global Impression of Change (PGIC and CGIC) on a 7-point Likert Scale | PGIC - No change | 4 participants |
Secondary
Quality of Life Measured by SF-36 Healthy Survey (SF-36)
The data for this outcome are not available for the analysis due to an issue with a company which provides software to calculate SF-36.
Time frame: At the fourth treatment week of each treatment period
Secondary
Use of Rescue Medication (Acetaminophen)
Time frame: During each treatment period and the subsequent cross-over (or final study week) period
Population: The analysis was per protocol. Because of a cross-over trial, the # of participants analyzed do not match with the flow chart. Any participant who took the rescue med during the study period (incl. cross-over period) was counted in this analysis. If a participant took the rescue med twice within the same period, the number is counted as one.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Duloxetine and Methadone | Use of Rescue Medication (Acetaminophen) | Treatment period (1-4, 6-9, 11-14, 16-19 weeks) | 0 participants |
| Duloxetine and Methadone | Use of Rescue Medication (Acetaminophen) | Cross-over period (5, 10, 15, 20 weeks) | 1 participants |
| Duloxetine and Methadone Placebo | Use of Rescue Medication (Acetaminophen) | Cross-over period (5, 10, 15, 20 weeks) | 0 participants |
| Duloxetine and Methadone Placebo | Use of Rescue Medication (Acetaminophen) | Treatment period (1-4, 6-9, 11-14, 16-19 weeks) | 0 participants |
| Duloxetine Placebo and Methadone | Use of Rescue Medication (Acetaminophen) | Cross-over period (5, 10, 15, 20 weeks) | 1 participants |
| Duloxetine Placebo and Methadone | Use of Rescue Medication (Acetaminophen) | Treatment period (1-4, 6-9, 11-14, 16-19 weeks) | 0 participants |
| Duloxetine Placebo and Methadone Placebo | Use of Rescue Medication (Acetaminophen) | Treatment period (1-4, 6-9, 11-14, 16-19 weeks) | 2 participants |
| Duloxetine Placebo and Methadone Placebo | Use of Rescue Medication (Acetaminophen) | Cross-over period (5, 10, 15, 20 weeks) | 1 participants |
Other Pre-specified
Methadone Trough Level and Weekly Mean Pain Scores
This was one of the exploratory objectives and was not analyzed as the study was terminated. We do not have any plan to analyze this endpoint.
Time frame: During the fourth week of each treatment period
Population: This was one of the exploratory objectives and was not analyzed as the study was terminated.
Other Pre-specified
Sensory and Affective Qualities of Pain Measured by the McGill Pain Questionnaire - Short Form (MPQ-SF)
This was one of the exploratory objectives and was not analyzed as the study was terminated. We do not have any plan to analyze this endpoint in the future.
Time frame: At the fourth treatment week of each treatment period
Population: This was one of the exploratory objectives and was not analyzed as the study was terminated.