Peripheral Neuropathy, Neuropathic Pain
Conditions
Keywords
Diabetic Peripheral Neuropathy, Neuropathic Pain
Brief summary
The purpose of this study is to evaluate the effectiveness of ADL5859 in relieving the pain associated with diabetic peripheral neuropathy (DPN) compared with placebo and duloxetine (a marketed drug approved for the treatment of painful DPN). The pain symptoms of DPN are thought to be due to damage to nerves caused by the diabetes.
Detailed description
Participants were permitted to take acetaminophen 650 to 975 mg every 4 to 6 hours (up to a total of 4 grams in 24 hours) as needed for pain relief.
Interventions
Sponsors
Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Male and female participants between 18 and 75 years of age, inclusive * Body weight of at least 45 kilograms (kg) * Diabetes mellitus (type I or II) that is documented to be under stable glycemic control over a period of at least 3 months, as indicated by a glycosylated hemoglobin (HbgAIC) of less than or equal to 12% and a stable dose of insulin or oral diabetic medication for 90 days prior to starting study medication * No change in diabetic medications is planned for the duration of the study * Evidence of symmetrical, bilateral pain in the lower extremities due to diabetic peripheral neuropathy (DPN) * Presence of daily pain due to DPN for at least 3 months * Score greater than or equal to 3 on the physical examination portion of the Michigan Neuropathy Screening Instrument (MNSI) * Average weekly pain score of greater than or equal to 4 on the numeric pain rating scale (NPRS) for symmetrical neuropathic pain in the feet and legs * For male participants, be surgically sterile or agree to use an appropriate method of contraception * For female participants of childbearing potential, be surgically sterile or using an intrauterine device, or injectable, transdermal, or combination oral contraceptive deemed highly effective by the Food and Drug Administration (FDA) * Be willing and able to comply with the protocol requirements * Be able to understand and willing to provide written informed consent in English
Exclusion criteria
* Presence of pain conditions that cannot be distinguished from DPN * Presence of significant renal disease, as indicated by a serum creatinine greater than or equal to 2.0 milligrams per deciliter (mg/dL), or presence of significant hepatic disease * Have a history of a seizure disorder * Presence of serious or unstable cardiovascular disease, respiratory disease, hematologic illness, or a psychiatric condition * History of evidence of symptomatic orthostatic hypotension * History of a major depressive disorder, generalized anxiety disorder, eating disorder, or substance abuse (including alcohol) within the past year * History or evidence of mania, bipolar disorder, or psychosis * History of allergy to acetaminophen or duloxetine * Score of greater than or equal to 18 on the Beck Depression Inventory II (BDI-II) or score of greater than zero on Item 9 of the BDI-II * Use of any of the following concomitant medications: fluvoxamine; quinolone antimicrobials (ciprofloxacin and enoxacin); selective serotonin reuptake inhibitors (SSRIs); serotonin norepinephrine reuptake inhibitors (SNRIs); tricyclic antidepressants; opioids; nonsteroidal anti-inflammatory drugs (NSAIDS); anticonvulsants; aspirin (with the exception of low-dose aspirin as cardiovascular prophylaxis); or cytochrome P4503A (CYP3A) and P-glycoprotein transporter inhibitors * Pregnant, lactating, or plans to become pregnant during the study * Presence of foot or toe amputation * Participation in another study with an investigational compound within the previous 30 days prior to study medication administration, or concurrent participation in another clinical study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Numeric Pain Rating Scale (NPRS) Score | Baseline, Week 4 | The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. The mean of the daily average scores were calculated from the NPRS pain assessments obtained up to 3 times per day over a 7-day period. Least Squares (LS) means were calculated using analysis of covariance (ANCOVA) with treatment group as a main factor and baseline NPRS score as a covariate. Change from Baseline = NPRS at baseline - NPRS at Week 4; a positive number in the LS mean indicates a reduction in pain intensity from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Responders | Baseline, Week 4 | A responder was defined as a participant who showed a reduction in average pain (as measured by NPRS) of at least 30% from baseline to Week 4. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. The percentage of participants who qualified as responders is presented per treatment arm. |
| Patient Global Impression of Change (PGIC) | Week 4 | PGIC is a participant-rated instrument that measures the change in the participant's overall status for the previous 2 weeks based on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). The number of participants in each category is presented. |
| Change in Sleep Interference Scale (SIS) From Baseline | Baseline, Week 4 | Sleep Interference was assessed on an 11-point Numeric Rating Scale where a score of 0 indicated pain did not interfere with sleep and a score of 10 indicated pain completely interfered with sleep. Here, n signifies Number of participants for Baseline and Month 3 telephone interview whereas n signifies number of observations for Month 1, 2, and 3 because a participant could have had multiple visits during Month 1, 2, and 3 as this was a non-interventional study with no scheduled study visits, except Baseline visit and the Month 3 telephone interview. LS means were calculated using ANCOVA with treatment group as a main factor and baseline SIS score as a covariate. Change from baseline = SIS score at baseline - SIS score at Week 4. |
| Change From Baseline in the Evening Assessment of the 24-hour Overall Mean Pain Intensity Score | Baseline, Week 4 | At each of the evening pain assessments, participants assessed their overall pain intensity over the preceding 24 hours using NPRS. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. The mean of the daily average scores were calculated from the NPRS pain assessments obtained at Baseline and Week 4. Change from baseline = NPRS at baseline - NPRS at Week 4. |
| Change From Baseline in NPRS at Rest in the Clinic | Baseline, Week 1, Week 2, Week 3, Week 4 | The mean of the daily average scores were calculated from the NPRS pain assessments obtained 1 time per week over a 4-week period. NPRS assessments were taken while the participant was at rest. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. LS means were calculated using ANCOVA with treatment group as a main factor and baseline NPRS score as a covariate. Change from baseline = NPRS at baseline - NPRS at Weeks 1, 2, 3, and 4. |
| Change From Baseline in NPRS After Walking 50 Feet in the Clinic | Baseline, Week 1, Week 2, Week 3, Week 4 | The mean of the daily average scores were calculated from the NPRS pain assessments obtained 1 time per week over a 4-week period. NPRS assessments were taken after the participant walked 50 feet in the clinic. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. LS means were calculated using ANCOVA with treatment group as a main factor and baseline NPRS score as a covariate. Change from baseline = NPRS at baseline - NPRS at Weeks 1, 2, 3, and 4. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ADL5859 2 x 50 mg ADL5859 capsules administered orally once in the morning and once in the evening for 28 days | 75 |
| Duloxetine 2 x 30 mg duloxetine capsules administered orally once in the morning and 2 placebo capsules filled with lactose administered orally once in the evening for 28 days | 78 |
| Placebo 2 placebo capsules filled with lactose administered orally once in the morning and once in the evening for 28 days | 72 |
| Total | 225 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 11 | 1 |
| Overall Study | Lack of Efficacy | 3 | 0 | 3 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Out of Town, Ran Out of Study Drug | 0 | 1 | 0 |
| Overall Study | Participant Left Country, No Responses | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 1 |
Baseline characteristics
| Characteristic | ADL5859 | Duloxetine | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 59.7 Years STANDARD_DEVIATION 10.17 | 59.1 Years STANDARD_DEVIATION 8.71 | 56.2 Years STANDARD_DEVIATION 8.78 | 58.3 Years STANDARD_DEVIATION 9.33 |
| Sex: Female, Male Female | 35 Participants | 39 Participants | 27 Participants | 101 Participants |
| Sex: Female, Male Male | 40 Participants | 39 Participants | 45 Participants | 124 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 27 / 75 | 28 / 78 | 27 / 72 |
| serious Total, serious adverse events | 0 / 75 | 1 / 78 | 0 / 72 |
Outcome results
Primary
Change From Baseline in Mean Numeric Pain Rating Scale (NPRS) Score
The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. The mean of the daily average scores were calculated from the NPRS pain assessments obtained up to 3 times per day over a 7-day period. Least Squares (LS) means were calculated using analysis of covariance (ANCOVA) with treatment group as a main factor and baseline NPRS score as a covariate. Change from Baseline = NPRS at baseline - NPRS at Week 4; a positive number in the LS mean indicates a reduction in pain intensity from baseline.
Time frame: Baseline, Week 4
Population: All participants who received at least 1 dose of study medication and had evaluable NPRS data. Baseline-observation-carried-forward (BOCF) was used to impute missing postbaseline values for participants who were discontinued from the study early.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ADL5859 | Change From Baseline in Mean Numeric Pain Rating Scale (NPRS) Score | 1.02 units on a scale | Standard Error 0.225 |
| Duloxetine | Change From Baseline in Mean Numeric Pain Rating Scale (NPRS) Score | 1.74 units on a scale | Standard Error 0.221 |
| Placebo | Change From Baseline in Mean Numeric Pain Rating Scale (NPRS) Score | 1.51 units on a scale | Standard Error 0.229 |
Secondary
Change From Baseline in NPRS After Walking 50 Feet in the Clinic
The mean of the daily average scores were calculated from the NPRS pain assessments obtained 1 time per week over a 4-week period. NPRS assessments were taken after the participant walked 50 feet in the clinic. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. LS means were calculated using ANCOVA with treatment group as a main factor and baseline NPRS score as a covariate. Change from baseline = NPRS at baseline - NPRS at Weeks 1, 2, 3, and 4.
Time frame: Baseline, Week 1, Week 2, Week 3, Week 4
Population: All participants who received at least 1 dose of study medication, completed the 4-week treatment period, and had evaluable post-walk NPRS data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| ADL5859 | Change From Baseline in NPRS After Walking 50 Feet in the Clinic | Week 1 (n=67, 59, 64) | 0.88 units on a scale | Standard Error 0.215 |
| ADL5859 | Change From Baseline in NPRS After Walking 50 Feet in the Clinic | Week 2 (n=67, 61, 65) | 0.93 units on a scale | Standard Error 0.254 |
| ADL5859 | Change From Baseline in NPRS After Walking 50 Feet in the Clinic | Week 3 (n=67, 61, 63) | 1.24 units on a scale | Standard Error 0.281 |
| ADL5859 | Change From Baseline in NPRS After Walking 50 Feet in the Clinic | Week 4 (n=68, 61, 65) | 1.29 units on a scale | Standard Error 0.273 |
| Duloxetine | Change From Baseline in NPRS After Walking 50 Feet in the Clinic | Week 4 (n=68, 61, 65) | 2.36 units on a scale | Standard Error 0.288 |
| Duloxetine | Change From Baseline in NPRS After Walking 50 Feet in the Clinic | Week 1 (n=67, 59, 64) | 1.42 units on a scale | Standard Error 0.229 |
| Duloxetine | Change From Baseline in NPRS After Walking 50 Feet in the Clinic | Week 3 (n=67, 61, 63) | 2.25 units on a scale | Standard Error 0.294 |
| Duloxetine | Change From Baseline in NPRS After Walking 50 Feet in the Clinic | Week 2 (n=67, 61, 65) | 1.75 units on a scale | Standard Error 0.267 |
| Placebo | Change From Baseline in NPRS After Walking 50 Feet in the Clinic | Week 4 (n=68, 61, 65) | 1.79 units on a scale | Standard Error 0.279 |
| Placebo | Change From Baseline in NPRS After Walking 50 Feet in the Clinic | Week 2 (n=67, 61, 65) | 1.23 units on a scale | Standard Error 0.259 |
| Placebo | Change From Baseline in NPRS After Walking 50 Feet in the Clinic | Week 3 (n=67, 61, 63) | 1.43 units on a scale | Standard Error 0.29 |
| Placebo | Change From Baseline in NPRS After Walking 50 Feet in the Clinic | Week 1 (n=67, 59, 64) | 1.00 units on a scale | Standard Error 0.22 |
Secondary
Change From Baseline in NPRS at Rest in the Clinic
The mean of the daily average scores were calculated from the NPRS pain assessments obtained 1 time per week over a 4-week period. NPRS assessments were taken while the participant was at rest. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. LS means were calculated using ANCOVA with treatment group as a main factor and baseline NPRS score as a covariate. Change from baseline = NPRS at baseline - NPRS at Weeks 1, 2, 3, and 4.
Time frame: Baseline, Week 1, Week 2, Week 3, Week 4
Population: All participants who received at least 1 dose of study medication, completed the 4-week treatment period, and had evaluable at-rest NPRS data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| ADL5859 | Change From Baseline in NPRS at Rest in the Clinic | Week 1 (n=67, 59, 64) | 0.70 units on a scale | Standard Error 0.2 |
| ADL5859 | Change From Baseline in NPRS at Rest in the Clinic | Week 2 (n=68, 61, 65) | 0.80 units on a scale | Standard Error 0.237 |
| ADL5859 | Change From Baseline in NPRS at Rest in the Clinic | Week 3 (n=67, 61, 63) | 0.92 units on a scale | Standard Error 0.265 |
| ADL5859 | Change From Baseline in NPRS at Rest in the Clinic | Week 4 (n=68, 61, 65) | 1.13 units on a scale | Standard Error 0.269 |
| Duloxetine | Change From Baseline in NPRS at Rest in the Clinic | Week 4 (n=68, 61, 65) | 2.03 units on a scale | Standard Error 0.283 |
| Duloxetine | Change From Baseline in NPRS at Rest in the Clinic | Week 1 (n=67, 59, 64) | 1.15 units on a scale | Standard Error 0.213 |
| Duloxetine | Change From Baseline in NPRS at Rest in the Clinic | Week 3 (n=67, 61, 63) | 1.95 units on a scale | Standard Error 0.277 |
| Duloxetine | Change From Baseline in NPRS at Rest in the Clinic | Week 2 (n=68, 61, 65) | 1.44 units on a scale | Standard Error 0.25 |
| Placebo | Change From Baseline in NPRS at Rest in the Clinic | Week 4 (n=68, 61, 65) | 1.59 units on a scale | Standard Error 0.276 |
| Placebo | Change From Baseline in NPRS at Rest in the Clinic | Week 2 (n=68, 61, 65) | 1.16 units on a scale | Standard Error 0.243 |
| Placebo | Change From Baseline in NPRS at Rest in the Clinic | Week 3 (n=67, 61, 63) | 1.27 units on a scale | Standard Error 0.274 |
| Placebo | Change From Baseline in NPRS at Rest in the Clinic | Week 1 (n=67, 59, 64) | 0.75 units on a scale | Standard Error 0.205 |
Secondary
Change From Baseline in the Evening Assessment of the 24-hour Overall Mean Pain Intensity Score
At each of the evening pain assessments, participants assessed their overall pain intensity over the preceding 24 hours using NPRS. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. The mean of the daily average scores were calculated from the NPRS pain assessments obtained at Baseline and Week 4. Change from baseline = NPRS at baseline - NPRS at Week 4.
Time frame: Baseline, Week 4
Population: All participants who received at least 1 dose of study medication and had evaluable 24-hour NPRS data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ADL5859 | Change From Baseline in the Evening Assessment of the 24-hour Overall Mean Pain Intensity Score | 1.09 units on a scale | Standard Deviation 1.847 |
| Duloxetine | Change From Baseline in the Evening Assessment of the 24-hour Overall Mean Pain Intensity Score | 2.15 units on a scale | Standard Deviation 2.322 |
| Placebo | Change From Baseline in the Evening Assessment of the 24-hour Overall Mean Pain Intensity Score | 1.51 units on a scale | Standard Deviation 2.027 |
Secondary
Change in Sleep Interference Scale (SIS) From Baseline
Sleep Interference was assessed on an 11-point Numeric Rating Scale where a score of 0 indicated pain did not interfere with sleep and a score of 10 indicated pain completely interfered with sleep. Here, n signifies Number of participants for Baseline and Month 3 telephone interview whereas n signifies number of observations for Month 1, 2, and 3 because a participant could have had multiple visits during Month 1, 2, and 3 as this was a non-interventional study with no scheduled study visits, except Baseline visit and the Month 3 telephone interview. LS means were calculated using ANCOVA with treatment group as a main factor and baseline SIS score as a covariate. Change from baseline = SIS score at baseline - SIS score at Week 4.
Time frame: Baseline, Week 4
Population: All participants who received at least 1 dose of study medication, completed the 4-week treatment period, and had evaluable SIS data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ADL5859 | Change in Sleep Interference Scale (SIS) From Baseline | 1.92 units on a scale | Standard Error 0.291 |
| Duloxetine | Change in Sleep Interference Scale (SIS) From Baseline | 2.27 units on a scale | Standard Error 0.304 |
| Placebo | Change in Sleep Interference Scale (SIS) From Baseline | 1.56 units on a scale | Standard Error 0.297 |
Secondary
Patient Global Impression of Change (PGIC)
PGIC is a participant-rated instrument that measures the change in the participant's overall status for the previous 2 weeks based on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). The number of participants in each category is presented.
Time frame: Week 4
Population: All participants who received at least 1 dose of study medication, completed the 4-week treatment period, and had evaluable PGIC data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ADL5859 | Patient Global Impression of Change (PGIC) | Minimally Improved | 20 participants |
| ADL5859 | Patient Global Impression of Change (PGIC) | Not Reported | 0 participants |
| ADL5859 | Patient Global Impression of Change (PGIC) | Much Worse | 3 participants |
| ADL5859 | Patient Global Impression of Change (PGIC) | No Change | 19 participants |
| ADL5859 | Patient Global Impression of Change (PGIC) | Minimally Worse | 0 participants |
| ADL5859 | Patient Global Impression of Change (PGIC) | Much Improved | 20 participants |
| ADL5859 | Patient Global Impression of Change (PGIC) | Very Much Improved | 7 participants |
| ADL5859 | Patient Global Impression of Change (PGIC) | Very Much Worse | 0 participants |
| Duloxetine | Patient Global Impression of Change (PGIC) | No Change | 14 participants |
| Duloxetine | Patient Global Impression of Change (PGIC) | Minimally Worse | 2 participants |
| Duloxetine | Patient Global Impression of Change (PGIC) | Very Much Improved | 11 participants |
| Duloxetine | Patient Global Impression of Change (PGIC) | Much Improved | 15 participants |
| Duloxetine | Patient Global Impression of Change (PGIC) | Minimally Improved | 17 participants |
| Duloxetine | Patient Global Impression of Change (PGIC) | Much Worse | 1 participants |
| Duloxetine | Patient Global Impression of Change (PGIC) | Very Much Worse | 1 participants |
| Duloxetine | Patient Global Impression of Change (PGIC) | Not Reported | 2 participants |
| Placebo | Patient Global Impression of Change (PGIC) | Very Much Improved | 11 participants |
| Placebo | Patient Global Impression of Change (PGIC) | Much Worse | 1 participants |
| Placebo | Patient Global Impression of Change (PGIC) | Much Improved | 11 participants |
| Placebo | Patient Global Impression of Change (PGIC) | Not Reported | 1 participants |
| Placebo | Patient Global Impression of Change (PGIC) | Very Much Worse | 0 participants |
| Placebo | Patient Global Impression of Change (PGIC) | No Change | 21 participants |
| Placebo | Patient Global Impression of Change (PGIC) | Minimally Worse | 0 participants |
| Placebo | Patient Global Impression of Change (PGIC) | Minimally Improved | 22 participants |
Secondary
Percentage of Responders
A responder was defined as a participant who showed a reduction in average pain (as measured by NPRS) of at least 30% from baseline to Week 4. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. The percentage of participants who qualified as responders is presented per treatment arm.
Time frame: Baseline, Week 4
Population: All participants who received at least 1 dose of study medication, completed the 4-week treatment period, and had evaluable NPRS data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ADL5859 | Percentage of Responders | 26.1 percentage of participants |
| Duloxetine | Percentage of Responders | 52.4 percentage of participants |
| Placebo | Percentage of Responders | 38.8 percentage of participants |