Diabetic Peripheral Neuropathy
Conditions
Brief summary
The main purpose of this study is to determine the safety and efficacy of LY3556050 versus placebo in participants with diabetic peripheral neuropathic pain (DPNP). The study will lasts approximately 24 weeks, across 3 study periods.
Interventions
DRUGMazisotine
Administered orally.
DRUGPlacebo
Administered orally.
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have a history and current diagnosis of Type 1 Diabetes (T1D) or Type 2 Diabetes (T2D) diagnosed for at least 6 months prior to screening. * Have a stable glycemic control on stable diabetes treatment regimen for at least 90 days prior to day 1 with a hemoglobin A1c (HbA1c) ≤10 for T1D and HbA1c ≤11 for participants with T2D at time of screening. * Have a history of daily peripheral neuropathic pain for at least 12 weeks based on participant report or medical history. * Have a visual analog scale (VAS) pain value ≥40 and \<95 during screening. * Have presence of diabetic peripheral neuropathy of symmetrical nature and in lower extremities for ≥6 months and diagnosed by a score of Part B ≥3 on Michigan Neuropathy Screening Instrument * Are willing to maintain a consistent regimen of any ongoing nonpharmacologic pain-relieving therapies (for example, physical therapy) and will not start any new nonpharmacologic pain-relieving therapies during study participation. * Are willing to discontinue all medications taken for chronic pain conditions, except allowed concomitant pain medication permitted per protocol, for the duration of the study * Have a body mass index ≤45 kilogram/square meter (kg/m²) (inclusive). * Are men, or women able to abide by reproductive and contraceptive requirements.
Exclusion criteria
* History of other potentially causative and/or confounding sources of pain that may impair self-assessment of pain due to DPNP. * Have had a procedure within the past 6 months intended to produce permanent sensory loss in the target area of interest (for example, ablation techniques. * Have had cancer within 2 years of baseline, except for cutaneous basal cell or squamous cell carcinoma resolved by excision. * Are, in the judgment of the investigator, actively suicidal and therefore deemed to be at significant risk for suicide. * Have in the judgement of the investigator, an acute, serious, or unstable medical condition or a history or presence of any other medical illness that would preclude study participation. * Have a positive HIV test result at screening. * Have a surgery planned during the study for any reason. * Have a substance use disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders (5th edition; DSM-5; American Psychiatric Association)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Average Pain Intensity (API) as Measured by Weekly Average of Numeric Rating Scale (NRS) - Bayesian Model Averaging (BMA) Dose-response Model | Baseline, Week 12 | * The NRS was a single-item numeric scale used to describe pain severity. Participants were asked to rate their average pain over the past 24 hours, on a scale of 0 to 10: 0 = no pain, and 10 = pain as bad as you can imagine; a higher score indicates worse outcome (greater pain severity). * The mixed-model repeated measures (MMRM) model included the fixed, centered, categorical effects of region, baseline NRS average pain score, as well as concurrent use of allowed concomitant medications (yes vs. no based on interactive web response system \[IWRS\]), and visit. The adjusted dose response value from the MMRM was used for fitting a Bayesian model averaging (BMA) dose-response model. * Posterior mean change from baseline, 95 percent (%) credible interval was derived using Bayesian mixed model repeated measures. Data presented were posterior mean with 95% credible interval. |
| Mean Change From Baseline in Average Pain Intensity (API) as Measured by Weekly Average of Numeric Rating Scale (NRS) - Frequentist Repeated Measures (FRM) Analysis | Baseline, Week 12 | * The NRS was a single-item numeric scale used to describe pain severity. Participants were asked to rate their average pain over the past 24 hours, on a scale of 0 to 10: 0 = no pain, and 10 = pain as bad as you can imagine; a higher score indicates worse outcome (greater pain severity). * The Least Squares (LS) Mean was calculated using a frequentist repeated measures (FRM) analysis, where Change = treatment, time interval, treatment \* time interval, region, average baseline pain severity category (mild or moderate versus \[vs.\] severe), concurrent use of allowed concomitant medication as entered in IWRS (yes versus no). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Worst Pain Intensity (WPI) as Measured by Weekly Average of Numeric Rating Scale (NRS) | Baseline, Week 12 | * The NRS was a single-item numeric scale used to describe pain severity. Participants were asked to rate their worst pain intensity over the past 24 hours, on a scale of 0 to 10: 0 = no pain, and 10 = pain as bad as you can imagine; a higher score indicates worse outcome (greater pain severity). * The LS Mean was calculated using an FRM analysis, where Change = treatment, time interval, treatment \* time interval, region, average baseline pain severity category (mild or moderate versus severe), concurrent use of allowed concomitant medication (yes versus no based on IWRS). |
| Mean Change From Baseline in Patient-Reported Outcomes Measurement Information System Pain Interference Short Form 8a (PROMIS PI SF8a) | Baseline, Week 12 | The Patient-Reported Outcomes Measurement Information System Pain Interference Short Form 8a (PROMIS PI SF8a) was administered to measure self-reported consequences of pain on various aspects of the participant's life within the previous 7 days. The scale consists of 8 items, all measuring a single domain of pain interference, including impact on day-to-day activities, work around the home, household chores, family life, social activities, activities done for fun, enjoyment of social activities, and enjoyment of life. Each item was rated on a 5-point response scale ranging from "not at all" (1) to "very much" (5); the 8 item scores were summed to produce a raw score ranging from 8 (minimum) to 40 (maximum). The raw score was then converted to a T-score with a mean of 50 and a standard deviation of 10; higher T-scores indicate worse outcome (greater pain interference). Range cannot be specified in norm-based scores. |
| Mean Change From Baseline in Pain Interference With Sleep | Baseline, Week 12 | * Pain Interference with Sleep was assessed using a single-item measure: "To what extent did diabetic nerve pain interfere with your sleep last night?" Participants responded on a scale from 0 (minimum, "Not at all") to 4 (maximum, "Unable to sleep at all"); higher scores indicate worse outcome (greater sleep interference due to pain). * LS Mean was calculated using an FRM analysis, where Change = treatment, time interval, treatment \* time interval, region, average baseline pain severity category (mild or moderate vs. severe), concurrent use of concomitant medication (yes vs. no based on IWRS). |
| Mean Change From Baseline in Patient-Reported Outcomes Measurement Information System Physical Functioning Short Form 10a (PROMIS PF SF10a) | Baseline, Week 12 | The PROMIS PF SF10a was administered to assess self-reported physical function and physical activities across 10 items at the present time.The first 5 items assess current physical limitations (health in doing vigorous activities, walking more than one mile, climbing stairs, lifting or carrying groceries, and bending, kneeling, or stooping), each rated on a 5-point Likert scale ranging from "not at all" to "cannot do". The remaining 5 items are self-reported ability to perform specific physical activities such as chores,dressing themselves, bathing,sitting on and getting up from the toilet, each rated on a 5-point likert scale ranging from "without any difficulty" to "unable to do". The 10 item scores were summed to produce a raw score ranging from 10 (minimum) to 50 (maximum).The raw score was then converted to a T-score with a mean of 50 and a standard deviation of 10; higher T-scores indicate better outcome (greater physical function).Range cannot be specified in norm-based scores. |
| Mean Change From Baseline in Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b (PROMIS SD SF8b) | Baseline, Week 12 | The Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b (PROMIS SD SF8b) was administered to assess perceptions of sleep quality, sleep depth, and restoration associated with sleep within the previous 7 days, including perceived difficulties and concerns with getting to sleep or staying asleep, and perceptions of the adequacy of and satisfaction with sleep. The scale consists of 8 items, all measuring a single domain of sleep disturbance. Each item was rated on a 5-point response scale ranging from "not at all" to "very much," "never" to "always," or "very poor" to "very good"; the 8 item scores were summed to produce a raw score ranging from 8 (minimum) to 40 (maximum). The raw score was then converted to a T-score with a mean of 50 and a standard deviation of 10; higher T-scores indicate worse outcome (greater sleep disturbance). Range cannot be specified in norm-based scores. |
| Mean Change From Baseline in Patient's Global Impression of Illness Severity as Measured by Patient's Global Impression-Severity (PGI-Severity) | Baseline, Week 12 | * The Patient's Global Impression-Severity (PGI-Severity) is a patient-reported single-item instrument designed to assess the participant's severity of diabetic nerve pain over the past week. The single item is rated on a 5-point Likert scale ranging from 1 (minimum, "very severe") to 5 (maximum, "none"); higher scores indicate better outcome (less pain severity). * The LS Mean was calculated using an FRM analysis, where Change = treatment, time interval, treatment \* time interval, region, average baseline pain severity category (mild or moderate vs. severe), concurrent use of allowed concomitant medication (yes vs. no based on IWRS). |
| Mean Change From Baseline in Patient's Global Impression (PGI) of Illness Status as Measured by PGI-Status | Baseline, Week 12 | The Patient's Global Impression-Status (PGI-Status) is a patient-reported single-item instrument designed to assess the participant's status with diabetic nerve pain. Three PGI-Status scales were administered to assess physical activity, usual activity, and sleep disturbance. For physical activity, participants rated their status at the present time; for usual activity and sleep disturbance, participants rated their overall status over the past week. Physical activity and usual activity were each rated on a 5-point Likert scale ranging from 1 (minimum, "extremely limited") to 5 (maximum, "not at all limited"); higher scores indicate better outcome (less limitation). Sleep disturbance was rated on a 5-point Likert scale ranging from 1 (minimum, "very much") to 5 (maximum, "not at all"); higher scores indicate better outcome (less sleep disturbance). |
| Patient's Global Impression of Change as Measured by Patient's Global Impression-Change (PGI-Change) | Week 12 | The Patient's Global Impression-Change (PGI-Change) is a patient-reported single-item instrument designed to assess the participant's rating of change in diabetic nerve pain since they began taking the study medication. Four PGI-Change scales were administered to assess diabetic nerve pain's impact on physical activities, usual activities, sleep disturbance, and overall change. Each item was rated on a 5-point Likert scale ranging from 1 (minimum, "much worse") to 5 (maximum, "much better"); higher scores indicate better outcome (greater improvement). |
| Mean Change From Baseline in Neuropathy Total Symptom Score-6 (NTSS-6) | Baseline, Week 12 | The NTSS-6 assessed the frequency and intensity of 6 diabetic peripheral neuropathic symptoms over the previous 7 days: (1) numbness and/or insensitivity, (2) prickling and/or tingling sensation, (3) burning sensation, (4) aching pain and/or tightness, (5) sharp, shooting, lancinating pain, and (6) allodynia and/or hyperalgesia. Each of the 6 symptoms was rated on two separate response scales: an intensity scale (Does not apply \[0\], Mild \[1\], Moderate \[2\], or Severe \[3\]) and a frequency scale (Never \[0\], Occasionally, less than 1/3 of the time \[0\], Often, 1/3 to 2/3 of the time \[0.33\], or Almost always, more than 2/3 of the time \[0.66\]). The total score was calculated as the weighted sum across all 6 symptoms, where intensity was given a weight of 1 and frequency was given a weight of 1/3, yielding a total score ranging from 0 (minimum, no symptoms) to 21.96 (maximum, most severe); higher scores indicate worse outcome (greater neuropathic symptom burden). |
| Total Amount of Rescue Medication Use as Measured by Average Daily Dosage | Week 12 | Acetaminophen was used as rescue medication during the treatment period. The total amount of rescue medication use was summarized as the average daily dosage at Week 12. |
| Percentage of Participants With at Least One Use of Rescue Medication | Week 12 | Acetaminophen was used as rescue medication during the treatment period. The percentage of participants with at least one use of rescue medication at Week 12 was reported. |
| Pharmacokinetics (PK): Plasma Concentration of Mazisotine | Postdose at Week 12 | Mazisotine plasma concentration was reported. The Measure Type was Median and the Measure of Dispersion/Precision was Inter-Quartile Range, where the lower and upper limits represented the 5th and 95th percentiles, respectively. |
Countries
Czechia, Japan, Poland, South Korea, United States
Contacts
STUDY_DIRECTORCall 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)
Eli Lilly and Company
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 63.70 years STANDARD_DEVIATION 10.12 |
| Average Pain Intensity (API) as Measured by the Numeric Rating Scale (NRS) | 5.95 score on a scale STANDARD_DEVIATION 1.23 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 68 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 106 Participants |
| Race (NIH/OMB) Black or African American | 41 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 106 Participants |
| Region of Enrollment Czechia | 37 Participants |
| Region of Enrollment Japan | 16 Participants |
| Region of Enrollment Poland | 11 Participants |
| Region of Enrollment South Korea | 8 Participants |
| Region of Enrollment United States | 37 Participants |
| Sex: Female, Male Female | 30 Participants |
| Sex: Female, Male Male | 44 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 / 162 | 0 / 79 | 1 / 81 | 0 / 80 |
| other Total, other adverse events | 18 / 162 | 17 / 79 | 23 / 81 | 13 / 80 |
| serious Total, serious adverse events | 4 / 162 | 1 / 79 | 3 / 81 | 3 / 80 |
Outcome results
None listed