Diabetic Neuropathy, Painful
Conditions
Brief summary
This study will investigate the efficacy of a combination treatment of duloxetine + pregabalin compared with the maximal dose of each drug in monotherapy, in patients with diabetic peripheral neuropathic pain (DPNP) who have not responded to the standard recommended dose of either drug. It will provide an answer to a common clinical question, namely, is it better to increase the dose of the current monotherapy or to combine both treatments early on, in patients who do not respond to standard doses of duloxetine or pregabalin.
Interventions
DRUGDuloxetine
Administered orally
DRUGPregabalin
Administered orally
DRUGPlacebo
Administered orally, daily as a blind for duloxetine and/or pregabalin for 8 or 16 weeks
Sponsors
Boehringer Ingelheim
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pain due to bilateral peripheral neuropathy (caused by type 1 or type 2 diabetes mellitus. Pain must begin in the feet, with relatively symmetrical onset. Daily pain should be present for more than 3 months \[assessed by questioning patient\]). * Score of at least 4 on the 24-hour average pain severity score on an 11-point Likert scale \[on Brief Pain Inventory (BPI) Modified Short Form\] at screening and at randomization. * Patient is currently not receiving treatment for diabetic peripheral neuropathic pain (DPNP) or was receiving treatment for DPNP, with a drug other than pregabalin or duloxetine, and completed the required washout * Patient has never received treatment with duloxetine or pregabalin. (However, a short course of less than 15 days of treatment, at any time previously, will be allowed.) * Stable glycemic control, as assessed by a physician investigator, and hemoglobin A1c (HbA1c) less than or equal to 12% at screening.
Exclusion criteria
* Have a known hypersensitivity to duloxetine or pregabalin or any of the inactive ingredients or have any contraindication for the use of duloxetine or pregabalin. * Have uncontrolled narrow-angle glaucoma. * Have received treatment with a monoamine oxidase inhibitor (MAOI) within 14 days prior to randomization, or have a potential need to use a MAOI during the study or within 5 days after discontinuation of study drug. * Have received fluoxetine within 30 days prior to randomization. * Have acute liver injury (such as hepatitis) or severe cirrhosis (Child-Pugh Class C). * Have a serum creatinine greater than or equal to 1.5 milligram per deciliter (mg/dL) or a creatinine clearance less than 60 milliliter per minute (mL/min), at screening. * Are judged clinically by the investigator to be at suicidal risk or as defined by a score of 2 or greater on Question 9 of the Beck Depression Inventory-II (BDI-II), at screening or randomization * Have a historical exposure to drugs known to cause neuropathy (for example, vincristine), or a history of a medical condition, including pernicious anemia and hypothyroidism, that could have been responsible for neuropathy. * Have pain that cannot be clearly differentiated from or conditions that interfere with the assessment of the DPNP. * Have serious or unstable cardiovascular, hepatic, renal, respiratory or hematological illness; symptomatic peripheral vascular disease; a history of seizure disorder; or other medical (including unstable hypertension and not clinically euthyroid) or psychological conditions that, in the opinion of the investigator, would compromise participation or be likely to require hospitalization during the course of the study. * Have received non-pharmacological treatment for pain within 14 days prior to randomization, or do not agree to abstain from non-pharmacological treatment during the study. * Have a history of frequent and/or severe allergic reactions with multiple medications.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Week 8 to Week 16 Endpoint in 24 Hour Average Pain Item Score on the Brief Pain Inventory (BPI) Modified Short Form | Week 8, Week 16 | BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment\*visit, baseline\*visit and treatment in Study Period II. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Reduction of Greater Than or Equal to 30% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 16 Endpoint | Week 8 through Week 16 | BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). |
| Percentage of Participants With a Reduction of Greater Than or Equal to 50% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 16 Endpoint | Week 8 through Week 16 | BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). |
| Percentage of Participants With a Decrease of Greater Than or Equal to 2 Points on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 16 Endpoint | Week 8 through Week 16 | BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). |
| Clinical Global Impression of Improvement (CGI-I) at Week 16 Endpoint | Week 16 | Measures clinician's perception of participant improvement at the time of assessment compared with the start of treatment for Study Period III. Scores range from 1 (very much better) to 7 (very much worse). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment\*visit, baseline\*visit and treatment in Study Period II. |
| Mean Change From Week 8 to Week 16 Endpoint on the Neuropathic Pain Symptom Inventory (NPSI) Questionnaire | Week 8, Week 16 | The NPSI is a 12-item self-administered questionnaire to assess 5 different dimensions of neuropathic pain: superficial spontaneous burning pain, deep spontaneous pressing pain, paroxysmal pain, evoked pains, and paresthesias/dysesthesias. A total score ranges from 0 to 100. Higher score indicates a greater intensity of pain. Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment\*visit, baseline\*visit and treatment in Study Period II. |
| Mean Change From Week 8 to Week 16 Endpoint in Sheehan Disability Scale (SDS) | Week 8, Week 16 | The SDS is completed by the participant and is used to assess the effect of the participant's symptoms on their work (Item 1), social (Item 2), and family life (Item 3). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. Total scores is the sum of the 3 items and range from 0 to 30 with higher values indicating greater disruption in the participant's work/social/family life. Least Squares (LS) Mean values are controlled for treatment, site, baseline value, treatment\*site and treatment in Study Period II. |
| Mean Change From Week 8 to Week 16 Endpoint in Items of the Brief Pain Inventory (BPI) Modified Short Form Worst Pain Score | Week 8, Week 16 | BPI Modified Short Form worst pain score is a self-reported scale that measures the severity of pain based on the worst pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment\*visit, baseline\*visit and treatment in Study Period II. |
| Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Week 8 Through Week 16 | Week 8 through Week 16 | Data presented are the number of days hospitalized and work/school missed (sick leave) due to diabetic peripheral neuropathic pain (DPNP) during the last 8 weeks. |
| Patient Global Impression of Improvement (PGI-I) Score at Week 16 Endpoint | Week 16 | Measures participant's perception of improvement at the time of assessment compared with the start of treatment for Study Period III. The score ranges from 1 (very much better) to 7 (very much worse). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment\*visit, baseline\*visit and treatment in Study Period II. |
| Mean Change in Blood Pressure (BP) From Week 8 to Week 16 Endpoint | Week 8, Week 16 | Least Squares (LS) mean values are controlled for treatment, site, baseline value, treatment\*site and treatment in Study Period II. |
| Mean Change in Heart Rate From Week 8 to Week 16 Endpoint | Week 8, Week 16 | Least Squares (LS) mean values are controlled for treatment, site, baseline value, treatment\*site and treatment in Study Period II. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) Between Week 8 and Week 16 Endpoint | Week 8 through Week 16 | TEAEs in Study Period III are events that began or worsened after Week 8 compared with the period before Week 8. |
| Number of Participants Who Discontinued From Study Between Week 8 and Week 16 Endpoint | Week 8 through Week 16 | — |
| Mean Change From Week 8 to Week 16 Endpoint in Hospital Anxiety and Depression Scale (HADS) | Week 8, Week 16 | A 14-item questionnaire with 2 subscales: anxiety and depression. Each item is rated on a 4-point scale (0-3), giving maximum scores of 21 for anxiety and for depression. Scores of 11 or more on either subscale are considered to be a significant case of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7 represent 'normal.' Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment\*visit, baseline\*visit and treatment in Study Period II. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline to Week 8 Endpoint in 24 Hour Average Pain Item Score on the Brief Pain Inventory (BPI) Modified Short Form | Baseline, Week 8 | BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment\*visit and baseline\*visit. |
| Number of Participants Who Discontinued From Study Between Baseline and Week 8 Endpoint | Baseline through Week 8 | — |
| Percentage of Participants With a Reduction of Greater Than or Equal to 30% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 8 Endpoint | Baseline through Week 8 | BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). |
| Percentage of Participants With a Reduction of Greater Than or Equal to 50% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 8 Endpoint | Baseline through Week 8 | BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). |
| Percentage of Participants With a Decrease of Greater Than or Equal to 2 Points on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 8 Endpoint | Baseline through Week 8 | BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). |
| Clinical Global Impression of Improvement (CGI-I) at Week 8 Endpoint | Week 8 | Measures clinician's perception of participant improvement at the time of assessment compared with the start of treatment. Scores range from 1 (very much better) to 7 (very much worse). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, visit, and treatment\*visit. |
| Mean Change From Baseline to Week 8 Endpoint on the Neuropathic Pain Symptom Inventory (NPSI) Questionnaire | Baseline, Week 8 | The NPSI is a 12-item self-administered questionnaire to assess 5 different dimensions of neuropathic pain: superficial spontaneous burning pain, deep spontaneous pressing pain, paroxysmal pain, evoked pains, and paresthesias/dysesthesias. A total score ranges from 0 to 100. Higher score indicates a greater intensity of pain. Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment\*visit and baseline\*visit. |
| Mean Change From Baseline to Week 8 Endpoint in Sheehan Disability Scale (SDS) | Baseline, Week 8 | The SDS is completed by the participant and is used to assess the effect of the participant's symptoms on their work (Item 1), social (Item 2), and family life (Item 3). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. Total scores is the sum of the 3 items and range from 0 to 30 with higher values indicating greater disruption in the participant's work/social/family life. Least Squares (LS) mean values are controlled for treatment, site, baseline value and treatment\*site. |
| Mean Change From Baseline to Week 8 Endpoint in Hospital Anxiety and Depression Scale (HADS) | Baseline, Week 8 | A 14-item questionnaire with 2 subscales: anxiety and depression. Each item is rated on a 4-point scale (0-3), giving maximum scores of 21 for anxiety and for depression. Scores of 11 or more on either subscale are considered to be a significant case of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7 represent 'normal.' Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment\*visit and baseline\*visit. |
| Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Baseline Through Week 8 | Baseline through Week 8 | Data presented are the number of days hospitalized and work/school missed (sick leave) due to diabetic peripheral neuropathic pain (DPNP) during the last 8 weeks. |
| Average Number of Hours Worked for Pay Per Week Baseline Through Week 8 | Baseline through Week 8 | Data presented are the average number of hours worked for pay per week during the last 8 weeks. |
| Average Number of Hours Worked for Pay Per Week Week 8 Through Week 16 | Week 8 through Week 16 | Data presented are the average number of hours worked for pay per week during the last 8 weeks. |
| Patient Global Impression of Improvement (PGI-I) Score at Week 8 Endpoint | Week 8 | Measures participant's perception of improvement at the time of assessment compared with the start of treatment. The score ranges from 1 (very much better) to 7 (very much worse). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, visit, and treatment\*visit. |
| Mean Change in Blood Pressure (BP) From Baseline to Week 8 Endpoint | Baseline, Week 8 | Least Squares (LS) mean values are controlled for treatment, site, baseline value, and treatment\*site. |
| Mean Change in Heart Rate From Baseline to Week 8 Endpoint | Baseline, Week 8 | Least Squares (LS) mean values are controlled for treatment, site, baseline value, and treatment\*site. |
| Number of Participants With Treatment Emergent Adverse Events (TEAE) Between Baseline and Week 8 Endpoint | Baseline through Week 8 | TEAEs in Study Period II are events that began or worsened after Week 0 compared with the period before Week 0. |
Countries
Australia, Canada, Croatia, France, Germany, Greece, Italy, Mexico, Netherlands, Poland, South Korea, Spain, Sweden, Switzerland, Turkey (Türkiye), United Kingdom
Participant flow
Pre-assignment details
The study consisted of 4 study periods (SP): 2 weeks screening and washout (SP I), 8 weeks initial treatment (SP II), 8 weeks intensive treatment (SP III), 2 weeks tapering (SP IV). Participants who did not achieve good pain control during SP II (\<30% improvement) were considered non-responders and continued in the study and entered SP III.
Participants by arm
| Arm | Count |
|---|---|
| Duloxetine Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II. | 401 |
| Pregabalin Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II. | 403 |
| Total | 804 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Study Period III (Weeks 9-16) | Adverse Event | 0 | 0 | 4 | 2 | 4 | 3 |
| Study Period III (Weeks 9-16) | Entry Criteria Not Met | 0 | 0 | 1 | 1 | 1 | 1 |
| Study Period III (Weeks 9-16) | Lack of Efficacy | 0 | 0 | 0 | 2 | 1 | 0 |
| Study Period III (Weeks 9-16) | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 | 0 |
| Study Period III (Weeks 9-16) | Protocol Violation | 0 | 0 | 1 | 1 | 1 | 0 |
| Study Period III (Weeks 9-16) | Satisfactory Response | 0 | 0 | 4 | 3 | 4 | 1 |
| Study Period III (Weeks 9-16) | Withdrawal by Subject | 0 | 0 | 3 | 0 | 1 | 2 |
| Study Period II (Weeks 1-8) | Adverse Event | 35 | 39 | 0 | 0 | 0 | 0 |
| Study Period II (Weeks 1-8) | Entry Criteria Not Met | 12 | 8 | 0 | 0 | 0 | 0 |
| Study Period II (Weeks 1-8) | Lack of Efficacy | 1 | 2 | 0 | 0 | 0 | 0 |
| Study Period II (Weeks 1-8) | Lost to Follow-up | 0 | 3 | 0 | 0 | 0 | 0 |
| Study Period II (Weeks 1-8) | Not received any study drug | 3 | 4 | 0 | 0 | 0 | 0 |
| Study Period II (Weeks 1-8) | Physician Decision | 4 | 0 | 0 | 0 | 0 | 0 |
| Study Period II (Weeks 1-8) | Protocol Violation | 4 | 4 | 0 | 0 | 0 | 0 |
| Study Period II (Weeks 1-8) | Withdrawal by Subject | 12 | 14 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Pregabalin | Duloxetine |
|---|---|---|---|
| Age Continuous | 61.7 years STANDARD_DEVIATION 10.78 | 61.9 years STANDARD_DEVIATION 10.95 | 61.5 years STANDARD_DEVIATION 10.62 |
| Average number of hours worked for pay per week | 40.4 hours STANDARD_DEVIATION 18.47 | 41.4 hours STANDARD_DEVIATION 16.36 | 39.5 hours STANDARD_DEVIATION 20.33 |
| Blood pressure (BP) Diastolic BP | 77.1 millimeter of mercury (mm Hg) STANDARD_DEVIATION 9.74 | 76.7 millimeter of mercury (mm Hg) STANDARD_DEVIATION 9.43 | 77.6 millimeter of mercury (mm Hg) STANDARD_DEVIATION 10.04 |
| Blood pressure (BP) Systolic BP | 134.7 millimeter of mercury (mm Hg) STANDARD_DEVIATION 15.94 | 134.3 millimeter of mercury (mm Hg) STANDARD_DEVIATION 15.62 | 135.0 millimeter of mercury (mm Hg) STANDARD_DEVIATION 16.27 |
| Brief Pain Inventory (BPI) Severity: Average Pain Score | 6.0 units on a scale STANDARD_DEVIATION 1.56 | 6.0 units on a scale STANDARD_DEVIATION 1.57 | 6.0 units on a scale STANDARD_DEVIATION 1.55 |
| Clinical Global Impressions of Severity Scale (CGI-S) | 4.0 units on a scale STANDARD_DEVIATION 1.08 | 4.0 units on a scale STANDARD_DEVIATION 1.09 | 4.0 units on a scale STANDARD_DEVIATION 1.07 |
| Hospital Anxiety and Depression Scale (HADS) - Anxiety Subscale Score | 6.7 units on a scale STANDARD_DEVIATION 4.31 | 6.6 units on a scale STANDARD_DEVIATION 4.32 | 6.8 units on a scale STANDARD_DEVIATION 4.31 |
| Hospital Anxiety and Depression Scale (HADS) - Depression Subscale Score | 5.5 units on a scale STANDARD_DEVIATION 4.04 | 5.5 units on a scale STANDARD_DEVIATION 3.88 | 5.5 units on a scale STANDARD_DEVIATION 4.19 |
| Neuropathic Pain Symptom Inventory (NPSI) | 47.5 units on a scale STANDARD_DEVIATION 19.81 | 47.7 units on a scale STANDARD_DEVIATION 20.46 | 47.3 units on a scale STANDARD_DEVIATION 19.16 |
| Number of days hospitalized | 0.1 days STANDARD_DEVIATION 0.57 | 0.1 days STANDARD_DEVIATION 0.67 | 0.0 days STANDARD_DEVIATION 0.45 |
| Number of days of work/school missed | 1.8 days STANDARD_DEVIATION 6.56 | 1.3 days STANDARD_DEVIATION 4.69 | 2.3 days STANDARD_DEVIATION 7.98 |
| Patient Global Impressions of Severity Scale (PGI-S) | 3.4 units on a scale STANDARD_DEVIATION 1.42 | 3.4 units on a scale STANDARD_DEVIATION 1.41 | 3.4 units on a scale STANDARD_DEVIATION 1.42 |
| Pulse rate | 75.8 beats per minute (bpm) STANDARD_DEVIATION 10.92 | 75.6 beats per minute (bpm) STANDARD_DEVIATION 11.05 | 76.0 beats per minute (bpm) STANDARD_DEVIATION 10.81 |
| Race (NIH/OMB) American Indian or Alaska Native | 73 Participants | 36 Participants | 37 Participants |
| Race (NIH/OMB) Asian | 68 Participants | 34 Participants | 34 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) White | 652 Participants | 328 Participants | 324 Participants |
| Region of Enrollment Australia | 49 participants | 22 participants | 27 participants |
| Region of Enrollment Canada | 38 participants | 19 participants | 19 participants |
| Region of Enrollment Croatia | 56 participants | 29 participants | 27 participants |
| Region of Enrollment France | 46 participants | 24 participants | 22 participants |
| Region of Enrollment Germany | 106 participants | 54 participants | 52 participants |
| Region of Enrollment Greece | 28 participants | 12 participants | 16 participants |
| Region of Enrollment Italy | 34 participants | 18 participants | 16 participants |
| Region of Enrollment Korea, Republic of | 63 participants | 32 participants | 31 participants |
| Region of Enrollment Mexico | 146 participants | 71 participants | 75 participants |
| Region of Enrollment Netherlands | 9 participants | 4 participants | 5 participants |
| Region of Enrollment Poland | 113 participants | 57 participants | 56 participants |
| Region of Enrollment Spain | 14 participants | 8 participants | 6 participants |
| Region of Enrollment Sweden | 28 participants | 15 participants | 13 participants |
| Region of Enrollment Turkey | 12 participants | 7 participants | 5 participants |
| Region of Enrollment United Kingdom | 62 participants | 31 participants | 31 participants |
| Sex: Female, Male Female | 356 Participants | 174 Participants | 182 Participants |
| Sex: Female, Male Male | 448 Participants | 229 Participants | 219 Participants |
| Sheehan Disability Scale (SDS) | 13.3 units on a scale STANDARD_DEVIATION 7.52 | 13.3 units on a scale STANDARD_DEVIATION 7.59 | 13.3 units on a scale STANDARD_DEVIATION 7.47 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 216 / 401 | 225 / 403 | 18 / 73 | 21 / 75 | 39 / 94 | 37 / 97 |
| serious Total, serious adverse events | 12 / 401 | 13 / 403 | 3 / 73 | 3 / 75 | 5 / 94 | 2 / 97 |
Outcome results
Primary
Change From Week 8 to Week 16 Endpoint in 24 Hour Average Pain Item Score on the Brief Pain Inventory (BPI) Modified Short Form
BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment\*visit, baseline\*visit and treatment in Study Period II.
Time frame: Week 8, Week 16
Population: All randomized participants who received at least one dose of study drug, and had Week 8 and at least one BPI measurements during Weeks 9-16 (Study Period III).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Combination | Change From Week 8 to Week 16 Endpoint in 24 Hour Average Pain Item Score on the Brief Pain Inventory (BPI) Modified Short Form | -2.353 units on a scale |
| Monotherapy | Change From Week 8 to Week 16 Endpoint in 24 Hour Average Pain Item Score on the Brief Pain Inventory (BPI) Modified Short Form | -2.161 units on a scale |
p-value: 0.37Mixed Models Analysis
Secondary
Clinical Global Impression of Improvement (CGI-I) at Week 16 Endpoint
Measures clinician's perception of participant improvement at the time of assessment compared with the start of treatment for Study Period III. Scores range from 1 (very much better) to 7 (very much worse). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment\*visit, baseline\*visit and treatment in Study Period II.
Time frame: Week 16
Population: All randomized participants who received at least one dose of study drug, and had at least one CGI-I measurement during Weeks 9-16 (Study Period III).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Combination | Clinical Global Impression of Improvement (CGI-I) at Week 16 Endpoint | 2.286 units on a scale |
| Monotherapy | Clinical Global Impression of Improvement (CGI-I) at Week 16 Endpoint | 2.359 units on a scale |
p-value: 0.475Mixed Models Analysis
Secondary
Mean Change From Week 8 to Week 16 Endpoint in Hospital Anxiety and Depression Scale (HADS)
A 14-item questionnaire with 2 subscales: anxiety and depression. Each item is rated on a 4-point scale (0-3), giving maximum scores of 21 for anxiety and for depression. Scores of 11 or more on either subscale are considered to be a significant case of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7 represent 'normal.' Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment\*visit, baseline\*visit and treatment in Study Period II.
Time frame: Week 8, Week 16
Population: All randomized participants who received at least one dose of study drug, and had Week 8 and at least one HADS measurements during Weeks 9-16 (Study Period III).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Combination | Mean Change From Week 8 to Week 16 Endpoint in Hospital Anxiety and Depression Scale (HADS) | Anxiety Subscale Score (n=169, 169) | -0.860 units on a scale |
| Combination | Mean Change From Week 8 to Week 16 Endpoint in Hospital Anxiety and Depression Scale (HADS) | Depression Subscale Score (n=168, 170) | -0.461 units on a scale |
| Monotherapy | Mean Change From Week 8 to Week 16 Endpoint in Hospital Anxiety and Depression Scale (HADS) | Anxiety Subscale Score (n=169, 169) | -0.245 units on a scale |
| Monotherapy | Mean Change From Week 8 to Week 16 Endpoint in Hospital Anxiety and Depression Scale (HADS) | Depression Subscale Score (n=168, 170) | -0.083 units on a scale |
p-value: 0.049Mixed Models Analysis
p-value: 0.198Mixed Models Analysis
Secondary
Mean Change From Week 8 to Week 16 Endpoint in Items of the Brief Pain Inventory (BPI) Modified Short Form Worst Pain Score
BPI Modified Short Form worst pain score is a self-reported scale that measures the severity of pain based on the worst pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment\*visit, baseline\*visit and treatment in Study Period II.
Time frame: Week 8, Week 16
Population: All randomized participants who received at least one dose of study drug, and had Week 8 and at least one BPI measurements during Weeks 9-16 (Study Period III).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Combination | Mean Change From Week 8 to Week 16 Endpoint in Items of the Brief Pain Inventory (BPI) Modified Short Form Worst Pain Score | -2.374 units on a scale |
| Monotherapy | Mean Change From Week 8 to Week 16 Endpoint in Items of the Brief Pain Inventory (BPI) Modified Short Form Worst Pain Score | -2.371 units on a scale |
p-value: 0.991Mixed Models Analysis
Secondary
Mean Change From Week 8 to Week 16 Endpoint in Sheehan Disability Scale (SDS)
The SDS is completed by the participant and is used to assess the effect of the participant's symptoms on their work (Item 1), social (Item 2), and family life (Item 3). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. Total scores is the sum of the 3 items and range from 0 to 30 with higher values indicating greater disruption in the participant's work/social/family life. Least Squares (LS) Mean values are controlled for treatment, site, baseline value, treatment\*site and treatment in Study Period II.
Time frame: Week 8, Week 16
Population: All randomized participants who received at least one dose of study drug, and had Week 8 and at least one SDS measurement during Weeks 9-16 (Study Period III). Last observation carried forward (LOCF) principle was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Combination | Mean Change From Week 8 to Week 16 Endpoint in Sheehan Disability Scale (SDS) | -2.625 units on a scale |
| Monotherapy | Mean Change From Week 8 to Week 16 Endpoint in Sheehan Disability Scale (SDS) | -2.431 units on a scale |
p-value: 0.78ANCOVA
Secondary
Mean Change From Week 8 to Week 16 Endpoint on the Neuropathic Pain Symptom Inventory (NPSI) Questionnaire
The NPSI is a 12-item self-administered questionnaire to assess 5 different dimensions of neuropathic pain: superficial spontaneous burning pain, deep spontaneous pressing pain, paroxysmal pain, evoked pains, and paresthesias/dysesthesias. A total score ranges from 0 to 100. Higher score indicates a greater intensity of pain. Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment\*visit, baseline\*visit and treatment in Study Period II.
Time frame: Week 8, Week 16
Population: All randomized participants who received at least one dose of study drug, and had Week 8 and at least one NPSI measurements during Weeks 9-16 (Study Period III).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Combination | Mean Change From Week 8 to Week 16 Endpoint on the Neuropathic Pain Symptom Inventory (NPSI) Questionnaire | -13.734 units on a scale |
| Monotherapy | Mean Change From Week 8 to Week 16 Endpoint on the Neuropathic Pain Symptom Inventory (NPSI) Questionnaire | -11.801 units on a scale |
p-value: 0.289Mixed Models Analysis
Secondary
Mean Change in Blood Pressure (BP) From Week 8 to Week 16 Endpoint
Least Squares (LS) mean values are controlled for treatment, site, baseline value, treatment\*site and treatment in Study Period II.
Time frame: Week 8, Week 16
Population: All randomized participants who received at least one dose of study drug, and had Week 8 and at least one BP measurement during Weeks 9-16 (Study Period III). Last observation carried forward (LOCF) principle was used.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Combination | Mean Change in Blood Pressure (BP) From Week 8 to Week 16 Endpoint | Systolic BP | -1.206 millimeter of mercury (mm Hg) |
| Combination | Mean Change in Blood Pressure (BP) From Week 8 to Week 16 Endpoint | Diastolic BP | -0.555 millimeter of mercury (mm Hg) |
| Monotherapy | Mean Change in Blood Pressure (BP) From Week 8 to Week 16 Endpoint | Systolic BP | 0.124 millimeter of mercury (mm Hg) |
| Monotherapy | Mean Change in Blood Pressure (BP) From Week 8 to Week 16 Endpoint | Diastolic BP | -0.551 millimeter of mercury (mm Hg) |
p-value: 0.354ANCOVA
p-value: 0.997ANCOVA
Secondary
Mean Change in Heart Rate From Week 8 to Week 16 Endpoint
Least Squares (LS) mean values are controlled for treatment, site, baseline value, treatment\*site and treatment in Study Period II.
Time frame: Week 8, Week 16
Population: All randomized participants who received at least one dose of study drug, and had Week 8 and at least one heart rate measurement during Weeks 9- 16 (Study Period III). Last observation carried forward (LOCF) principle was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Combination | Mean Change in Heart Rate From Week 8 to Week 16 Endpoint | 1.025 beats per minute (bpm) |
| Monotherapy | Mean Change in Heart Rate From Week 8 to Week 16 Endpoint | 1.968 beats per minute (bpm) |
p-value: 0.332ANCOVA
Secondary
Number of Participants Who Discontinued From Study Between Week 8 and Week 16 Endpoint
Time frame: Week 8 through Week 16
Population: All randomized participants who received at least one dose of study drug during Weeks 9-16 (Study Period III).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination | Number of Participants Who Discontinued From Study Between Week 8 and Week 16 Endpoint | 21 participants |
| Monotherapy | Number of Participants Who Discontinued From Study Between Week 8 and Week 16 Endpoint | 21 participants |
p-value: 1Fisher Exact
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Between Week 8 and Week 16 Endpoint
TEAEs in Study Period III are events that began or worsened after Week 8 compared with the period before Week 8.
Time frame: Week 8 through Week 16
Population: All randomized participants who received at least one dose of study drug during Weeks 9-16 (Study Period III).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Between Week 8 and Week 16 Endpoint | 62 participants |
| Monotherapy | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Between Week 8 and Week 16 Endpoint | 57 participants |
p-value: 0.571Fisher Exact
Secondary
Patient Global Impression of Improvement (PGI-I) Score at Week 16 Endpoint
Measures participant's perception of improvement at the time of assessment compared with the start of treatment for Study Period III. The score ranges from 1 (very much better) to 7 (very much worse). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment\*visit, baseline\*visit and treatment in Study Period II.
Time frame: Week 16
Population: All randomized participants who received at least one dose of study drug, and at least one PGI-I measurement during Weeks 9-16 (Study Period III).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Combination | Patient Global Impression of Improvement (PGI-I) Score at Week 16 Endpoint | 2.256 units on a scale |
| Monotherapy | Patient Global Impression of Improvement (PGI-I) Score at Week 16 Endpoint | 2.350 units on a scale |
p-value: 0.385Mixed Models Analysis
Secondary
Percentage of Participants With a Decrease of Greater Than or Equal to 2 Points on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 16 Endpoint
BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine).
Time frame: Week 8 through Week 16
Population: All randomized participants who received at least one dose of study drug, and had Week 8 and at least one BPI measurements during Weeks 9-16 (Study Period III). Last observation carried forward (LOCF) principle was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination | Percentage of Participants With a Decrease of Greater Than or Equal to 2 Points on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 16 Endpoint | 66.7 percentage of participants |
| Monotherapy | Percentage of Participants With a Decrease of Greater Than or Equal to 2 Points on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 16 Endpoint | 64.4 percentage of participants |
p-value: 0.84395% CI: [0.842, 1.151]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With a Reduction of Greater Than or Equal to 30% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 16 Endpoint
BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine).
Time frame: Week 8 through Week 16
Population: All randomized participants who received at least one dose of study drug, and had Week 8 and at least one BPI measurements during Weeks 9-16 (Study Period III). Last observation carried forward (LOCF) principle was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination | Percentage of Participants With a Reduction of Greater Than or Equal to 30% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 16 Endpoint | 61.8 percentage of participants |
| Monotherapy | Percentage of Participants With a Reduction of Greater Than or Equal to 30% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 16 Endpoint | 55.8 percentage of participants |
p-value: 0.56595% CI: [0.884, 1.253]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With a Reduction of Greater Than or Equal to 50% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 16 Endpoint
BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine).
Time frame: Week 8 through Week 16
Population: All randomized participants who received at least one dose of study drug, and had Week 8 and at least one BPI measurements during Weeks 9-16 (Study Period III). Last observation carried forward (LOCF) principle was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination | Percentage of Participants With a Reduction of Greater Than or Equal to 50% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 16 Endpoint | 52.1 percentage of participants |
| Monotherapy | Percentage of Participants With a Reduction of Greater Than or Equal to 50% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 16 Endpoint | 39.3 percentage of participants |
p-value: 0.06895% CI: [0.98, 1.55]Cochran-Mantel-Haenszel
Secondary
Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Week 8 Through Week 16
Data presented are the number of days hospitalized and work/school missed (sick leave) due to diabetic peripheral neuropathic pain (DPNP) during the last 8 weeks.
Time frame: Week 8 through Week 16
Population: All randomized participants who received at least one dose of study drug and provided information of hospitalization and sick leave during Weeks 9-16 (Study Period III).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Combination | Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Week 8 Through Week 16 | Days hospitalized (n=140, 146) | 0 days | Standard Deviation 0 |
| Combination | Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Week 8 Through Week 16 | Days of sick leave (n=41, 36) | 0.1 days | Standard Deviation 0.65 |
| Monotherapy | Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Week 8 Through Week 16 | Days hospitalized (n=140, 146) | 0 days | Standard Deviation 0 |
| Monotherapy | Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Week 8 Through Week 16 | Days of sick leave (n=41, 36) | 0.4 days | Standard Deviation 2.67 |
Other Pre-specified
Average Number of Hours Worked for Pay Per Week Baseline Through Week 8
Data presented are the average number of hours worked for pay per week during the last 8 weeks.
Time frame: Baseline through Week 8
Population: All randomized participants who received at least one dose of study drug and had worked for pay during Weeks 1-8 (Study Period II).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination | Average Number of Hours Worked for Pay Per Week Baseline Through Week 8 | 37.6 hours | Standard Deviation 18.72 |
| Monotherapy | Average Number of Hours Worked for Pay Per Week Baseline Through Week 8 | 42.4 hours | Standard Deviation 15.52 |
Other Pre-specified
Average Number of Hours Worked for Pay Per Week Week 8 Through Week 16
Data presented are the average number of hours worked for pay per week during the last 8 weeks.
Time frame: Week 8 through Week 16
Population: All randomized participants who received at least one dose of study drug and had worked for pay during Weeks 9-16 (Study Period III).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination | Average Number of Hours Worked for Pay Per Week Week 8 Through Week 16 | 39.8 hours | Standard Deviation 15.98 |
| Monotherapy | Average Number of Hours Worked for Pay Per Week Week 8 Through Week 16 | 34.7 hours | Standard Deviation 21.46 |
Other Pre-specified
Clinical Global Impression of Improvement (CGI-I) at Week 8 Endpoint
Measures clinician's perception of participant improvement at the time of assessment compared with the start of treatment. Scores range from 1 (very much better) to 7 (very much worse). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, visit, and treatment\*visit.
Time frame: Week 8
Population: All randomized participants who received at least one dose of study drug, and had at least one post-baseline CGI-I measurement during Weeks 1-8 (Study Period II).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Combination | Clinical Global Impression of Improvement (CGI-I) at Week 8 Endpoint | 2.508 units on a scale |
| Monotherapy | Clinical Global Impression of Improvement (CGI-I) at Week 8 Endpoint | 2.848 units on a scale |
p-value: <0.001Mixed Models Analysis
Other Pre-specified
Mean Change From Baseline to Week 8 Endpoint in 24 Hour Average Pain Item Score on the Brief Pain Inventory (BPI) Modified Short Form
BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment\*visit and baseline\*visit.
Time frame: Baseline, Week 8
Population: All randomized participants who received at least one dose of study drug, and had baseline and at least one post-baseline BPI measurements during Weeks 1-8 (Study Period II).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Combination | Mean Change From Baseline to Week 8 Endpoint in 24 Hour Average Pain Item Score on the Brief Pain Inventory (BPI) Modified Short Form | -2.295 units on a scale |
| Monotherapy | Mean Change From Baseline to Week 8 Endpoint in 24 Hour Average Pain Item Score on the Brief Pain Inventory (BPI) Modified Short Form | -1.682 units on a scale |
p-value: <0.001Mixed Models Analysis
Other Pre-specified
Mean Change From Baseline to Week 8 Endpoint in Hospital Anxiety and Depression Scale (HADS)
A 14-item questionnaire with 2 subscales: anxiety and depression. Each item is rated on a 4-point scale (0-3), giving maximum scores of 21 for anxiety and for depression. Scores of 11 or more on either subscale are considered to be a significant case of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7 represent 'normal.' Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment\*visit and baseline\*visit.
Time frame: Baseline, Week 8
Population: All randomized participants who received at least one dose of study drug, and had baseline and at least one post-baseline HADS measurements during Weeks 1-8 (Study Period II).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Combination | Mean Change From Baseline to Week 8 Endpoint in Hospital Anxiety and Depression Scale (HADS) | Anxiety Subscale Score (n= 398, 400) | -1.991 units on a scale |
| Combination | Mean Change From Baseline to Week 8 Endpoint in Hospital Anxiety and Depression Scale (HADS) | Depression Subscale Score | -1.064 units on a scale |
| Monotherapy | Mean Change From Baseline to Week 8 Endpoint in Hospital Anxiety and Depression Scale (HADS) | Anxiety Subscale Score (n= 398, 400) | -1.433 units on a scale |
| Monotherapy | Mean Change From Baseline to Week 8 Endpoint in Hospital Anxiety and Depression Scale (HADS) | Depression Subscale Score | -0.642 units on a scale |
p-value: 0.008Mixed Models Analysis
p-value: 0.031Mixed Models Analysis
Other Pre-specified
Mean Change From Baseline to Week 8 Endpoint in Sheehan Disability Scale (SDS)
The SDS is completed by the participant and is used to assess the effect of the participant's symptoms on their work (Item 1), social (Item 2), and family life (Item 3). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. Total scores is the sum of the 3 items and range from 0 to 30 with higher values indicating greater disruption in the participant's work/social/family life. Least Squares (LS) mean values are controlled for treatment, site, baseline value and treatment\*site.
Time frame: Baseline, Week 8
Population: All randomized participants who received at least one dose of study drug, and had baseline and at least one post-baseline SDS measurement during Weeks 1-8 (Study Period II). Last observation carried forward (LOCF) principle was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Combination | Mean Change From Baseline to Week 8 Endpoint in Sheehan Disability Scale (SDS) | -4.387 units on a scale |
| Monotherapy | Mean Change From Baseline to Week 8 Endpoint in Sheehan Disability Scale (SDS) | -3.367 units on a scale |
p-value: 0.071ANCOVA
Other Pre-specified
Mean Change From Baseline to Week 8 Endpoint on the Neuropathic Pain Symptom Inventory (NPSI) Questionnaire
The NPSI is a 12-item self-administered questionnaire to assess 5 different dimensions of neuropathic pain: superficial spontaneous burning pain, deep spontaneous pressing pain, paroxysmal pain, evoked pains, and paresthesias/dysesthesias. A total score ranges from 0 to 100. Higher score indicates a greater intensity of pain. Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment\*visit and baseline\*visit.
Time frame: Baseline, Week 8
Population: All randomized participants who received at least one dose of study drug, and had baseline and at least one post-baseline NPSI measurements during Weeks 1-8 (Study Period II).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Combination | Mean Change From Baseline to Week 8 Endpoint on the Neuropathic Pain Symptom Inventory (NPSI) Questionnaire | -19.442 units on a scale |
| Monotherapy | Mean Change From Baseline to Week 8 Endpoint on the Neuropathic Pain Symptom Inventory (NPSI) Questionnaire | -14.684 units on a scale |
p-value: <0.001Mixed Models Analysis
Other Pre-specified
Mean Change in Blood Pressure (BP) From Baseline to Week 8 Endpoint
Least Squares (LS) mean values are controlled for treatment, site, baseline value, and treatment\*site.
Time frame: Baseline, Week 8
Population: All randomized participants who received at least one dose of study drug, and had baseline and at least one post-baseline BP measurement during Week 1-8 (Study Period II). Last observation carried forward (LOCF) principle was used.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Combination | Mean Change in Blood Pressure (BP) From Baseline to Week 8 Endpoint | Systolic BP | -3.702 millimeter of mercury (mm Hg) |
| Combination | Mean Change in Blood Pressure (BP) From Baseline to Week 8 Endpoint | Diastolic BP | -0.816 millimeter of mercury (mm Hg) |
| Monotherapy | Mean Change in Blood Pressure (BP) From Baseline to Week 8 Endpoint | Systolic BP | -1.682 millimeter of mercury (mm Hg) |
| Monotherapy | Mean Change in Blood Pressure (BP) From Baseline to Week 8 Endpoint | Diastolic BP | -0.951 millimeter of mercury (mm Hg) |
p-value: 0.064ANCOVA
p-value: 0.843ANCOVA
Other Pre-specified
Mean Change in Heart Rate From Baseline to Week 8 Endpoint
Least Squares (LS) mean values are controlled for treatment, site, baseline value, and treatment\*site.
Time frame: Baseline, Week 8
Population: All randomized participants who received at least one dose of study drug, and had baseline and at least one post-baseline heart rate measurement during Weeks 1-8 (Study Period II). Last observation carried forward (LOCF) principle was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Combination | Mean Change in Heart Rate From Baseline to Week 8 Endpoint | 0.839 beats per minute (bpm) |
| Monotherapy | Mean Change in Heart Rate From Baseline to Week 8 Endpoint | -2.478 beats per minute (bpm) |
p-value: <0.001ANCOVA
Other Pre-specified
Number of Participants Who Discontinued From Study Between Baseline and Week 8 Endpoint
Time frame: Baseline through Week 8
Population: All randomized participants who received at least one dose of study drug during Weeks 1-8 (Study Period II).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination | Number of Participants Who Discontinued From Study Between Baseline and Week 8 Endpoint | 68 participants |
| Monotherapy | Number of Participants Who Discontinued From Study Between Baseline and Week 8 Endpoint | 70 participants |
p-value: 0.744Fisher Exact
Other Pre-specified
Number of Participants With Treatment Emergent Adverse Events (TEAE) Between Baseline and Week 8 Endpoint
TEAEs in Study Period II are events that began or worsened after Week 0 compared with the period before Week 0.
Time frame: Baseline through Week 8
Population: All randomized participants who received at least one dose of study drug during Weeks 1-8 (Study Period II).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination | Number of Participants With Treatment Emergent Adverse Events (TEAE) Between Baseline and Week 8 Endpoint | 223 participants |
| Monotherapy | Number of Participants With Treatment Emergent Adverse Events (TEAE) Between Baseline and Week 8 Endpoint | 232 participants |
p-value: 0.618Fisher Exact
Other Pre-specified
Patient Global Impression of Improvement (PGI-I) Score at Week 8 Endpoint
Measures participant's perception of improvement at the time of assessment compared with the start of treatment. The score ranges from 1 (very much better) to 7 (very much worse). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, visit, and treatment\*visit.
Time frame: Week 8
Population: All randomized participants who received at least one dose of study drug, and at least one post-baseline PGI-I measurement during Weeks 1-8 (Study Period II).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Combination | Patient Global Impression of Improvement (PGI-I) Score at Week 8 Endpoint | 2.601 units on a scale |
| Monotherapy | Patient Global Impression of Improvement (PGI-I) Score at Week 8 Endpoint | 2.944 units on a scale |
p-value: <0.001Mixed Models Analysis
Other Pre-specified
Percentage of Participants With a Decrease of Greater Than or Equal to 2 Points on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 8 Endpoint
BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine).
Time frame: Baseline through Week 8
Population: All randomized participants who received at least one dose of study drug, and had baseline and at least one post-baseline BPI measurements during Weeks 1-8 (Study Period II). Last observation carried forward (LOCF) principle was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination | Percentage of Participants With a Decrease of Greater Than or Equal to 2 Points on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 8 Endpoint | 57.1 percentage of participants |
| Monotherapy | Percentage of Participants With a Decrease of Greater Than or Equal to 2 Points on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 8 Endpoint | 45.7 percentage of participants |
p-value: <0.00195% CI: [1.125, 1.456]Cochran-Mantel-Haenszel
Other Pre-specified
Percentage of Participants With a Reduction of Greater Than or Equal to 30% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 8 Endpoint
BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine).
Time frame: Baseline through Week 8
Population: All randomized participants who received at least one dose of study drug, and had baseline and at least one post-baseline BPI measurements during Weeks 1-8 (Study Period II). Last observation carried forward (LOCF) principle was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination | Percentage of Participants With a Reduction of Greater Than or Equal to 30% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 8 Endpoint | 52.0 percentage of participants |
| Monotherapy | Percentage of Participants With a Reduction of Greater Than or Equal to 30% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 8 Endpoint | 36.9 percentage of participants |
p-value: <0.00195% CI: [1.233, 1.662]Cochran-Mantel-Haenszel
Other Pre-specified
Percentage of Participants With a Reduction of Greater Than or Equal to 50% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 8 Endpoint
BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine).
Time frame: Baseline through Week 8
Population: All randomized participants who received at least one dose of study drug, and had baseline and at least one post-baseline BPI measurements during Weeks 1-8 (Study Period II). Last observation carried forward (LOCF) principle was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination | Percentage of Participants With a Reduction of Greater Than or Equal to 50% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 8 Endpoint | 40.3 percentage of participants |
| Monotherapy | Percentage of Participants With a Reduction of Greater Than or Equal to 50% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 8 Endpoint | 27.8 percentage of participants |
p-value: <0.00195% CI: [1.214, 1.771]Cochran-Mantel-Haenszel
Other Pre-specified
Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Baseline Through Week 8
Data presented are the number of days hospitalized and work/school missed (sick leave) due to diabetic peripheral neuropathic pain (DPNP) during the last 8 weeks.
Time frame: Baseline through Week 8
Population: All randomized participants who received at least one dose of study drug and provided information of hospitalization and sick leave during Weeks 1-8 (Study Period II).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Combination | Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Baseline Through Week 8 | Days hospitalized | 0 days | Standard Deviation 0 |
| Combination | Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Baseline Through Week 8 | Days of sick leave (n=108, 101) | 1.9 days | Standard Deviation 8.34 |
| Monotherapy | Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Baseline Through Week 8 | Days hospitalized | 0 days | Standard Deviation 0 |
| Monotherapy | Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Baseline Through Week 8 | Days of sick leave (n=108, 101) | 0.3 days | Standard Deviation 2.04 |