Chronic Pain, Diabetes Mellitus, Diabetic Neuropathies
Conditions
Keywords
Painful Diabetic Peripheral Neuropathy
Brief summary
The purpose of this trial is to evaluate if cebranopadol is safe and can decrease pain in patients when compared to placebo (a tablet that does not contain active product) and when compared to a marketed product containing pregabalin (Lyrica®). Furthermore, this trial will be undertaken to find out if the patient's general health and well-being improves under trial treatment. The concentrations of cebranopadol in the blood will be investigated to get a better understanding of how it is absorbed from the gut, distributed and broken down in the body, and eliminated from the body.
Interventions
DRUGCebranopadol 100 µg
Participants randomized to 100 μg cebranopadol will start with 100 μg per day and will remain on 100 µg per day.
DRUGCebranopadol 300 µg
Participants randomized to 300 μg cebranopadol will start with 100 μg per day and increase to 300 µg per day on day 4 and will remain on 300 µg per day.
Participants randomized to 600 μg cebranopadol will start with 200 μg per day and increase to 400 µg per day on day 4 and to 600 µg on day 7, thereafter they will remain on 600 µg per day.
DRUGPregabalin
Stepwise titration from 75 mg twice a day to 300 mg twice a day over 2 weeks.
DRUGMatching Placebo
Placebo will be matched to pregabalin and cebranopadol.
Sponsors
Tris Pharma, Inc.
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 80 Years
Healthy volunteers
No
Inclusion criteria
* written signed informed consent * type 1 or type 2 diabetes mellitus * clinical diagnosis of painful Diabetic Polyneuropathic Neuropathy (DPN) with symptoms and signs for at least 3 months * must require medication (e.g., non-opioids or opioids up to an equivalent dose of 160 mg oral morphine/day) for the treatment of pain due to DPN for at least 1 month prior to Visit 1 and must be dissatisfied with the current treatment (in terms of efficacy and/or tolerability). Medication for the treatment of pain due to DPN should be required on at least 4 of 7 consecutive days. * blood glucose to be controlled by a diet, oral anti-hyperglycemic medication, and/or insulin for at least 3 months prior. Glycosylated hemoglobin (HbA1C) should not be greater than 11% * baseline pain intensity score greater or equal to 5 on the 11-point Numerical Rating Scale (NRS) without intake of any analgesic at allocation. For each of the last 3 days prior to allocation of treatment, a 24 hour NRS score greater or equal to 4 is required * women of childbearing potential must have a negative urine pregnancy test at enrollment * using medically acceptable and highly effective methods of birth control (and willing to use them during the trial).
Exclusion criteria
* presence of other pain that could confound the painful Diabetic Polyneuropathy (DPN) assessments, e.g. pain due to nerve entrapment (tarsal tunnel syndrome, osteoarthritis of the knee etc), peripheral vascular disease, radiculopathy, plantar fasciitis, tendonitis, mononeuritis multiplex, postherpetic neuralgia, complex regional pain syndrome, or fibromyalgia. * neuropathy due to etiologies other than diabetes, e.g. autoimmune disorders, inflammatory neuropathies (e.g. chronic inflammatory demyelinating polyneuropathy), thyroid disease or endocrine disorders (other than diabetes), heavy metal or toxic neuropathy, nutritional deficiency, metabolic disorders, vasculitis, infections, injury, or paraneoplastic syndromes. * severe or extensive diabetic ulcers or amputations due to diabetes * Charcot's joints due to diabetes. * any clinically significant disease or laboratory findings, e.g., significant unstable cardiac, vascular, pulmonary, gastrointestinal, endocrine, metabolic, neurological, or psychiatric disorders. * inability to comply with the protocol and with the intake of trial medication that, in the investigator's opinion, might indicate that the participant is unsuitable for the trial. * conditions that require treatment with medication that is not allowed to be taken during the trial * previous or current alcohol or drug abuse or opioid dependency. * severe functional hepatic impairment corresponding to Child-Pugh classification C. * history of acute hepatitis * impaired renal function, a creatinine clearance less than 60 mL/min at the enrollment (Cockcroft-Gault calculated). * history of any major gastrointestinal procedures (e.g., gastric bypass) or gastrointestinal conditions (e.g. acute diarrhea, blind loop syndrome, gastric dumping syndrome, Whipple's disease) that might affect the absorption or metabolism of cebranopadol or pregabalin. * risk factors for or history of torsade de pointes and/or marked prolongation of the QT interval (e.g. heart failure, hypokalemia, or bradycardia). * history of seizure disorder and/or epilepsy or any condition associated with a significant risk for seizure disorder or epilepsy at the discretion of the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Average Pain Intensity. | Baseline; to End of Week 6 of the Maintenance Phase | Participants will be asked to record their pain intensity in the evening. Participants are asked to rate how much pain they had on average in the past 24 hours. The participant scores their pain intensity on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine. Baseline average pain scores are calculated from the averages of all scores recorded during the 3 days prior to randomization. The average pain at week 6 will be the average pain scores calculated from all pain scores measured during week 6. |
Countries
Austria, Denmark, France, Germany, Italy, Netherlands, Spain, United States
Participant flow
Recruitment details
The trial started on 27 Sep 2013 with the enrollment of the first participants and was completed on 28 Jan 2015 when the last participant completed the last follow-up examination according to the protocol.
Pre-assignment details
Of the 699 participants enrolled 370 participants were not allocated (322 did not meet the eligibility criteria, 29 withdrew consent, 6 due to Adverse Events, 2 due to protocol deviations, 11 due to other reasons). 13 participants allocated to treatment were excluded from the PPS, FAS & SAF analyses populations due to GCP non-compliance at 2 sites.
Participants by arm
| Arm | Count |
|---|---|
| Cebranopadol 100 µg Cebranopadol 100 µg: Participants randomized to 100 μg cebranopadol will start with 100 μg per day and will remain on 100 µg per day. | 64 |
| Cebranopadol 300 µg Cebranopadol 300 µg: Participants randomized to 300 μg cebranopadol will start with 100 μg per day and increase to 300 µg per day on day 4 and will remain on 300 µg per day. | 61 |
| Cebranopadol 600 µg Cebranopadol 600 µg: Participants randomized to 600 μg cebranopadol will start with 200 μg per day and increase to 400 µg per day on day 4 and to 600 µg on day 7, thereafter they will remain on 600 µg per day. | 62 |
| Pregabalin Pregabalin: Stepwise titration from 75 mg twice a day to 300 mg twice a day over 2 weeks. | 65 |
| Matching Placebo Matching Placebo: Placebo will be matched to pregabalin and cebranopadol. | 62 |
| Total | 314 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 8 | 17 | 30 | 8 | 5 |
| Overall Study | GCP non-compliance at site | 2 | 3 | 2 | 3 | 3 |
| Overall Study | Inclusion criteria not met | 0 | 1 | 1 | 0 | 1 |
| Overall Study | Lack of Efficacy | 2 | 1 | 1 | 1 | 3 |
| Overall Study | Lost to Follow-up | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Other | 0 | 0 | 2 | 2 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Sponsor decision | 0 | 0 | 0 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 2 | 2 | 3 |
Baseline characteristics
| Characteristic | Cebranopadol 100 µg | Total | Matching Placebo | Pregabalin | Cebranopadol 600 µg | Cebranopadol 300 µg |
|---|---|---|---|---|---|---|
| Age, Continuous | 62.2 years STANDARD_DEVIATION 8.6 | 62.2 years STANDARD_DEVIATION 9.1 | 63.3 years STANDARD_DEVIATION 10.3 | 61.7 years STANDARD_DEVIATION 9.9 | 62.2 years STANDARD_DEVIATION 8.1 | 61.6 years STANDARD_DEVIATION 8.7 |
| BMI | 32.30 kilogram per square meter STANDARD_DEVIATION 4.41 | 31.86 kilogram per square meter STANDARD_DEVIATION 4.62 | 32.80 kilogram per square meter STANDARD_DEVIATION 4.53 | 30.66 kilogram per square meter STANDARD_DEVIATION 5.26 | 31.70 kilogram per square meter STANDARD_DEVIATION 4.29 | 31.87 kilogram per square meter STANDARD_DEVIATION 4.39 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 34 Participants | 5 Participants | 10 Participants | 6 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 57 Participants | 280 Participants | 57 Participants | 55 Participants | 56 Participants | 55 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 1.721 meter STANDARD_DEVIATION 0.098 | 1.729 meter STANDARD_DEVIATION 0.097 | 1.736 meter STANDARD_DEVIATION 0.076 | 1.736 meter STANDARD_DEVIATION 0.11 | 1.717 meter STANDARD_DEVIATION 0.104 | 1.736 meter STANDARD_DEVIATION 0.092 |
| Pain Assessment - Average 24-hour pain | 6.92 units on a scale STANDARD_DEVIATION 1.34 | 6.83 units on a scale STANDARD_DEVIATION 1.26 | 6.84 units on a scale STANDARD_DEVIATION 1.15 | 6.78 units on a scale STANDARD_DEVIATION 1.22 | 6.80 units on a scale STANDARD_DEVIATION 1.25 | 6.80 units on a scale STANDARD_DEVIATION 1.37 |
| Pain Assessment - Current Evening Pain | 6.98 units on a scale STANDARD_DEVIATION 1.5 | 6.80 units on a scale STANDARD_DEVIATION 1.4 | 6.55 units on a scale STANDARD_DEVIATION 1.34 | 6.75 units on a scale STANDARD_DEVIATION 1.36 | 6.68 units on a scale STANDARD_DEVIATION 1.33 | 6.87 units on a scale STANDARD_DEVIATION 1.46 |
| Pain Assessment - Current Morning Pain | 6.60 units on a scale STANDARD_DEVIATION 1.58 | 6.56 units on a scale STANDARD_DEVIATION 1.49 | 6.58 units on a scale STANDARD_DEVIATION 1.48 | 6.61 units on a scale STANDARD_DEVIATION 1.44 | 6.44 units on a scale STANDARD_DEVIATION 1.46 | 6.58 units on a scale STANDARD_DEVIATION 1.53 |
| Pain Assessment - Worst 24-hour pain | 7.41 units on a scale STANDARD_DEVIATION 1.36 | 7.35 units on a scale STANDARD_DEVIATION 1.23 | 7.33 units on a scale STANDARD_DEVIATION 1.14 | 7.32 units on a scale STANDARD_DEVIATION 1.16 | 7.38 units on a scale STANDARD_DEVIATION 1.21 | 7.32 units on a scale STANDARD_DEVIATION 1.28 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 4 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 9 Participants | 1 Participants | 4 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 6 Participants | 0 Participants | 3 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 61 Participants | 295 Participants | 61 Participants | 58 Participants | 57 Participants | 58 Participants |
| Region of Enrollment Austria | 5 participants | 27 participants | 5 participants | 6 participants | 5 participants | 6 participants |
| Region of Enrollment Denmark | 2 participants | 9 participants | 2 participants | 1 participants | 2 participants | 2 participants |
| Region of Enrollment France | 7 participants | 38 participants | 8 participants | 8 participants | 8 participants | 7 participants |
| Region of Enrollment Germany | 31 participants | 154 participants | 31 participants | 32 participants | 30 participants | 30 participants |
| Region of Enrollment Italy | 2 participants | 9 participants | 1 participants | 2 participants | 2 participants | 2 participants |
| Region of Enrollment Netherlands | 3 participants | 16 participants | 4 participants | 2 participants | 4 participants | 3 participants |
| Region of Enrollment Spain | 1 participants | 6 participants | 1 participants | 1 participants | 2 participants | 1 participants |
| Region of Enrollment United States | 13 participants | 55 participants | 10 participants | 13 participants | 9 participants | 10 participants |
| Sex: Female, Male Female | 20 Participants | 94 Participants | 13 Participants | 16 Participants | 22 Participants | 23 Participants |
| Sex: Female, Male Male | 44 Participants | 220 Participants | 49 Participants | 49 Participants | 40 Participants | 38 Participants |
| Weight | 95.77 kilogram STANDARD_DEVIATION 15.62 | 95.42 kilogram STANDARD_DEVIATION 16.69 | 99.00 kilogram STANDARD_DEVIATION 15.99 | 92.25 kilogram STANDARD_DEVIATION 17.28 | 93.72 kilogram STANDARD_DEVIATION 16.05 | 96.51 kilogram STANDARD_DEVIATION 18.12 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 64 | 0 / 61 | 0 / 62 | 0 / 65 | 0 / 62 |
| other Total, other adverse events | 47 / 64 | 50 / 61 | 53 / 62 | 49 / 65 | 43 / 62 |
| serious Total, serious adverse events | 1 / 64 | 2 / 61 | 4 / 62 | 1 / 65 | 2 / 62 |
Outcome results
Primary
Change in Average Pain Intensity.
Participants will be asked to record their pain intensity in the evening. Participants are asked to rate how much pain they had on average in the past 24 hours. The participant scores their pain intensity on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine. Baseline average pain scores are calculated from the averages of all scores recorded during the 3 days prior to randomization. The average pain at week 6 will be the average pain scores calculated from all pain scores measured during week 6.
Time frame: Baseline; to End of Week 6 of the Maintenance Phase
Population: Full Analysis Set (FAS). Mixed-effects model for repeated measures (MMRM).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cebranopadol 100 µg | Change in Average Pain Intensity. | -2.24 units on a scale |
| Cebranopadol 300 µg | Change in Average Pain Intensity. | -2.28 units on a scale |
| Cebranopadol 600 µg | Change in Average Pain Intensity. | -2.56 units on a scale |
| Pregabalin | Change in Average Pain Intensity. | -2.79 units on a scale |
| Matching Placebo | Change in Average Pain Intensity. | -1.55 units on a scale |
Comparison: The mixed model repeated measurement (MMRM) model included fixed effects of pooled sites, treatment, week, treatment-by-week interaction, baseline pain, and a subject-specific random effect. The model was based on the weekly average 24-hour pain intensity of the 2 weeks in the Titration Phase and 6 weeks in the Maintenance Phase. An unstructured covariance matrix was used to model the covariance structure, denominator degrees of freedom were estimated using the Kenward-Roger approximation.p-value: 0.062195% CI: [-1.43, 0.04]Mixed Models Analysis
Comparison: The mixed model repeated measurement (MMRM) model included fixed effects of pooled sites, treatment, week, treatment-by-week interaction, baseline pain, and a subject-specific random effect. The model was based on the weekly average 24-hour pain intensity of the 2 weeks in the Titration Phase and 6 weeks in the Maintenance Phase. An unstructured covariance matrix was used to model the covariance structure, denominator degrees of freedom were estimated using the Kenward-Roger approximation.p-value: 0.056495% CI: [-1.5, 0.02]Mixed Models Analysis
Comparison: The mixed model repeated measurement (MMRM) model included fixed effects of pooled sites, treatment, week, treatment-by-week interaction, baseline pain, and a subject-specific random effect. The model was based on the weekly average 24-hour pain intensity of the 2 weeks in the Titration Phase and 6 weeks in the Maintenance Phase. An unstructured covariance matrix was used to model the covariance structure, denominator degrees of freedom were estimated using the Kenward-Roger approximation.p-value: 0.015395% CI: [-1.83, -0.2]Mixed Models Analysis