Diabetic Neuropathy, Painful; Diabetic Neuropathies
Conditions
Brief summary
This is a 2-part study. In Part 1 of the study, subjects will undergo a pain reporting training program in which a painful stimulus will be applied to the subject's hand, and the subjects will be asked to report how painful the stimulus is. Over the course of the pain training sessions, feedback will be provided to the subject about how accurately they are reporting their degree of pain, relative to the amount of pressure stimulus applied to evoke pain. Those subjects who have adequate pain reporting ability will be asked to continue into Part 2 of the study in which 3 different blinded study drugs will be administered to each subject, in a crossover design to compare whether or not the study drugs improve pain associated with diabetic neuropathy.
Detailed description
This is a multi-center, randomized, two-part study in adults (ages 18-75 years) with Painful Diabetic Neuropathy (PDN). In Part 1 of the study, eligible subjects will enter a 4-week Pain Training Period. During the Pain Training Period, subjects will receive three weekly in-clinic training sessions using repeated rating of experimental pressure pain stimuli. Subjects will receive feedback during this training and will be evaluated on their pain-reporting ability during each in-clinic session. Subjects with acceptable pain-reporting ability at the conclusion of the Pain Training Period will be eligible to enter Part 2 of the study. Subjects with unacceptable pain-reporting ability at the conclusion of the Pain Training Period will be discontinued from the study. Part 2 of the study will consist of three consecutive double-blind crossover periods. Each crossover period will include 31 days of double-blind treatment. A follow-up visit will occur 14 ± 7 days after the last dose of study medication. One of three treatments (placebo, pregabalin, or pregabalin + AZD5213) will be administered during each crossover treatment period, as determined by a randomly assigned treatment sequence. Approximately 65 subjects will be screened in Part 1 of the study, in order to randomize up to approximately 32 subjects in Part 2 of the study.
Interventions
DRUGAZD5213 + pregabalin
Double blind Investigational drug AZD5213 (capsules) given in combination with pregabalin (capsules)
DRUGPlacebo
Double blind placebo capsules to match AZD5213 and pregabalin
Double blind pregabalin capsules to match AZD5213 and placebo
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1\. Male or female, age 18 to 75 years, inclusive, at Screen. 2. Subjects must provide informed consent in accordance with local regulations before the conduct of any study-related procedures. The informed consent should reflect the protocol stipulations concerning the use of contraception. 3. Diagnosis of Type 1 or Type 2 diabetes mellitus for at least 1 year prior to Screen. 4. Diabetes-related painful neuropathy for at least 6 months prior to Screen. 5. Pain that began in the feet and is symmetric or nearly symmetric. 6. Diabetes has been clinically stable for at least 2 months prior to Screen, and between Screen and baseline (Day 35). 7. At Screen and baseline, score of at least 4 on Item 5 (average pain) of the modified Brief Pain Inventory for patients with painful diabetic peripheral neuropathy (BPI-DPN). 8. Able to participate in all scheduled evaluations and to complete all required tests and procedures. 9. In the opinion of the investigator, the subject must be considered likely to comply with the study protocol and to have a high probability of completing the study.
Exclusion criteria
1\. Known or suspected hypersensitivity to pregabalin. 2. Clinically important illness or infection (e.g., chronic, persistent, or acute infection) within 30 days prior to screen or between screen adn baseline. 3. Presence of any psychiatric or neurologic disorder or any other disorder or symptom, if, in the judgement of the investigator, the disorder or symptom is likely to confound interpretation of drug effect or affect the subject's ability to complete the study. Any clinically important abnormality, as determined by investigator at Screen or baseline, in physical or neurologic examination, vital sign, ECG, or clinical laboratory test results that could be detrimental to the subject, or could affect the subject's ability to complete the study. 4. Initiation or change in intensity or frequency of non-pharmacologic therapy for PDN, including psychotherapy, physical therapy, massage, acupuncture, acupressure, or chiropractic care, within 3 months prior to baseline).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brief Pain Index - Item 5, Average Daily Pain Score (Range 0-10) Higher Values Indicate Worse Pain | 3 weeks of treatment | Brief pain Index - diabetic painful neuropathy (BPI-DPN) - average daily pain, Item 5 (final 2 day diary + in clinic assessment at end of 3 week treatment period) |
Countries
United States
Participant flow
Recruitment details
143 adults with painful diabetic neuropathy were screened, in a total of 146 screenings, 83 met eligibility criteria and entered Pain Training - Part 1. To be randomized into Part 2 (3 period treatment crossover study), participants had to successfully complete Part 1 Pain Training and meet all study entry criteria at Visit 6 (\ Day 36) .
Pre-assignment details
Crossover data starting with First Intervention excludes 3 participants who were randomized but not treated in the double-blind crossover periods. The 3 are included as withdrawals in Part 1 - Placebo run-in (single blind) period.
Participants by arm
| Arm | Count |
|---|---|
| Overall Study Overall Study - Starting with Part 1 | 83 |
| Total | 83 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Part 1 - Pain Training | Lost to Follow-up | 4 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part 1 - Pain Training | Pain training criteria not met | 29 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part 1 - Pain Training | Protocol Violation | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part 1 - Pain Training | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part 2 - First Intervention | Eligibility criterion not met | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Part 2 - First Intervention | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Part 2 - First Intervention | Study specific withdrawal criteria | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Part 2 - First Intervention | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Part 2 - Post Third Intervention | Protocol Violation | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Part 2 - Second Intervention | Lost to Follow-up | 0 | 1 | 0 | 1 | 0 | 0 | 0 |
| Placebo run-in & Part 2 Eligibility | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Placebo run-in & Part 2 Eligibility | Eligibility for Part 2 not met | 10 | 0 | 0 | 0 | 0 | 0 | 0 |
| Placebo run-in & Part 2 Eligibility | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Placebo run-in & Part 2 Eligibility | Withdrawal by Subject | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Screening for Pain Training | Did not qualify (inclusion/Exclusion) | 60 | 0 | 0 | 0 | 0 | 0 | 0 |
| Washout First Intervention | Protocol Violation | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Overall Study |
|---|---|
| Age, Continuous | 57.6 years STANDARD_DEVIATION 9.25 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 78 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 35 Participants |
| Race (NIH/OMB) More than one race | 2 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 | 43 Participants |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 60 Participants |
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 | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 19 / 83 | 8 / 30 | 11 / 28 | 11 / 30 | 32 / 83 |
| serious Total, serious adverse events | 0 / 83 | 0 / 30 | 0 / 28 | 0 / 30 | 0 / 83 |
Outcome results
Primary
Brief Pain Index - Item 5, Average Daily Pain Score (Range 0-10) Higher Values Indicate Worse Pain
Brief pain Index - diabetic painful neuropathy (BPI-DPN) - average daily pain, Item 5 (final 2 day diary + in clinic assessment at end of 3 week treatment period)
Time frame: 3 weeks of treatment
Population: Full Analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part 2 - Placebo | Brief Pain Index - Item 5, Average Daily Pain Score (Range 0-10) Higher Values Indicate Worse Pain | 4.24 Average daily pain score | Standard Error 0.38 |
| Part 2 - Pregabalin + AZD5213 | Brief Pain Index - Item 5, Average Daily Pain Score (Range 0-10) Higher Values Indicate Worse Pain | 4.41 Average daily pain score | Standard Error 0.38 |
| Part 2 - Pregabalin | Brief Pain Index - Item 5, Average Daily Pain Score (Range 0-10) Higher Values Indicate Worse Pain | 4.27 Average daily pain score | Standard Error 0.38 |
p-value: 0.569595% CI: [-0.34, 0.61]Mixed Models Analysis
p-value: 0.890595% CI: [-0.43, 0.49]Mixed Models Analysis
p-value: 0.482295% CI: [-0.3, 0.64]Mixed Models Analysis
Post Hoc
Brief Pain Index - Item 5, Average Daily Pain Score (Range 0-10) Higher Score Indicates Worse Pain - Per Protocol
Brief pain Index - diabetic painful neuropathy (BPI-DPN) - average daily pain, Item 5 (final 2 day home diary + in clinic assessment at end of 3 week treatment)
Time frame: 3 weeks of treatment
Population: Per Protocol
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part 2 - Placebo | Brief Pain Index - Item 5, Average Daily Pain Score (Range 0-10) Higher Score Indicates Worse Pain - Per Protocol | 4.46 Average daily pain score | Standard Error 0.45 |
| Part 2 - Pregabalin + AZD5213 | Brief Pain Index - Item 5, Average Daily Pain Score (Range 0-10) Higher Score Indicates Worse Pain - Per Protocol | 4.35 Average daily pain score | Standard Error 0.45 |
| Part 2 - Pregabalin | Brief Pain Index - Item 5, Average Daily Pain Score (Range 0-10) Higher Score Indicates Worse Pain - Per Protocol | 4.04 Average daily pain score | Standard Error 0.45 |
p-value: 0.223795% CI: [-0.2, 0.82]Mixed Models Analysis
p-value: 0.097895% CI: [-0.93, 0.08]Mixed Models Analysis
p-value: 0.66195% CI: [-0.62, 0.4]Mixed Models Analysis