Cryptogenic Sensory Polyneuropathy
Conditions
Keywords
CSPN, neuropathy, pain, pain management
Brief summary
The purpose of this large comparative effectiveness study led by Richard J. Barohn, MD, of the University of Kansas Medical Center, is to learn about the safety and effectiveness of nortriptyline, duloxetine, pregabalin and mexiletine in treating cryptogenic sensory polyneuropathy (CSPN).
Detailed description
The goal of this research project is to find the best drug for the treatment of pain in patients with CSPN. While the pharmaceutical industry has focused attention on drugs for treating diabetic sensory neuropathy (DSPN), and two drugs are now FDA approved, there have not been any prospective trials in CSPN. And, because there are no studies with CSPN patients, insurance carriers often reject authorizing prescriptions for some drugs for patients with CSPN. There are four drugs that will be tested in this study: nortriptyline, duloxetine, pregabalin and mexiletine. These drugs are not approved by the FDA for the treatment of CSPN and are considered investigational in this study. There are two periods in this study: Screening/Baseline and Study Drug. During the Screening/Baseline period the researchers will determine eligibility for potential subjects. During the second period, eligible patients who consented to participate will take the study drug. Participants will be randomized to receive one of the four drugs in this study. Participants will know which drug they are taking. Participants will not be allowed to switch groups and receive a different drug during the study. This study uses an adaptive study design. This means the study can enroll less participants and provide better conclusions. The study design allows the researchers the ability to make changes to the approach of the study or to stop the study early if there are strong results.
Interventions
DRUGNortriptyline
DRUGDuloxetine
DRUGPregabalin
DRUGMexiletine
Sponsors
Patient-Centered Outcomes Research Institute
University of Kansas Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of cryptogenic sensory polyneuropathy. * Likert Pain Score of greater than or equal to 4. * Must not currently be on nortriptyline, duloxetine, pregabalin or mexiletine or similar class of medication for at least 7 days from baseline study visit.
Exclusion criteria
* Any medical condition or current medication that would prevent them from taking either nortriptyline, duloxetine, pregabalin or mexiletine. * Unable to give consent. * Unable or not willing to comply with the study. * Other causes for polyneuropathy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Co-Primary Measures: Percent of Patients With at Least a 50% Decrease in Likert Pain Scale From Baseline to Week 12 Follow Up and Percent of Patients That Quit | 12 weeks | The final outcome of the study is a combination of two endpoints, efficacy and quit or treatment discontinuation rates. The first endpoint was a patient responder-defined measure of efficacy. A patient was deemed efficacious if a 50% or more reduction was observed in the Likert pain-scale from the baseline visit to the 12 week visit (i.e. 6 at baseline to 3 or less at week 12). The second endpoint was the observed percentage of patients who discontinued treatment prior to the last follow up visit for any reason or were lost to follow up. The utility function, which combines efficacy and quit rates, was used to drive the adaptive randomization, stopping criteria, and final analysis conclusions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| SF12 Health Composite Scores | 12 weeks | SF-12v2® Health Survey Standard The Optum™ SF-12v2® Health Survey is a shorter version of the SF-36v2® Health Survey that uses just 12 questions to measure functional health and well-being from the patient's point of view. Survey provides psychometrically-based physical component summary (PCS) and mental component summary (MCS) scores. Scores are calibrated so that 50 is the average score or norm, standard deviation = 10. Higher scores indicate better health for both mental and physical component summary scores. |
| PROMIS Pain Interference Short Form v1.0 8a T Score | 12 weeks | Higher scores for pain interference represents worse outcome (more pain interference) T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population. |
| PROMIS Fatigue Short Form v1.0 8a | 12 Weeks | Higher scores for fatigue represents worse outcome (more fatigue). T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population. |
| PROMIS Sleep Disturbance Short Form v1.0 8a | 12 weeks | Higher scores for sleep disturbance represents worse outcome (more sleep disturbance). T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population. Higher scores equals more of the concept being measured |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nortriptyline Nortriptyline - 25 mg daily for 1 week at bedtime, then 50 mg daily at bedtime for 1 week, then 75 mg daily at bedtime for the remainder of the study.
Nortriptyline | 134 |
| Duloxetine Duloxetine - 20 mg daily for 1 week, then 40 mg daily for 1 week, then 60 mg daily for the remainder of the study.
Duloxetine | 126 |
| Pregabalin Pregabalin - 100 mg at bedtime for 1 week, then 100 mg 2 times per day for 1 week, then 100 mg 3 times per day for the remainder of the study.
Pregabalin | 73 |
| Mexiletine Mexiletine - 200 mg at bedtime for 1 week, then 200 mg 2 times per day for 1 week, then 200 mg 3 times per day for the remainder of the study.
Mexiletine | 69 |
| Total | 402 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 8 | 3 | 4 |
Baseline characteristics
| Characteristic | Nortriptyline | Duloxetine | Pregabalin | Mexiletine | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 43 Participants | 40 Participants | 23 Participants | 28 Participants | 134 Participants |
| Age, Categorical Between 18 and 65 years | 91 Participants | 86 Participants | 50 Participants | 41 Participants | 268 Participants |
| Age, Continuous | 60.3 years STANDARD_DEVIATION 12.7 | 59.9 years STANDARD_DEVIATION 14 | 59.5 years STANDARD_DEVIATION 13.6 | 60.7 years STANDARD_DEVIATION 13.7 | 60.1 years STANDARD_DEVIATION 13.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 6 Participants | 4 Participants | 3 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 126 Participants | 119 Participants | 68 Participants | 66 Participants | 379 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Likert Pain Scale | 6.9 units on a scale STANDARD_DEVIATION 1.5 | 6.7 units on a scale STANDARD_DEVIATION 1.6 | 6.4 units on a scale STANDARD_DEVIATION 1.6 | 6.5 units on a scale STANDARD_DEVIATION 1.7 | 6.7 units on a scale STANDARD_DEVIATION 1.6 |
| Patient-Reported Outcomes Measurement Information System (PROMIS) Scale T-Scores PROMIS Fatigue T-Score | 59.6 T-Score STANDARD_DEVIATION 3.4 | 59.7 T-Score STANDARD_DEVIATION 3.3 | 59.1 T-Score STANDARD_DEVIATION 3.7 | 59.7 T-Score STANDARD_DEVIATION 3.2 | 59.6 T-Score STANDARD_DEVIATION 3.4 |
| Patient-Reported Outcomes Measurement Information System (PROMIS) Scale T-Scores PROMIS Pain Interference T-Score | 63.1 T-Score STANDARD_DEVIATION 7 | 62.4 T-Score STANDARD_DEVIATION 6.8 | 63.3 T-Score STANDARD_DEVIATION 5.5 | 60.9 T-Score STANDARD_DEVIATION 7.9 | 62.5 T-Score STANDARD_DEVIATION 6.9 |
| Patient-Reported Outcomes Measurement Information System (PROMIS) Scale T-Scores PROMIS Sleep Disturbance T-Score | 59.1 T-Score STANDARD_DEVIATION 9.8 | 60.6 T-Score STANDARD_DEVIATION 8.3 | 59.8 T-Score STANDARD_DEVIATION 8.7 | 57.0 T-Score STANDARD_DEVIATION 11.4 | 59.3 T-Score STANDARD_DEVIATION 9.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 4 Participants | 4 Participants | 3 Participants | 17 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 11 Participants | 4 Participants | 1 Participants | 26 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 7 Participants | 3 Participants | 1 Participants | 15 Participants |
| Race (NIH/OMB) White | 113 Participants | 104 Participants | 62 Participants | 64 Participants | 343 Participants |
| Region of Enrollment United States | 134 Participants | 126 Participants | 73 Participants | 69 Participants | 402 Participants |
| Sex: Female, Male Female | 59 Participants | 68 Participants | 34 Participants | 28 Participants | 189 Participants |
| Sex: Female, Male Male | 75 Participants | 58 Participants | 39 Participants | 41 Participants | 213 Participants |
| SF12 Health Component Scores Mental Component Score | 48.0 Norm-Based Standardization Score STANDARD_DEVIATION 10.4 | 46.7 Norm-Based Standardization Score STANDARD_DEVIATION 10.1 | 46.8 Norm-Based Standardization Score STANDARD_DEVIATION 11.3 | 47.2 Norm-Based Standardization Score STANDARD_DEVIATION 11.1 | 47.2 Norm-Based Standardization Score STANDARD_DEVIATION 10.6 |
| SF12 Health Component Scores Physical Component Score | 38.0 Norm-Based Standardization Score STANDARD_DEVIATION 9.3 | 38.5 Norm-Based Standardization Score STANDARD_DEVIATION 9.3 | 37.9 Norm-Based Standardization Score STANDARD_DEVIATION 9.1 | 41.1 Norm-Based Standardization Score STANDARD_DEVIATION 10.1 | 38.7 Norm-Based Standardization Score STANDARD_DEVIATION 9.4 |
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 / 134 | 0 / 126 | 0 / 73 | 0 / 69 |
| other Total, other adverse events | 75 / 134 | 59 / 126 | 29 / 73 | 27 / 69 |
| serious Total, serious adverse events | 0 / 134 | 0 / 126 | 0 / 73 | 0 / 69 |
Outcome results
Primary
Co-Primary Measures: Percent of Patients With at Least a 50% Decrease in Likert Pain Scale From Baseline to Week 12 Follow Up and Percent of Patients That Quit
The final outcome of the study is a combination of two endpoints, efficacy and quit or treatment discontinuation rates. The first endpoint was a patient responder-defined measure of efficacy. A patient was deemed efficacious if a 50% or more reduction was observed in the Likert pain-scale from the baseline visit to the 12 week visit (i.e. 6 at baseline to 3 or less at week 12). The second endpoint was the observed percentage of patients who discontinued treatment prior to the last follow up visit for any reason or were lost to follow up. The utility function, which combines efficacy and quit rates, was used to drive the adaptive randomization, stopping criteria, and final analysis conclusions.
Time frame: 12 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nortriptyline | Co-Primary Measures: Percent of Patients With at Least a 50% Decrease in Likert Pain Scale From Baseline to Week 12 Follow Up and Percent of Patients That Quit | Efficacious and Non-Quit | 34 Participants |
| Nortriptyline | Co-Primary Measures: Percent of Patients With at Least a 50% Decrease in Likert Pain Scale From Baseline to Week 12 Follow Up and Percent of Patients That Quit | Quit | 51 Participants |
| Nortriptyline | Co-Primary Measures: Percent of Patients With at Least a 50% Decrease in Likert Pain Scale From Baseline to Week 12 Follow Up and Percent of Patients That Quit | Non-Efficacious and Non-Quit | 49 Participants |
| Duloxetine | Co-Primary Measures: Percent of Patients With at Least a 50% Decrease in Likert Pain Scale From Baseline to Week 12 Follow Up and Percent of Patients That Quit | Efficacious and Non-Quit | 29 Participants |
| Duloxetine | Co-Primary Measures: Percent of Patients With at Least a 50% Decrease in Likert Pain Scale From Baseline to Week 12 Follow Up and Percent of Patients That Quit | Quit | 47 Participants |
| Duloxetine | Co-Primary Measures: Percent of Patients With at Least a 50% Decrease in Likert Pain Scale From Baseline to Week 12 Follow Up and Percent of Patients That Quit | Non-Efficacious and Non-Quit | 50 Participants |
| Pregabalin | Co-Primary Measures: Percent of Patients With at Least a 50% Decrease in Likert Pain Scale From Baseline to Week 12 Follow Up and Percent of Patients That Quit | Non-Efficacious and Non-Quit | 31 Participants |
| Pregabalin | Co-Primary Measures: Percent of Patients With at Least a 50% Decrease in Likert Pain Scale From Baseline to Week 12 Follow Up and Percent of Patients That Quit | Efficacious and Non-Quit | 11 Participants |
| Pregabalin | Co-Primary Measures: Percent of Patients With at Least a 50% Decrease in Likert Pain Scale From Baseline to Week 12 Follow Up and Percent of Patients That Quit | Quit | 31 Participants |
| Mexiletine | Co-Primary Measures: Percent of Patients With at Least a 50% Decrease in Likert Pain Scale From Baseline to Week 12 Follow Up and Percent of Patients That Quit | Efficacious and Non-Quit | 14 Participants |
| Mexiletine | Co-Primary Measures: Percent of Patients With at Least a 50% Decrease in Likert Pain Scale From Baseline to Week 12 Follow Up and Percent of Patients That Quit | Quit | 40 Participants |
| Mexiletine | Co-Primary Measures: Percent of Patients With at Least a 50% Decrease in Likert Pain Scale From Baseline to Week 12 Follow Up and Percent of Patients That Quit | Non-Efficacious and Non-Quit | 15 Participants |
Secondary
PROMIS Fatigue Short Form v1.0 8a
Higher scores for fatigue represents worse outcome (more fatigue). T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population.
Time frame: 12 Weeks
Population: No secondary data were collected for participants who 'Quit' taking the study medication prior to study completion. Thus, only participants that were deemed efficacious and non-quit, or non-efficacious and non-quit at the primary outcome were collected and analyzed for the secondary outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nortriptyline | PROMIS Fatigue Short Form v1.0 8a | 53.6 T-Score | Standard Deviation 9.5 |
| Duloxetine | PROMIS Fatigue Short Form v1.0 8a | 55.4 T-Score | Standard Deviation 10.2 |
| Pregabalin | PROMIS Fatigue Short Form v1.0 8a | 56.7 T-Score | Standard Deviation 10.6 |
| Mexiletine | PROMIS Fatigue Short Form v1.0 8a | 51.6 T-Score | Standard Deviation 10.7 |
Secondary
PROMIS Pain Interference Short Form v1.0 8a T Score
Higher scores for pain interference represents worse outcome (more pain interference) T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population.
Time frame: 12 weeks
Population: No secondary data were collected for participants who 'Quit' taking the study medication prior to study completion. Thus, only participants that were deemed efficacious and non-quit, or non-efficacious and non-quit at the primary outcome were collected and analyzed for the secondary outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nortriptyline | PROMIS Pain Interference Short Form v1.0 8a T Score | 56.4 T-Score | Standard Deviation 8.4 |
| Duloxetine | PROMIS Pain Interference Short Form v1.0 8a T Score | 56.5 T-Score | Standard Deviation 8.3 |
| Pregabalin | PROMIS Pain Interference Short Form v1.0 8a T Score | 60.0 T-Score | Standard Deviation 7.5 |
| Mexiletine | PROMIS Pain Interference Short Form v1.0 8a T Score | 54.5 T-Score | Standard Deviation 8.8 |
Secondary
PROMIS Sleep Disturbance Short Form v1.0 8a
Higher scores for sleep disturbance represents worse outcome (more sleep disturbance). T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population. Higher scores equals more of the concept being measured
Time frame: 12 weeks
Population: No secondary data were collected for participants who 'Quit' taking the study medication prior to study completion. Thus, only participants that were deemed efficacious and non-quit, or non-efficacious and non-quit at the primary outcome were collected and analyzed for the secondary outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nortriptyline | PROMIS Sleep Disturbance Short Form v1.0 8a | 58.9 T-Score | Standard Deviation 2.5 |
| Duloxetine | PROMIS Sleep Disturbance Short Form v1.0 8a | 58.9 T-Score | Standard Deviation 2.6 |
| Pregabalin | PROMIS Sleep Disturbance Short Form v1.0 8a | 58.3 T-Score | Standard Deviation 2.3 |
| Mexiletine | PROMIS Sleep Disturbance Short Form v1.0 8a | 59.1 T-Score | Standard Deviation 2 |
Secondary
SF12 Health Composite Scores
SF-12v2® Health Survey Standard The Optum™ SF-12v2® Health Survey is a shorter version of the SF-36v2® Health Survey that uses just 12 questions to measure functional health and well-being from the patient's point of view. Survey provides psychometrically-based physical component summary (PCS) and mental component summary (MCS) scores. Scores are calibrated so that 50 is the average score or norm, standard deviation = 10. Higher scores indicate better health for both mental and physical component summary scores.
Time frame: 12 weeks
Population: No secondary data were collected for participants who 'Quit' taking the study medication prior to study completion. Thus, only participants that were deemed efficacious and non-quit, or non-efficacious and non-quit at the primary outcome were collected and analyzed for the secondary outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nortriptyline | SF12 Health Composite Scores | Mental Component Score | 51.0 Norm-Based Standardization Score | Standard Deviation 8.9 |
| Nortriptyline | SF12 Health Composite Scores | Physical Component Score | 42.8 Norm-Based Standardization Score | Standard Deviation 8.7 |
| Duloxetine | SF12 Health Composite Scores | Physical Component Score | 42.1 Norm-Based Standardization Score | Standard Deviation 9.5 |
| Duloxetine | SF12 Health Composite Scores | Mental Component Score | 50.9 Norm-Based Standardization Score | Standard Deviation 9.9 |
| Pregabalin | SF12 Health Composite Scores | Mental Component Score | 47.2 Norm-Based Standardization Score | Standard Deviation 11.2 |
| Pregabalin | SF12 Health Composite Scores | Physical Component Score | 40.0 Norm-Based Standardization Score | Standard Deviation 8.2 |
| Mexiletine | SF12 Health Composite Scores | Mental Component Score | 51.3 Norm-Based Standardization Score | Standard Deviation 10.8 |
| Mexiletine | SF12 Health Composite Scores | Physical Component Score | 43.7 Norm-Based Standardization Score | Standard Deviation 9.6 |