HIV Infections, Pain, Peripheral Nervous System Diseases
Conditions
Keywords
Analgesics, Capsaicin, Neuropathic pain, Neuropathy, Distal sensory polyneuropathy, Peripheral neuropathy, Dermal assessment, Pain measurement
Brief summary
The purpose of the study was to assess the efficacy and safety of NGX-4010 applied for 30 or 60 minutes for the treatment of painful HIV-associated neuropathy.
Detailed description
Study C119 was a multicenter, randomized, double-blind, controlled evaluation of the efficacy and safety of NGX-4010 for the treatment of painful HIV-associated neuropathy. Eligible subjects had painful HIV-associated neuropathy resulting from HIV disease and/or antiretroviral drug exposure in both feet, with average numeric pain rating scale (NPRS) scores during screening of 3 to 9 (inclusive). Up to four patches covering an area of up to 1120 square centimeters could be used during a single treatment administration in this study. Subjects were randomly assigned to receive active NGX-4010 patches (8% capsaicin) or low-concentration control patches (0.04% capsaicin) identical in appearance, at doses (patch application duration) of either 30 or 60 minutes, according to a 2:1:2:1 allocation scheme. Subjects could be on stable chronic oral pain medication regimens, but could not be using any topical pain medications on the affected areas. NPRS scores for the average pain in the past 24 hours were recorded daily in the evening, beginning on the day of the Screening Visit (usually on Day -14). Subjects continued to record NPRS scores in a take-home diary from the evening on the day of treatment through the evening before the Termination Visit at Week 12. Subjects returned for interim follow-up visits at Weeks 4 and 8 following study treatment.
Interventions
DRUGNGX-4010, 8% capsaicin patch
Up to 4 NGX-4010 patches of 280 cm\^2 each were applied to the feet (2 per foot) for 60 minutes.
DRUG0.04% capsaicin patch
Up to 4 control patches of 280 cm\^2 each were applied to the feet (2 per foot) for 60 minutes.
Sponsors
NeurogesX
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
* Documented evidence of HIV-1 infection * Documented diagnosis of painful HIV-associated distal symmetric polyneuropathy resulting from HIV disease and/or antiretroviral drug exposure To be confirmed based on symptoms of pain, burning or dysesthetic discomfort in both feet for at least 2 months prior to Screening Visit, AND absent or diminished ankle reflexes OR at least one of following: distal diminution of vibration sensation or pain or temperature sensation in legs * Average NPRS scores during screening period of 3 to 9, inclusive * Life expectancy of 12 months or longer per Investigator's judgment * Intact, unbroken skin over painful areas to be treated * If taking chronic pain medications, be on stable regimen for at least 21 days prior to Day 0 and willing to maintain medications at same stable dose(s) and schedule throughout study * Female subjects with child-bearing potential: negative serum pregnancy test performed at Screening Visit * Willing to use effective methods of birth control and/or refrain from conception process during study and for 30 days following study drug exposure * Willing and able to comply with protocol for duration of study
Exclusion criteria
* Concomitant opioid medication, unless orally or transdermally administered and not exceeding total daily dose of morphine 80 mg/day or equivalent; parenteral opioids not allowed * Unavailability of effective rescue medication strategy for subject, such as unwillingness to use opioid analgesics during study treatment or high tolerance to opioids precluding ability to relieve treatment-associated discomfort as judged by investigator * Active substance abuse or history of chronic substance abuse within past year or prior chronic substance abuse (including alcoholism) judged likely to recur during study period by investigator * Recent use (within 21 days preceding Day 0) of any topically applied pain medication, such as non-steroidal anti-inflammatory drugs, menthol, methyl salicylate, local anesthetics including Lidoderm® (lidocaine patch 5%), steroids or capsaicin products on painful areas * Started or stopped treatment with one or more neurotoxic antiretroviral agents (ie, didanosine \[ddI\], zalcitabine \[ddC\], or stavudine \[d4T\] during 8 weeks prior to Day 0 * Participation in previous clinical trial in which subject received either blinded or open-label NGX-4010 * Current use of any investigational agent or Class 1 anti-arrhythmic drugs (such as tocainide and mexiletine) * Evidence of another contributing cause for peripheral neuropathy, e.g., current uncontrolled diabetes mellitus (HbA1c≥9%) or history of diabetes mellitus preceding onset of HIV-associated neuropathy (HIV-AN); hereditary neuropathy; vitamin B12 deficiency (B12 level ≤200pg/mL at screening); or treatment within 90 days prior to Screening Visit with any drug that may have contributed to sensory neuropathy * Hypertension, unless adequately controlled by medication * Significant ongoing pain from other cause(s) that may interfere with judging HIV-AN related pain * Any implanted medical device for treatment of neuropathic pain * Hypersensitivity to capsaicin (i.e., chili peppers or over-the-counter (OTC) capsaicin products), local anesthetics, opioid-based oral analgesics or adhesives * Significant medical conditions (including active malignancy defined as treatment required in last 5 years) that in opinion of investigator would interfere with ability to complete study or evaluation of AEs * Recent significant medical-surgical intervention that in judgment of Investigator would interfere with ability to complete study or evaluation of AEs; examples include to major surgery, or receipt of immunosuppressive therapy within 3 months prior to Day 0 * Evidence of cognitive impairment including dementia that may interfere with subject's ability to complete daily pain diaries requiring recall of average HIV-associated neuropathy pain level in past 24 hours
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Measure of Efficacy Was the Percent Change in the Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12. | Weeks 2-12 | Efficacy was assessed by daily Numeric Pain Rating Scale (NPRS) capturing average pain for the past 24 hours for painful HIV-associated neuropathy area(s) at approximately 9 PM every evening throughout the 12-week study period. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. |
Secondary
| Measure | Time frame |
|---|---|
| Absolute Change in the Mean Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12. | Weeks 2-12. |
| Proportion of Subjects Reaching 30% Decrease in Their Mean Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12 | Weeks 2-12 |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| NGX-4010, 60 Minutes Treatment with capsaicin patches consisted of a one time application administered at any time of the day on Study Day 0. Subjects were randomized to receive NGX 4010 (high concentration capsaicin, 640 mcg/cm\^2) for 60 minutes. | 165 |
| Control Group, 60 Minutes Treatment consisted of a one time application administered at any time of the day on Study Day 0. Subjects were randomized to receive a Control patch (low concentration capsaicin, 3.2 mcg/cm\^2) for 60 minutes. The low dose of 3.2 mcg/cm\^2 (0.04% w/w) used as the Control in this study was selected because it was expected to cause perceptible local sensation, thereby preserving the blind. | 90 |
| NGX-4010, 30 Minutes Treatment with capsaicin patches consisted of a one time application administered at any time of the day on Study Day 0. Subjects were randomized to receive NGX 4010 (high concentration capsaicin, 640 mcg/cm\^2) for 30 minutes. | 167 |
| Control Group , 30 Minutes Treatment consisted of a one time application administered at any time of the day on Study Day 0. Subjects were randomized to receive a Control patch (low concentration capsaicin, 3.2 mcg/cm\^2) for 30 minutes. The low dose of 3.2 mcg/cm\^2 (0.04% w/w) used as the Control in this study was selected because it was expected to cause perceptible local sensation, thereby preserving the blind. | 72 |
| Total | 494 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 0 | 0 |
| Overall Study | Death | 1 | 0 | 0 | 0 |
| Overall Study | Diagnosis of testicular cancer | 0 | 1 | 0 | 0 |
| Overall Study | Extensive travel required for new job | 0 | 1 | 0 | 0 |
| Overall Study | Incarcerated | 0 | 0 | 2 | 0 |
| Overall Study | Lack of Efficacy | 1 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 2 | 0 | 4 | 2 |
| Overall Study | Moved out of state | 0 | 1 | 1 | 0 |
| Overall Study | Noncompliance | 1 | 2 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 1 | 0 |
| Overall Study | Too far to travel for visits | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 1 | 2 | 0 |
Baseline characteristics
| Characteristic | NGX-4010, 60 Minutes | Control Group, 60 Minutes | NGX-4010, 30 Minutes | Control Group , 30 Minutes | Total |
|---|---|---|---|---|---|
| Age Continuous | 49.0 years STANDARD_DEVIATION 8.52 | 50.1 years STANDARD_DEVIATION 9.33 | 50.5 years STANDARD_DEVIATION 8.34 | 49.3 years STANDARD_DEVIATION 7.78 | 49.7 years STANDARD_DEVIATION 8.5 |
| Sex: Female, Male Female | 17 Participants | 11 Participants | 25 Participants | 9 Participants | 62 Participants |
| Sex: Female, Male Male | 148 Participants | 79 Participants | 142 Participants | 63 Participants | 432 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 | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 160 / 165 | 73 / 90 | 149 / 167 | 61 / 72 | 309 / 332 | 134 / 162 |
| serious Total, serious adverse events | 13 / 165 | 7 / 90 | 6 / 167 | 2 / 72 | 19 / 332 | 9 / 162 |
Outcome results
Primary
The Primary Measure of Efficacy Was the Percent Change in the Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12.
Efficacy was assessed by daily Numeric Pain Rating Scale (NPRS) capturing average pain for the past 24 hours for painful HIV-associated neuropathy area(s) at approximately 9 PM every evening throughout the 12-week study period. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain.
Time frame: Weeks 2-12
Population: Analyses were intention to treat (ITT). A modified last observation carried forward (LOCF) approach was used to impute missing data. Each NGX-4010 group was compared with its respective control group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NGX-4010, 60 Minutes | The Primary Measure of Efficacy Was the Percent Change in the Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12. | -32.8 Percent Change from baseline | Standard Error 2.41 |
| Control Group, 60 Minutes | The Primary Measure of Efficacy Was the Percent Change in the Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12. | -30.0 Percent Change from baseline | Standard Error 3.27 |
| NGX-4010, 30 Minutes | The Primary Measure of Efficacy Was the Percent Change in the Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12. | -26.2 Percent Change from baseline | Standard Error 2.39 |
| Control Group , 30 Minutes | The Primary Measure of Efficacy Was the Percent Change in the Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12. | -19.1 Percent Change from baseline | Standard Error 3.61 |
| NGX-4010 Total | The Primary Measure of Efficacy Was the Percent Change in the Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12. | -29.5 Percent Change from baseline | Standard Error 1.7 |
| Control, Total | The Primary Measure of Efficacy Was the Percent Change in the Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12. | -24.5 Percent Change from baseline | Standard Error 2.43 |
Comparison: The null hypothesis was that there was no difference between the average percent change in NPRS scores from baseline to weeks 2-12 between the total control and total NGX-4010 groups. The ratio of means between the 30- and 60-minute control group \[1.57 (90% CI: 1.12-2.35)\] was \> than the pre-specified equivalence margin ratio of 80-125%. Hence, the control groups could not be pooled and comparisons were performed between the 30- and 60-minute NGX-4010 groups and their respective control groups.p-value: 0.0967ANCOVA
p-value: 0.4884ANCOVA
p-value: 0.1031ANCOVA
Secondary
Absolute Change in the Mean Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12.
Time frame: Weeks 2-12.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NGX-4010, 60 Minutes | Absolute Change in the Mean Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12. | -2.0 Numeric Pain Rating Scale (0 to 10) | Standard Error 0.15 |
| Control Group, 60 Minutes | Absolute Change in the Mean Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12. | -1.8 Numeric Pain Rating Scale (0 to 10) | Standard Error 0.2 |
| NGX-4010, 30 Minutes | Absolute Change in the Mean Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12. | -1.6 Numeric Pain Rating Scale (0 to 10) | Standard Error 0.14 |
| Control Group , 30 Minutes | Absolute Change in the Mean Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12. | -1.1 Numeric Pain Rating Scale (0 to 10) | Standard Error 0.22 |
| NGX-4010 Total | Absolute Change in the Mean Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12. | -1.8 Numeric Pain Rating Scale (0 to 10) | Standard Error 0.1 |
| Control, Total | Absolute Change in the Mean Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12. | -1.4 Numeric Pain Rating Scale (0 to 10) | Standard Error 0.15 |
Comparison: The null hypothesis was: There is no difference between the total Control and total NGX-4010 in the absolute change in NPRS scores from Baseline during Weeks 2-12.p-value: 0.0831ANCOVA
p-value: 0.468ANCOVA
p-value: 0.0896ANCOVA
Secondary
Proportion of Subjects Reaching 30% Decrease in Their Mean Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12
Time frame: Weeks 2-12
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NGX-4010, 60 Minutes | Proportion of Subjects Reaching 30% Decrease in Their Mean Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12 | 48 Percentage of Participants |
| Control Group, 60 Minutes | Proportion of Subjects Reaching 30% Decrease in Their Mean Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12 | 45 Percentage of Participants |
| NGX-4010, 30 Minutes | Proportion of Subjects Reaching 30% Decrease in Their Mean Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12 | 39 Percentage of Participants |
| Control Group , 30 Minutes | Proportion of Subjects Reaching 30% Decrease in Their Mean Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12 | 26 Percentage of Participants |
| NGX-4010 Total | Proportion of Subjects Reaching 30% Decrease in Their Mean Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12 | 43 Percentage of Participants |
| Control, Total | Proportion of Subjects Reaching 30% Decrease in Their Mean Average Pain for the Past 24 Hours Numeric Pain Rating Scale (NPRS) Score From Baseline During Weeks 2 to 12 | 36 Percentage of Participants |
Comparison: The null hypothesis was: There is no difference between the total Control and total NGX-4010 group in the Proportion of Subjects Reaching 30% Decrease in Their Mean Average Pain for the Past 24 Hours NPRS Score From Baseline During Weeks 2 to 12.p-value: 0.0662Regression, Logistic
p-value: 0.5582Regression, Logistic
p-value: 0.0553Regression, Logistic