Study of NGX-4010 for the Treatment of Painful HIV-Associated Neuropathy

• Sponsor: NeurogesX (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00321672
• Collaborator: (none)
• Enrollment: 494
• Arms: 4
• Duration (Months): 18

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pain; HIV Infections; Peripheral Nervous System Diseases	Drug: NGX-4010, 8% capsaicin patch; Drug: 0.04% capsaicin patch; Drug: NGX-4010, 8% capsaicin patch; Drug: 0.04% capsaicin patch	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 494 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter Randomized, Double-Blind, Controlled Study of NGX-4010 for the Treatment of Painful HIV-Associated Neuropathy
• Study Start Date: Jun 1, 2006
• Actual Primary Completion Date: Dec 1, 2007
• Actual Study Completion Date: Dec 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NGX-4010, 60 minutes	Drug: NGX-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.; Other Names: the brandname of NGX-4010, 8% capsaicin patch is Qutenza.
Experimental: NGX-4010, 30 minutes	Drug: NGX-4010, 8% capsaicin patch; Up to 4 NGX-4010 patches of 280 cm^2 each were applied to the feet (2 per foot) for 30 minutes.; Other Names: The brandname of NGX-4010, 8% capsaicin patch is Qutenza.
Other: 0.04% conc. capsaicin patch, 60 min.	Drug: 0.04% capsaicin patch; Up to 4 control patches of 280 cm^2 each were applied to the feet (2 per foot) for 60 minutes.; Other Names: NGX-4010
Other: 0.04% conc. capsaicin patch, 30 min.	Drug: 0.04% capsaicin patch; Up to 4 control patches of 280 cm^2 each were applied to the feet (2 per foot) for 30 minutes.; Other Names: NGX-4010

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.]

2. 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]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• NeurogesX

Investigators

• Study Director: Trudy F Vanhove, MD, NeurogesX

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00321672
• Other Study ID Numbers: C119
• First Posted: May 4, 2006
• Last Update Posted: Jun 14, 2011
• Last Verified: May 1, 2011

• Keywords provided by , ,: Analgesics; Capsaicin; Neuropathic pain; Neuropathy; Distal sensory polyneuropathy; Peripheral neuropathy; Dermal assessment; Pain measurement
• Additional relevant MeSH terms: Nervous System Diseases; Peripheral Nervous System Diseases; Capsaicin

Study Results

Participant Flow

Arm/Group Title	NGX-4010, 60 Minutes	Control Group, 60 Minutes	NGX-4010, 30 Minutes	Control Group , 30 Minutes
Arm/Group Description	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.	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.	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.	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.
Period Title: Overall Study
STARTED	165	89	167	73
COMPLETED	153	81	156	71
NOT COMPLETED	12	8	11	2

Baseline Characteristics

Arm/Group Title	NGX-4010, 60 Minutes	Control Group, 60 Minutes	NGX-4010, 30 Minutes	Control Group , 30 Minutes	Total
Arm/Group Description	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.	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.	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.	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.	Total of all reporting groups
Overall Participants	165	90	167	72	494
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.0 (8.52)	50.1 (9.33)	50.5 (8.34)	49.3 (7.78)	49.7 (8.5)
Sex: Female, Male (Count of Participants)
Female	17 10.3%	11 12.2%	25 15%	9 12.5%	62 12.6%
Male	148 89.7%	79 87.8%	142 85%	63 87.5%	432 87.4%

Outcome Measures

1. Primary Outcome

Title	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.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	NGX-4010, 60 Minutes	Control Group, 60 Minutes	NGX-4010, 30 Minutes	Control Group , 30 Minutes	NGX-4010 Total	Control, Total
Arm/Group Description	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.	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.	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.	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.	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 or 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 30 or 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.
Measure Participants	165	90	167	72	332	162
Least Squares Mean (Standard Error) [Percent Change from baseline]	-32.8 (2.41)	-30.0 (3.27)	-26.2 (2.39)	-19.1 (3.61)	-29.5 (1.70)	-24.5 (2.43)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NGX-4010 Total, Control, Total
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0967
	Comments	All stastical tests of hypotheses were two-sided and at the 5% level of significance.
	Method	ANCOVA
	Comments	Treatment differences were compared by a gender stratified analysis of covariance (ANCOVA) model with Baseline pain score as the only covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NGX-4010, 60 Minutes, Control Group, 60 Minutes
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4884
	Comments	All stastical tests of hypotheses were two-sided and at the 5% level of significance. No multiplicity adjustment were made.
	Method	ANCOVA
	Comments	Treatment differences were compared by a gender stratified analysis of covariance (ANCOVA) model with Baseline pain score as the only covariate.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	NGX-4010, 30 Minutes, Control Group , 30 Minutes
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1031
	Comments	All stastical tests of hypotheses were two-sided and at the 5% level of significance. No multiplicity adjustment were made.
	Method	ANCOVA
	Comments	Treatment differences were compared by a gender stratified analysis of covariance (ANCOVA) model with Baseline pain score as the only covariate.

2. Secondary Outcome

Title	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NGX-4010, 60 Minutes	Control Group, 60 Minutes	NGX-4010, 30 Minutes	Control Group , 30 Minutes	NGX-4010 Total	Control, Total
Arm/Group Description	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.	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.	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.	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.	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 or 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 30 or 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.
Measure Participants	165	90	167	72	332	162
Least Squares Mean (Standard Error) [Numeric Pain Rating Scale (0 to 10)]	-2.0 (0.15)	-1.8 (0.20)	-1.6 (0.14)	-1.1 (0.22)	-1.8 (0.10)	-1.4 (0.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NGX-4010 Total, Control, Total
	Comments	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."
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0831
	Comments	All statistical tests of hypotheses were two-sided and at the 5% level of significance.
	Method	ANCOVA
	Comments	Treatment differences were compared by a gender stratified analysis of covariance (ANCOVA) model with Baseline pain score as the only covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NGX-4010, 60 Minutes, Control Group, 60 Minutes
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4680
	Comments	All statistical tests of hypotheses were two-sided and at the 5% level of significance. No multiplicity adjustments were made.
	Method	ANCOVA
	Comments	Treatment differences were compared by a gender stratified analysis of covariance (ANCOVA) model with Baseline pain score as the only covariate.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	NGX-4010, 30 Minutes, Control Group , 30 Minutes
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0896
	Comments	All statistical tests of hypotheses were two-sided and at the 5% level of significance. No multiplicity adjustments were made.
	Method	ANCOVA
	Comments	Treatment differences were compared by a gender stratified analysis of covariance (ANCOVA) model with Baseline pain score as the only covariate.

3. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NGX-4010, 60 Minutes	Control Group, 60 Minutes	NGX-4010, 30 Minutes	Control Group , 30 Minutes	NGX-4010 Total	Control, Total
Arm/Group Description	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.	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.	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.	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.	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 or 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 30 or 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.
Measure Participants	165	90	167	72	332	162
Number [Percentage of Participants]	48 29.1%	45 50%	39 23.4%	26 36.1%	43 8.7%	36 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NGX-4010 Total, Control, Total
	Comments	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."
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0662
	Comments	All statistical tests of hypotheses were two-sided and at the 5% level of significance.
	Method	Regression, Logistic
	Comments	A logistic regression analysis, with the Baseline NPRS score and gender as covariates, was performed.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NGX-4010, 60 Minutes, Control Group, 60 Minutes
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5582
	Comments	All statistical tests of hypotheses were two-sided and at the 5% level of significance. No multiplicity adjustments were made.
	Method	Regression, Logistic
	Comments	A logistic regression analysis, with the Baseline NPRS score and gender as covariates, was performed.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	NGX-4010, 30 Minutes, Control Group , 30 Minutes
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0553
	Comments	All statistical tests of hypotheses were two-sided and at the 5% level of significance. No multiplicity adjustments were made.
	Method	Regression, Logistic
	Comments	A logistic regression analysis, with the Baseline NPRS score and gender as covariates, was performed.

Adverse Events

Time Frame	12 weeks
Arm/Group Title	NGX-4010, 60 Minutes		Control Group, 60 Minutes		NGX-4010, 30 Minutes		Control Group , 30 Minutes		NGX-4010 Total		Control, Total
Arm/Group Description	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.		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.		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.		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.		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 or 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 30 or 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.
All Cause Mortality
	NGX-4010, 60 Minutes		Control Group, 60 Minutes		NGX-4010, 30 Minutes		Control Group , 30 Minutes		NGX-4010 Total		Control, Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	NGX-4010, 60 Minutes		Control Group, 60 Minutes		NGX-4010, 30 Minutes		Control Group , 30 Minutes		NGX-4010 Total		Control, Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/165 (7.9%)		7/90 (7.8%)		6/167 (3.6%)		2/72 (2.8%)		19/332 (5.7%)		9/162 (5.6%)
Cardiac disorders
Acute coronary syndrome	0/165 (0%)	0	1/90 (1.1%)	1	0/167 (0%)	0	0/72 (0%)	0	0/332 (0%)	0	1/162 (0.6%)	1
Mitral valve incompetence	0/165 (0%)	0	1/90 (1.1%)	1	0/167 (0%)	0	0/72 (0%)	0	0/332 (0%)	0	1/162 (0.6%)	1
Myocardial infarction	0/165 (0%)	0	2/90 (2.2%)	2	0/167 (0%)	0	0/72 (0%)	0	0/332 (0%)	0	2/162 (1.2%)	2
Gastrointestinal disorders
Abdominal pain	0/165 (0%)	0	0/90 (0%)	0	1/167 (0.6%)	1	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Gastrooesophageal reflux disease	1/165 (0.6%)	1	0/90 (0%)	0	0/167 (0%)	0	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Odynophagia	0/165 (0%)	0	0/90 (0%)	0	1/167 (0.6%)	1	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Oesophageal varices haemorrhage	0/165 (0%)	0	0/90 (0%)	0	1/167 (0.6%)	1	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Pancreatitis acute	0/165 (0%)	0	1/90 (1.1%)	1	0/167 (0%)	0	0/72 (0%)	0	0/332 (0%)	0	1/162 (0.6%)	1
General disorders
Non-cardiac chest pain	0/165 (0%)	0	1/90 (1.1%)	1	0/167 (0%)	0	0/72 (0%)	0	0/332 (0%)	0	1/162 (0.6%)	1
Hepatobiliary disorders
Cholecystitis	1/165 (0.6%)	1	0/90 (0%)	0	0/167 (0%)	0	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Cholecystitis acute	0/165 (0%)	0	0/90 (0%)	0	1/167 (0.6%)	1	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Infections and infestations
Appendicitis	1/165 (0.6%)	1	0/90 (0%)	0	0/167 (0%)	0	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Gastroenteritis	0/165 (0%)	0	0/90 (0%)	0	0/167 (0%)	0	1/72 (1.4%)	1	0/332 (0%)	0	1/162 (0.6%)	1
Giardiasis	0/165 (0%)	0	1/90 (1.1%)	1	0/167 (0%)	0	0/72 (0%)	0	0/332 (0%)	0	1/162 (0.6%)	1
Hepatitis C	1/165 (0.6%)	1	0/90 (0%)	0	0/167 (0%)	0	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Lower respiratory tract infection	2/165 (1.2%)	2	0/90 (0%)	0	0/167 (0%)	0	0/72 (0%)	0	2/332 (0.6%)	2	0/162 (0%)	0
Meningitis	1/165 (0.6%)	1	0/90 (0%)	0	0/167 (0%)	0	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Meningitis tuberculous	0/165 (0%)	0	1/90 (1.1%)	1	0/167 (0%)	0	0/72 (0%)	0	0/332 (0%)	0	1/162 (0.6%)	1
Peritonitis bacterial	1/165 (0.6%)	1	0/90 (0%)	0	0/167 (0%)	0	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Pneumonia	0/165 (0%)	0	0/90 (0%)	0	1/167 (0.6%)	1	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Subcutaneous abscess	1/165 (0.6%)	1	0/90 (0%)	0	0/167 (0%)	0	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Urosepsis	0/165 (0%)	0	0/90 (0%)	0	1/167 (0.6%)	1	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Injury, poisoning and procedural complications
Polytraumatism	1/165 (0.6%)	1	0/90 (0%)	0	0/167 (0%)	0	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Nervous system disorders
Haemorrhagic stroke	0/165 (0%)	0	0/90 (0%)	0	1/167 (0.6%)	1	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Subarachnoid haemorhage	1/165 (0.6%)	1	0/90 (0%)	0	0/167 (0%)	0	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Psychiatric disorders
Depression	1/165 (0.6%)	1	0/90 (0%)	0	0/167 (0%)	0	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Suicidal ideation	0/165 (0%)	0	0/90 (0%)	0	0/167 (0%)	0	1/72 (1.4%)	1	0/332 (0%)	0	1/162 (0.6%)	1
Renal and urinary disorders
Nephrolithiasis	0/165 (0%)	0	0/90 (0%)	0	1/167 (0.6%)	1	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/165 (0.6%)	1	0/90 (0%)	0	0/167 (0%)	0	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Pneumothorax	1/165 (0.6%)	1	0/90 (0%)	0	0/167 (0%)	0	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Vascular disorders
Arteriosclerosis	1/165 (0.6%)	1	0/90 (0%)	0	0/167 (0%)	0	0/72 (0%)	0	1/332 (0.3%)	1	0/162 (0%)	0
Other (Not Including Serious) Adverse Events
	NGX-4010, 60 Minutes		Control Group, 60 Minutes		NGX-4010, 30 Minutes		Control Group , 30 Minutes		NGX-4010 Total		Control, Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	160/165 (97%)		73/90 (81.1%)		149/167 (89.2%)		61/72 (84.7%)		309/332 (93.1%)		134/162 (82.7%)
General disorders
Application site erythema	97/165 (58.8%)	97	34/90 (37.8%)	34	79/167 (47.3%)	79	24/72 (33.3%)	24	176/332 (53%)	176	58/162 (35.8%)	58
Application site pain	139/165 (84.2%)	139	29/90 (32.2%)	29	135/167 (80.8%)	135	33/72 (45.8%)	33	274/332 (82.5%)	274	62/162 (38.3%)	62
Musculoskeletal and connective tissue disorders
Pain in extremity	10/165 (6.1%)	10	4/90 (4.4%)	4	10/167 (6%)	10	2/72 (2.8%)	2	20/332 (6%)	20	6/162 (3.7%)	6
Nervous system disorders
Peripheral sensory neuropathy	5/165 (3%)	5	7/90 (7.8%)	7	7/167 (4.2%)	7	12/72 (16.7%)	12	12/332 (3.6%)	12	19/162 (11.7%)	19
Skin and subcutaneous tissue disorders
Erythema	2/165 (1.2%)	2	5/90 (5.6%)	5	3/167 (1.8%)	3	4/72 (5.6%)	4	5/332 (1.5%)	5	9/162 (5.6%)	9

Limitations/Caveats

Differences between the 60- and 30-minute Control groups prevented pooling according to prespecified criteria resulting in treatment comparisons between 60- and 30-minute NGX-4010 groups and their respective Control groups with relatively low power.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days from the time submitted to the sponsor for review. The PI shall comply with the sponsor's requests to delete references to trade secrets, intellectual properties or other proprietary information.