Trial Outcomes & Findings for A Study to Evaluate the Safety and Efficacy of Topically Applied TV 45070 Ointment in Patients With Postherpetic Neuralgia (PHN) (NCT NCT02365636)

NCT ID: NCT02365636

Last Updated: 2021-11-09

Results Overview

The primary efficacy endpoint was the change from baseline to week 4 in the weekly average of the daily average NRS scores. The NRS is a widely-used, standard one-dimensional 11-point scale from 0=no pain to 10=worst pain imaginable as reported by patients. The daily average NRS scores is the average of the 2 NRS scores (recorded in the morning and evening) of average pain, defined as the patient-reported average pain intensity over the prior 12 hours. At least 1 of the 2 daily scores had to be recorded (non-missing) or the daily average was considered missing. Negative change from baseline values indicate a lessening of pain. The Mixed Model Repeated Measures (MMRM) model with change from baseline in the weekly average of the daily average NRS scores at week 4 as the dependent variable; week, pooled study center, treatment, and treatment by visit interaction as fixed factors, baseline weekly average of the daily average NRS scores as covariate; and patient as a random effect.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 300 participants
• Primary outcome timeframe: Baseline (day -7 to day -1), Week 4 (day 22 to day 28)
• Results posted on: 2021-11-09

Participant Flow

658 patients with chronic postherpetic neuralgia (PHN) were screened; reasons for not enrolling included: inclusion criteria not met (144), exclusion criteria met (171), consent withdrawn (28), lost to follow-up (6), adverse event (1), other (8).

300 participants were randomly assigned in a 1:1:1 ratio to 1 of 3 treatment groups.

Participant milestones

Measure	TV-45070 4% TV-45070 ointment in a 4% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	TV-45070 8% TV-45070 ointment in a 8% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	Placebo Placebo ointment applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.
Overall Study STARTED	100	100	100
Overall Study Safety Population	100	98	100
Overall Study Full Analysis Set	100	98	100
Overall Study COMPLETED	94	93	97
Overall Study NOT COMPLETED	6	7	3

Reasons for withdrawal

Measure	TV-45070 4% TV-45070 ointment in a 4% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	TV-45070 8% TV-45070 ointment in a 8% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	Placebo Placebo ointment applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.
Overall Study Adverse Event	3	3	2
Overall Study Protocol Violation	1	4	0
Overall Study Lost to Follow-up	0	0	1
Overall Study Other	2	0	0

Baseline Characteristics

A Study to Evaluate the Safety and Efficacy of Topically Applied TV 45070 Ointment in Patients With Postherpetic Neuralgia (PHN)

Baseline characteristics by cohort

Measure	TV-45070 4% n=100 Participants TV-45070 ointment in a 4% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	TV-45070 8% n=100 Participants TV-45070 ointment in a 8% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	Placebo n=100 Participants Placebo ointment applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	Total n=300 Participants Total of all reporting groups
Age, Continuous	57.2 years STANDARD_DEVIATION 15.99 • n=5 Participants	57.6 years STANDARD_DEVIATION 16.61 • n=7 Participants	58.6 years STANDARD_DEVIATION 15.80 • n=5 Participants	57.8 years STANDARD_DEVIATION 16.09 • n=4 Participants
Sex: Female, Male Female	57 Participants n=5 Participants	50 Participants n=7 Participants	65 Participants n=5 Participants	172 Participants n=4 Participants
Sex: Female, Male Male	43 Participants n=5 Participants	50 Participants n=7 Participants	35 Participants n=5 Participants	128 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	56 Participants n=5 Participants	53 Participants n=7 Participants	70 Participants n=5 Participants	179 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	43 Participants n=5 Participants	47 Participants n=7 Participants	30 Participants n=5 Participants	120 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized White	81 Participants n=5 Participants	79 Participants n=7 Participants	90 Participants n=5 Participants	250 Participants n=4 Participants
Race/Ethnicity, Customized Black or African American	13 Participants n=5 Participants	17 Participants n=7 Participants	7 Participants n=5 Participants	37 Participants n=4 Participants
Race/Ethnicity, Customized Asian	3 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	7 Participants n=4 Participants
Race/Ethnicity, Customized American Indian or Alaskan Native	1 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants
Race/Ethnicity, Customized Other	2 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants
Weight	77.02 kg STANDARD_DEVIATION 13.775 • n=5 Participants	77.41 kg STANDARD_DEVIATION 13.383 • n=7 Participants	77.86 kg STANDARD_DEVIATION 15.111 • n=5 Participants	77.43 kg STANDARD_DEVIATION 14.066 • n=4 Participants
Height	167.27 cm STANDARD_DEVIATION 10.258 • n=5 Participants	168.03 cm STANDARD_DEVIATION 8.203 • n=7 Participants	165.82 cm STANDARD_DEVIATION 10.355 • n=5 Participants	167.04 cm STANDARD_DEVIATION 9.668 • n=4 Participants
Body Mass Index	27.42 kg/m^2 STANDARD_DEVIATION 3.457 • n=5 Participants	27.30 kg/m^2 STANDARD_DEVIATION 3.452 • n=7 Participants	28.15 kg/m^2 STANDARD_DEVIATION 3.798 • n=5 Participants	27.62 kg/m^2 STANDARD_DEVIATION 3.580 • n=4 Participants
R1150W Polymorphism Status Homozygous minor allele (positive, AA)	1 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants
R1150W Polymorphism Status Heterozygous (positive, AG)	17 Participants n=5 Participants	25 Participants n=7 Participants	22 Participants n=5 Participants	64 Participants n=4 Participants
R1150W Polymorphism Status Homozygous common allele (negative, GG)	82 Participants n=5 Participants	73 Participants n=7 Participants	78 Participants n=5 Participants	233 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline (day -7 to day -1), Week 4 (day 22 to day 28)

Population: Full analysis set; patients from one site are excluded due to lack of data integrity.

The primary efficacy endpoint was the change from baseline to week 4 in the weekly average of the daily average NRS scores. The NRS is a widely-used, standard one-dimensional 11-point scale from 0=no pain to 10=worst pain imaginable as reported by patients. The daily average NRS scores is the average of the 2 NRS scores (recorded in the morning and evening) of average pain, defined as the patient-reported average pain intensity over the prior 12 hours. At least 1 of the 2 daily scores had to be recorded (non-missing) or the daily average was considered missing. Negative change from baseline values indicate a lessening of pain. The Mixed Model Repeated Measures (MMRM) model with change from baseline in the weekly average of the daily average NRS scores at week 4 as the dependent variable; week, pooled study center, treatment, and treatment by visit interaction as fixed factors, baseline weekly average of the daily average NRS scores as covariate; and patient as a random effect.

Outcome measures

Measure	TV-45070 4% n=100 Participants TV-45070 ointment in a 4% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	TV-45070 8% n=98 Participants TV-45070 ointment in a 8% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	Placebo n=100 Participants Placebo ointment applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.
Change From Baseline to Week 4 in the Weekly Average of the Daily Average Numeric Rating Scale (NRS) Pain Scores Using a Mixed Model for Repeated Measures Baseline	5.37 units on a scale Standard Deviation 0.992	5.60 units on a scale Standard Deviation 1.236	5.51 units on a scale Standard Deviation 0.963
Change From Baseline to Week 4 in the Weekly Average of the Daily Average Numeric Rating Scale (NRS) Pain Scores Using a Mixed Model for Repeated Measures Change from baseline at week 4	-1.64 units on a scale Standard Deviation 1.360	-1.71 units on a scale Standard Deviation 1.500	-1.90 units on a scale Standard Deviation 1.670

SECONDARY outcome

Timeframe: Baseline (day -7 to day -1), Week 4 (day 22 to day 28)

Population: Full analysis set. Participants from one site are excluded due to lack of data integrity.

The NRS is a widely-used, standard one-dimensional 11-point scale from 0=no pain to 10=worst pain imaginable as reported by patients. The NRS pain scores recorded in the evening is defined as the patient-reported average pain intensity over the prior 12 hours. Negative change from baseline values indicate a lessening of pain. The Mixed Model Repeated Measures (MMRM) model with change from baseline in the weekly average of the evening NRS scores at week 4 as the dependent variable; week, pooled study center, treatment, and treatment by visit interaction as fixed factors, baseline weekly average of the evening NRS scores as covariate; and patient as a random effect.

Outcome measures

Measure	TV-45070 4% n=100 Participants TV-45070 ointment in a 4% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	TV-45070 8% n=98 Participants TV-45070 ointment in a 8% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	Placebo n=100 Participants Placebo ointment applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.
Change From Baseline to Week 4 in the Weekly Average of the Average Numeric Rating Scale (NRS) Pain Scores Recorded in the Evening Using a Mixed Model for Repeated Measures Baseline	5.45 units on a scale Standard Deviation 1.073	5.66 units on a scale Standard Deviation 1.320	5.58 units on a scale Standard Deviation 0.994
Change From Baseline to Week 4 in the Weekly Average of the Average Numeric Rating Scale (NRS) Pain Scores Recorded in the Evening Using a Mixed Model for Repeated Measures Change from baseline at week 4	-1.70 units on a scale Standard Deviation 1.412	-1.73 units on a scale Standard Deviation 1.506	-1.96 units on a scale Standard Deviation 1.745

SECONDARY outcome

Timeframe: Baseline (day -7 to day -1), Week 4 (day 22 to day 28)

Population: Full analysis set. Participants from one site are excluded due to lack of data integrity.

The NRS is a widely-used, standard one-dimensional 11-point scale from 0=no pain to 10=worst pain imaginable as reported by patients. The NRS pain scores recorded in the morning is defined as the patient-reported average pain intensity over the prior 12 hours. Negative change from baseline values indicate a lessening of pain. The Mixed Model Repeated Measures (MMRM) model with change from baseline in the weekly average of the evening NRS scores at week 4 as the dependent variable; week, pooled study center, treatment, and treatment by visit interaction as fixed factors, baseline weekly average of morning NRS scores as covariate; and patient as a random effect.

Outcome measures

Measure	TV-45070 4% n=100 Participants TV-45070 ointment in a 4% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	TV-45070 8% n=98 Participants TV-45070 ointment in a 8% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	Placebo n=100 Participants Placebo ointment applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.
Change From Baseline to Week 4 in the Weekly Average of the Average Numeric Rating Scale (NRS) Pain Scores Recorded in the Morning Using a Mixed Model for Repeated Measures Baseline	5.30 units on a scale Standard Deviation 0.980	5.53 units on a scale Standard Deviation 1.226	5.44 units on a scale Standard Deviation 0.968
Change From Baseline to Week 4 in the Weekly Average of the Average Numeric Rating Scale (NRS) Pain Scores Recorded in the Morning Using a Mixed Model for Repeated Measures Change from baseline at week 4	-1.60 units on a scale Standard Deviation 1.386	-1.68 units on a scale Standard Deviation 1.548	-1.84 units on a scale Standard Deviation 1.623

SECONDARY outcome

Timeframe: Baseline (day -7 to day -1), Week 4 (day 22 to day 28)

Population: Full analysis set. Participants from one site are excluded due to lack of data integrity.

The NRS is a widely-used, standard one-dimensional 11-point scale from 0=no pain to 10=worst pain imaginable as reported by patients. The worst pain is defined as the patient-reported worst pain intensity over the prior 24 hours. Negative change from baseline values indicate a lessening of pain. The Mixed Model Repeated Measures (MMRM) model with change from baseline in the weekly average of the worst pain NRS scores at week 4 as the dependent variable; week, pooled study center, treatment, and treatment by visit interaction as fixed factors, baseline weekly average of the evening NRS scores as covariate; and patient as a random effect.

Outcome measures

Measure	TV-45070 4% n=100 Participants TV-45070 ointment in a 4% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	TV-45070 8% n=98 Participants TV-45070 ointment in a 8% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	Placebo n=100 Participants Placebo ointment applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.
Change From Baseline to Week 4 in the Weekly Average of the Worst Numeric Rating Scale (NRS) Pain Scores Recorded in the Evening Using a Mixed Model for Repeated Measures Baseline	6.09 units on a scale Standard Deviation 1.060	6.35 units on a scale Standard Deviation 1.378	6.09 units on a scale Standard Deviation 1.041
Change From Baseline to Week 4 in the Weekly Average of the Worst Numeric Rating Scale (NRS) Pain Scores Recorded in the Evening Using a Mixed Model for Repeated Measures Change from baseline at week 4	-1.73 units on a scale Standard Deviation 1.576	-1.83 units on a scale Standard Deviation 1.657	-1.97 units on a scale Standard Deviation 1.883

SECONDARY outcome

Timeframe: Baseline (day -7 to day -1), Week 4 (day 22 to day 28)

Population: Full analysis set. Participants from one site are excluded due to lack of data integrity.

The NRS is a 11-point scale from 0=no pain to 10=worst pain imaginable as reported by patients. The daily average NRS scores is the average of the 2 NRS scores (recorded in the morning and evening) of average pain, defined as the patient-reported average pain intensity over the prior 12 hours. Percent improvement is calculated as 100 × (the weekly average of the daily average NRS pain score at week 4 - weekly average of the daily average NRS pain scores at baseline /weekly average of the daily average NRS pain scores at baseline. Patients missing a week 4 average are considered non-responders (<50% improvement or <30% improvement). The Mixed Model Repeated Measures (MMRM) model with change from baseline in the weekly average of the daily average NRS scores at week 4 as the dependent variable; week, pooled study center, treatment, and treatment by visit interaction as fixed factors, baseline weekly average of the daily average NRS scores as covariate; and patient as a random effect.

Outcome measures

Measure	TV-45070 4% n=98 Participants TV-45070 ointment in a 4% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	TV-45070 8% n=98 Participants TV-45070 ointment in a 8% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	Placebo n=100 Participants Placebo ointment applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.
Percentage of Participants With >=30% and >=50% Improvement From Baseline in the Weekly Average of the Daily Average Numeric Rating Scale (NRS) Pain Scores at Week 4 Using a Mixed Model for Repeated Measures >=30% improvement from baseline	43.9 percentage of participants	43.9 percentage of participants	47.0 percentage of participants
Percentage of Participants With >=30% and >=50% Improvement From Baseline in the Weekly Average of the Daily Average Numeric Rating Scale (NRS) Pain Scores at Week 4 Using a Mixed Model for Repeated Measures >=50% improvement from baseline	22.4 percentage of participants	25.5 percentage of participants	28.0 percentage of participants

SECONDARY outcome

Timeframe: Baseline (day 1 prior to dosing), Weeks 2 (day 15) and Week 4 (day 29)

Population: Full analysis set. Participants from one site are excluded due to lack of data integrity.

NPSI is a patient-reported questionnaire to evaluate the severity of different symptoms of neuropathic pain. The questionnaire contains 10 descriptors representing 5 distinct dimensions of pain: burning pain, deep pain, paroxysmal pain, evoked pain, and paresthesia/dysesthesia, plus 2 temporal items. Descriptors are scored from 0 through 10, where higher scores represent worse pain. The total score is the sum of the scores of the 10 descriptors (Bouhassira et al 2004). The total score ranges from 0 (no pain) through 100 (worst pain imaginable). If the score for one question was missing the total score was computed as 10 times sum of scores of 9 descriptors divided by 9. If more than one question was missing then the total score was missing. Negative change from baseline scores indicated less pain.

The MMRM used pooled study center, week, treatment, and treatment by week interaction as fixed factors and patient as a random factor.

Outcome measures

Measure	TV-45070 4% n=100 Participants TV-45070 ointment in a 4% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	TV-45070 8% n=98 Participants TV-45070 ointment in a 8% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	Placebo n=100 Participants Placebo ointment applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.
Change From Baseline to Weeks 2 and 4 in the Neuropathic Pain Symptom Inventory (NPSI) Total Score Using a Mixed Model for Repeated Measures (MMRM) Change from baseline at week 2	-8.1 units on a scale Standard Deviation 14.13	-9.9 units on a scale Standard Deviation 15.65	-10.8 units on a scale Standard Deviation 14.68
Change From Baseline to Weeks 2 and 4 in the Neuropathic Pain Symptom Inventory (NPSI) Total Score Using a Mixed Model for Repeated Measures (MMRM) Change from baseline at week 4	-13.1 units on a scale Standard Deviation 15.76	-14.3 units on a scale Standard Deviation 15.47	-16.8 units on a scale Standard Deviation 17.78
Change From Baseline to Weeks 2 and 4 in the Neuropathic Pain Symptom Inventory (NPSI) Total Score Using a Mixed Model for Repeated Measures (MMRM) Baseline	41.9 units on a scale Standard Deviation 16.45	44.0 units on a scale Standard Deviation 16.50	44.0 units on a scale Standard Deviation 15.18

SECONDARY outcome

Timeframe: Baseline (day 1), Week 4 (day 29)

Population: Full analysis set. Participants from one site are excluded due to lack of data integrity.

NePIQoL is a questionnaire that contains 41 items to evaluate quality of life in patients with neuropathic pain. Each question has responses ranging from strongly agree or always to strongly disagree or never. Questions are scored on a 5-point scale from 1 through 5, where higher scores represent greater pain-related interference in quality of life. Total range is 41 (great quality of life) to 205 (worst quality of life). Negative change from baseline scores indicated an improving quality of life.

Outcome measures

Measure	TV-45070 4% n=100 Participants TV-45070 ointment in a 4% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	TV-45070 8% n=98 Participants TV-45070 ointment in a 8% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	Placebo n=100 Participants Placebo ointment applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.
Change From Baseline to Week 4 in the Neuropathic Pain Impact on Quality of Life (NePIQoL) Total Score Baseline	127.1 units on a scale Standard Deviation 18.73	126.5 units on a scale Standard Deviation 20.36	127.6 units on a scale Standard Deviation 19.03
Change From Baseline to Week 4 in the Neuropathic Pain Impact on Quality of Life (NePIQoL) Total Score Change from baseline at week 4	-11.5 units on a scale Standard Deviation 17.98	11.3 units on a scale Standard Deviation 20.09	-12.6 units on a scale Standard Deviation 19.93

SECONDARY outcome

Timeframe: Weeks 2 (day 15) and Week 4 (day 29)

Population: Full analysis set. Participants from one site are excluded due to lack of data integrity. Data collected beyond last dose of study medication plus 3 days are excluded from the analysis.

PGIC is a standardized self-report tool that measures the change in a patient's overall status rating since the start of treatment on 7-point scale (Hurst and Bolton 2004). The 7-point scale is defined as: 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse.

The MMRM used pooled study center, week, treatment, and treatment by week interaction as fixed factors and patient as a random factor.

Outcome measures

Measure	TV-45070 4% n=100 Participants TV-45070 ointment in a 4% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	TV-45070 8% n=98 Participants TV-45070 ointment in a 8% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	Placebo n=100 Participants Placebo ointment applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.
Participants' Global Assess of Treatment as Measured by the Patient Global Impression of Change (PGIC) at Weeks 2 and 4 Using a Mixed Model for Repeated Measures (MMRM) Week 2	2.9 units on a scale Standard Deviation 0.87	2.9 units on a scale Standard Deviation 0.92	2.7 units on a scale Standard Deviation 0.82
Participants' Global Assess of Treatment as Measured by the Patient Global Impression of Change (PGIC) at Weeks 2 and 4 Using a Mixed Model for Repeated Measures (MMRM) Week 4	2.6 units on a scale Standard Deviation 1.08	2.5 units on a scale Standard Deviation 1.12	2.4 units on a scale Standard Deviation 1.07

SECONDARY outcome

Timeframe: Baseline (day 1 prior to dosing), Weeks 2 (day 15) and Week 4 (day 29)

Population: Full analysis set. Participants from one site are excluded due to lack of data integrity. Data collected beyond last dose of study medication plus 3 days are excluded from the analysis.

DSIS is an 11-point scale that asks the patient to "select the number that best describes how much your pain has interfered with your sleep during the past 24 hours." Response options range from 0 (Did not interfere with sleep) to 10 (Completely interfered with sleep/unable to sleep due to pain). Negative change from baseline scores indicate improvement (lessening) of how much pain interfered with sleep.

The MMRM used pooled study center, week, treatment, and treatment by week interaction as fixed factors and patient as a random factor.

Outcome measures

Measure	TV-45070 4% n=100 Participants TV-45070 ointment in a 4% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	TV-45070 8% n=98 Participants TV-45070 ointment in a 8% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	Placebo n=100 Participants Placebo ointment applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.
Change From Baseline to Weeks 2 and 4 in the Daily Sleep Interference Scale (DSIS) Using a Mixed Model for Repeated Measures Baseline	4.5 units on a scale Standard Deviation 1.94	4.4 units on a scale Standard Deviation 2.26	4.4 units on a scale Standard Deviation 2.00
Change From Baseline to Weeks 2 and 4 in the Daily Sleep Interference Scale (DSIS) Using a Mixed Model for Repeated Measures Change from baseline at week 2	-1.1 units on a scale Standard Deviation 1.54	-1.1 units on a scale Standard Deviation 1.99	-1.3 units on a scale Standard Deviation 1.99
Change From Baseline to Weeks 2 and 4 in the Daily Sleep Interference Scale (DSIS) Using a Mixed Model for Repeated Measures Change from baseline at week 4	-1.4 units on a scale Standard Deviation 1.78	-1.5 units on a scale Standard Deviation 2.16	-1.7 units on a scale Standard Deviation 2.24

SECONDARY outcome

Timeframe: Baseline (days -7 to -1), Week 1 (days 1-7), Week 2 (day 8-14), Week 3 (days 15-21), Week 4 (days 22-29)

Population: Full analysis set. Participants from one site are excluded due to lack of data integrity.

Percent improvement is calculated as 100*(the weekly average of the daily average NRS pain score - weekly average of the daily average NRS pain scores at baseline [days -7 to -1])/weekly average of the daily average NRS pain scores at baseline. Patients who do not reach >= 30% improvement are censored at their last non-missing weekly average. Patients who reach >= 30% improvement, but the improvement is not sustained through the end of the treatment period are censored at their last non-missing weekly average. For patients who reach >= 30% improvement that is sustained through the end through the end of the of the treatment, the time >= 30% improvement is first reached is used.

Outcome measures

Measure	TV-45070 4% n=98 Participants TV-45070 ointment in a 4% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	TV-45070 8% n=98 Participants TV-45070 ointment in a 8% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	Placebo n=100 Participants Placebo ointment applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.
Kaplan-Meier Estimates for First Time to Reach 30% or More Sustained Improvement in Weekly Average of the Daily Average NRS Pain Scores	NA days The median and 95% CI is not estimable if the proportion of participants' with 30% improvement is less than 0.5	NA days The median and 95% CI is not estimable if the proportion of participants' with 30% improvement is less than 0.5	NA days Interval 15.0 to The median and 95% CI is not estimable if the proportion of participants' with 30% improvement is less than 0.5

SECONDARY outcome

Timeframe: Baseline (day 1 prior to dosing), Weeks 2 (day 15) and Week 4 (day 29)

Population: Full analysis set. Participants from one site are excluded due to lack of data integrity. Participants from two other sites are excluded dince the two sites incorrectly assessed allodynia. If brush-evoked allodynia was not present at screening, it was not rechecked on subsequent visits.

Allodynia refers to central pain sensitization (increased response of neurons) following normally non-painful, often repetitive, stimulation. In this case, pain evoked by innocuous brush is measured on an 11-point NRS where 0=no pain and 11=worst pain imaginable as reported by patients Negative change from baseline scores indicate improvement (lessening) of pain.

Outcome measures

Measure	TV-45070 4% n=100 Participants TV-45070 ointment in a 4% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	TV-45070 8% n=98 Participants TV-45070 ointment in a 8% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	Placebo n=100 Participants Placebo ointment applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.
Change From Baseline to Weeks 2 and 4 in Maximal Intensity of Brush-Evoked Allodynia as Measured on an 11-point Numeric Rating Scale (NRS) Using a Mixed Model for Repeated Measures (MMRM) Baseline	1.6 units on a scale Standard Deviation 1.54	1.8 units on a scale Standard Deviation 2.28	2.0 units on a scale Standard Deviation 2.24
Change From Baseline to Weeks 2 and 4 in Maximal Intensity of Brush-Evoked Allodynia as Measured on an 11-point Numeric Rating Scale (NRS) Using a Mixed Model for Repeated Measures (MMRM) Change from baseline at week 2	-0.7 units on a scale Standard Deviation 1.47	-1.0 units on a scale Standard Deviation 2.25	-0.8 units on a scale Standard Deviation 1.53
Change From Baseline to Weeks 2 and 4 in Maximal Intensity of Brush-Evoked Allodynia as Measured on an 11-point Numeric Rating Scale (NRS) Using a Mixed Model for Repeated Measures (MMRM) Change from baseline at week 4	-0.7 units on a scale Standard Deviation 1.45	-0.7 units on a scale Standard Deviation 2.30	-0.7 units on a scale Standard Deviation 1.76

SECONDARY outcome

Timeframe: Baseline (day 1 prior to dosing), Weeks 2 (day 15) and Week 4 (day 29)

Population: Full analysis set. Participants from one site are excluded due to lack of data integrity. Participants from two other sites are excluded since the two sites incorrectly assessed allodynia. If punctate-evoked hyperalgesia was not present at screening, it was not rechecked on subsequent visits.

Hyperalgesia refers to increased pain from a stimulus that normally provokes pain. In this case, pain is evoked by punctate skin stimulation using a Medipin® and is measured on an 11-point NRS where 0=no pain and 11=worst pain imaginable as reported by patients. Negative change from baseline scores indicate improvement (lessening) of pain.

The MMRM used pooled study center, week, treatment, and treatment by week interaction as fixed factors and patient as a random factor. The unstructured covariance matrix for repeated observations within patients was used.

Outcome measures

Measure	TV-45070 4% n=100 Participants TV-45070 ointment in a 4% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	TV-45070 8% n=98 Participants TV-45070 ointment in a 8% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	Placebo n=100 Participants Placebo ointment applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.
Change From Baseline to Weeks 2 and 4 in Maximal Intensity of Punctate-Evoked Hyperalgesia as Measured on an 11-point Numeric Rating Scale (NRS) Using a Mixed Model for Repeated Measures (MMRM) Baseline	2.4 units on a scale Standard Deviation 2.03	3.0 units on a scale Standard Deviation 2.48	2.8 units on a scale Standard Deviation 2.57
Change From Baseline to Weeks 2 and 4 in Maximal Intensity of Punctate-Evoked Hyperalgesia as Measured on an 11-point Numeric Rating Scale (NRS) Using a Mixed Model for Repeated Measures (MMRM) Change from baseline at week 2	-1.0 units on a scale Standard Deviation 2.02	-1.3 units on a scale Standard Deviation 2.16	-1.1 units on a scale Standard Deviation 1.91
Change From Baseline to Weeks 2 and 4 in Maximal Intensity of Punctate-Evoked Hyperalgesia as Measured on an 11-point Numeric Rating Scale (NRS) Using a Mixed Model for Repeated Measures (MMRM) Change from baseline at week 4	-1.0 units on a scale Standard Deviation 2.08	-1.5 units on a scale Standard Deviation 2.36	-1.4 units on a scale Standard Deviation 2.00

SECONDARY outcome

Timeframe: day 1 up to day 57

Population: Safety population

An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.

Outcome measures

Measure	TV-45070 4% n=100 Participants TV-45070 ointment in a 4% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	TV-45070 8% n=98 Participants TV-45070 ointment in a 8% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	Placebo n=100 Participants Placebo ointment applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.
Participants With Treatment-Emergent Adverse Events Any treatment-emergent adverse event	15 Participants	32 Participants	24 Participants
Participants With Treatment-Emergent Adverse Events Severe TEAE	0 Participants	1 Participants	0 Participants
Participants With Treatment-Emergent Adverse Events Treatment-related TEAE	5 Participants	10 Participants	11 Participants
Participants With Treatment-Emergent Adverse Events Deaths	0 Participants	0 Participants	0 Participants
Participants With Treatment-Emergent Adverse Events Serious TEAE	0 Participants	1 Participants	0 Participants
Participants With Treatment-Emergent Adverse Events Withdrawn from treatment due to TEAE	4 Participants	4 Participants	3 Participants

Adverse Events

TV-45070 4%

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

TV-45070 (8%)

Serious events: 1 serious events

Other events: 5 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Measure	TV-45070 4% n=100 participants at risk TV-45070 ointment in a 4% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	TV-45070 (8%) n=98 participants at risk TV-45070 ointment in a 8% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	Placebo n=100 participants at risk Placebo ointment applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/100 • day 1 up to day 57	1.0% 1/98 • Number of events 1 • day 1 up to day 57	0.00% 0/100 • day 1 up to day 57

Other adverse events

Measure	TV-45070 4% n=100 participants at risk TV-45070 ointment in a 4% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	TV-45070 (8%) n=98 participants at risk TV-45070 ointment in a 8% strength applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.	Placebo n=100 participants at risk Placebo ointment applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.
General disorders Application site erythema	2.0% 2/100 • Number of events 3 • day 1 up to day 57	5.1% 5/98 • Number of events 5 • day 1 up to day 57	1.0% 1/100 • Number of events 2 • day 1 up to day 57

Additional Information

Director, Clinical Research

Teva Branded Pharmaceutical Products, R&D Inc

Phone: 1-888-483-8279

Email: USMedInfo@tevapharm.com

Results disclosure agreements

• Principal investigator is a sponsor employee Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.
• Publication restrictions are in place

Restriction type: OTHER