Clinical trial NCT02365636
Conditions: Postherpetic Neuralgia
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2015-02-26; Completion date: 2017-05-09
Enrollment: 300 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study to evaluate the safety and efficacy of 4% and 8% w/w TV 45070 ointment compared with placebo ointment applied topically and twice daily to the area of PHN pain for 4 weeks in patients with PHN

Detailed description:

Arms: arm 1: 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. arm 2: 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. arm 3: Placebo ointment applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28.
Interventions: intervention 1: TV-45070 intervention 2: Placebo
Intervention descriptions: intervention 1: TV-45070 is an ointment applied topically twice daily to area of pain. intervention 2: The matching placebo ointment contained only the excipients of the active treatment; also applied topically twice daily to area of pain.

Protocol documents:
Prot_001.pdf: 
Clinical Study Protocol with Amendment 03
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Safety and Efficacy of Topically Applied TV-45070 (4% and 8% w/w Ointment)
in Patients with Postherpetic Neuralgia
Study TV45070-CNS-20013
NCT02365636
Protocol With Amendment 03 Approval Date: 21 April 2016


Placebo-Controlled Study–Postherpetic Neuralgia
Clinical Study Protocol with Amendment 03
Study TV45070-CNS-20013
1
 
Clinical Study Protocol with Amendment 03
Study TV45070-CNS-20013
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety 
and Efficacy of Topically Applied TV-45070 (4% and 8% w/w Ointment) in Patients with 
Postherpetic Neuralgia
Phase 2
IND 108802
Protocol Approval Date: 21 April 2016
Sponsor
Monitor
Teva Branded Pharmaceutical Products R&D, Inc.
INC Research, LLC
41 Moores Road
3201 Beechleaf Court, Suite 600
Frazer, PA 19355
Raleigh, NC 27604
USA
USA
Authorized Representative (Signatory)
Teva Branded Pharmaceutical Products R&D, Inc.
Sponsor’s Medical Expert
Sponsor’s Safety Officer
Teva Pharmaceuticals
Teva Pharmaceuticals
Confidentiality Statement
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as directed by the 
provisions of the International Conference on Harmonisation (ICH); United States (US) Code of Federal 
Regulations (CFR) and European Union (EU) Directives (as applicable in the region of the study); local country 
regulations; and the Sponsor’s Standard Operating Procedures (SOPs). 
This document contains confidential and proprietary information (including confidential commercial information 
pursuant to 21CFR§20.61) and is a confidential communication of Teva Branded Pharmaceutical Products R&D, 
Inc., and its affiliate, Cephalon, Inc. (collectively the “Sponsor”). The recipient agrees that no information contained 
herein may be published or disclosed without written approval from the Sponsor.
© 2016 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved.


Placebo-Controlled Study–Postherpetic Neuralgia
Clinical Study Protocol with Amendment 03
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AMENDMENT HISTORY
The protocol for Study TV45070-CNS-20013 (original protocol dated 20 November 2014) has 
been amended and reissued as follows:
Amendment 03
21 April 2016
107 patients enrolled to date
Administrative Letter
28 September 2015
41 patients enrolled
Amendment 02
09 September 2015
41 patients enrolled to date
Amendment 01
18 February 2015
0 patients enrolled to date
Administrative Letter 
17 December 2014
0 patients enrolled
Details about the changes and rationale for each change are provided in Section 17. 


Placebo-Controlled Study–Postherpetic Neuralgia
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INVESTIGATOR AGREEMENT


Placebo-Controlled Study–Postherpetic Neuralgia
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CLINICAL LABORATORY AND OTHER DEPARTMENTS AND 
INSTITUTIONS
This study employs the services of multiple third-party vendors (central clinical laboratory, 
bioanalytical laboratory, pharmacogenomics laboratory, electronic data capture, electronic diary 
[eDiary] services, electrocardiogram [ECG] services, radiography services, interactive response
technology [IRT] services, etc). The names and addresses of the vendors are provided in the 
Study Laboratory Manual and/or manuals from the various vendors. These manuals will be in the 
trial master file (TMF).


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CLINICAL STUDY PERSONNEL CONTACT INFORMATION
For medical issues, contact the physician listed below: 
INC Research, LLC
Role in the Study: Medical Monitor
For operational issues, contact the operational lead listed below: 
INC Research, LLC
Role in the Study: Project Manager
For serious adverse events:
The serious adverse event form should be sent to the Sponsor’s local safety officer (LSO). The 
LSO will forward the report to the Sponsor’s Global Patient Safety & Pharmacovigilance
Department. For this study, the e-mail address for the USA LSO is: 
 
In the event of difficulty transmitting the form, contact the Sponsor’s study personnel identified 
above for further instruction.
These instructions also apply to pregnancy reporting (see Section 7.2).


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CLINICAL STUDY PROTOCOL SYNOPSIS
With Amendment 03
Study Number: TV45070-CNS-20013
Title of Study: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and 
Efficacy of Topically Applied TV-45070 (4% and 8% w/w Ointment) in Patients with Postherpetic Neuralgia
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
IND Number: 108802
Name of Active Ingredient: TV-45070
Name of Investigational Product: Topical TV-45070 ointment
Phase of Clinical Development: 2
Number of Study Sites Planned: Up to approximately 70 study sites
Country Planned: United States
Planned Study Period: March 2015 (first patient randomly assigned to treatment) to late 2016 up to mid 2017 (last 
patient last visit)
Number of Patients Planned: 330 patients randomly assigned to treatment (110 per arm) to have up to 
approximately 88 patients who complete the study per arm, assuming a 20% dropout rate
Study Population: Men and women 18 years of age or older, with chronic postherpetic neuralgia (PHN)
Primary Objective: The primary objective of this study is to evaluate the efficacy of 4 weeks of topical 
administration of TV-45070 (4% and 8% weight per weight [w/w] ointment) compared with placebo for the relief of 
pain due to PHN, as assessed by the change from baseline to week 4 in the weekly average of the daily average
Numeric Rating Scale (NRS) scores. The daily average NRS score is the average of the 2 NRS scores (recorded in 
the morning and in the evening) of average pain, defined as the patient-reported average pain intensity over the prior 
12 hours.
Secondary Objectives: The secondary objectives of the study are as follows: 

to evaluate the efficacy of topical TV-45070 (4% and 8% w/w ointment) compared with placebo by 
examining the following: 

change from baseline to week 4 in the weekly average of the average pain score recorded in the 
evening

change from baseline to week 4 in the weekly average of the average pain score recorded in the 
morning

change from baseline to week 4 in the weekly average of the worst pain score recorded in the 
evening (worst pain is defined as the patient-reported worst pain intensity over the prior 24 hours)

percentage of patients with ≥30% improvement from baseline in the weekly average of the daily 
average NRS scores at week 4

percentage of patients with ≥50% improvement from baseline in the weekly average of the daily 
average NRS scores at week 4

change from baseline (randomization visit) to weeks 2 and 4 in the Neuropathic Pain Symptom 
Inventory (NPSI) score


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
change from baseline (randomization visit) to week 4 in the Neuropathic Pain Impact on Quality 
of Life (NePIQoL) score

patients’ global assessment of treatment, as measured by the Patient Global Impression of Change 
(PGIC) scores, at weeks 2 and 4

change from baseline (randomization visit) in the Daily Sleep Interference Scale (DSIS) at 
weeks 2 and 4

time to reach ≥30% improvement from baseline (randomization visit) in the weekly average of the 
daily average NRS scores

change from baseline (randomization visit) in maximal intensity of patients’ brush-evoked 
allodynia, as measured on the 11-point NRS, at weeks 2 and 4

change from baseline (randomization visit) in maximal intensity of patients’ punctate-evoked 
hyperalgesia, as measured on the 11-point NRS using a Medipin® (US Neurologicals, LLC / 
Medipin Ltd), at weeks 2 and 4

to characterize the pharmacokinetics of TV-45070 in terms of the following:

establishing the dose-exposure relationship of topical TV-45070 (4% and 8% w/w ointment under 
multiple-dose conditions in patients with PHN)

estimating the apparent clearance (CL/F) and volume of distribution (V/F) of TV-45070 by 
incorporating the concentration data of this study into an enriched TV-45070 pharmacokinetics
database and performing population pharmacokinetic modeling

identifying clinically relevant covariates (eg, age, body weight, gender, and indication) affecting 
the pharmacokinetics of TV-45070 using the population pharmacokinetics model

to evaluate the safety of topical TV-45070 (4% and 8% w/w ointment) treatment compared with 
placebo, as assessed by the following at specific time points throughout the study based on the 
schedule of study procedures and assessments:

occurrence of adverse events throughout the study

clinical safety laboratory (serum chemistry, hematology, and urinalysis) test results

vital signs (heart rate, respiratory rate, body temperature, and blood pressure) measurements

electrocardiogram (ECG) findings

physical examination findings

dermal irritation findings

concomitant medication usage throughout the study
 
 
 


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
 
 
 
 
 
Study Endpoints:
Primary Efficacy Endpoint: The primary efficacy endpoint for this study is the change from baseline to week 4 in 
the weekly average of the daily average NRS scores. The daily average NRS score is the average of the 2 NRS 
scores (recorded in the morning and in the evening) of average pain, defined as the patient-reported average pain 
intensity over the prior 12 hours.
Secondary Efficacy Endpoints:
The secondary efficacy endpoints are as follows: 

change from baseline to week 4 in the weekly average of the average pain score recorded in the 
evening

change from baseline to week 4 in the weekly average of the average pain score recorded in the 
morning

change from baseline to week 4 in the weekly average of the worst pain score recorded in the evening 
(worst pain is defined as the patient-reported worst pain intensity over the prior 24 hours)

percentage of patients with ≥30% improvement from baseline in the weekly average of the daily 
average NRS scores at week 4

percentage of patients with ≥50% improvement from baseline in the weekly average of the daily 
average NRS scores at week 4

change from baseline (randomization visit) to weeks 2 and 4 in the NPSI score 

change from baseline (randomization visit) to week 4 in the NePIQoL score 

patients’ global assessment of treatment at weeks 2 and 4, as measured by PGIC scores

change from baseline (randomization visit) in DSIS scores at weeks 2 and 4

time to reach ≥30% improvement from baseline in the weekly average of the daily average NRS scores

change from baseline (randomization visit) to weeks 2 and 4 in maximal intensity of patients’ 
brush-evoked allodynia, as measured on the 11-point NRS

change from baseline (randomization visit) to weeks 2 and 4 in maximal intensity of patients’ 
punctate-evoked hyperalgesia, as measured on the 11-point NRS using a Medipin


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Safety Variables and Endpoints: The safety of TV-45070 (4% and 8% w/w ointment) will be assessed throughout 
the study by evaluating adverse events, clinical safety laboratory test results, vital signs measurements, ECG and 
physical examination results, dermal irritation, and concomitant medication usage. Skin rashes or skin irritation in 
the area of ointment application will be evaluated using a dermal irritation evaluation (modified Draize scale) at 
day 1 (at 1 hour [±30 minutes] after application of study drug), week 2, week 4, and week 8 for follow-up.
Tolerability Measures and Endpoints: The tolerability of TV-45070 (4% and 8% w/w ointment) will be assessed 
during the study using safety endpoints that also represent patients’ experience of treatment, such as skin rashes and 
skin irritation.
Pharmacokinetic Measures and Endpoints: Two blood samples will be taken from each patient, following 2
weeks of treatment with either 4% or 8% w/w TV-45070 ointment or matching placebo ointment, to quantitate the 
concentration of TV-45070 in plasma. Patients will go to the study center after applying study drug at home so that 
the 2 pharmacokinetic samples can be taken. The first sample will be taken within approximately 1 to 4 hours after 
the dose of study drug in the morning and the second sample taken approximately 2 hours after collection of the first 
sample. The date and time of the morning dose and the date and exact time for each of the 2 pharmacokinetic 
samples will be recorded. Plasma samples will be analyzed for TV-45070. Population pharmacokinetic parameters, 
such as CL/F and V/F, following topical TV-45070 administration to patients with PHN, will be estimated when the 
sparse data from this study are combined with enriched pharmacokinetic data from other studies with topical TV-
45070. Clinically relevant covariates affecting the pharmacokinetics of TV-45070 will be identified as data permit. 
These results will be reported separately from the main study results.
Pharmacodynamic Measures and Endpoints: Pharmacodynamic endpoints assessed during the study are the 
secondary efficacy endpoints change from baseline in maximal intensity of patients’ brush-evoked allodynia and 
change from baseline in maximal intensity of punctate-evoked hyperalgesia. Exploratory analyses, if performed,
may be reported separately from the main study results.
Pharmacogenomic Analyses: Two blood samples (approximately 10 mL total) for pharmacogenomic analyses will 
be taken from all patients at the screening visit. Patients who refuse to give these blood samples will be excluded 


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from the study. One sample will be analyzed to identify the nucleotide (G or A) underlying the R1150W 
polymorphism in the SCN9A gene and may identify whether there are any other sequence variants in the SCN9A
gene region. All samples will be retained for a maximum of 15 years after completion of the study 
 
 
A pharmacogenomic blood sample may be used to assess the polymorphisms of 
the CYP3A4 and CYP2C19 genes. Depending on the distribution of allelic variations for CYP3A4 and CYP2C19, 
these results may be incorporated as covariates in the current or future population pharmacokinetic analyses. 
 
 
 
General Design and Methodology: This is a Phase 2, multicenter, randomized, double-blind, parallel-group, 
placebo-controlled study to evaluate the safety and efficacy of 4% and 8% w/w TV-45070 ointment compared with 
placebo ointment applied topically and twice daily to the area of PHN pain for 4 weeks (days 1 through 28) in 
patients with PHN. For each patient, there will be a total of 6 visits to the study site and 1 telephone contact as 
follows:

screening period

visit 1: screening (up to 28 days before randomization/first administration of study drug)

washout phone contact (approximately 1 week after visit 1 for screening)

washout interval (if needed) of variable/flexible length during which the patient will discontinue 
oral analgesic therapy, topical pain therapy, and/or non-pharmacologic therapies before initiation 
of the baseline period (Appendix A, Table 2)

visit 2: baseline visit (day –10)

baseline pain assessment period (days –7 to –1; baseline pain score [average pain intensity score 
over this interval] obtained)

treatment period

visit 3: randomization (day 1 [this is the day after day –1 and the first day of study drug 
application])

visit 4: day 15 ±1, week 2

visit 5: day 29, week 4

follow-up period

visit 6: follow-up (day 57 ±3) or early termination (ET)
The screening period consists of a screening visit (informed consent and preliminary eligibility assessment are 
obtained); a washout phone contact during which eligibility based on laboratory test results will be reviewed and, as 
needed, patients will be given instructions to washout (discontinue) oral analgesic or topical pain therapy; a washout 
interval (if needed) of variable/flexible length during which appropriate patients will discontinue oral analgesic
therapy, topical pain therapy, and/or non-pharmacologic therapies; and a baseline pain assessment interval, when 
each eligible patient will be given an eDiary to record pain intensity from days –10 to –1. (To allow for training in
the use of eDiaries, patients will use eDiaries from day –10, but baseline pain assessment will be defined as the last 
7 days prior to randomization, ie, calculated from the values recorded from days –7 through –1). During the baseline 


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pain assessment interval, rescue medications for PHN pain will not be allowed. Rescue medication will also not be 
allowed during the last 7 days of treatment. Starting with the baseline pain assessment interval, patients will use 
eDiaries to record pain, using an 11-point NRS each morning (0700 ±2 hours) and evening (1900 ±2 hours), and any 
rescue pain medication usage. 
 
 
At visit 3 (day 1, randomization), visit 4 (day 15 ±1, week 2), and visit 5 (day 29, week 4), the NPSI and the DSIS
will be administered, and the results will be recorded. On the same visit days, the results of maximal intensity 
evoked allodynia and maximal intensity evoked hyperalgesia will be recorded. The NePIQoL will be evaluated at 
visit 3 and visit 5. The PGIC will be evaluated at visits 4 and 5. Efficacy measures are not collected at visit 6
(day 57 ±3), except for ET visits.
At visit 1 (screening), the patient will identify the location of his/her most severe allodynia, and this location will be 
used for assessments at all subsequent visits. If allodynia or hyperalgesia is not present at screening, it will not be 
tested at subsequent visits. The investigator will establish normal sensation by using a standardized 1-inch foam 
brush (light pressure just sufficient to bend the tip of the brush) to stroke an area of skin that is unaffected by pain. 
The region of allodynia will then be mapped by applying brush strokes moving from normal skin toward the painful 
region. A felt-tip pen will be used to mark the point where sensation changes from normal to painful. This process 
will be repeated until 8 to 10 points are marked in a radial fashion to define the area of allodynia. The marks will 
then be connected with a continuous line. To assess the intensity of allodynia, the investigator will use the brush to 
perform 3 brush strokes within the mapped area of allodynia. The patient will then assess pain intensity using an 
11-point NRS to answer the question “Please rate the intensity of pain caused by brushing the area of skin where 
0=not painful at all and 10=worst pain possible.” The pain will be rated for intensity (using the highest pain rating 
reported) both at prebrush testing and during application of the brush and recorded; additionally, the difference 
between the 2 scores will be calculated and recorded. 
In addition, at visit 1 (screening), the patient will identify the location of his/her most severe hyperalgesia, and this 
location will be used for assessments at all subsequent visits. To assess the intensity of punctate hyperalgesia, a 
Medipin will be applied in 3 successive applications to the area of skin identified at screening. The patient will then
assess the pain intensity using an 11-point NRS to answer the question “Please rate the intensity of pain caused by 
application of the Medipin where 0=not painful at all and 10=worst pain possible.” The highest pain rating will be 
recorded.
Patients will be provided with acetaminophen (TYLENOL®, McNeil Consumer Healthcare Division of 
McNEIL-PPC, Inc) as 325-mg tablets in bottles of 100 tablets and allowed to take 1 to 2 tablets per dose every 
6 hours, as needed, and up to 6 tablets or 1950 mg per day (over a 24-hour period) for rescue relief of PHN pain. 
Rescue medication will be provided at the screening visit. Rescue medication compliance will be checked at all 
visits until used rescue medication is collected after the baseline pain assessment interval or at randomization for 
patients not continuing in the study, at visit 5 (day 29, week 4) for patients who complete the treatment period or at 
the ET visit for patients who prematurely discontinue study drug.
No other rescue medications will be provided or allowed from the washout phone contact through visit 5 (day 29, 
week 4) or the ET visit. Patients will not be permitted to use rescue medication during the baseline pain assessment 
interval (days –10 through –1) and during the final week of treatment (the 7-day period before visit 5). During the 
washout interval, rescue medication use (dates of use and dose taken) will be recorded as concomitant medication. 
During the baseline period and the treatment period, rescue medication use will be recorded using the eDiary.
At the randomization visit (visit 3, day 1), eligible patients will be randomly assigned via IRT in a 1:1:1 fashion to 
1 of 3 treatment groups: 4% w/w TV-45070 ointment, 8% w/w TV-45070 ointment, or placebo ointment. 


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Randomization will be stratified by test results of the pharmacogenomic sample collected at the screening visit 
(homozygous minor allele [positive, AA], heterozygous [positive, AG], and homozygous common allele [negative, 
GG]) for R1150W polymorphism in the SCN9A gene. The patient will be instructed on how to apply the study drug. 
Under study site staff supervision, the area affected by PHN pain will be carefully defined by mapping the area of 
pain, and dosing will be prescribed to fully cover the affected area. 
Efficacy assessments of pain NRS, NPSI, NePIQoL, and DSIS scores will be conducted at visit 3 (day 1, 
randomization) to establish baseline measurements. The site staff will apply the first dose of blinded study drug and 
the patient will record the date/time in the eDiary. Subsequent study drug applications will be performed by the 
patient at home. (If the affected area is not within reach of application by the patient [such as the posterior thoracic 
region], the patient’s designated caregiver will apply the ointment, but the patient will record the time of application 
in the eDiary.) 
During the 4-week treatment period, patients will apply double-blind study drug to the area of PHN pain twice daily
in the morning (0700 ±2 hours) and again in the evening (1900 ±2 hours). The first dose of study drug will be 
applied at the clinic on day 1 (visit 3). Regardless of the clock time of the first dose application at visit 3, the 
evening dose for day 1 should be applied at 1900 ±2 hours. The last dose of study drug will be applied at home on 
the evening of day 28, which is the day before visit 5. In the event that the patient cannot keep the scheduled 
appointment on day 29, it is nevertheless important for the patient to stop dosing on the evening of day 28. The 
morning and evening drug applications will be done after recording the response for the NRS pain score. At the start 
of the baseline pain assessment interval when the eDiary is provided, the eDiary will be used to record the NRS 
responses, PHN rescue medication use, and then, after randomization, the dates/times of study drug administration. 
Patients will return to the study site for visit 4 (day 15 ±1, week 2) and again for visit 5 (day 29, week 4). Routine 
efficacy evaluations (including pain NRS, NPSI, DSIS, and PGIC scores) and safety assessments will be done at 
visit 4 (day 15 ±1, week 2) and visit 5 (day 29, week 4). At visit 4 (day 15 ±1, week 2), 2 blood samples will be 
taken from each patient for pharmacokinetic analysis: the first sample within approximately 1 to 4 hours after the
dose of study drug in the morning and the second sample approximately 2 hours after collection of the first sample. 
The dates and times of the pharmacokinetic sample collections and time of the morning dose will be recorded.
At visit 5 (day 29, week 4), the efficacy evaluation NePIQoL will also be performed, and the eDiary will be 
collected along with the tubes of study drug and bottles of rescue medication. Patients will be instructed to return to 
their primary care physician to resume therapy deemed appropriate for their PHN.
Four weeks after visit 5, the patients who completed the double-blind treatment period will return to the study site 
for a follow-up (visit 6, day 57 ±3). Activities will include safety assessments for all patients.
Patients who prematurely discontinue study drug will have an ET visit within 2 weeks after the last study drug 
administration. During the ET visit, the same activities will be conducted as those administered for follow-up at 
visit 6, the eDiary and any unused study drug/rescue medication will be collected, and compliance checks will be 
performed. Any treatment-emergent adverse event or serious adverse event will be monitored at suitable intervals 
until resolved, stabilized, or returned to baseline; until the patient is referred to the care of a health care professional; 
or until a determination of a cause unrelated to the study drug or study procedure is made during the study period. 
For adverse event recording, the study period is defined for each patient as that time period from signature of the 
ICF through the end of the follow-up period, day 57 (±3). For patients who prematurely discontinue study drug and 
do not have a treatment-emergent adverse event or serious adverse event, the ET visit will be the last study visit.
Method of Blinding and Randomization: All tubes of the study drug will be identical, and the ointments will be 
indistinguishable. Patients, investigators, and all clinical study site staff will remain blinded to treatment assignment 
during the study. Eligible patients will be randomly assigned via interactive response technology (IRT) in a 1:1:1 


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ratio to 4% w/w TV-45070 ointment, 8% w/w TV-45070 ointment, or placebo ointment. Randomization will be 
stratified by the R1150W underlying genotype in the SCN9A gene: homozygous minor allele (positive, AA), 
heterozygous (positive, AG), and homozygous common allele (negative, GG).
Study Drug Dose, Mode of Administration, and Administration Rate: The study drug is double-blind TV-45070 
ointment (4% or 8% w/w) or placebo ointment for topical administration. Study drug will be applied twice daily to 
the painful area in the morning (0700 ±2 hours) and again in the evening (1900 ±2 hours) from days 1 through 28. 
Study drug will be applied at approximately 3 μL/cm2 per application. The actual amount (mg of ointment) of study 
drug per application will be measured (as length of ointment) using one or more dosing cards based upon the area of 
pain determined at randomization (visit 3, day 1).
Investigational Product: TV-45070 ointment (4% or 8% w/w)
Reference Therapy: 
Placebo: Matching placebo ointment
Duration of Patient Participation: Approximately 12 weeks (up to 4 weeks screening, 4 weeks double-blind 
treatment, 4 weeks follow-up)
Diagnosis and Criteria for Inclusion: Patients may be included in the study only if they meet all of the following 
criteria: 
a.
[Revision 1] Patient has chronic PHN, defined as pain present for more than 6 months and less than 10
years after onset of herpes zoster skin rash affecting a single dermatome. Patients with more than 
1 involved dermatome may also be included, provided the affected dermatomes are contiguous.
Patients excluded under this criterion before implementation of Amendment 03 may be rescreened to 
determine eligibility under the revised criterion.
b.
Patient has average daily pain of at least 4 on the 11-point NRS at screening and during the baseline 
pain assessment interval (days –7 to –1) immediately before randomization.
c.
Patient must properly assess and record pain intensity in an electronic diary (eDiary) for at least 5 of 
the 7 daily morning measurements and at least 5 of the 7 daily evening measurements during the 
7 days immediately before randomization. 
d.
[Revision 1] Patient is ≥18 years of age, with a body mass index (BMI) between 18 and 34 kg/m2, 
inclusive, at the screening visit.
e.
If the patient is a woman:

The patient cannot become pregnant because she is surgically sterile (hysterectomy or tubal 
ligation) or postmenopausal for at least 6 months.
OR

If fertile, the patient is not pregnant and has negative pregnancy tests at both the screening and 
randomization visits, and agrees to use an acceptable method of contraception (ie, oral 
contraceptives, hormone implant, intrauterine device, spermicide with barrier method, surgically 
sterile male sexual partner[s], or no sexual partners) for the duration of the study, including 
follow-up.
f.
If the patient is a man:

The patient is surgically sterile.
OR


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
If capable of producing offspring, the patient must agree to use a barrier method of contraception 
in combination with a spermicide with any female partner, unless the partner cannot become 
pregnant because she is surgically sterile (hysterectomy or tubal ligation), she has been 
postmenopausal for at least 6 months, or she is fertile but using an acceptable method of 
contraception (ie, oral contraceptives, hormone implant, or intrauterine device) for the duration of 
the study, including follow-up.
g.
Patient must sign the written Informed Consent Form (ICF) for the study and be willing to comply 
with all study procedures and restrictions.
h.
Patient must be judged by the investigator to be medically healthy (except for PHN) and able to 
participate in the study.
Criteria for Exclusion: Patients will be excluded from participating in this study if they meet 1 or more of the 
following criteria: 
a.
Patient has any other severe pain that might confound assessment or self-evaluation of pain due to 
PHN.
b.
Patient has PHN affecting the face (trigeminal nerve distribution). 
c.
[Revision 1] Patient has a history, in the judgment of the investigator, of inadequate response to more 
than 3 adequate courses of treatment with other medications used to treat neuropathic pain (eg, 
tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, anticonvulsants, topical 
lidocaine, and/or topical capsaicin). Patients excluded under this criterion before implementation of 
Amendment 03 may be rescreened to determine eligibility under the revised criterion.
d.
Patient is taking oral analgesics (either opioid or non-opioid) or is receiving topical therapy such as the 
5% topical lidocaine patch for the treatment of pain and is unwilling or unable to complete a washout 
period during which the patient will discontinue analgesic therapy or topical pain therapy.
e.
Patient has been treated with topical capsaicin at any time in the past 6 months for neuropathic pain.
f.
Patient has an NRS score of 10 on 1 or more occasions during the baseline pain assessment interval 
(days –7 to –1) immediately before randomization or NRS scores of 9 on 3 or more occasions during 
the same time frame.
g.
Patient used rescue medication during the 7-day baseline period.
h.
Patient has a history of fibromyalgia.
i.
Patient has uncontrolled cardiac, renal, hepatic, or other systemic disorders that, in the opinion of the 
investigator, may jeopardize the patient.
j.
Patient uses Class Ic anti-arrhythmic drugs such as flecainide or propafenone.
k.
Patient has a resting heart rate <45 or >100 beats per minute (bpm), QRS ≥120 milliseconds (including 
complete left and/or right bundle branch block), QT interval corrected for heart rate by Fridericia’s 
formula (QTcF) ≤320 milliseconds or ≥470 milliseconds, and, for patients in sinus rhythm, 
PR <120 milliseconds or ≥220 milliseconds. (These numerical exclusion criteria will be applied using 
the mean values of 3 ECGs.)
l.
Patient has second- or third-degree atrioventricular block unless treated with a permanent pacemaker.
m. Patient has uncontrolled atrial fibrillation or flutter (ventricular rate >100 bpm).


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n.
Patient has a congenital arrhythmia syndrome (eg, Brugada syndrome or long or short QT syndrome).
o.
Patient has had myocardial infarction within the past 12 months or current unstable angina, coronary 
ischemia, or heart failure.
p.
Patient has significant edema or loss of skin integrity (including sores or ulcers) other than healed
herpes zoster skin rash affecting the region of pain and surrounding area.
q.
Patient is intolerant to study drug, its excipients, and/or acetaminophen.
r.
Patient uses any over-the-counter (OTC) analgesic medication/topical therapy for the duration of the 
study except for permitted rescue (for PHN pain) medications. Stable therapy of more than 30 days for 
aspirin (up to 81 mg/day) is allowed as cardiovascular prophylaxis.
s.
Patient uses any non-pharmacologic pain management techniques (eg, physical techniques, 
physiotherapy, massage therapy, acupuncture, biofeedback, and/or psychological support) and is 
unable or unwilling to discontinue prior to baseline pain assessment.
t.
[Criterion removed].
u.
Patient uses any topical/cosmetic products (eg, lotions and tanning products) on the skin in the painful 
region of PHN.
v.
Patient has a history of alcohol or drug abuse within 1 year before the screening visit, or a positive 
urine drug test at the screening visit for cocaine, marijuana, opioids, amphetamines, 
methamphetamines, benzodiazepines, barbiturates, methadone, and/or tricyclic antidepressants unless 
explained by the use of prescription medication. (The use of medical marijuana is not permitted and 
excludes the patient from the study.)
w.
Patient is pregnant or breast-feeding at the time of the screening visit.
x.
Patient has findings in laboratory data, vital signs measurements, or physical examination at the 
screening, baseline pain assessment interval, or randomization visit that, in the opinion of the 
investigator, may pose undue risk to the patient or may interfere with study data interpretation.
y.
Patient was previously randomly assigned to treatment in this study and received/subsequently 
discontinued study drug.
z.
Patient used another investigational drug within 30 days or 5 half-lives (whichever is longer) before 
the planned first day of study drug application (day 1) in this study.
aa. Patient refuses to provide 2 blood samples at the screening visit for pharmacogenomic analyses.
bb. Patient is a study site or Sponsor employee who is directly involved in the study or the relative of such 
an employee.
cc. There is any other reason that would make the patient, in the opinion of either the investigator or the 
Sponsor, unsuitable for the study.
Allowed and Disallowed Medications Before and During the Study: Prior to the study, patients taking opioid or 
non-opioid oral analgesics or topical therapy must discontinue therapy as part of a washout period. Patients cannot 
have been treated with topical capsaicin for neuropathic pain at any time in the past 6 months, and cannot use Class 
Ic anti-arrhythmic drugs such as flecainide or propafenone. During the study, the following medications are not 
permitted: oral analgesics; topical analgesics including lidocaine (gels, creams and patches) and capsaicin patches; 
Class Ic anti-arrhythmic drugs such as flecainide or propafenone; rescue pain medication except for permitted


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acetaminophen rescue. Permitted acetaminophen rescue consisted of 325 mg tablets, in doses of up to 1 to 2 tablets 
per 6 hours as needed, up to 6 tablets per 24 hours.
Statistical Considerations: Patient demographic and baseline characteristics, including medical history, prior 
medications, and ECG findings, will be examined to assess the comparability of the treatment groups and will be 
summarized using descriptive statistics. For continuous variables, descriptive statistics (number [n], mean, standard 
deviation, standard error, median, minimum, and maximum) will be provided. For categorical variables, patient 
counts and percentages will be provided. 
The full analysis set (FAS), defined as all patients in the intent-to-treat (ITT) population (all patients randomly 
assigned to treatment) who receive at least 1 dose of study drug and have at least 1 post-baseline efficacy 
assessment, will be used for all efficacy analyses. Summaries will be presented by treatment group.
The primary efficacy variable, change from baseline to week 4 in the weekly average of the daily average NRS
scores, will be analyzed using a Mixed Model Repeated Measures (MMRM) with change from baseline in the 
weekly average of the daily average NRS scores at weeks 2 and 4 as the dependent variable; visit in weeks, 
treatment, and treatment by visit interaction as fixed factors; baseline weekly average of the daily average NRS 
scores as covariate; and patient as random effect. The unstructured covariance matrix for repeated observations
within patients will be used. The primary treatment comparison will be conducted at week 4 in this model. All tests
will be 2-sided at a significance level of 0.05. More details will be provided in the Statistical Analysis Plan.
All adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Each patient 
will be counted only once in each preferred term or system organ class (SOC) category for the analyses of safety. 
Summaries will be presented for all adverse events (overall and by severity), adverse events determined by the 
investigator to be related to study treatment (ie, based on reasonable possibility; adverse events defined as related or 
with missing relationship will be summarized overall and by severity), serious adverse events, and adverse events 
causing withdrawal from study drug treatment and/or the study. Summaries will be presented by treatment group 
and for all patients. Patient listings of serious adverse events and adverse events leading to withdrawal will be 
presented.
Changes in laboratory and vital signs measurement data will be summarized descriptively. All values will be 
compared with prespecified boundaries to identify potentially clinically significant changes or values, and such 
values will be listed.
The use of concomitant medications will be summarized by therapeutic class using descriptive statistics. 
Concomitant medications will include all medications taken while the patient is treated with study drug.
For continuous variables, descriptive statistics (n, mean, standard deviation, standard error, median, minimum, and 
maximum) will be provided for actual values and changes from baseline to each time point. For categorical 
variables, patient counts and percentages will be provided. Descriptive summaries of serious adverse events, patient 
withdrawals due to adverse events, and potentially clinically significant abnormal values (clinical laboratory or vital 
signs) based on predefined criteria will also be provided.
The population pharmacokinetic analyses will be detailed in a population pharmacokinetic analysis plan for this 
study. Results will be reported separately from the main study results.
Sample Size Rationale: In prior studies of gabapentin or pregabalin treatment of PHN, the difference in mean pain 
scores between active- and placebo-treated groups ranged from 1.0 (Rice et al 2001) to 1.3 (Dworkin et al 2003). 
For this decision-making, proof-of-concept study, it is reasonable to use a conservative estimate of 1.0. If we assume 
a standard deviation of 2.35, a sample size of up to approximately 88 per arm (a total of 264 patients) would be 
needed to provide 80% power with a 2-sided test at 5% significance level to detect a 1.0-point difference. Assuming 


Placebo-Controlled Study–Postherpetic Neuralgia
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an approximately 20% dropout rate, 110 patients per arm (a total of 330 patients) will be randomly assigned to each 
treatment group. During the study, the ultimate sample size may be adjusted on the basis of the actual dropout rate.
Amendment 03: The primary reason for amendment 03 is to facilitate timely enrollment of patients by broadening
the inclusion criterion for the maximum duration of PHN and the exclusion criterion for the number of adequate 
courses of treatment with other medications for which response was inadequate; by allowing rescreening of patients 
excluded under these criteria before implementation of amendment 03; and by increasing the number of study sites.
Amendment 02: The primary reason for amendment 02 is to remove the stipulation in exclusion criterion “t” that 
excludes patients from participating in the study if they used any of the CYP3A4 or CYP2C19 inhibitors or 
substrates that were listed in Table 2 under Appendix A to this protocol. Related editorial changes have been made
as a result of this removal, including: 1) replacement of the previous Table 2 (CYP3A4 and CYP2C19 Substrates 
and Inhibitors with Documented Clinically Significant Interactions) in Appendix A with a new Table 2 entitled 
Washout Periods for Specific Drugs; and 2) revision of any statement(s) and cross-reference(s) within the protocol 
referring to information previously provided in Table 2 of Appendix A.
An additional reason for amendment 02 is to revise inclusion criterion “d” to broaden the recruitment criterion for 
BMI by increasing the upper limit of the range for BMI from 32 to 34 kg/m2.
Amendment 02 also serves to correct the list of drugs, as described in Section 7.3.4.2 that are detected by the urine 
drug screen performed to detect the presence of drugs prohibited by protocol. Alcohol was incorrectly listed in 
Section 7.3.4.2 as a substance detected by the drug screen, and has been deleted from Section 7.3.4.2 as part of this 
amendment.
Time windows have been added for the timing of the dermal irritation test and for the triplicate ECGs to allow for 
natural variability in timing and to avoid unnecessary protocol deviations.
Minor editorial changes for improved text flow and clarity have been incorporated into the protocol text as part of 
this amendment.
Finally, the protocol is now presented in an updated protocol template maintained by the Sponsor. The change to an 
updated template is an administrative change per Sponsor policy, and is not intended to alter the clinical conduct of 
the study.


Placebo-Controlled Study–Postherpetic Neuralgia
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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
AMENDMENT HISTORY .............................................................................................................2
INVESTIGATOR AGREEMENT...................................................................................................3
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS ..............4
CLINICAL STUDY PERSONNEL CONTACT INFORMATION ...............................................5
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................6
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................27
1.
BACKGROUND INFORMATION...........................................................................30
1.1.
Introduction.................................................................................................................30
1.2.
Name and Description of Investigational Product......................................................31
1.3.
Findings from Nonclinical and Clinical Studies.........................................................31
1.3.1.
Nonclinical Studies.....................................................................................................31
1.3.1.1.
Pharmacology Studies ................................................................................................31
1.3.1.2.
Pharmacokinetic Studies.............................................................................................32
1.3.1.3.
Toxicology Studies and Toxicokinetics......................................................................33
1.3.1.4.
Safety Pharmacology Studies .....................................................................................34
1.3.2.
Clinical Studies...........................................................................................................35
1.3.2.1.
Clinical Pharmacology Studies...................................................................................35
1.3.2.2.
Clinical Safety and Efficacy Studies ..........................................................................36
1.3.2.3.
Pharmacogenomic Studies..........................................................................................37
1.4.
Known and Potential Risks and Benefits to Human Subjects....................................37
1.4.1.
Risks of TV-45070 .....................................................................................................37
1.4.2.
Benefits of TV-45070.................................................................................................38
1.4.3.
Overall Risk and Benefit Assessment for This Study ................................................38
1.5.
Selection of Drugs and Dosages.................................................................................38
1.5.1.
Justification for Dosage of Active Drug.....................................................................38
1.5.2.
Justification for Use of Placebo..................................................................................39
1.6.
Compliance Statement................................................................................................39
1.7.
Population To Be Studied and Justification................................................................39
1.8.
Location and Timing of Study....................................................................................40
1.9.
Relevant Literature and Data......................................................................................40


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2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES.....................................41
2.1.
Purpose of the Study...................................................................................................41
2.2.
Study Objectives.........................................................................................................41
2.2.1.
Primary Objective.......................................................................................................41
2.2.2.
Secondary Objectives .................................................................................................41
2.2.3.
Exploratory/Other Efficacy Objectives ......................................................................42
3.
STUDY DESIGN .......................................................................................................44
3.1.
General Design and Study Schema.............................................................................44
3.2.
Justification for Study Design ....................................................................................49
3.3.
Primary and Secondary Measures and Endpoints ......................................................49
3.3.1.
Primary Efficacy Measure and Endpoint....................................................................49
3.3.2.
Secondary Efficacy Measures and Endpoints.............................................................49
3.3.3.
Exploratory Efficacy Measures and Endpoints ..........................................................50
3.3.4.
Safety Measures and Endpoints..................................................................................50
3.3.5.
Tolerability Measures and Endpoints.........................................................................50
3.3.6.
Pharmacokinetic Measures and Endpoints.................................................................50
3.3.7.
Pharmacodynamic Measures and Endpoints ..............................................................51
3.3.8.
Pharmacogenomic Analyses.......................................................................................51
3.4.
Randomization and Blinding......................................................................................51
3.5.
Maintenance of Randomization and Blinding............................................................52
3.5.1.
Randomization............................................................................................................52
3.5.2.
Blinding/Unblinding...................................................................................................52
3.6.
Drugs used in the Study..............................................................................................53
3.6.1.
Investigational Product ...............................................................................................53
3.6.2.
Placebo........................................................................................................................54
3.7.
Drug Supply and Accountability ................................................................................54
3.7.1.
Drug Storage and Security..........................................................................................54
3.7.2.
Drug Accountability ...................................................................................................54
3.8.
Duration of Patient Participation and Justification.....................................................55
3.9.
Stopping Rules and Discontinuation Criteria .............................................................55
3.10.
Source Data Recorded on the Case Report Form .......................................................55
3.11.
Study Procedures ........................................................................................................56
3.11.1.
Procedures for the Screening Period (Day –28 to Day –1) ........................................62


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3.11.1.1.
Screening Visit (Visit 1, Day –28) .............................................................................62
3.11.1.2.
Washout Phone Contact (Approximately 1 Week After the Screening Visit) ...........63
3.11.1.3.
Washout Period (Variable Duration Period Between the Washout Phone 
Contact and the Baseline Visit) ..................................................................................63
3.11.1.4.
Baseline Visit (Visit 2, Day –10, weekday) ...............................................................63
3.11.2.
Randomization Visit (Visit 3, Day 1, weekday).........................................................64
3.11.3.
Procedures During Double-Blind Treatment Period (Day 1 Through 
Day 29 Visit)...............................................................................................................66
3.11.3.1.
Daily Routine..............................................................................................................66
3.11.3.2.
Week 2 Visit (Visit 4, Day 15 [±1]) ...........................................................................66
3.11.3.3.
Week 4 Visit (Visit 5, Day 29 [±0]) ...........................................................................67
3.11.3.4.
Early Termination Visit ..............................................................................................68
3.11.4.
Procedures After Study Drug Treatment ....................................................................69
3.11.4.1.
Follow-up Period (After the Week 4 Visit)................................................................69
3.11.4.2.
Follow-up Visit or ET visit (Visit 6, Day 57 [±3]).....................................................69
3.11.5.
Unscheduled Visits .....................................................................................................70
4.
SELECTION AND WITHDRAWAL OF PATIENTS..............................................71
4.1.
Patient Inclusion Criteria ............................................................................................71
4.2.
Patient Exclusion Criteria...........................................................................................72
4.3.
Justification of Key Inclusion and Exclusion Criteria................................................74
4.4.
Withdrawal Criteria and Procedures...........................................................................74
5.
TREATMENT OF PATIENTS..................................................................................76
5.1.
Drugs Administered During the Study .......................................................................76
5.2.
Restrictions .................................................................................................................77
5.3.
Prior and Concomitant Therapy or Medication..........................................................77
5.4.
Rescue Medications for PHN Pain .............................................................................77
5.5.
Procedures for Monitoring Patient Compliance .........................................................78
5.6.
Total Blood Volume ...................................................................................................78
6.
ASSESSMENT OF EFFICACY ................................................................................79
6.1.
Primary Efficacy Variable..........................................................................................79
6.2.
Secondary Efficacy Variables.....................................................................................79
6.3.
Exploratory Efficacy Variables ..................................................................................79


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6.4.
Methods and Timing of Assessing, Recording, and Analyzing Efficacy and 
Clinical Pharmacology Data.......................................................................................79
7.
ASSESSMENT OF SAFETY.....................................................................................80
7.1.
Adverse Events ...........................................................................................................80
7.1.1.
Definition of an Adverse Event..................................................................................80
7.1.2.
Recording and Reporting Adverse Events..................................................................81
7.1.3.
Severity of an Adverse Event .....................................................................................82
7.1.4.
Relationship of an Adverse Event to the Study Drug.................................................82
7.1.5.
Serious Adverse Events..............................................................................................82
7.1.5.1.
Definition of a Serious Adverse Event .......................................................................82
7.1.5.2.
Expectedness...............................................................................................................83
7.1.5.3.
Reporting a Serious Adverse Event............................................................................83
7.1.6.
Protocol-Defined Adverse Events for Expedited Reporting ......................................85
7.1.7.
Withdrawal Due to an Adverse Event ........................................................................85
7.1.8.
Medical Emergencies..................................................................................................86
7.1.9.
Protocol Deviations Because of an Adverse Event ....................................................86
7.2.
Pregnancy ...................................................................................................................86
7.3.
Clinical Laboratory Tests ...........................................................................................87
7.3.1.
Serum Chemistry ........................................................................................................87
7.3.2.
Hematology.................................................................................................................88
7.3.3.
Urinalysis....................................................................................................................88
7.3.4.
Other Clinical Laboratory Tests .................................................................................89
7.3.4.1.
Pregnancy Tests..........................................................................................................89
7.3.4.2.
Urine Drug Screen ......................................................................................................89
7.4.
Vital Signs ..................................................................................................................89
7.5.
Electrocardiography....................................................................................................90
7.6.
Physical Examinations................................................................................................90
7.7.
Other Safety Measures and Variables: Concomitant Therapy or Medication............90
7.8.
Methods and Timing of Assessing, Recording, and Analyzing Safety Data..............90
7.9.
Dermal Irritation Evaluation.......................................................................................90
8.
ASSESSMENT OF PHARMACOKINETICS / PHARMACODYNAMICS / 
PHARMACOGENOMICS.........................................................................................92
8.1.
Pharmacokinetic Variables.........................................................................................92


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8.2.
Pharmacodynamic Variables ......................................................................................92
8.3.
Pharmacogenomic Variables ......................................................................................92
9.
STATISTICS ..............................................................................................................94
9.1.
Study Design and Randomization ..............................................................................94
9.2.
Sample Size and Power Considerations .....................................................................94
9.3.
Analysis Sets/Populations...........................................................................................94
9.3.1.
Intent-to-Treat Population ..........................................................................................94
9.3.2.
Safety Population........................................................................................................94
9.3.3.
Full Analysis Set.........................................................................................................94
9.3.4.
Per Protocol Population..............................................................................................94
9.3.5.
Additional Analysis Sets.............................................................................................95
9.4.
Data Handling Conventions........................................................................................95
9.5.
Study Population.........................................................................................................95
9.5.1.
Patient Disposition......................................................................................................95
9.5.2.
Demographic and Baseline Characteristics ................................................................95
9.6.
Efficacy Analysis........................................................................................................95
9.6.1.
Planned Method of Analysis.......................................................................................95
9.6.1.1.
Primary Efficacy Analysis..........................................................................................95
9.6.1.2.
Sensitivity Analysis ....................................................................................................96
9.6.1.3.
Secondary Efficacy Analysis......................................................................................96
9.6.1.4.
Exploratory Efficacy Analysis....................................................................................96
9.7.
Multiple Comparisons and Multiplicity......................................................................96
9.8.
Safety Variables and Analysis....................................................................................97
9.8.1.
Safety Variables..........................................................................................................97
9.8.2.
Safety Analysis ...........................................................................................................97
9.9.
Pharmacokinetic Analysis ..........................................................................................97
9.10.
Pharmacodynamic Analysis........................................................................................98
9.11.
Pharmacogenomic Analysis........................................................................................98
9.12.
Planned Interim Analysis............................................................................................98
9.13.
Reporting Deviations from the Statistical Plan ..........................................................98
10.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................99
11.
QUALITY CONTROL AND QUALITY ASSURANCE .......................................100
11.1.
Protocol Amendments and Protocol Deviations and Violations ..............................100


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11.1.1.
Protocol Amendments ..............................................................................................100
11.1.2.
Protocol Deviations ..................................................................................................100
11.2.
Information to Study Personnel................................................................................100
11.3.
Study Monitoring......................................................................................................101
11.4.
Clinical Product Complaints.....................................................................................101
11.4.1.
Product Complaint Information Needed from the Study Site ..................................102
11.4.2.
Handling the Study Drug at the Study Site...............................................................102
11.4.3.
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint .................................................................................................................103
11.4.4.
Documenting a Product Complaint ..........................................................................103
11.5.
Audit and Inspection.................................................................................................103
12.
ETHICS ....................................................................................................................104
12.1.
Informed Consent .....................................................................................................104
12.2.
Health Authorities and Institutional Review Boards................................................104
12.3.
Confidentiality Regarding Study Patients ................................................................104
12.4.
Declaration of the End of the Clinical Study............................................................104
12.5.
Registration of the Clinical Study.............................................................................104
13.
DATA HANDLING, DATA QUALITY ASSURANCE, AND RECORD 
KEEPING .................................................................................................................105
13.1.
Data Collection.........................................................................................................105
13.2.
Data Quality Assurance ............................................................................................105
13.3.
Archiving of Case Report Forms and Source Documents........................................106
13.3.1.
Investigator Responsibilities.....................................................................................106
13.3.2.
Sponsor Responsibilities...........................................................................................106
14.
FINANCING AND INSURANCE...........................................................................107
15.
REPORTING AND PUBLICATION OF RESULTS..............................................108
16.
REFERENCES .........................................................................................................109
17.
SUMMARY OF CHANGES TO PROTOCOL .......................................................110
17.1.
Amendment 03 Dated 21 April 2016........................................................................110
17.2.
Administrative Letter Dated 28 September 2015 .....................................................116
17.3.
Amendment 02 Dated 09 September 2015...............................................................117
17.4.
Amendment 01 Dated 18 February 2015..................................................................122
17.5.
Administrative Letter Dated 17 December 2014......................................................124


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APPENDIX A.
WASHOUT PERIODS FOR COMMON MEDICATIONS TAKEN 
BY PATIENTS WITH POSTHERPETIC NEURALGIA .......................................125


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LIST OF TABLES
Table 1:
Study Procedures and Assessments............................................................................57
Table 2:
Washout Periods for Specific Drugs.........................................................................125


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LIST OF FIGURES
Figure 1:
Study Design...............................................................................................................48


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Table of Abbreviations
Abbreviation
Term
(A)
adenine
ALT
alanine aminotransferase (SGPT)
ANCOVA
analysis of covariance
AST
aspartate aminotransferase (SGOT)
AUC
area under the drug concentration by time curve
AUC0-24h
area under the concentration-time curve from 0 to 24 hours
AUC0-inf
area under the concentration-time curve from time 0 to infinity
average pain
the patient-reported average pain intensity over the prior 12 hours
BMI
body mass index 
bpm
beats per minute
BSA
body surface area
CCI
chronic constriction injury
CDMS
clinical data management system 
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences 
CL
clinical leader
CL/F
apparent clearance
Cmax
maximum observed plasma drug concentration
CNS
central nervous system
CPP
clinical project physician
CRF
case report form (refers to any media used to collect study data [ie, paper or 
electronic])
CRO
contract research organization
CSR
clinical study report
CYP450
cytochrome P450
CYP2C19
cytochrome P450 2C19
CYP3A4
cytochrome P450 3A4
daily average 
NRS score
the average of the two Numeric Rating Scale scores recorded per day (the score in the 
morning and the score in the evening)
DDI
drug-drug interaction(s)


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Abbreviation
Term
DNA
deoxyribonucleic acid
DRF
dose range-finding
DSIS
Daily Sleep Interference Scale
EDTA
ethylenediaminetetraacetic acid
ECG
electrocardiography, electrocardiogram(s)
eDiary
electronic diary
EM
erythromelalgia
ET
early termination
EU
European Union
FAS
full analysis set 
FDA
Food and Drug Administration (US)
(G)
guanine
GCP
Good Clinical Practice
GD
gestation day
GGT
gamma-glutamyl transpeptidase
GLP
Good Laboratory Practice
hERG
human ether-a-go-go-related gene
IC50
50% inhibitory concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
International Ethics Committee
IEM
inherited or primary erythromelalgia
INR
International Normalized Ratio 
IRB
Institutional Review Board
IRT
interactive response technology
ITT
intent-to-treat 
iv
intravenous
LDH
lactic dehydrogenase
LOCF
last observation carried forward
LSO
local safety officer 
MAD
multiple ascending dose
MedDRA
Medical Dictionary for Regulatory Activities 


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Abbreviation
Term
MMRM
Mixed Model Repeated Measures
MTD
maximum tolerated dose
NaV
voltage-dependent sodium channel
NePIQoL
Neuropathic Pain Impact on Quality of Life (questionnaire, score)
NNT
number-needed-to-treat
NOAEL
no-observed-adverse-effect level
non-GLP
not conducted according to Good Laboratory Practice
NPSI
Neuropathic Pain Symptom Inventory
NRS
Numeric Rating Scale
OA
osteoarthritis
OTC
over-the-counter
PGIC
Patient Global Impression of Change (scale, score)
PHN
postherpetic neuralgia
PP
per protocol
QTc
corrected QT interval 
QTcF
QT interval corrected for heart rate by Fridericia’s formula
RBC
red blood cell
SAD
single-ascending dose
SDV
source document verification
SOC
System Organ Class
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
ULN
upper limit of the normal range
US(A)
United States (of America)
V/F
volume of distribution
w/w
weight per weight
WBC
white blood cell
WHO Drug
World Health Organization (WHO) drug dictionary
worst pain
the patient-reported worst pain intensity over the prior 24 hours


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1.
BACKGROUND INFORMATION
1.1.
Introduction 
Postherpetic neuralgia (PHN) is a complication of herpes zoster in which pain persists for more 
than 3 months after resolution of the rash. (Three months is the most commonly identified
duration, although definitions of duration for PHN vary from >1 months to >6 months.) 
Postherpetic neuralgia affects between 10% to 15% of people who have herpes zoster and 
increases with age, affecting up to 70% of those infected who are more than 70 years old (Davies
and Galer 2004, Dubinsky et al 2004, Kost and Straus 1996). Elderly patients tend to have more 
severe and longer lasting PHN.
Postherpetic neuralgia is a classical neuropathic pain condition in which damage to peripheral 
sensory nerves (and the dorsal horn regions of the spinal cord) is believed to generate 
spontaneous peripheral neural discharges that lead secondarily to hyperexcitability of dorsal horn 
sensory neurons and result in exaggerated central nervous system (CNS) responses to all input, a 
condition known as central sensitization (Kost and Straus 1996). Typically, patients with PHN 
have both a zone of loss of sensation and zones of altered sensation to light touch and 
temperature. Pain is described as deep aching or burning in quality and may be triggered by 
non-painful stimulus (mechanical allodynia) or temperature change (warm or cold allodynia). It 
may last for years, although there is a tendency for it to wane over time. In those patients whose 
pain is persistent and severe, PHN becomes debilitating, markedly restricting the patient’s 
activity and quality of life.
Despite the numerous compounds available for treating PHN, 40% to 50% of PHN patients do
not respond to any treatment (Rowbotham and Petersen 2001). Antiviral therapy for acute herpes 
zoster has been shown to speed clearing of the rash, but a recent meta-analysis showed that it 
does not reduce the likelihood of the development of PHN (Li et al 2009). Antivirals also have 
no demonstrable benefit after the rash has cleared and are of no use once PHN is established. 
Tricyclic antidepressants were the first analgesic agents that showed efficacy in randomized 
controlled trials of PHN, and, subsequently, anticonvulsant agents, strong opioids, and topical 
analgesics have also demonstrated efficacy.
A topical patch containing 5% lidocaine, a nonselective sodium channel blocker (LIDODERM®, 
Endo Pharmaceuticals Inc), was approved by the United States (US) Food and Drug 
Administration (FDA) for the treatment of PHN. In 2004, a subcommittee of the American 
Academy of Neurology determined that there was solid Class I evidence of efficacy for the 
lidocaine patch in PHN (Dubinsky et al 2004). The lidocaine patch, if perhaps less effective than 
other approved treatments such as gabapentin and pregabalin (Dworkin et al 2003), is considered 
highly efficacious in PHN, although there have been no head-to-head comparisons with other 
agents and the number-needed-to-treat (NNT) varies from study to study (Davies and Galer 
2004). The safety and tolerability of the lidocaine patch has probably contributed most to its 
widespread use in PHN. Safety and the reduced risk of drug-drug interactions (DDIs) with a 
topical formulation are particularly relevant, given the elderly age of most patients affected by 
PHN and their need for concomitant medications. 


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TV-45070 is a novel, potent, voltage-dependent sodium channel (NaV) blocker being developed 
for the treatment of patients with various neuropathic pain indications. Unlike lidocaine, 
TV-45070 has been designed to selectively block activity in the NaV1.7 channel, which is 
believed to be the most important sodium channel contributing to spontaneous and hyperactive 
discharges emanating from peripheral nociceptive neurons. Nonclinical studies have
demonstrated that TV-45070 has efficacy in several classical neuropathic pain models, with 
comparable efficacy to gabapentin in the chronic constriction injury (CCI) model and superior 
efficacy to 5% lidocaine in a topical streptozotocin-induced diabetic neuropathic pain model. 
TV-45070 has been studied in a 2-period crossover trial (each period lasting 3 weeks) in 62 PHN 
patients who received 1 or more TV-45070 doses. Although it did not meet the primary endpoint 
(change in mean daily pain score during the last week compared to baseline as measured by the 
Numeric Rating Scale [NRS]), a significantly larger percentage of patients with 50% reductions 
in pain were seen during the TV-45070 treatment period in the efficacy evaluable and per 
protocol (PP) analysis groups. The current study is designed to further evaluate the efficacy of 
TV-45070 in a larger, parallel-group study design.
1.2.
Name and Description of Investigational Product
TV-45070 (formerly known as XEN402 [active pharmaceutical ingredient]) is a white to 
yellowish crystalline powder. Its chemical name is (S)-1’-{[5-(trifluoromethyl)furan-2-
yl]methyl}spiro[furo [2,3 f][1,3]benzodioxole-7,3’-indol]-2’(1H)-one. Its chemical formula is 
C22H14F3NO5. 
Topical TV-45070 is an unscented, off-white to yellowish, opaque ointment with a smooth 
texture. The clinical formulation contains 4% or 8% (weight per weight [w/w]) TV-45070 with 
the excipients described in Section 4 of the Investigator’s Brochure. The matching placebo 
ointment contains only the excipients.
A more detailed description of the product is given in Section 3.6.
1.3.
Findings from Nonclinical and Clinical Studies
1.3.1.
Nonclinical Studies
Nonclinical studies have been completed to characterize the tolerability, toxicity, 
pharmacokinetics, and efficacy of TV-45070 following dermal application and oral 
administration. Prior to development of TV-45070, a package of nonclinical studies was 
conducted using the racemic compound XEN401 (where TV-45070 comprises 50% of the 
racemate by weight).
1.3.1.1.
Pharmacology Studies
In vitro electrophysiologic studies indicated that TV-45070 is a potent NaV blocker active against 
several NaV subtypes, including those associated with pain signaling.
 
 


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In vivo studies in neuropathic and inflammatory pain models in the rat demonstrated that topical 
administration of TV-45070 provides analgesic relief superior to current marketed topical 
therapeutics such as lidocaine and diclofenac. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Based on these data, the 
analgesic effect of topical TV-45070 in these animal models is considered to be due to a local 
rather than a systemic drug effect.
1.3.1.2.
Pharmacokinetic Studies
 
 
 
 
 
 
 
 
 
 


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1.3.1.3.
Toxicology Studies and Toxicokinetics
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.3.1.4.
Safety Pharmacology Studies
 
As suggested by previously published data (Redfern et al 2003), a 
30-fold margin between the unbound maximal plasma concentration and the hERG IC50 is 
considered adequate to ensure an acceptable degree of safety from arrhythmogenesis. 
 
 
 
 
 
 
 
 
 
 
 
 


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Further details may be found in the current Investigator’s Brochure. 
1.3.2.
Clinical Studies
To date, topically administered TV-45070 (formerly known as XEN402) has been evaluated in 
3 clinical studies: a Phase 1 study in healthy subjects, a Phase 2a study in patients with PHN, and 
a Phase 2a study in patients with inherited erythromelalgia (IEM). Eighty-nine subjects 
(20 healthy subjects, 62 PHN patients, and 7 IEM patients) received multiple applications of 
TV-45070 ointment.
Additionally, topical TV-45070 has been evaluated in a Phase 2 study in patients with 
osteoarthritis (OA) of the knee, a Phase 1 dose-escalation study in healthy volunteers, and a 
Phase 1 DDI study with midazolam and omeprazole. Final data are not yet available from these 
studies.
Oral TV-45070 has been evaluated in 3 clinical studies: a Phase 1 single ascending dose (SAD) 
and multiple ascending dose (MAD) study, a Phase 2a study in patients with pain following third 
molar extractions, and a Phase 2a study in patients with IEM. 
The clinical conduct of the OA study, the dose-escalation study, and the DDI study have been 
completed, but analysis is ongoing. A brief summary of the results of all completed topical and 
selected oral TV-45070 studies is presented below with more details available in the 
Investigator’s Brochure. The results of the other oral TV-45070 studies are available in the 
Investigator’s Brochure.
1.3.2.1.
Clinical Pharmacology Studies
Topical TV-45070 results in minimal to negligible systemic exposure to TV-45070. The 
TV-45070 plasma concentrations in this paragraph are maximum individual (not group mean)
values. Topical TV-45070 was administered to 20 healthy subjects for 21 days in a Phase 1 study 
(Study XPF-002-101) in which topical TV-45070 was shown to be safe and well tolerated with 
low plasma exposure (highest observed plasma TV-45070 concentrations <1 ng/mL). In a 
Phase 2a study (Study XPF-002-201) conducted in 68 patients with PHN, 62 patients were 
treated with topical TV-45070 for 21 days, and in a Phase 2a study (Study XPF-002-202) 
conducted in 8 patients with IEM, 7 patients were treated with topical TV-45070 for 14 or
21 days. The amount of drug applied was calculated based on the patient’s BSA and a 
pre-determined fixed-dose volume. The highest plasma TV-45070 concentration observed in any 
patient was approximately 14 ng/mL.
In the oral TV-45070 SAD/MAD study (Study XPF-001-101), oral TV-45070 was shown to be 
safe at single doses up to 500 mg (ie, maximum tolerated dose [MTD]) and at doses up to 
400 mg twice daily for 5.5 days. The SAD pharmacokinetic profiles had a mean Cmax of 
1410 ng/mL and a mean area under the concentration-time curve from time 0 to infinity 
(AUC0-inf) of 7305 ng•h/mL in cohort 5 (500 mg). Dose-limiting toxicity due to dizziness and 
somnolence was seen in healthy subjects following single oral doses of 800 mg TV-45070. 
No QTc interval changes were observed in any of the oral TV-45070 clinical studies.
Furthermore, except for single reports of non-sustained ventricular tachycardia and ventricular 


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extrasystoles, no other observations of clinically significant QRS prolongation were observed in 
studies of orally or topically administered TV-45070. More details are available in Section 7.11.3
of the Investigator’s Brochure.
The highest (maximum individual) Cmax values observed in the topical TV-45070 studies were 
100-fold lower than the mean Cmax at the oral MTD for a single dose.
1.3.2.2.
Clinical Safety and Efficacy Studies
The safety, tolerability, pharmacokinetics, and efficacy of topical TV-45070 were evaluated in 
68 patients with PHN in a Phase 2a, randomized, double-blind, placebo-controlled, crossover 
study using 8% w/w TV-45070 ointment applied twice daily for 3 weeks (Study XPF-002-201). 
Topical TV-45070 was found to be safe and well tolerated with low plasma exposure (mean Cmax
2 ng/mL). The primary endpoint of mean change from baseline in pain scores in the last week 
was similar between topical TV-45070 and placebo treatments. However, a responder analysis 
demonstrated that a greater proportion of patients achieved at least 50% reduction in pain from 
baseline while using topical TV-45070 treatment (26.8%) compared with placebo (10.7%) 
(p=0.0039). There were no fatal events reported during the study. Two serious adverse events 
were reported in 2 patients: a tooth abscess that occurred during placebo treatment and 
worsening coronary artery disease that occurred during topical TV-45070 treatment. Treatment 
was discontinued in the patient with coronary artery disease. Neither serious adverse event was 
considered related to study drug treatment. Seven other patients discontinued treatment due to 
local skin reactions (5 patients during placebo treatment and 2 during topical TV-45070 
treatment). The most frequently reported treatment-emergent adverse events were application 
site reactions, which were more common with placebo treatment than with topical TV-45070 
treatment. The majority of application site reactions were mild or moderate; no patient had a 
severe application site reaction while on TV-45070 treatment.
Additionally, topical TV-45070 was tested in 8 patients with IEM in an exploratory Phase 2a, 
randomized, double-blind, placebo-controlled study using 8% w/w TV-45070 ointment applied 
twice daily for 14 or 21 days (Study XPF-002-202). Topical TV-45070 was found to be safe and 
well tolerated with low plasma exposure (mean Cmax 4.64 ng/mL). For 3 of the 7 patients treated 
with topical TV-45070, pain was consistently inhibited by TV-45070 (as measured by the 
standard heat inductions, self-provoked inductions, and daily pain scores) with corresponding 
trends in sleep interference scores and minimal use of rescue measures in treatment period 2 
compared with baseline. These 3 patients were considered to be responders. There were no fatal 
events. No serious adverse events were reported during the study. However, several months 
following study completion and 131 days after the last dose of study drug, a patient (Patient 
, 
topical TV-45070 treatment) was hospitalized for worsening EM pain. The serious adverse event 
was considered by both the investigator and Sponsor to be unrelated to study drug treatment. One 
patient (Patient 
, topical TV-45070 treatment) was withdrawn from the study due to 2 
adverse events (nodules on hands and cyanosis on hands) considered unrelated to study drug 
treatment. The most frequently reported treatment-emergent adverse events were headache and 
nasopharyngitis. The vast majority of treatment-emergent adverse events were considered 
unrelated to study drug treatment. The most frequently occurring, study drug-related treatment-
emergent adverse events appeared to be local reactions to the ointment. These events were 
experienced by patients treated with TV-45070 and the patient treated with placebo.


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1.3.2.3.
Pharmacogenomic Studies
Although not an endpoint itself, R1150W polymorphism status will be used to stratify patients 
for randomization 
. 
Those who carry the R1150W polymorphism have a nucleotide containing adenine (A) instead 
of guanine (G) in the rs6746030 single nucleotide polymorphism in the SCN9A gene. This 
change causes an arginine to tryptophan amino acid residue change at position 1150 in the alpha 
subunit of the voltage-gated sodium channel NaV1.7. Those who carry the R1150W 
polymorphism may be heterozygous (GA) or homozygous (AA) for the minor allele. This 
R1150W polymorphism in the SCN9A gene may affect pain perception (Reimann et al 2010).
 
In the Phase 2a PHN study 
(Study XPF-002-201), the prevalence of R1150W in exon 19 of the SCN9A gene among study 
patients was investigated. Of the 52 patients tested, 9 patients had the R1150W polymorphism. 
Of the subgroup of patients test who were efficacy evaluable (n=45), 8 patients had the R1150W 
polymorphism. The rate of response to treatment was summarized by genotype. Patients who 
were heterozygous for the R1150W polymorphism showed higher response rates to TV-45070
than those without the polymorphism, although this result did not reach statistical significance. 
In addition, patients with the R1150W polymorphism were less likely to respond to placebo, 
although this subgroup was too small to demonstrate statistical significance.
Further details may be found in the current Investigator’s Brochure. 
1.4.
Known and Potential Risks and Benefits to Human Subjects
1.4.1.
Risks of TV-45070
Following topical administration, no observed CNS adverse events were considered related to 
TV-45070 treatment by the investigator. Similarly, with the exception of 1 case of worsening 
coronary artery disease assessed as unrelated to study drug treatment, no significant ECG 
findings or cardiac arrhythmias were observed in studies of topical TV-45070.
In nonclinical dermal toxicology studies performed in minipigs, skin irritation was seen 
frequently in animals dosed either with TV-45070 or vehicle ointment, most often within the first 
week of dosing. The skin reactions are predominantly erythema and appear to be due to the 
ointment vehicle itself. In prior clinical studies, however, local reactions at the site of topical
application of TV-45070 or matching placebo were seen infrequently. These reactions usually 
consisted of erythema or skin dryness with scaling of skin, were generally mild to moderate, and 
were approximately the same in frequency and severity for patients treated with either TV-45070 
or placebo. Although the skin reactions may appear within a couple of days of exposure, they 
more often occur after a delay of 2 to 3 weeks and resolve soon after cessation of dosing.
Worsening skin reactions should be monitored closely.
Due to low systemic exposure following topical administration of TV-45070 in humans, the DDI 
risk due to effects on CYP450 enzymes is thought to be low following topical administration. In 
vitro data using human liver microsomes have shown that TV-45070 is an inhibitor of several 
CYP450 enzymes. However, the compound is also highly bound to constituents in human 
plasma, so distribution into hepatocytes may be hindered, reducing the inhibition potential. In 


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vitro data using human cryopreserved hepatocytes have also shown that TV-45070 metabolite 
(M3) is an inhibitor of CYP3A4 and CYP2C19, which indicates a potential DDI risk between 
TV-45070 and medications that are primarily metabolized by CYP3A4 or CYP2C19. However, 
the preliminary results of a clinical study designed to assess the risk of these DDIs revealed no 
significant risk of an interaction.
1.4.2.
Benefits of TV-45070
The difficulty of treating PHN adequately, with many patients refractory to available therapies, 
means that there is an ongoing medical need for new treatment options providing effective 
topical pain relief with a good safety profile. As a topical sodium channel blocker, TV-45070 
may have potent local effects in terms of reducing pain in PHN.
1.4.3.
Overall Risk and Benefit Assessment for This Study
In summary, topically administered TV-45070 showed a generally favorable safety profile in 
nonclinical and clinical studies. Overall, the data for both oral and topically administered 
TV-45070 support the continued evaluation of topical TV-45070 in clinical studies conducted in 
patients with chronic pain.
A listing of adverse events observed during studies of topical TV-45070, which were judged to 
represent adverse drug reactions, is provided in the Investigator’s Brochure.
Additional information regarding risks and benefits of TV-45070 to humans may be found in the 
Investigator’s Brochure.
1.5.
Selection of Drugs and Dosages 
The dosage regimens selected for this study are 4% and 8% w/w TV-45070 ointment, each 
administered twice daily.
1.5.1.
Justification for Dosage of Active Drug
The selected dosage regimens are based on results from animal pharmacology studies, safety 
information from previous toxicology and clinical studies, and clinical efficacy previously 
observed with the topical TV-45070 formulation.
TV-45070 has been administered topically to 20 healthy subjects for 21 days, 62 patients with 
PHN for 21 days, and 7 patients with EM for 14 or 21 days. In all of these studies, the treatment 
was safe and well tolerated. In the healthy subject study, the ointment was found to be a 
nonirritant. In the PHN and EM studies, local application site reactions were the most common 
treatment-emergent adverse events. In addition, TV-45070 has been administered orally to 
93 healthy subjects and 4 patients with EM. Exposure data from all of these studies are presented 
in Section 6.2 of the Investigator’s Brochure.
Given that the planned dosage regimens in this study are similar or lower than those employed 
previously in the PHN and IEM studies, and the amount applied per surface area is less than that 
used in previous studies (3 μL/cm2 in this study compared with 7.5 and 4 μL/cm2 in the previous 
PHN and EM studies, respectively), the safety profile is anticipated to be similar to that observed 
previously in the topical PHN and EM studies. In addition, signals of efficacy were observed in 
both the PHN and EM studies in which 8% w/w TV-45070 ointment was applied twice daily. 


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Therefore, it is reasonable to include the 8% w/w TV-45070 dose as a high dose in this 
proof-of-concept study in PHN.
A more detailed description of study drug administration is presented in Section 5.1.
1.5.2.
Justification for Use of Placebo
The use of placebo is necessary because there is no alternative method for establishing the 
efficacy of TV-45070 for chronic pain. Pain is a subjective condition, and there is no gold 
standard treatment for PHN that provides universally effective pain relief. The risk to patients for 
withholding alternative therapies for pain relief is negligible, and patients are free to withhold 
their consent for doing so and may withdraw from the study at any time. Rescue medication will 
be permitted once the subject has completed their baseline period.
1.6.
Compliance Statement
This study will be conducted in full accordance with the International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any 
applicable national and local laws and regulations (eg, Title 21 Code of Federal Regulations 
[21CFR] Parts 11, 50, 54, 56, 312, and 314, European Union [EU] Directive 20/EC and 28/EC). 
Any episode of noncompliance will be documented.
The investigators are responsible for performing the study in accordance with this protocol and 
the applicable GCP guidelines referenced above for collecting, recording, and reporting the data 
accurately and properly. Agreement of each investigator to conduct and administer this study in 
accordance with the protocol will be documented in separate study agreements with the Sponsor
and other forms as required by national authorities.
Each investigator is responsible for ensuring the privacy, health, and welfare of the patients 
during and after the study and must ensure that trained personnel are immediately available in 
the event of a medical emergency. Each investigator and the applicable study staff must be 
familiar with the background and requirements of the study and the properties of the study 
drug(s) as described in the Investigator’s Brochure or prescribing information. 
The principal investigator at each study site has the overall responsibility for the conduct and 
administration of the study at that site and for contacts with study management, the Institutional 
Review Board (IRB), and local authorities.
1.7.
Population To Be Studied and Justification
The study population will comprise approximately 330 patients (men and women) 18 years of 
age or older and with chronic PHN. Approximately 330 patients (110 per treatment group) will 
be randomly assigned to 4% w/w TV-45070 ointment, 8% w/w TV-45070 ointment, or placebo 
to ensure that up to approximately 88 patients per group complete the treatment period, ie, have 
the week 4 visit (visit 5, day 29).
Patients must have chronic PHN according to the definition of pain present for more than 
6 months and less than 6 years after onset of herpes zoster skin rash affecting a single 
dermatome. Patients with more than 1 involved dermatome may also be included, provided the 
affected dermatomes are contiguous. The patient’s average daily pain must be at least 4 on the 
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immediately before study randomization. Patients with PHN involving trigeminal dermatomes 
are excluded from the study.
Detailed inclusion and exclusion criteria are listed in Section 4.
1.8.
Location and Timing of Study
The study is expected to start in March 2015 (first patient randomly assigned to treatment) and 
be completed in late 2016 up to mid 2017 (last patient last visit), with a duration of 
approximately 14 to 22 months.
Approximately 330 patients from up to approximately 70 study sites are planned to be enrolled 
in the study. The study is planned to be conducted in the US.
1.9.
Relevant Literature and Data
Relevant literature is cited above. Further literature and data may be found in the current 
Investigator’s Brochure.


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2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES
2.1.
Purpose of the Study
This is a Phase 2, multicenter, randomized, double-blind, parallel-group, placebo-controlled 
study to evaluate the safety and efficacy of 4% and 8% w/w TV-45070 ointment compared with 
placebo ointment applied topically and twice daily to the area of PHN pain for 4 weeks in 
patients with PHN.
2.2.
Study Objectives
2.2.1.
Primary Objective
The primary objective of this study is to evaluate the efficacy of 4 weeks of topical 
administration of TV-45070 (4% and 8% w/w ointment) compared with placebo for the relief of 
pain due to PHN, as assessed by the change from baseline to week 4 in the weekly average of the 
daily average NRS scores. The daily average NRS score is the average of the 2 NRS scores 
(recorded in the morning and in the evening) of average pain, defined as the patient-reported 
average pain intensity over the prior 12 hours.
2.2.2.
Secondary Objectives
The secondary objectives of the study are as follows:

to evaluate the efficacy of topical TV-45070 (4% and 8% w/w ointment) compared 
with placebo by examining the following: 

change from baseline to week 4 in the weekly average of the average pain score
recorded in the evening

change from baseline to week 4 in the weekly average of the average pain score
recorded in the morning

change from baseline to week 4 in the weekly average of the worst pain score
recorded in the evening (worst pain is defined as the patient-reported worst pain 
intensity over the prior 24 hours)

percentage of patients with ≥30% improvement from baseline in the weekly 
average of the daily average NRS scores at week 4

percentage of patients with ≥50% improvement from baseline in the weekly 
average of the daily average NRS scores at week 4

change from baseline (randomization visit) to weeks 2 and 4 in the Neuropathic 
Pain Symptom Inventory (NPSI) score 

change from baseline (randomization visit) to week 4 in the Neuropathic Pain 
Impact on Quality of Life (NePIQoL) score 

patients’ global assessment of treatment, as measured by the Patient Global 
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
change from baseline (randomization visit) in the Daily Sleep Interference Scale
(DSIS) at weeks 2 and 4

time to reach ≥30% improvement from baseline in the weekly average of the daily 
average NRS scores

change from baseline (randomization visit) in maximal intensity of patients’
brush-evoked allodynia, as measured on 11-point NRS, at weeks 2 and 4

change from baseline (randomization visit) in maximal intensity of patients’ 
punctate-evoked hyperalgesia, as measured on 11-point NRS using a Medipin®
(US Neurologicals, LLC / Medipin Ltd), at weeks 2 and 4

to characterize the pharmacokinetics of TV-45070 in terms of the following:

establishing the dose-exposure relationship of topical TV-45070 (4% and 8% w/w 
ointment under multiple-dose conditions in patients with PHN)

estimating the apparent clearance (CL/F) and volume of distribution (V/F) of 
TV-45070 by incorporating the concentration data of this study into an enriched 
TV-45070 pharmacokinetics database and performing population 
pharmacokinetic modeling

identifying clinically relevant covariates (eg, age, body weight, gender, and 
indication) affecting the pharmacokinetics of TV-45070 using the population 
pharmacokinetics model

to evaluate the safety of topical TV-45070 (4% and 8% w/w ointment) treatment 
compared with placebo, as assessed by the following at specific time points 
throughout the study based on the schedule of study procedures and assessments:

occurrence of adverse events throughout the study

clinical safety laboratory (serum chemistry, hematology, and urinalysis) test 
results

vital signs (heart rate, respiratory rate, body temperature, and blood pressure) 
measurements

ECG findings

physical examination findings

dermal irritation findings

concomitant medication usage throughout the study
2.2.3.
Exploratory/Other Efficacy Objectives
 


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3.
STUDY DESIGN
3.1.
General Design and Study Schema
This is a Phase 2, multicenter, randomized, double-blind, parallel-group, placebo-controlled 
study to evaluate the safety and efficacy of 4% and 8% w/w TV-45070 ointment compared with 
placebo ointment applied topically and twice daily to the area of PHN pain for 4 weeks (days 1 
through 28) in patients with PHN. The study schema is diagramed in Figure 1.
For each patient, there will be a total of 6 visits to the study site and 1 telephone contact as 
follows:

screening period

visit 1: screening (up to 28 days before randomization/first administration of 
study drug)

washout phone contact (approximately 1 week after visit 1 for screening)

washout interval (if needed) of variable/flexible length during which the patient 
will discontinue oral analgesic therapy, topical pain therapy, and/or 
non-pharmacologic therapies before initiation of the baseline period (Appendix A, 
Table 2)

visit 2: baseline visit (day –10)

baseline pain assessment period (days –7 to –1; baseline pain score [average pain 
intensity score over this interval] obtained)

treatment period

visit 3: randomization (day 1 [this is the day after day –1 and the first day of study 
drug application])

visit 4: day 15 ±1, week 2

visit 5: day 29, week 4

follow-up period

visit 6: follow-up (day 57 ±3) or early termination (ET)
The screening period consists of a screening visit (informed consent and preliminary eligibility 
assessment are obtained); a washout phone contact during which eligibility based on laboratory 
test results will be reviewed and, as needed, patients will be given instructions to washout 
(discontinue) oral analgesic or topical pain therapy; a washout interval (if needed) of 
variable/flexible length during which appropriate patients will discontinue oral analgesic therapy,
topical pain therapy, and/or non-pharmacologic therapies; and a baseline pain assessment 
interval, when each eligible patient will be given an electronic diary (eDiary) to record pain 
intensity from days –10 to –1. (To allow for training in the use of eDiaries, patients will use 
eDiaries from day –10, but baseline pain assessment will be defined as the last 7 days prior to 
randomization, ie, calculated from the values recorded from days -7 through –1.) During the 
baseline pain assessment interval, rescue medications for PHN pain will not be allowed. Rescue 


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medication will also not be allowed during the last 7 days of treatment. Starting with the baseline 
pain assessment interval, patients will use eDiaries to record pain, using an 11-point NRS each 
morning (0700 ±2 hours) and evening (1900 ±2 hours), and any rescue pain medication usage.
 
 
At visit 3 (day 1, randomization), visit 4 (day 15 ±1, week 2), and visit 5 (day 29, week 4), the 
NPSI and the DSIS will be administered, and the results will be recorded. On the same visit days, 
the results of maximal intensity evoked allodynia and maximal intensity evoked hyperalgesia 
will be recorded. The NePIQoL will be evaluated at visit 3 (day 1, randomization) and visit 5 
(day 29, week 4). The PGIC will be evaluated at visit 4 (day 15 ±1, week 2) and visit 5 (day 29, 
week 4). Efficacy measures are not collected at visit 6, except for ET visits.
At visit 1 (screening), the patient will identify the location of his/her most severe allodynia, and 
this location will be used for assessments at all subsequent visits. If allodynia or hyperalgesia is 
not present at screening, it will not be tested at subsequent visits. The investigator will establish 
normal sensation by using a standardized 1-inch foam brush (light pressure just sufficient to bend 
the tip of the brush) to stroke an area of skin that is unaffected by pain. The region of allodynia 
will then be mapped by applying brush strokes moving from normal skin toward the painful 
region. A felt-tip pen will be used to mark the point where sensation changes from normal to 
painful. This process will be repeated until 8 to 10 points are marked in a radial fashion to define 
the area of allodynia. The marks will then be connected with a continuous line. To assess the 
intensity of allodynia, the investigator will use the brush to perform 3 brush strokes within the 
mapped area of allodynia. The patient will then assess pain intensity using an 11-point NRS to 
answer the question “Please rate the intensity of pain caused by brushing the area of skin where 
0=not painful at all and 10=worst pain possible.” The pain will be rated for intensity (using the 
highest pain rating reported) both at prebrush testing and during application of the brush and 
recorded; additionally, the difference between the 2 scores will be calculated and recorded. 
In addition, at visit 1 (screening), the patient will identify the location of his/her most severe 
hyperalgesia, and this location will be used for assessments at all subsequent visits. To assess the 
intensity of punctate hyperalgesia, a Medipin will be applied in 3 successive applications to the 
area of skin identified at screening. The tip of the Medipin rests upon a flange, and the examiner 
should apply the pin so that the flange rests upon the skin without indenting it. The patient will 
then assess the pain intensity using an 11-point NRS to answer the question “Please rate the 
intensity of pain caused by application of the Medipin where 0=not painful at all and 10=worst 
pain possible.” The highest pain rating will be recorded.
Patients will be provided with acetaminophen (TYLENOL®, McNeil Consumer Healthcare 
Division of McNEIL-PPC, Inc) as 325-mg tablets in bottles of 100 tablets and allowed to take 
1 to 2 tablets per dose every 6 hours, as needed, and up to 6 tablets or 1950 mg per day (over a 
24-hour period) for rescue relief of PHN pain. Rescue medication will be provided at the 
screening visit. Rescue medication compliance will be checked at all visits until used rescue 
medication is collected after the baseline pain assessment interval or at randomization for 
patients not continuing in the study, at visit 5 (day 29, week 4) for patients who complete the 
treatment period, or at the ET visit for patients who prematurely discontinue study drug.
No other rescue medications will be provided or allowed from the washout phone contact 
through visit 5 (day 29, week 4) or the ET visit. Patients will not be permitted to use rescue 


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medication during the baseline pain assessment interval (days –10 through –1) and during the 
final week of treatment (the 7-day period before visit 5). During the washout interval, rescue 
medication use (dates of use and dose taken) will be recorded as concomitant medication. During 
the baseline period and the treatment period, rescue medication use will be recorded using the 
eDiary.
At the randomization visit (visit 3, day 1), eligible patients will be randomly assigned via 
interactive response technology (IRT) in a 1:1:1 fashion to 1 of 3 treatment groups: 4% w/w 
TV-45070 ointment, 8% w/w TV-45070 ointment, or placebo ointment. Randomization will be 
stratified by test results of the pharmacogenomic sample collected at the screening visit 
(homozygous minor allele [positive, AA], heterozygous [positive, AG], and homozygous 
common allele [negative, GG]) for R1150W polymorphism in the SCN9A gene. The patient will 
be instructed on how to apply the study drug. Under study site staff supervision, the area affected 
by PHN pain will be carefully defined by mapping the area of pain, and dosing will be prescribed 
to fully cover the affected area. 
Efficacy assessments of pain NRS, NPSI, NePIQoL, and DSIS scores will be conducted at visit 3
(day 1) to establish baseline measurements. The site staff will apply the first dose of blinded 
study drug and the patient will record the date/time in the eDiary. Subsequent study drug 
applications will be performed by the patient at home. (If the affected area is not within reach of 
application by the patient [such as the posterior thoracic region], the patient’s designated 
caregiver will apply the ointment, but the patient will record the time of application in the 
eDiary.)
During the 4-week treatment period, patients will apply double-blind study drug to the area of 
PHN pain twice daily in the morning (0700 ±2 hours) and again in the evening (1900 ±2 hours). 
The first dose of study drug will be applied at the clinic on day 1 (visit 3). Regardless of the 
clock time of the first dose application at visit 3, the evening dose for day 1 should be applied at 
1900 ±2 hours. The last dose of study drug will be applied at home on the evening of day 28, 
which is the day before visit 5. In the event that the patient cannot keep the scheduled 
appointment on day 29, it is nevertheless important for the patient to stop dosing on the evening 
of day 28. The morning and evening drug applications will be done after recording the response 
for the NRS pain score. At the start of the baseline pain assessment interval when the eDiary is 
provided, the eDiary will be used to record the NRS responses, PHN rescue medication use, and 
then, after randomization, the dates/times of study drug administration. 
Patients will return to the study site for visit 4 (day 15 ±1, week 2) and again for visit 5 (day 29, 
week 4). Routine efficacy evaluations (including pain NRS, NPSI, DSIS, and PGIC scores) and 
safety assessments will be obtained at visit 4 (day 15±1, week 2) and visit 5 (day 29, week 4).
At visit 4 (day 15 ±1, week 2), 2 blood samples will be taken from each patient for 
pharmacokinetics analysis: the first sample within approximately 1 to 4 hours after the dose of 
study drug in the morning and the second sample approximately 2 hours after collection of the 
first sample. The date and time of the morning dose and the date and exact time for each of the 
2 pharmacokinetics samples will be recorded.
At visit 5 (day 29, week 4), the efficacy evaluation NePIQoL will also be performed, and the 
eDiary will be collected along with the tubes of study drug and bottles of rescue medication.


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Patients will be instructed to return to their primary care physician to resume therapy deemed 
appropriate for their PHN.
Four weeks after visit 5 (day 29, week 4), the patients who completed the double-blind treatment 
period will return to the study site for a follow-up (visit 6, day 57 ±3). Activities will include 
safety assessments for all patients.
Patients who prematurely discontinue study drug will have an ET visit within 2 weeks after the 
last study drug administration. During the ET visit, the same activities will be conducted as those 
administered for follow-up at visit 6, the eDiary and any unused study drug/rescue medication 
will be collected, and compliance checks will be performed. Any treatment-emergent adverse 
event or serious adverse event will be monitored at suitable intervals until resolved, stabilized, or 
returned to baseline; until the patient is referred to the care of a health care professional; or until 
a determination of a cause unrelated to the study drug or study procedure is made during the 
study period. For adverse event recording, the study period is defined for each patient as that 
time period from signature of the Informed Consent Form (ICF) through the end of the follow-up 
period, day 57 (±3). For patients who prematurely discontinue study drug and do not have a 
treatment-emergent adverse event or serious adverse event, the ET visit will be the last study 
visit.


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Figure 1:
Study Design
eDiary = electronic diary; ET = early termination
Notes: The screening visit should take place within 28 days of randomization, thus, day –28 is the earliest that it can occur.
The washout phone contact should occur approximately 1 week after the screening visit, thus, day –21 is the earliest it can occur.
The length of the washout period will vary from patient to patient depending on what, if any, treatments (analgesic therapy, topical pain therapy, and/or 
non-pharmacologic therapy) need to be discontinued.
Patients who discontinue study drug prematurely (any time after randomization and before visit 5) will have an ET visit with the same procedures as those 
scheduled for the follow-up visit plus eDiary and unused study drug/rescue medication collection (and compliance checks). Depending on when the patient stops 
taking study drug, the patient may proceed directly from visit 3 or visit 4 to the ET visit.
day –28
Visit 1
day 57 
(±3)
day 15
(±1)
day 1
day –10
day –21
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Screening
Visit
Washout  
phone 
contact
Baseline visit
(weekday)
Randomization visit
(weekday)
Week 2 
visit
Week 4 
visit
Follow-up/ET 
visit
= On-site visits
Washout period 
(variable duration)
Baseline pain 
assessment period
Screening
period
Treatment
period
Follow-up
period
day 29
(±0)


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3.2.
Justification for Study Design
TV-45070 has previously been studied in a 2-period crossover study (each period lasting 3 
weeks) in 62 PHN patients who received 1 or more TV-45070 doses. Although it did not meet 
the primary endpoint (change in mean daily pain score during the last week compared to baseline 
as measured by the NRS), a significantly larger percentage of patients with 50% reductions in 
pain were seen during the TV-45070 treatment period in the efficacy evaluable and per protocol 
(PP) analysis groups. The current study is designed to more definitively evaluate the efficacy of 
TV-45070 in a larger, parallel-group study design.
3.3.
Primary and Secondary Measures and Endpoints
3.3.1.
Primary Efficacy Measure and Endpoint
The primary efficacy endpoint for this study is the change from baseline to week 4 in the weekly 
average of the daily average NRS scores. The daily average NRS score is the average of the 
2 NRS scores (recorded in the morning and in the evening) of average pain, defined as the 
patient-reported average pain intensity over the prior 12 hours.
3.3.2.
Secondary Efficacy Measures and Endpoints
The secondary efficacy measures and endpoints for this study are as follows: 

change from baseline to week 4 in the weekly average of the average pain score 
recorded in the evening

change from baseline to week 4 in the weekly average of the average pain score
recorded in the morning

change from baseline to week 4 in the weekly average of the worst pain score 
recorded in the evening (worst pain is defined as the patient-reported worst pain 
intensity over the prior 24 hours)

percentage of patients with ≥30% improvement from baseline in the weekly average 
of the daily average NRS scores at week 4

percentage of patients with ≥50% improvement from baseline in the weekly average 
of the daily average NRS scores at week 4

change from baseline (randomization visit) to weeks 2 and 4 in the NPSI score 

change from baseline (randomization visit) to week 4 in the NePIQoL score 

patients’ global assessment of treatment, as measured by PGIC scores, at weeks 2 
and 4

change from baseline (randomization visit) in DSIS scores at weeks 2 and 4 

time to reach ≥30% improvement from baseline (randomization visit) in the weekly 
average of the daily average NRS scores

change from baseline to weeks 2 and 4 in maximal intensity of patients’ brush-evoked 
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
change from baseline to weeks 2 and 4 in maximal intensity of patients’ 
punctate-evoked hyperalgesia, as measured on the 11-point NRS using a Medipin
3.3.3.
Exploratory Efficacy Measures and Endpoints
 
 
 
 
 
 
3.3.4.
Safety Measures and Endpoints
The safety of TV-45070 (4% and 8% w/w ointment) will be assessed throughout the study by 
evaluating adverse events, clinical safety laboratory test results, vital signs measurements, ECG 
and physical examination results, dermal irritation, and concomitant medication usage. Skin 
rashes or skin irritation in the area of ointment application will be evaluated using a dermal 
irritation scale (modified Draize scale) at day 1 (at 1 hour [±30 minutes] after application of 
study drug), week 2, week 4, and week 8 for follow-up.
3.3.5.
Tolerability Measures and Endpoints
The tolerability of TV-45070 (4% and 8% w/w ointment) will be assessed during the study using 
safety endpoints that also represent patients’ experience of treatment, such as skin rashes and 
skin irritation.
3.3.6.
Pharmacokinetic Measures and Endpoints
Two blood samples will be collected from each subject following 2 weeks of treatment with 
either 4% or 8% w/w TV-45070 ointment or matching placebo ointment, to quantitate the 
concentration of TV-45070 in plasma. Patients will go to the study center after applying study 
drug at home so that the 2 pharmacokinetic samples can be taken. The first sample will be taken 
within approximately 1 to 4 hours of the morning dose of study drug and the second sample 
taken approximately 2 hours after collection of the first sample. The date and time of the 
morning dose and the date and exact time for each of the 2 pharmacokinetic samples will be 


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recorded. Plasma samples will be analyzed for TV-45070. Population pharmacokinetic
parameters, such as CL/F and V/F, following topical TV-45070 administration to patients with 
PHN, will be estimated when the sparse data from this study are combined with enriched 
pharmacokinetic data from other studies with topical TV-45070. Clinically relevant covariates 
affecting the pharmacokinetics of TV-45070 will be identified as data permit. These results will 
be reported separately from the main study results.
3.3.7.
Pharmacodynamic Measures and Endpoints
Pharmacodynamic endpoints assessed during the study are the following secondary efficacy 
endpoints: change from baseline in maximal intensity of patients’ brush-evoked allodynia and 
maximal intensity of punctate-evoked hyperalgesia, as presented in Section 3.3.2.
3.3.8.
Pharmacogenomic Analyses
Two blood samples (approximately 10 mL total) for pharmacogenomic analyses will be taken 
from all patients at the screening visit (visit 1) at approximately the same time as the clinical 
safety laboratory samples are collected. Patients who refuse to give these blood samples will be 
excluded from the study. One sample will be analyzed to identify the nucleotide (G or A) 
underlying the R1150W polymorphism in the SCN9A gene and may identify whether there are
any other sequence variants in the SCN9A gene region. All samples will be retained for a 
maximum of 15 years after completion of the study 
 
 
 A pharmacogenomic blood sample may be used to assess the 
polymorphisms of the CYP3A4 and CYP2C19 genes. Depending on the distribution of allelic 
variations for CYP3A4 and CYP2C19, these results may be incorporated as covariates in the 
current or future population pharmacokinetic analyses. 
 
 
 
3.4.
Randomization and Blinding
This is a randomized, double-blind, placebo-controlled study. All tubes of the study drug will be 
identical, and the ointments will be indistinguishable. Patients, investigators, and all clinical 
study site staff will remain blinded to treatment assignment during the study. Eligible patients 
will be randomly assigned via IRT in a 1:1:1 ratio to 4% w/w TV-45070 ointment, 8% w/w 
TV-45070 ointment, or placebo ointment. Randomization will be stratified by the R1150W 
underlying genotype in the SCN9A gene: homozygous minor allele (positive, AA), heterozygous 
(positive, AG), and homozygous common allele (negative, GG).
The randomization code will be generated by a qualified service provider, following 
specifications from the Biostatistics Department. 
In addition, the Sponsor’s clinical personnel involved in the study will be blinded to the study 
drug identity until the database is locked for analysis and the treatment assignment revealed. A 
statistician not assigned to the study will be responsible for reviewing the randomization code, 
and the final randomization code will be maintained by the service provider.


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Patients will be randomly assigned to treatment through a qualified randomization service 
provider (eg, IRT). This system will be used to ensure a balance across treatment groups; no 
effort will be made to maintain a balance among treatment groups within a study site.
All patients will be provided with tubes of blinded study drug ointment (4% w/w TV-45070, 
8% w/w TV-45070, or placebo) to be applied twice daily to area of PHN pain during the 4-week 
treatment period. Placebo ointment is a vehicle-only ointment with identical excipients, content 
(other than the active pharmaceutical ingredient), appearance, packaging, and labeling to the 
active treatments. 
The clinical study site will receive study drug kits, and kits will be assigned to individual patients 
by the IRT system based on the patients’ randomization assignments. The IRT system will 
record the kit numbers for all patients. Designated study site staff, who will remain blinded to the 
treatment assignments, will dispense the kits to the patients based on the kit numbers assigned to 
patients by the IRT system. In case of emergency, the investigator and designated study site staff 
can call the IRT system to unblind the treatment for a specific patient. Details related to 
maintenance of blinding for study conduct, including pharmacokinetic analysis, and the 
unblinding process are in Section 3.5. 
3.5.
Maintenance of Randomization and Blinding
3.5.1.
Randomization 
The randomization code will be maintained in a secure location by a qualified service provider. 
At the time of analyses, when treatment codes are revealed, the service provider will provide the 
randomization code to the statistician assigned to this study.
3.5.2.
Blinding/Unblinding
Pharmacokinetic data may be assessed during the study. For patients who have pharmacokinetic 
sample bioanalysis and/or population pharmacokinetic analysis conducted, the individuals 
responsible for these analyses will receive the randomization allocation and will know who 
received study drug and who received placebo during the study. Staff responsible for bioanalysis 
and pharmacokinetic data analysis will not directly interact with clinical study sites and will not 
have direct involvement in study conduct. All other study team members will remain blinded. 
Pharmacokinetic analyses performed during the conduct of the study will be provided to the 
clinical pharmacologist and other staff members in a manner that will not identify individual 
patients (ie, a dummy patient identifier will be linked to an individual patient’s concentration 
data).
For information on other personnel who may be aware of treatment assignments, see Section 3.4. 
These individuals will not be involved in the conduct of any study procedures or assessment of 
any adverse events.
For a serious adverse event considered related (ie, reasonable possibility; see Section 7.1.4) to 
the study drug, the Sponsor’s Global Patient Safety & Pharmacovigilance Department may 
independently request that the treatment code be revealed (on a case-by-case basis). If this 
occurs, the investigator will remain blinded to treatment, but the Sponsor’s clinical project 
physician (CPP)/clinical leader (CL) may be unblinded to treatment in order to decide on the 
action to be taken, as described in Section 3.9.


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In the event of an emergency, if it is necessary to know what treatment a specific patient has 
received, the investigator may determine the patient’s treatment using IRT after consulting the 
Sponsor. In an extreme emergency, if the investigator is unable to contact the Sponsor, the 
investigator may determine the patient’s treatment using IRT without prior authorization. When 
this occurs, the investigator must contact the individual identified in the Clinical Study Personnel 
Contact Information section of this protocol immediately; the patient will be withdrawn from the 
study, and the event will be recorded on the study completion record. Proper documentation must 
be maintained when a treatment code is revealed. For a serious and unexpected adverse event 
considered related to the study drug or study procedure, the Sponsor’s Global Patient Safety & 
Pharmacovigilance Department may independently request that the treatment code be revealed 
(on a case-by-case basis). If this occurs, personnel involved in the conduct, analysis, and 
reporting of the data will remain blinded to treatment.
3.6.
Drugs used in the Study
3.6.1.
Investigational Product
The study drug is a double-blind TV-45070 ointment (4% or 8% w/w) or placebo ointment for 
topical administration. TV-45070 and matching placebo ointments are unscented, off-white to 
yellowish, opaque ointments with a smooth texture. The ointments contain the same excipients 
(described in Section 4 of the Investigator’s Brochure) and differ only in the amount of active 
pharmaceutical ingredient. (The matching placebo ointment contains only the excipients.) They 
will be supplied to the study sites as 50-g fills in 60-mL plastic laminate tubes with 
tamper-evident seals. The tubes will be stored at ambient room temperature (15°C to 25°C). 
Blinded study drug will be given to the patients as described in Section 3.4. Study drug will be 
applied twice daily to the painful area in the morning (0700 ±2 hours) and again in the evening 
(1900 ±2 hours) from days 1 through 28. Study drug will be applied at approximately 3 μL/cm2
per application. The actual amount (mg of ointment) of study drug per application will be 
measured (as length of ointment) using one or more dosing cards based upon the area of pain 
determined at randomization (visit 3, day 1).
Patients will be provided with a laminated instruction sheet, including pictures, that will both 
describe and illustrate how the ointment is to be spread over the entire area of PHN pain in a thin 
layer that fully covers the area. The ointment should be lightly massaged into the skin to cover 
the entire area of PHN pain.
The first application of study drug will occur at the study site on the day of the randomization 
visit (visit 3, day 1). The study coordinator or designated site staff member will apply blinded 
study drug and will define the amount of ointment to be used for all subsequent treatment 
applications for that patient. Dosing cards and instructions will be provided on how to measure 
the appropriate amount of ointment for each application. Caretakers will be provided instructions 
at the randomization visit on how to apply ointment to areas inaccessible to the study patient.
The patients will apply blinded study drug twice daily (morning [0700 ±2 hours] and evening 
[1900 ±2 hours]) on the target area for 4 weeks from days 1 through 28. On day 1, the morning 
dose might not be applied at 0700 ±2 hours because the first dose of study drug will be applied at 
the randomization visit (visit 3, day 1). Regardless of the clock time of the first dose application 


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at the randomization visit, the evening dose for day 1 should be applied at 1900 ±2 hours. Details 
about the timing of study drug applications are provided in Section 3.11.3.
Compliance will be assessed by weighing tubes at visit 3 (baseline), visit 4 (day 15 ±1, week 2),
and visit 5 (day 29, week 4), or ET visit. A patient will be considered compliant during the 
interval between the previous 2 visits if the tube weighs between 70% and 120% of the expected 
weight.
A more detailed description of administration procedures is provided in Section 5.1. 
3.6.2.
Placebo
The placebo control for this study is placebo ointment for topical administration. The matching 
placebo ointment is an unscented, off-white to yellowish, opaque ointment with a smooth 
texture. The placebo ointment contains the same excipients (described in Section 4 of the 
Investigator’s Brochure) as TV-45070, and differs only in that it contains no active 
pharmaceutical ingredient. The placebo ointment will be supplied to the study sites as 50-g fills 
in 60-mL plastic laminate tubes with tamper-evident seals. The tubes will be stored at ambient 
room temperature (15°C to 25°C). 
3.7.
Drug Supply and Accountability
3.7.1.
Drug Storage and Security
Topical TV-45070 (4% and 8% w/w) and matching placebo ointment will be supplied as 50-g 
fills in 60-mL plastic laminated tubes with tamper-evident seals. The tubes must be stored at 
ambient room temperature (15°C to 25°C) both at the study site and at the patient’s home.
Only authorized personnel will have access to the study drug at the study sites. The authorized 
study site personnel at each study site will be responsible for the proper storage and handling of 
the study drug products. Study site personnel will acknowledge receipt of the study drug using 
the IRT.
3.7.2.
Drug Accountability
Each study drug shipment will include a packing slip that lists the contents of the shipment. 
Study drug accountability records must be maintained at the study site at all times. A record of 
study drug accountability (ie, study drug and other materials received, used, or retained) with 
accounts/explanations given for any discrepancies should be documented in the IRT and signed 
by the principal investigator or designee.
At each study site, the investigator is responsible for ensuring that deliveries of study drug and 
other study materials from the Sponsor are correctly received and recorded, handled and stored 
safely and properly in accordance with applicable regulations, and used in accordance with this 
protocol. 
At each study site, a record of study drug accountability (ie, study drug and other materials 
received, used, retained, returned, or destroyed) must be prepared and signed by the principal 
investigator or designee, with an account given for any discrepancies so that possible diversions, 
abuse, and loss of study drug are documented. Empty/partially used/unused tubes of study drug,
upon the Sponsor’s approval, will either be destroyed by the study sites or will be returned to a 


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depot for destruction, according to local and national regulations at specified time intervals as 
described in the Study Pharmacy Manual. Documented evidence of destruction should be made 
available to the Sponsor and/or its designees. The investigator or designee will prepare an overall 
summary of all drug supplies received and used for the study. The investigator, pharmacist, or 
drug administrator and monitor must verify that no drug supplies remain in the study site’s 
possession.
3.8.
Duration of Patient Participation and Justification
This study will consist of a screening period of up to 4 weeks, including a variable-length 
washout of oral analgesic therapy or topical pain therapy if needed, a 4-week double-blind 
treatment period, and a 4-week follow-up period. Patients are expected to participate in this study 
for about 12 weeks. This duration is needed to allow the therapeutic properties of TV-45070 to 
take effect and to be assessed as part of a controlled clinical trial.
3.9.
Stopping Rules and Discontinuation Criteria
There are no formal rules for early termination of this study. During the conduct of the study, 
serious adverse events will be reviewed (see Section 7.1.5) as they are reported from the study
site to identify safety concerns. 
In prior clinical studies with topical TV-45070, skin irritation was seen in some patients exposed 
to either TV-45070 or vehicle, as described in the Investigator Brochure (Appendix A, also
Sections 7.2.2 and 7.11.1). These skin reactions included pain, pruritus, exfoliation, rash, and 
erythema; were nearly all mild to moderate in severity; and showed complete resolution after 
cessation of dosing. Skin reactions are evaluated using the dermal irritation evaluation (modified 
Draize scale) as described in Section 7.9 at visits 2 (baseline visit), 3 (randomization visit, 1 hour 
[±30 minutes] after application of the ointment), 4 (day 15 ±1, week 2 visit), 5 (day 29, week 4 
visit), and 6 (follow-up or ET visit). Good clinical judgment is advised in evaluating skin 
reactions. In the event that a patient develops progressive or severe skin reaction, the Investigator 
should carefully evaluate the patient and decide whether or not to stop dosing. The Investigator is 
reminded to follow the adverse event reporting practices described in the protocol (Section 7.1) 
when recording and reporting any adverse events, including dermal findings. 
A patient may withdraw participation in the study at any time for any reason (eg, lack of 
efficacy, consent withdrawn, or adverse event). The investigator and/or Sponsor can withdraw a 
patient from the study at any time for any reason (eg, protocol violation or deviation as defined 
in Section 11.1.2, noncompliance, or adverse event).
Also, the Sponsor may terminate the study for any reason and at any time.
3.10.
Source Data Recorded on the Case Report Form
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed onto the case report form (CRF). Data may not be 
recorded directly onto the CRF and considered as source data unless the study site obtains 
written documentation from the Sponsor before the beginning of the study, indicating which data 
are permitted to be recorded directly onto the CRF. 


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If data are processed from other institutions (eg, clinical laboratory, central image center, or 
eDiary), the results will be sent to the study site where they will be retained but not entered into 
the CRF unless otherwise noted in the protocol. These data may also be sent electronically to the 
Sponsor (or organization performing data management) for direct entry into the clinical database 
(see Section 13.1). All data from other institutions will be available to the investigator(s).
The CRFs are filed in the Sponsor’s central file. 
3.11.
Study Procedures
Study procedures and assessments with their timing are summarized in Table 1. 


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Table 1:
Study Procedures and Assessments
Study period
Screening Period
Randomization
Double-blind treatment 
period
Follow-up/ET
Visit number
Visit 1
--
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit day (window)a
Day –28b
Day –21c
Day –10c,d
Day 1d
Day 15
(±1)
Day 29e
(±0)
Day 57 (±3)/ 
Not applicable
Procedures and assessments
Screening 
visit
Washoutf
phone 
contact
Baselineg
visit
Day of first 
dose
Week 2 
visit
Week 4 
visit
Follow-
up
ET
Informed consent
X
Inclusion and exclusion criteria
X
X
X
Xh
Medical history and demography
X
Adverse event inquiry
X
X
Xh
X
X
X
X
Prior/concomitant medications
Xi
X
X
Xh
X
X
X
X
Start washout of prior neuropathic pain 
therapy (if needed)
X
Clinical laboratory tests (serum chemistry, 
hematology, and urinalysis)
X
Xh
X
X
X
X
Urine drug screen
X
Xh
X
Vital signs measurementsj
X
X
Xh
X
X
X
X
Physical examination
Xk
Xh
X
X
Xk
Xk
12-lead ECGl
X
Xh
X
X
X
X
Pregnancy test (urine)m
X
Xh
X
X
X
X
Blood samples for pharmacogenomics 
assessments
X


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Table 1:
Study Procedures and Assessments (Continued)
Study period
Screening Period
Randomization
Double-blind treatment 
period
Follow-up/ET
Visit number
Visit 1
--
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit day (window)a
Day –28b
Day –21c
Day –10c,d
Day 1d
Day 15
(±1)
Day 29e
(±0)
Day 57 (±3)/ 
Not applicable
Procedures and assessments
Screening 
visit
Washoutf
phone 
contact
Baselineg
visit
Day of first 
dose
Week 2 
visit
Week 4 
visit
Follow-
up
ET
NPSI
X
Xh
X
X
X
DSIS
X
Xh
X
X
X
NePIQoL
X
Xh
X
X
Measure maximal intensity of brush-evoked 
allodynian
X
Xh
X
X
X
Measure maximal intensity of 
punctate-evoked hyperalgesian
X
Xh
X
X
X
Record average daily pain intensity (NRS) 
at study site
X
Record worst daily pain intensity (NRS) at 
study site
X
Dispense/collect rescue medication (review 
accountability)
X
Xo
X
X
(collect 
only)
X
(collect 
only)
Record rescue pain medication usage for 
PHN as a concomitant medication (ie, not 
using eDiary)
X
X
Provide/review/collect patient eDiary
Xp
Xh,q
Xq
Xr
Xr
Record average daily pain intensity (over 
the previous 12 hours [NRS]) in the morning 
and in the evening using eDiarys
Xt
Xh,u
Xv
Xv


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Table 1:
Study Procedures and Assessments (Continued)
Study period
Screening Period
Randomization
Double-blind treatment 
period
Follow-up/ET
Visit number
Visit 1
--
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit day (window)a
Day –28b
Day –21c
Day –10c,d
Day 1d
Day 15
(±1)
Day 29e
(±0)
Day 57 (±3)/ 
Not applicable
Procedures and assessments
Screening 
visit
Washoutf
phone 
contact
Baselineg
visit
Day of first 
dose
Week 2 
visit
Week 4 
visit
Follow-
up
ET
Randomization and instructions on 
application of drug
Xh
Study drug compliance check
Xh,x
X
X
X
Rescue drug compliance check
X
Xh
X
X
X
Dispense/collect study drug
Xh
(dispense study 
drug only)
X
X
(collect 
study drug 
only)
X
(collect 
if prior 
to V5)
Apply study drug twice daily to area of PHN 
painy
Xz,aa
Xbb
Dermal irritation evaluation
X
Xcc,dd
X
X
X
X
Record date/time of study drug application 
using eDiary
Xaa,cc
Xbb
X
(if prior 
to V5)
Record rescue pain medication usage for 
PHN via eDiaryee
Xt
Xcc
(at home)
Xff
Xgg
X
(if prior 
to V5)
Record worst daily pain intensity (NRS) in 
the evening using eDiary
Xt
Xcc
(at home)
Xhh
X
(if prior 
to V5)


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Table 1:
Study Procedures and Assessments (Continued)
Study period
Screening Period
Randomization
Double-blind treatment 
period
Follow-up/ET
Visit number
Visit 1
--
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit day (window)a
Day –28b
Day –21c
Day –10c,d
Day 1d
Day 15
(±1)
Day 29e
(±0)
Day 57 (±3)/ 
Not applicable
Procedures and assessments
Screening 
visit
Washoutf
phone 
contact
Baselineg
visit
Day of first 
dose
Week 2 
visit
Week 4 
visit
Follow-
up
ET
Blood samples (including recording of 
sampling dates/times) for PK assessmentsii
Xjj
PGIC
X
X
X
a There is no day 0 for this study. Day –1 is the day before study day 1. Day 1 is the day of both randomization and the first dose (application) of study drug.
b The screening visit should occur no more than 28 days before randomization; day –28 is the earliest possible day for the screening visit.
c Variable/flexible date, depending on the need for washout and the drug(s) to be washed out.
d The baseline visit (day –10) and the randomization visit (baseline +10; day 1) must be confirmed as weekdays.
e No time window (in days) is permitted for visit 5 (day 29, week 4).
f The washout phone contact (approximately 1 week after the screening visit or day –21 at the earliest) will be the start of the washout interval (day of the phone 
contact through the day before the baseline visit) during which, if needed, the patient will discontinue medications used to treat PHN pain, including opioids 
(rescue medications [protocol-specified and provided acetaminophen only] permitted during the washout interval). The duration of the washout interval will 
vary from patient to patient depending on which (if any) medications need to be discontinued. For patients who do not need to washout medications, the other 
activities in this phone contact (review of eligibility based on laboratory test results and scheduling the baseline visit) will be performed.
g The baseline visit (day –10) will be the start of the baseline period during which baseline information regarding pain will be collected while the patient refrains 
from all PHN rescue medications.
h Performed prior to first dose of study drug.
i Includes specific query regarding past use of topical therapy such as the 5% lidocaine patch or capsaicin.
j Includes heart rate, respiration rate, body temperature, and blood pressure.
k Includes body weight (screening and follow-up/ET visits only) and height (screening visit only).
l All ECGs will be taken in triplicate tracings taken at least 1 minute apart (with an upper limit of 5 minutes apart) and read by a central reader for the study.The 
central reader will be blinded (will not know the randomization assignment of the patients).
m Only for women of child-bearing potential.
n For brush or punctate mechanical hyperalgesia. If either is not present at screening, it will not be rechecked on subsequent visits.
o Collect from patients not eligible to continue in the study.


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p Provide eDiary to eligible patients and instructions on using it to record daily pain (11-point NRS), date/time of study drug applications, and rescue medication 
usage.
q Review eDiary and review eDiary data via website. Also, for patients not eligible to be randomly assigned to treatment, collect eDiary at the randomization 
visit (visit 3, day 1).
r Review eDiary, review eDiary data via website, and collect eDiary.
s The eDiary will be used to record responses to 11-point NRS each morning (0700 ±2 hours) and each evening (1900 ±2 hours) before applying the study drug.
t At home after baseline visit until randomization visit.
u At home before dosing and in the evening before dosing.
v At home through the morning of day 29.
x Note that tubes must be weighed at visit 3, to obtain a baseline weight for checking study drug compliance at visit 4 (day 15 ±1, week 2) and visit 5 (day 29, 
week 4) or ET visit. 
y Patients will apply study drug twice daily in the morning (0700 ±2 hours) and again in the evening (1900 ±2 hours). The morning applications should take 
place after recording the morning (0700 ±2 hours) responses to the 11-point NRS, and the evening applications should take place after recording the evening 
(1900 ±2 hours) responses to the 11-point NRS. On day 1, the morning dose might not be applied at 0700 ±2 hours because this first dose of study drug will be 
applied at the randomization visit. Regardless of the clock time of the first dose application at the randomization visit, the evening dose for day 1 should be 
applied at 1900 ±2 hours.
z First dose will be applied by study site staff at randomization visit (visit 3, day 1) as per Section 3.6.
aaAt visit and home on day 1; at home from day 2 onward.
bbAt home through the evening of day 28.
ccPerformed after first dose of study drug.
ddAt the randomization visit, dermal irritation will be assessed 1 hour (±30 minutes) after application of the study drug.
eeAlthough rescue medication is not allowed during the baseline period and during the 7-day period before the week 4 visit (visit 5) of the treatment period, the 
eDiary will be used to record rescue medication usage, including usage when it is prohibited per protocol.
ff At home on day 2 through the morning of day 29.
ggAt home on the morning of day 29.
hhAt home on day 2 through the evening of day 28.
ii All patients will have blood samples drawn for pharmacokinetic assessments.
jj For visit 4 (day 15 ±1, week 2), patients will go to the study site after applying study drug at home so that 2 pharmacokinetics samples can be taken, with the 
first sample taken within approximately 1 to 4 hours of the morning dose of study drug and the second taken approximately 2 hours after collection of the first 
sample. The date and time of morning dose and the date and exact time for each of the 2 pharmacokinetics samples will be recorded.
DSIS=Daily Sleep Interference Scale; ECG=electrocardiogram; eDiary=electronic diary; ET=early termination; NePIQoL=Neuropathic Pain Impact on Quality 
of Life questionnaire; NPSI=Neuropathic Pain Symptom Inventory; NRS=Numeric Rating Scale; PGIC=Patient Global Impression of Change; 
PHN=postherpetic neuralgia; PK=pharmacokinetics; V5=visit 5.


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3.11.1.
Procedures for the Screening Period (Day –28 to Day –1)
3.11.1.1.
Screening Visit (Visit 1, Day –28)
The screening visit will be no more than 28 days before randomization/first dose of study drug. 
A signed and dated ICF will be obtained before screening procedures commence. 
After informed consent is obtained, patients who are screened will be assigned an 8-digit 
permanent identification number such that all patients from each study site are given consecutive 
identification numbers in successive order of inclusion. The first 2 digits of this screening 
number will be the number assigned to the country where the study site is located, the next 3 
digits will be the designated study site number, and the last 3 digits will be assigned at the study 
site (eg, if the number assigned to the country is 01, the third patient screened at study site 5 
would be given the number of 01005003).
A patient who is screened and does not meet study entry criteria will not be considered for 
screening again, except that patients who were excluded from enrollment under inclusion or 
exclusion criteria that have since been revised may be rescreened to determine their eligibility 
under these criteria as amended. However, a patient taking prohibited concomitant medications 
may be allowed to continue with study procedures if the investigator or designee believes that 
the patient can discontinue the prohibited medications during the 4-week screening period and 
remain off the prohibited medications through the week 4 (visit 5, day 29) or the ET visit.
The screening visit (visit 1) will take place ≤28 days before the first dose (application) of study 
drug scheduled to be given in the clinic at the randomization visit (visit 3) on day 1. The 
following procedures to determine patient eligibility for the study will be performed at the 
screening visit:

obtain written informed consent before any other study-related procedures are 
performed

review inclusion/exclusion criteria 

review medical history and demography

review prior medication history and concomitant medications

perform clinical laboratory tests (serum chemistry, hematology, and urinalysis)

perform urine drug screen

perform vital signs measurements

perform physical examination (including body weight and height)

perform 12-lead ECG (all ECGs taken in triplicate tracings obtained at least 1 minute 
apart [with an upper limit of 5 minutes apart])

obtain urine pregnancy test (women of child-bearing potential only)

measure maximal intensity of brush-evoked allodynia and maximal intensity of 
punctate-evoked hyperalgesia


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
obtain NRS, NPSI, DSIS, and NePIQoL assessments

dispense rescue medication
In addition, at visit 1 (screening), the patient will identify the location of his/her most severe 
hyperalgesia, and this location will be used for assessments at all subsequent visits. 
Patients will also be informed of all study restrictions and compliance requirements at visit 1.
Two blood samples will be collected for pharmacogenomic analysis. A patient’s refusal to 
provide the pharmacogenomic blood samples will disqualify the patient from participation in the 
study.
3.11.1.2.
Washout Phone Contact (Approximately 1 Week After the Screening Visit)
The washout phone contact will be no more than 21 days before randomization/first dose of 
study drug, since it takes place 1 week after visit 1. During the washout phone contact, study
eligibility based on laboratory test results will be reviewed, the initial adverse event inquiry will 
be performed, rescue medication use (if any) will be reviewed and recorded as concomitant 
medication, prior/concomitant medications will be reviewed, and as needed, patients will be 
given instructions to washout (discontinue) oral analgesic therapy, topical pain therapy, or 
non-pharmacologic therapy.
For patients who do not need medication washout, this phone contact will be used for other 
activities needed at this point in the study (review of eligibility based on laboratory test results, 
initial inquiry for adverse events, review and recording of any rescue medication use, review of 
prior/concomitant medications as needed, and scheduling the baseline visit).
3.11.1.3.
Washout Period (Variable Duration Period Between the Washout Phone 
Contact and the Baseline Visit)
If needed, a washout period of variable/flexible length will take place, during which the patient 
will discontinue oral analgesic therapy, topical pain therapy, and/or non-pharmacologic therapies
before initiation of the baseline period. The duration of the washout interval will vary from 
patient to patient, depending on which (if any) medications need to be discontinued. Please refer 
to Appendix A.
Patients will be provided with acetaminophen (TYLENOL, McNeil Consumer Healthcare 
Division of McNEIL-PPC, Inc) as 325-mg tablets in bottles of 100 tablets and allowed to take
1 to 2 tablets per dose every 6 hours, as needed, and up to 6 tablets or 1950 mg per 24-hour day.
No other rescue medications will be provided or allowed from the washout phone contact 
through visit 5 (day 29, week 4) or the ET visit. During the washout interval, rescue medication 
use (dates of use and dose taken) will be recorded as concomitant medication.
3.11.1.4.
Baseline Visit (Visit 2, Day –10, weekday)
All patients who successfully complete the washout period or who did not need the washout 
period will return to the study site for a baseline visit (visit 2). The baseline visit marks the 
beginning of the baseline period, and must be confirmed as a weekday upon scheduling. 
Activities at this visit will include the following:


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
review inclusion/exclusion criteria 

perform adverse event inquiry

review prior/concomitant medications

perform vital signs measurement

dispense/collect rescue medication (collect rescue medication from patients not 
eligible to continue in the study), perform accountability, and return unused portion to 
patients continuing in the study

provide eligible patient with an eDiary and instruct patient on its use

review rescue drug compliance

evaluate area of PHN pain for dermal irritation
A patient who does not meet study entry criteria on the basis of results of baseline assessments 
and is not randomly assigned to treatment/enrolled in the study will not be considered for 
screening again.
At the baseline visit, patients should be instructed to:

record average daily pain intensity (over the previous 12 hours [NRS]), in the 
morning and in the evening using eDiary

record rescue pain medication usage for PHN via eDiary (patients will be reminded of 
the restrictions on rescue medication use during the baseline period, and will be
instructed to record any use of rescue medications in the eDiary)

after the baseline visit, record worst daily pain intensity (NRS) in the evening using 
eDiary
3.11.2.
Randomization Visit (Visit 3, Day 1, weekday)
Patients who continue to meet the inclusion/exclusion criteria will be assigned a permanent 
unique randomization number and a treatment number using an IRT. These 2 newly assigned 
numbers will be entered into the CRF, and study drug will be dispensed.
The randomization visit occurs on the same day as the start of study drug treatment. This visit 
must be confirmed as a weekday upon scheduling. 
At the randomization visit (visit 3, day 1), eligible patients will be randomly assigned via IRT in 
a 1:1:1 fashion to 1 of 3 treatment groups: 4% w/w TV-45070 ointment, 8% w/w TV-45070 
ointment, or placebo ointment. Randomization will be stratified by test results of the 
pharmacogenomic sample collected at the screening visit (homozygous minor allele [positive, 
AA], heterozygous [positive, AG], and homozygous common allele [negative, GG]) for R1150W 
polymorphism in the SCN9A gene.
The following procedures/assessments will be performed at visit 3 prior to study drug dose:

review inclusion/exclusion criteria 

perform adverse event inquiry


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
review prior/concomitant medications

perform clinical laboratory tests (serum chemistry, hematology, and urinalysis)

perform urine drug screen

perform vital signs measurements

perform physical examination

perform 12-lead ECG (all ECGs taken in triplicate tracings obtained at least 1 minute 
apart [with an upper limit of 5 minutes apart])

obtain urine pregnancy test (women of child-bearing potential only)

obtain NPSI, DSIS, and NePIQoL assessments

measure maximal intensity of brush-evoked allodynia and maximal intensity of 
punctate-evoked hyperalgesia

review rescue drug compliance, perform accountability, and return unused portion to 
patient if continuing

review eDiary and review eDiary data via website (for patients not eligible to be 
randomly assigned to treatment, collect eDiary)

weigh tube of study drug ointment, to obtain baseline tube weight prior to study drug 
dispensing for study drug compliance checks at subsequent visits

 
 
At visit 3 (day 1), the area affected by PHN pain will be carefully defined by the investigator and 
the patient by mapping the area of pain. Dosing of TV-45070 ointment will be prescribed to fully 
cover the affected area.
The following procedures/assessments will be performed at visit 3 
immediately prior to or at the time of the first study drug dose:

instruct the patient to apply study drug twice daily to area of PHN pain, with the first 
dose administered by site staff 

provide patient with instructions on how to apply study drug

dispense study drug

record date and time of study drug application using eDiary
The following procedures/assessments will be performed at visit 3 after the first study drug dose:

evaluate area of PHN pain for dermal irritation 1 hour (±30 minutes) after first dose
At the randomization visit, patients should be instructed to perform the following procedures in 
the evening at 1900 ±2 hours:


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
apply study drug

record date/time of study drug application using eDiary

record rescue pain medication usage for PHN via eDiary

record worst daily pain intensity (NRS) in the evening using eDiary

record average daily pain intensity (over the previous 12 hours [NRS]) in the evening 
using eDiary
Patients should also be instructed to record average daily pain intensity (over the previous 12 
hours [NRS]) in the morning at 0700 ±2 hours using eDiary.
3.11.3.
Procedures During Double-Blind Treatment Period (Day 1 Through 
Day 29 Visit)
The start of study drug treatment occurs on the randomization visit (visit 3, day 1), as detailed in 
Section 3.11.2. Study drug treatment continues until the evening of day 28.
3.11.3.1.
Daily Routine
During this treatment period (and after the morning study drug application at the clinic on day 1), 
patients will self-administer topical study drug (4% or 8% w/w TV-45070 ointment or placebo 
ointment) according to the instructions provided by the study site. Study drug will be applied 
twice daily (in the morning [0700 ±2 hours] and again in the evening [1900 ±2 hours]). The first 
dose of study drug will be applied at the clinic on day 1 during the randomization visit. 
Regardless of the clock time of the first dose application at the randomization visit, the evening 
dose for day 1 should be applied at 1900 ±2 hours. The last dose of study drug will be applied at 
home on the evening of day 28. No study drug will be applied on day 29, the day of visit 5 
(week 4).
Patients who participate in the study in compliance with the protocol from the screening visit 
through the week 4 visit (visit 5, day 29) will be considered to have completed the study for 
statistical purposes.
3.11.3.2.
Week 2 Visit (Visit 4, Day 15 [±1])
On day 15 (±1 day), patients will visit the study site (visit 4) in addition to the normal at-home 
routine (Section 3.11.3.1). Activities at this visit will include the following:

perform adverse event inquiry

review prior/concomitant medications

perform clinical laboratory tests (serum chemistry, hematology, and urinalysis)

perform vital signs measurements

perform physical examination

perform 12-lead ECG (all ECGs taken in triplicate tracings obtained at least 1 minute 
apart [with an upper limit of 5 minutes apart])

obtain urine pregnancy test (women of child-bearing potential only)


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
obtain NPSI, DSIS, and PGIC assessments

evaluate area of PHN pain for dermal irritation

measure maximal intensity of brush-evoked allodynia and maximal intensity of 
punctate-evoked hyperalgesia

dispense/collect rescue medication, perform rescue medication accountability, and 
return unused portion to patients continuing in the study

review patient eDiary and review eDiary data via website

review study drug compliance and rescue drug compliance

dispense/collect study drug

obtain 2 blood samples (with recording of sampling dates/times) for pharmacokinetics
assessments (the first sample taken within approximately 1 to 4 hours after morning
study drug and the second sample taken approximately 2 hours after collection of the 
first sample)
At visit 4, patients should be instructed to continue to:

record average daily pain intensity (over the previous 12 hours [NRS]) in the morning 
and in the evening using eDiary

apply study drug twice daily to area of PHN pain

record date/time of study drug application using eDiary

record rescue pain medication usage for PHN via eDiary

record worst daily pain intensity (NRS) in the evening using eDiary
3.11.3.3.
Week 4 Visit (Visit 5, Day 29 [±0])
The following procedures/assessments will be performed:

perform adverse event inquiry

review prior/concomitant medications

perform clinical laboratory tests (serum chemistry, hematology, and urinalysis)

perform urine drug screen

perform vital signs measurements

perform physical examination

perform 12-lead ECG (all ECGs taken in triplicate tracings obtained at least 1 minute 
apart [with an upper limit of 5 minutes apart])

obtain urine pregnancy test (women of child-bearing potential only)

obtain NPSI, DSIS, NePIQoL, and PGIC assessments

evaluate area of PHN pain for dermal irritation


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
measure maximal intensity of brush-evoked allodynia and maximal intensity of 
punctate-evoked hyperalgesia

collect rescue medication and review accountability

review eDiary and review eDiary data via website, including the following data 
recorded by the patient at home:

average daily pain intensity (over the previous 12 hours [NRS]) through the 
morning of day 29

date/time of study drug application through the evening of day 28

rescue pain medication usage for PHN

worst daily pain intensity (NRS) through the evening of day 28

collect eDiary

review study drug compliance and rescue drug compliance

collect study drug
3.11.3.4.
Early Termination Visit
For patients who discontinue the study drug prematurely (do not complete the per protocol 
treatment period), there will be an ET visit as soon as possible after the last study drug 
administration. General procedures for patients who withdraw prematurely from the study are 
described in Section 4.3. 
The follow-up visit activities (Section 3.11.4.2) plus eDiary and unused study drug/rescue 
medication collection (and compliance checks) will be conducted at the ET visit, for ET visits 
occurring prior to visit 5 (day 29, week 4). (An ET visit may also occur after visit 5 but before 
the day that visit 6 would normally be scheduled, on day 57 ±3.) If adverse events or other safety 
findings are present at the ET visit, the clinical course of each adverse event will be monitored at 
suitable intervals until resolved or stabilized or returned to baseline, until the patient is referred 
to the care of a health care professional, or until a determination of a cause unrelated to the study 
drug or study procedure is made. Otherwise, the ET visit will be the last study visit for these 
patients.
Because premature discontinuations of treatment may occur at any time between randomization 
and the week 4 visit (visit 5, day 29), patients will be permitted to proceed directly from either 
visit 3 (day 1, randomization), visit 4 (day 15 ±1, week 2), or visit 5 (day 29, week 4) to the ET 
visit. For example, a patient who discontinues study drug on day 20 will have visit 4 (day 15 ±1, 
week 2) followed by visit 6 (ET) as soon as possible after day 20 with no visit 5 (day 29, week 4) 
in between.
The following procedures/assessments will be performed at the ET visit:

perform adverse event inquiry

review prior/concomitant medications


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
review and record rescue medication use (if any) as concomitant medication, not 
using eDiary

perform clinical laboratory tests (serum chemistry, hematology, and urinalysis)

perform vital signs measurements

perform physical examination (including body weight)

perform 12-lead ECG (all ECGs taken in triplicate tracings obtained at least 1 minute 
apart [with an upper limit of 5 minutes apart])

obtain urine pregnancy test (women of child-bearing potential only)

obtain NPSI, DSIS, NePIQoL, and PGIC assessments

evaluate area of PHN pain for dermal irritation

measure maximal intensity of brush-evoked allodynia and maximal intensity of 
punctate-evoked hyperalgesia

collect rescue medication (if prior to visit 5) and review accountability

review eDiary and review eDiary data via website, including the following data 
recorded by the patient the previous evening (if prior to visit 5):

date/time of study drug application

rescue pain medication usage for PHN

worst daily pain intensity (NRS) in the evening

collect eDiary (if prior to visit 5)

review study and rescue drug compliance

collect study drug (if prior to visit 5)
3.11.4.
Procedures After Study Drug Treatment
3.11.4.1.
Follow-up Period (After the Week 4 Visit)
At the week 4 visit (visit 5, day 29), patients who completed the double-blind treatment period 
will enter a 4-week follow-up period, during which they will not use study drug. They should be 
instructed to return to their primary care physician to resume therapy deemed appropriate for 
their PHN.
3.11.4.2.
Follow-up Visit or ET visit (Visit 6, Day 57 [±3])
At the end of the follow-up period (visit 6, day 57 ±3), patients will return to the study site for
the follow-up visit. This visit will be the final visit of the study. Activities at the follow-up visit 
will include the following:

perform adverse event inquiry

review medications taken since previous visit


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
perform clinical laboratory tests (serum chemistry, hematology, and urinalysis)

perform vital signs measurements

perform physical examination (including body weight)

perform 12-lead ECG (all ECGs taken in triplicate tracings obtained at least 1 minute 
apart [with an upper limit of 5 minutes apart])

obtain urine pregnancy test (women of child-bearing potential only)

evaluate area of PHN pain for dermal irritation
Activities performed at the ET visit only will include the following:

obtain NPSI, DSIS, NePIQoL, and PGIC assessments

measure maximal intensity of brush-evoked allodynia and maximal intensity of 
punctate-evoked hyperalgesia 

collect rescue medication (if prior to visit 5)

review and record rescue medication use (if any) as concomitant medication, not 
using eDiary

review eDiary and review eDiary data via website, including the following data 
recorded by the patient the previous evening (if prior to visit 5):

date/time of study drug application

rescue pain medication usage for PHN

worst daily pain intensity (NRS) in the evening

collect eDiary (if prior to visit 5)

review study and rescue drug compliance 

collect study drug (if prior to visit 5)
3.11.5.
Unscheduled Visits
An unscheduled visit may be performed at any time during the study at the patient’s request or as 
deemed necessary by the investigator. The date and reason for the unscheduled visit will be 
recorded on the CRF as well as any other data obtained (eg, adverse events, concomitant 
medications and treatments, and results from procedures or tests).


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4.
SELECTION AND WITHDRAWAL OF PATIENTS
4.1.
Patient Inclusion Criteria
Patients may be included in the study only if they meet all of the following criteria:
a.
[Revision 1] Patient has chronic PHN, defined as pain present for more than 6 
months and less than 10 years after onset of herpes zoster skin rash affecting a single 
dermatome. Patients with more than 1 involved dermatome may also be included, 
provided the affected dermatomes are contiguous. Patients excluded under this 
criterion before implementation of Amendment 03 may be rescreened to determine 
eligibility under the revised criterion.
b. Patient has average daily pain of at least 4 on the 11-point NRS at screening and 
during the baseline pain assessment interval (days –7 to –1) immediately before 
randomization.
c.
Patient must properly assess and record pain intensity in an eDiary for at least 5 of the 
7 daily morning measurements and at least 5 of the 7 daily evening measurements 
during the 7 days immediately before randomization. 
d. [Revision 1] Patient is ≥18 years of age, with a body mass index (BMI) between 
18 and 34 kg/m2, inclusive, at screening visit.
e.
If the patient is a woman:

The patient cannot become pregnant because she is surgically sterile 
(hysterectomy or tubal ligation) or postmenopausal for at least 6 months.
OR

If fertile, the patient is not pregnant and has negative pregnancy tests at both the 
screening and randomization visits and agrees to use an acceptable method of 
contraception (ie, oral contraceptives, hormone implant, intrauterine device, 
spermicide with barrier method, surgically sterile male sexual partner[s], or no 
sexual partners) for the duration of the study, including follow-up.
f.
If the patient is a man:

The patient is surgically sterile.
OR

If capable of producing offspring, the patient must agree to use a barrier method 
of contraception in combination with a spermicide with any female partner, unless 
the partner cannot become pregnant because she is surgically sterile 
(hysterectomy or tubal ligation), she has been postmenopausal for at least 
6 months, or she is fertile but using an acceptable method of contraception (ie, 
oral contraceptives, hormone implant, or intrauterine device) for the duration of 
the study, including follow-up.


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g. Patient must sign the written ICF for the study and be willing to comply with all study 
procedures and restrictions.
h. Patient must be judged by the investigator to be medically healthy (except for PHN) 
and able to participate in the study.
4.2.
Patient Exclusion Criteria
Patients will be excluded from participating in this study if they meet 1 or more of the following 
criteria: 
a.
Patient has any other severe pain that might confound assessment or self-evaluation 
of pain due to PHN.
b. Patient has PHN affecting the face (trigeminal nerve distribution).
c.
[Revision 1] Patient has a history, in the judgment of the investigator, of inadequate 
response to more than 3 adequate courses of treatment with other medications used to 
treat neuropathic pain (eg, tricyclic antidepressants, serotonin-norepinephrine 
reuptake inhibitors, anticonvulsants, topical lidocaine, and/or topical capsaicin).
Patients excluded under this criterion before implementation of Amendment 03 may 
be rescreened to determine eligibility under the revised criterion.
d. Patient is taking oral analgesics (either opioid or non-opioid) or is receiving topical 
therapy such as the 5% topical lidocaine patch for the treatment of pain and is 
unwilling or unable to complete a washout period during which the patient will 
discontinue analgesic therapy or topical pain therapy.
e.
Patient has been treated with topical capsaicin at any time in the past 6 months for 
neuropathic pain.
f.
Patient has an NRS score of 10 on 1 or more occasions during the baseline pain 
assessment interval (days –7 to –1) immediately before randomization or NRS scores 
of 9 on 3 or more occasions during the same time frame
g. Patient used rescue medication during the 7-day baseline period
h. Patient has a history of fibromyalgia.
i.
Patient has uncontrolled cardiac, renal, hepatic, or other systemic disorders that, in the 
opinion of the investigator, may jeopardize the patient.
j.
Patient uses Class Ic anti-arrhythmic drugs such as flecainide or propafenone.
k. Patient has a resting heart rate <45 or >100 beats per minute (bpm), 
QRS ≥120 milliseconds (including complete left and/or right bundle branch block), 
QT interval corrected for heart rate by Fridericia’s formula (QTcF) ≤320 milliseconds 
or ≥470 milliseconds, and, for patients in sinus rhythm, PR <120 milliseconds or 
≥220 milliseconds. (These numerical exclusion criteria will be applied using the mean 
values of 3 ECGs.)
l.
Patient has second- or third-degree atrioventricular block unless treated with a 
permanent pacemaker.


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m. Patient has uncontrolled atrial fibrillation or flutter (ventricular rate >100 bpm).
n. Patient has a congenital arrhythmia syndrome (eg, Brugada syndrome or long or short 
QT syndrome).
o. Patient has had myocardial infarction within the past 12 months or current unstable 
angina, coronary ischemia, or heart failure
p. . Patient has significant edema or loss of skin integrity (including sores or ulcers) 
other than healed herpes zoster skin rash affecting the region of pain and surrounding 
area.
q. Patient is intolerant to study drug, its excipients, and/or acetaminophen.
r.
Patient uses any over-the-counter (OTC) analgesic medication/topical therapy for the 
duration of the study except for permitted rescue (for PHN pain) medications. Stable 
therapy of more than 30 days for aspirin (up to 81 mg/day) is allowed as 
cardiovascular prophylaxis.
s.
Patient uses any non-pharmacologic pain management techniques (eg, physical 
techniques, physiotherapy, massage therapy, acupuncture, biofeedback, and/or 
psychological support) and is unable or unwilling to discontinue prior to baseline pain 
assessment.
t.
[Criterion Removed] 
u. Patient uses any topical/cosmetic products (eg, lotions and tanning products) on the 
skin in the painful region of PHN.
v. Patient has a history of alcohol or drug abuse within 1 year before the screening visit, 
or a positive urine drug test at the screening visit for cocaine, marijuana, opioids, 
amphetamines, methamphetamines, benzodiazepines, barbiturates, methadone, and/or 
tricyclic antidepressants unless explained by the use of prescription medication. (The 
use of medical marijuana is not permitted and excludes the patient from the study.)
w. Patient is pregnant or breast-feeding at the time of the screening visit.
x. Patient has findings in laboratory data, vital signs measurements, or physical 
examination at the screening, baseline pain assessment interval, or randomization 
visit that, in the opinion of the investigator, may pose undue risk to the patient or may 
interfere with study data interpretation.
y. Patient was previously randomly assigned to treatment in this study and 
received/subsequently discontinued study drug.
z. Patient used another investigational drug within 30 days or 5 half-lives (whichever is 
longer) before the planned first day of study drug application (day 1) in this study.
aa. Patient refuses to provide 2 blood samples at the screening visit for pharmacogenomic 
analyses.
bb. Patient is a study site or Sponsor employee who is directly involved in the study or 
the relative of such an employee.


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cc. There is any other reason that would make the patient, in the opinion of either the 
investigator or the Sponsor, unsuitable for the study.
4.3.
Justification of Key Inclusion and Exclusion Criteria
The inclusion criteria for this study have been selected to identify an appropriate patient 
population to evaluate the efficacy of topical TV-45070 in PHN. The exclusion criteria have 
been selected to exclude patients with characteristics that would put them at risk if they 
participated in the study, and to exclude patients with potentially confounding characteristics that 
would make data interpretation difficult.
4.4.
Withdrawal Criteria and Procedures
In accordance with the Declaration of Helsinki (and/or with the applicable country’s acceptance), 
each patient is free to withdraw from the study and/or study drug treatment at any time. The 
investigator also has the right to withdraw a patient from the study and/or study drug treatment in 
the event of intercurrent illness, adverse events, pregnancy (see Section 7.3.4.1), other reasons 
concerning the health or well-being of the patient, or lack of cooperation. In addition, a patient 
may be withdrawn from the study and/or drug treatment as described in Sections 3.9, 3.5, and 
7.1.7.
Should a patient decide to withdraw (from either the study or study drug treatment) after starting 
study drug or should the investigator decide to withdraw the patient at such time, all reasonable 
efforts will be made to complete and report all observations up to the time of withdrawal. A 
complete final evaluation at the time of the patient’s withdrawal should be made, and an 
explanation given as to why the patient is withdrawing or being withdrawn from the study and/or 
study drug treatment.
The reason for and date of withdrawal from study and/or study drug treatment must be recorded 
on the source documentation and transcribed onto the CRF. If a patient withdraws consent, every 
attempt will be made to determine the reason. If the reason for withdrawal is an adverse event or 
a clinically significant abnormal laboratory test result, monitoring will be continued at the 
discretion of the investigator (eg, until the event has resolved or stabilized, until the patient is 
referred to the care of another health care professional, or until a determination of a cause 
unrelated to the study drug or study procedure is made). The specific event(s) or test result(s) 
must be recorded on the source documentation and transcribed onto the CRF. In addition, a 
blood sample will be obtained for the measurement of study drug concentrations. The sample 
date and time will be recorded on the source documentation and transcribed onto the CRF. 
An ET visit should be conducted within 2 weeks after the last study drug administration. The 
activities for the ET visit are described in Section 3.11.3.4. Because premature discontinuations 
of treatment may occur at any time between randomization and the week 4 visit (visit 5, day 29), 
patients will be permitted to proceed directly from either visit 3 (day 1, randomization) or visit 4 
(day 15 ±1, week 2) to the ET visit. For example, a patient who discontinues study drug on day 
20 will have visit 4 (day 15 ±1, week 2) followed by visit 6 (ET) within 2 weeks after day 20 
with no visit 5 (day 29, week 4) in between.
Data from any efficacy evaluations performed after the specified time will not be collected on 
the CRF; in the event, however, if such data are collected, these data will not be analyzed. 


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Patients with ongoing adverse events or clinically significant abnormal laboratory test results (as 
interpreted by the investigator) will be monitored as described in Section 7.1.2 and Section 7.3, 
respectively.
A patient who is randomly assigned to treatment (enters the double-blind treatment period) but 
fails to complete the double-blind treatment period will not be replaced. Measures will be taken 
to increase the recruitment rate, as needed, to ensure that a minimum of 330 patients 
(110 patients per treatment arm) are randomly assigned to treatment and 264 patients (up to 
approximately 88 patients per treatment arm) complete the double-blind treatment period and are 
evaluable for the primary efficacy analysis.


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5.
TREATMENT OF PATIENTS
5.1.
Drugs Administered During the Study
At the baseline/randomization visit, eligible patients will be randomly assigned to 1 of 
3 treatment groups (4% w/w TV-45070 ointment, 8% w/w TV-45070 ointment, or placebo 
ointment) as described in Section 3.4. Blinded study drug will be applied twice daily to the area 
of PHN pain during the treatment period from days 1 through 28, as described in Sections 3.6
and 3.11.3.
Study drug will be packaged in tubes and provided for patients to apply at home (see 
Section 3.6). Patients will be instructed to store the tube of ointment at ambient room 
temperature (15°C to 25°C) at home. Study drug exposure will be measured, and compliance to 
study drug administration will be monitored. Compliance will be assessed by weighing tubes at 
visit 3 (baseline), visit 4 (day 15 ±1, week 2), and visit 5 (day 29, week 4) or ET visit. A patient 
will be considered compliant during the interval between the previous 2 visits if the tube weighs 
between 70% and 120% of the expected weight.
Each patient will be given an eDiary and instructions on using it to record daily pain (11-point 
NRS), the date/time of study drug applications, and rescue medication usage. The eDiary will be 
used to record responses to an 11-point NRS before applying the study drug twice daily. Patients 
will apply the study drug in the morning after recording the morning responses to the 11-point 
NRS at 0700 ±2 hours, and in the evening after recording the responses to the 11-point NRS at 
1900 ±2 hours.
Patients (and caregivers, as applicable) will receive instructions on how to apply the study drug. 
Under study site staff supervision, the area affected by PHN pain will be carefully defined by 
mapping the area of pain, and dosing will be prescribed to fully cover the affected area. Dosing 
cards and instructions will be provided on how to measure the appropriate amount of ointment 
for each application. A laminated instruction sheet, including pictures, will describe and illustrate 
how the ointment is to be spread over the entire area of PHN pain in a thin layer that fully covers 
the area and gently massaged into the skin.
The first application of study drug will occur at the study site on the day of the randomization 
visit (visit 3, day 1). The study coordinator or designated site staff member will apply blinded 
study drug and will define the amount of ointment to be used for all subsequent treatment 
applications for that patient. Subsequent study drug applications will be performed by the patient 
at home. (If the affected area is not within reach of application by the patient [such as the 
posterior thoracic region], the patient’s designated caregiver will apply the ointment, but the 
patient will record the time of application in the eDiary.)
Patients will return to the study site for visit 4 (day 15 ±1, week 2) and again for visit 5 (day 29, 
week 4). At visit 4, 2 blood samples will be taken from each patient for pharmacokinetic 
analysis: the first sample taken within approximately 1 to 4 hours after the dose of study drug in 
the morning and the second sample taken approximately 2 hours after collection of the first 
sample. Patients will go to the study site after applying study drug at home so that the 
2 pharmacokinetic samples can be taken.


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At visit 5, the eDiary will be collected along with the tubes of study drug and bottles of rescue 
medication. Patients will be instructed to return to their primary care physician to resume therapy 
deemed appropriate for their PHN.
5.2.
Restrictions
Patients will be required to comply with the following restrictions with respect to activity:

After applying ointment, patients should wait for 10 minutes before covering the area 
with clothing, to allow the ointment to be absorbed by the skin. After the ointment 
has fully penetrated the skin, the area will be dry.

After applying ointment, patients must not apply pressure to the area of skin treated 
with ointment by leaning against surfaces, such as furniture, for 10 minutes, to allow 
the ointment to be absorbed by the skin. After the ointment has fully penetrated the 
skin, the area will be dry.
In addition, patients must maintain (hold constant) their current level of physical activity from 
the baseline visit through the end of treatment (visit 5, day 29, week 4).
5.3.
Prior and Concomitant Therapy or Medication
Any prior or concomitant therapy or medication that a patient has had within 90 days before 
study drug administration and up to the end of the study period, including follow-up, will be 
recorded on the CRF. Generic or trade name, indication, and dosage will be recorded. The 
Sponsor will encode all therapy and medication according to the World Health Organization 
drug dictionary (WHO Drug).
The following medications will not be allowed during this study:

Oral analgesics

Topical analgesics, including lidocaine (gels, creams and patches) and capsaicin 
patches

Rescue pain medication except permitted acetaminophen rescue

Class Ic anti-arrhythmic drugs such as flecainide or propafenone
At each clinic visit after the screening visit, the investigator will ask patients whether they have 
taken any medications (other than study drug), including OTC medications, vitamins, or herbal 
or nutritional supplements, since the previous visit. Indication, dosage, and start and end dates 
should be entered on the CRF. 
5.4.
Rescue Medications for PHN Pain
Patients will be provided with acetaminophen (TYLENOL, McNeil Consumer Healthcare 
Division of McNEIL-PPC, Inc) as 325-mg tablets in bottles of 100 tablets and allowed to take 
1 to 2 tablets per dose every 6 hours, as needed, and up to 6 tablets or 1950 mg per day (over a 
24-hour period) for rescue relief of PHN pain. Rescue medication will be provided at the 
screening visit. Rescue medication compliance will be checked at all visits until used rescue 
medication is collected after the baseline pain assessment interval for patients not continuing in 


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the study, at visit 5 (day 29, week 4) for patients who complete the treatment period, or at the ET 
visit for patients who prematurely discontinue study drug.
No other rescue medications will be provided or allowed from the washout phone contact 
through visit 5 (day 29, week 4) or the ET visit. Patients will not be permitted to use rescue 
medication during the baseline pain assessment interval (days –10 through –1) and during the 
final week of treatment (the 7-day period before visit 5). During the washout interval, rescue 
medication use (dates of use and dose taken) will be recorded as concomitant medication. During 
baseline and the treatment period, rescue medication use will be recorded using the eDiary.
5.5.
Procedures for Monitoring Patient Compliance
Each investigator or designee will be responsible for monitoring patient compliance. Study drug 
exposure will be measured, and compliance to study drug administration will be monitored by 
weighing the tubes of blinded study drug at the week 2 (visit 4, day 15 ±1) and week 4 (visit 5, 
day 29) or ET visits. (At visit 3, the tubes will be weighed to obtain a baseline weight.) A patient 
will be considered compliant during the interval between the previous 2 visits if the tube weighs 
between 70% and 120% of the expected weight. Also, study drug accountability records will be 
completed. Patients will not be discontinued for noncompliance at week 2 (visit 4, day 15 ±1);
however, they will be retrained in proper medication dispensing.
5.6.
Total Blood Volume
The total amount of blood drawn during the study from each patient will be approximately 
50 mL.


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6.
ASSESSMENT OF EFFICACY
6.1.
Primary Efficacy Variable
The primary efficacy endpoint for this study is the change from baseline to week 4 in the weekly 
average of the daily average NRS scores (the daily average NRS score is the average of daily 
morning and evening patient-reported measurements) of average pain intensity over the prior 
12 hours.
The NRS is a widely-used, standard one-dimensional scale from 0 to 10 for patient self-reporting 
of pain.
6.2.
Secondary Efficacy Variables
The secondary efficacy endpoints, including those defined using the NePIQoL, DSIS, NPSI, and 
PGIC, are listed in Section 3.3.2.
6.3.
Exploratory Efficacy Variables
The exploratory efficacy endpoints are described in Section 3.3.3.
6.4.
Methods and Timing of Assessing, Recording, and Analyzing 
Efficacy and Clinical Pharmacology Data
Methods for assessing efficacy data are described in Section 3.3. Methods for obtaining samples 
for pharmacokinetic analyses are described in Section 3.3.6. Methods for obtaining samples for 
pharmacogenomic analyses are described in Section 3.3.8. Timing of assessing efficacy, 
pharmacokinetic, and pharmacogenomic data are discussed in Section 3.11. Procedures for 
recording efficacy data are discussed in Section 13.1, and methods of analyses of the efficacy 
data are discussed in Section 9.6. Procedures for obtaining pharmacokinetic and 
pharmacogenomic assay results and analyzing the data are described in separate documents. The 
population pharmacokinetic analyses results (including analyses of the effects of allelic variants 
of CYP3A4 and/or CYP2C19, if performed) will be reported separately from the main study 
results.


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7.
ASSESSMENT OF SAFETY
In this study, safety will be assessed by qualified study staff by evaluating the following: 
reported adverse events, clinical laboratory test results, vital signs measurements, ECG findings, 
physical examination findings (including body weight measurements), dermal irritation findings, 
and concomitant medication usage.
7.1.
Adverse Events 
7.1.1.
Definition of an Adverse Event
An adverse event is any untoward medical occurrence in a patient administered a pharmaceutical 
product, regardless of whether it has a causal relationship with this treatment. 
In this study, any adverse event occurring after the clinical study patient has signed the ICF
should be recorded and reported as an adverse event. Any adverse event occurring after the first 
application of study drug is considered a treatment-emergent adverse event.
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of the study, or 
significant worsening of the disease under study or of any concurrent disease, whether or not 
considered related to the study drug. A new condition or the worsening of a pre-existing 
condition will be considered an adverse event. Stable chronic conditions (such as arthritis) that 
are present before study entry and do not worsen during the study will not be considered adverse 
events. 
Worsening of the disease under study will be measured by increased PHN pain scores. 
Worsening of PHN should be recorded as an adverse event only if the presentation and/or 
outcome is more severe than would normally be expected from the normal course of the disease 
in a particular patient.
Accordingly, an adverse event can include any of the following:

Intercurrent illnesses.

Physical injuries.

Events possibly related to concomitant medication.

Significant worsening (change in nature, severity, or frequency) of the disease under 
study or other pre-existing conditions. Note: A condition recorded as pre-existing that 
is intermittently symptomatic (eg, headache) and that occurs during the study should 
be recorded as an adverse event.

Drug interactions.

Events occurring during diagnostic procedures or during any washout phase of the 
study.

Laboratory or diagnostic test abnormalities that result in the withdrawal of the patient 
from the study, are associated with clinical signs and symptoms or a serious adverse 
event, or require medical treatment or further diagnostic work-up, or are considered 


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by the investigator to be clinically significant. Note: Abnormal laboratory test results 
at the screening visit that preclude a patient from entering the study or receiving study 
treatment are not considered adverse events but will be evaluated to monitor data
from patients who do not meet screening criteria. 

All events of possible drug-induced liver injury with hyperbilirubinemia (defined as 
aspartate aminotransferase [AST] or alanine aminotransferase [ALT] ≥3 times the 
upper limit of the normal range [ULN] plus either bilirubin ≥2 times the ULN or 
International Normalized Ratio [INR] >1.5) or Hy’s Law events require immediate 
study treatment cessation and reporting as a serious adverse event.
7.1.2.
Recording and Reporting Adverse Events
For adverse event recording, the study period is defined for each patient as that time period from 
signature of the ICF through the end of the follow-up period. For this study, the follow-up period 
ends with the day 57 (±3) follow-up visit (visit 6) or ET visit, or it ends when a patient is 
confirmed as lost to follow-up. A patient is confirmed as lost to follow-up after all reasonable 
efforts to locate the patient have failed.
All adverse events that occur during the defined study period must be recorded on the source 
documentation and transcribed onto the CRF, regardless of the severity of the event or judged 
relationship to the study drug. For serious adverse events, the Serious Adverse Event Form must 
also be completed, and the serious adverse event must be reported immediately (see 
Section 7.1.5.3.1). The investigator does not need to actively monitor subjects for adverse events 
once the study has ended. Serious adverse events occurring to a patient after the follow-up period
should be reported to the Sponsor if the investigator becomes aware of them, following the 
procedures described in Section 7.1.5.3.1.
At each contact with the patient, the investigator or designee must query the patient for adverse 
events by asking an open-ended question such as “Have you had any unusual symptoms or 
medical problems since the last visit? If yes, please describe.” All reported or observed signs and 
symptoms will be recorded individually, except when considered manifestations of a medical 
condition or disease state. A precise diagnosis will be recorded whenever possible. When such a 
diagnosis is made, all related signs, symptoms, and any test findings will be recorded collectively 
as a single diagnosis on the CRF and, if it is a serious adverse event, on the Serious Adverse 
Event Form.
The clinical course of each adverse event will be monitored at suitable intervals until resolved or 
stabilized or returned to baseline, until the patient is referred to the care of a health care 
professional, or until a determination of a cause unrelated to the study drug or study procedure is 
made.
The onset and end dates and times, duration (in case of adverse event duration of less than 
24 hours), action taken regarding study drug, treatment administered, and outcome for each 
adverse event must be recorded on the source documentation and transcribed onto the CRF. 
The relationship of each adverse event to study drug treatment and study procedures, and the 
severity and seriousness of each adverse event, as judged by the investigator, must be recorded 
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7.1.3.
Severity of an Adverse Event
The severity of each adverse event must be recorded as 1 of the choices on the following scale:
Mild: 
No limitation of usual activities
Moderate: Some limitation of usual activities
Severe: 
Inability to carry out usual activities
7.1.4.
Relationship of an Adverse Event to the Study Drug
The relationship of an adverse event to the study drug is characterized as follows:
Term
Definition
Clarification
No reasonable 
possibility
(not related)
This category applies to adverse 
events that, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc) or to adverse 
events that, after careful medical 
consideration at the time they are 
evaluated, are judged to be unrelated 
to the study drug.
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if at least 2 of the following apply:

It does not follow a reasonable temporal sequence 
from the administration of the test drug.

It could readily have been produced by the patient’s 
clinical state, environmental or toxic factors, or other 
modes of therapy administered to the patient.

It does not follow a known pattern of response to the 
test drug. 

It does not reappear or worsen when the drug is 
re-administered.
Reasonable 
possibility
(related)
This category applies to adverse 
events for which, after careful 
medical consideration at the time 
they are evaluated, a connection with 
the test drug administration cannot be 
ruled out with certainty.
The relationship of an adverse event may be considered 
“reasonable possibility” if at least 2 of the following
apply:

It follows a reasonable temporal sequence from 
administration of the drug.

It cannot be reasonably explained by the known 
characteristics of the patient’s clinical state, 
environmental or toxic factors, or other modes of 
therapy administered to the patient.

It disappears or decreases on cessation or reduction in 
dose. There are important exceptions when an 
adverse event does not disappear upon 
discontinuation of the drug, yet drug-relatedness 
clearly exists.

It follows a known pattern of response to the test 
drug.
7.1.5.
Serious Adverse Events
7.1.5.1.
Definition of a Serious Adverse Event
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions:

Death.


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
A life-threatening adverse event (ie, the patient was at immediate risk of death from 
the event as it occurred); does not include an event that, had it occurred in a more 
severe form, might have caused death.

Inpatient hospitalization or prolongation of existing hospitalization, which means that 
hospital inpatient admission and/or prolongation of hospital stay were required for 
treatment of an adverse event or that they occurred as a consequence of the event. 
Hospitalizations scheduled for an elective procedure or for treatment of a pre-existing 
condition that has not worsened during participation in the study will not be 
considered serious adverse events. 

Persistent or significant disability or incapacity (refers to a substantial disruption of 
one’s ability to conduct normal life functions).

A congenital anomaly/birth defect.

An important medical event that may not result in death, be life-threatening, or 
require hospitalization but may jeopardize the patient and may require medical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization,
or the development of drug dependency or drug abuse. Note: Any suspected 
transmission of an infectious agent via a medicinal product is considered an important 
medical event.
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event.
7.1.5.2.
Expectedness
A serious adverse event that is not included in reference safety information for topical TV-45070 
by its specificity, severity, outcome, or frequency is considered an unexpected adverse event.
The reference safety information for this study is located in the TV-45070 Investigator’s 
Brochure.
The Sponsor’s Global Patient Safety & Pharmacovigilance Department will determine the 
expectedness for all serious adverse events.
7.1.5.3.
Reporting a Serious Adverse Event
7.1.5.3.1. Investigator Responsibility
To satisfy regulatory requirements, all serious adverse events (as described in Section 7.1.5.1) 
that occur during the study period (including the protocol-defined follow-up period), regardless 
of judged relationship to treatment with the study drug, must be reported to the Sponsor by the 
investigator within 24 hours when the investigator learns about it or, if the event occurs on a 
weekend or national holiday, on the next working day. Completing the Serious Adverse Event 
Form and reporting the event must not be delayed, even if not all the information is available.
The investigator does not need to actively monitor subjects for adverse events once the study has 
ended. Serious adverse events occurring to a patient after the follow-up period should be 
reported to the Sponsor if the investigator becomes aware of them.


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The Serious Adverse Event Form should be sent to the Sponsor’s local safety officer (LSO); for 
this study, the LSO is the Teva USA Pharmacovigilance Department.
The following information should be provided to record the event accurately and completely:

study number (Study TV45070-CNS-20013)

investigator and study site identification

patient number

onset date and description of adverse event

investigator’s assessment of the relationship of the adverse event to the study drug 
(no reasonable possibility, reasonable possibility)
Additional information may include the following:

age and sex of the patient

date of first dose of study drug

date and amount of last administered dose of study drug

action taken

outcome, if known

severity

concomitant therapy (including doses, routes, and regimens) and treatment of the 
event

pertinent laboratory or other diagnostic test data 

medical history

results of dechallenge/rechallenge, if known

for an adverse event resulting in death: 

cause of death (whether or not the death was related to study drug)

autopsy findings (if available)
Each report of a serious adverse event will be reviewed and evaluated by the investigator and the 
Sponsor to assess the nature of the event and the relationship of the event to the study drug, study 
procedures, and underlying disease. 
Additional information (follow-up) about any serious adverse event unavailable at the initial 
reporting should be forwarded by the study site within 24 hours when it becomes known to the 
same address as the initial report. 
The LSO will be responsible for submission of the MedWatch form 3500/Council for 
International Organizations of Medical Sciences (CIOMS) form/XML file to the regulatory 
authorities. In EU countries, the LSO will distribute for local submission to International Ethics 
Committees (IECs)/IRBs and investigators according to regulations. In non-EU countries, 
serious adverse events will be reported by the Sponsor or designee (contract research 


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organization [CRO]) to investigators. The investigators should report the serious adverse events 
to their local IRB as dictated by their board’s policies and procedures.
The study drug blinding will be maintained for the people who are involved directly in the study. 
Therefore, in case of a suspected unexpected serious adverse reaction (SUSAR), only the LSO 
will receive the unblinded report for regulatory submission; the others will receive a blinded 
report. 
Note: Although pregnancy is not a serious adverse event, the process for reporting a pregnancy is 
the same as that for reporting a serious adverse event but using the pregnancy form (see 
Section 7.2). 
7.1.5.3.2. Sponsor Responsibility
If a serious unexpected adverse event is believed to be related to the study drug or study 
procedures, the Sponsor will take appropriate steps to notify all investigators participating in 
sponsored clinical studies of TV-45070 and the appropriate regulatory authorities. 
In addition to notifying the investigators and regulatory authorities, other measures may be 
required, including the following:

altering existing research by modifying the protocol

discontinuing or suspending the study

altering the process of informed consent by modifying the existing consent form and 
informing current study participants of new findings

modifying listings of expected toxicities to include adverse events newly identified as 
related to TV-45070
7.1.6.
Protocol-Defined Adverse Events for Expedited Reporting
No protocol-defined adverse events for expedited reporting were identified for this study.
7.1.7.
Withdrawal Due to an Adverse Event
Any patient who experiences an adverse event may be withdrawn from study drug treatment at 
any time at the discretion of the investigator. If a patient is withdrawn wholly or in part because 
of an adverse event, both the adverse events page and the termination page of the CRF will be 
completed at that time. If possible, a blood sample will be obtained for the measurement of study 
drug concentrations.
The patient will be monitored at the discretion of the investigator (eg, until the event has 
resolved or stabilized, until the patient is referred to the care of a health care professional, or 
until a determination of a cause unrelated to the study drug or study procedure is made). The 
investigator must inform the CPP/CL as soon as possible of all patients who are being considered 
for withdrawal due to adverse events. Additional reports must be provided when requested.
If a patient is withdrawn from study drug treatment and/or the study for multiple reasons that 
include adverse events, the termination page of the CRF should indicate that the withdrawal was 
related to an adverse event. An exception to this requirement will be the occurrence of an 
adverse event that, in the opinion of the investigator, is not severe enough to warrant 


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discontinuation but that requires the use of a prohibited medication, thereby requiring 
discontinuation of the patient. In such a case, the reason for discontinuation would be need to 
take a prohibited medication, not the adverse event.
7.1.8.
Medical Emergencies
Medical emergencies must be reported to the individual identified in the Clinical Study 
Personnel Contact Information section of this protocol.
Equipment, supplies, and properly skilled medical personnel must be accessible for an adverse 
event requiring immediate treatment. Any dose of study drug (whether the investigational 
product, reference therapy, or a placebo), whether taken intentionally or unintentionally, in 
excess of that prescribed must be immediately reported to the Sponsor. When the identification 
of the study drug must be known, the investigator must follow the procedures outlined in 
Section 3.5. 
7.1.9.
Protocol Deviations Because of an Adverse Event
If a patient experiences an adverse event or medical emergency, departures from the protocol 
may be allowed on a case-by-case basis. After stabilization and/or treatment has been 
administered to ensure patient safety, the investigator or other physician in attendance must 
contact the individual identified in the Clinical Study Personnel Contact Information section of 
this protocol as soon as possible to discuss the situation. The investigator, in consultation with 
the Sponsor, will decide whether the patient should continue to participate in the study. Any 
departures from the protocol because of adverse events must be noted on the CRF and in source 
documents, along with the reason for such departures. 
7.2.
Pregnancy 
All pregnancies (pregnancies of women participating in the study and female partners of men 
participating in the study) that occur during the study, or within 30 days of completion of the 
study, are to be reported immediately to the individual identified in the Clinical Study Personnel 
Contact Information section of this protocol, and the investigator must provide the LSO with the 
Clinical Trial pregnancy form. The process for reporting a pregnancy is the same as that for 
reporting a serious adverse event (see Section 7.1.5.3). 
Any patient becoming pregnant during the study will be withdrawn from study drug treatment.
All patients (or female partners of male patients) who become pregnant will be monitored to the
completion or termination of the pregnancy. If the pregnancy continues to term, the outcome 
(health of the infant up to 8 weeks of age), details of birth, and presence or absence of any birth 
defect, congenital abnormalities, or maternal and newborn complications will be reported to the 
Sponsor. Any complication of pregnancy will be reported as an adverse event or serious adverse 
event, as appropriate.
If the pregnancy does not continue to term, 1 of the following actions will be taken:

For a spontaneous abortion, report as a serious adverse event.

For an elective abortion due to developmental anomalies, report as a serious adverse 
event.


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
For an elective abortion not due to developmental anomalies, report on the pregnancy 
form.
7.3.
Clinical Laboratory Tests
All clinical laboratory test results outside of the reference range will be interpreted by the 
investigator as belonging to 1 of the following categories:

abnormal but not a clinically significant worsening

abnormal and a clinically significant worsening
A laboratory test result that has significantly worsened (according to medical judgment) from the 
baseline result will be recorded on the source documentation, transcribed onto the CRF as an 
adverse event, and monitored as described in Section 7.1.2. An adverse event includes a 
laboratory or diagnostic test abnormality (once confirmed by repeat testing) that results in the 
withdrawal of the patient from the study, the temporary or permanent cessation of treatment with 
study drug, or medical treatment or further diagnostic work-up.
Clinical laboratory tests (serum chemistry and hematology) and urinalysis will be performed at 
the time points indicated in Table 1. The clinical laboratory tests will be performed using a 
central laboratory, with more details provided in the Laboratory Procedures Manual for this 
study. The urinalysis will be done macroscopically at the study site with a dipstick provided by 
the central laboratory. If any portion of the dipstick is positive, the urine sample will be sent to 
the central laboratory for microscopic evaluation. The dipstick results will be recorded in the 
CRF. Specific laboratory tests to be performed are listed below. 
7.3.1.
Serum Chemistry
The following serum chemistry tests will be performed:

calcium

phosphorus

sodium

potassium

chloride

bicarbonate or carbon dioxide

glucose

blood urea nitrogen (BUN)

creatinine

cholesterol

uric acid

ALT

AST


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
lactic dehydrogenase (LDH)

gamma-glutamyl transpeptidase (GGT)

alkaline phosphatase

creatine phosphokinase

total protein

albumin

total bilirubin

direct bilirubin

indirect bilirubin
7.3.2.
Hematology
The following hematology tests will be performed:

hemoglobin

hematocrit

red blood cell (RBC) count 

platelet count

absolute neutrophil count

white blood cell (WBC) count and differential count

polymorphonuclear leukocytes (neutrophils)

lymphocytes

eosinophils

monocytes

basophils

atypical lymphocytes
7.3.3.
Urinalysis
Urinalysis will include testing for the following:

protein

glucose

ketones

blood (hemoglobin)

pH

specific gravity


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
microscopic, as needed

bacteria

RBCs

WBCs

casts

crystals
7.3.4.
Other Clinical Laboratory Tests
Other clinical laboratory tests will be performed to ensure the safety of the patients but will not
be used to assess the safety of the study drug.
7.3.4.1.
Pregnancy Tests
Urine pregnancy tests will be performed at the study site (with test kits provided by a central 
laboratory) for all women of child-bearing potential at screening (visit 1), randomization (visit 3, 
day 1), visit 4 (day 15 ±1, week 2), visit 5 (day 29, week 4), and at the follow-up/ET visit 
(visit 6, day 57 ±3). Any patient who becomes pregnant during the study will be withdrawn. 
Procedures for reporting the pregnancy are provided in Section 7.2. 
7.3.4.2.
Urine Drug Screen
A urine drug screen will be performed at the time points indicated in Table 1. The urine drug 
screen includes a means to detect the presence of drugs prohibited according to the protocol, 
including cannabinoids, cocaine, amphetamines, barbiturates, benzodiazepine, and opiates. If a 
parameter noted above cannot be tested using urine, an alternative matrix (eg, serum) may be 
considered acceptable. The Sponsor’s medical expert must be made aware in advance of, and 
provide approval for, drug screen parameters to which this will apply. A positive result for any of 
the above drugs or their metabolites, without medical explanation, will preclude the patient from 
enrollment or continued participation in the study.
7.4.
Vital Signs
Vital signs will be measured at the time points indicated in Table 1. Vital signs include the 
following:

heart rate

respiration rate

body temperature

blood pressure
Before pulse and blood pressure are measured, the patient must be in a supine or seated position
and resting for at least 5 minutes. (The same position and arm should be used each time vital 
signs are measured for a given patient.) For any abnormal vital sign finding, the measurement 
should be repeated as soon as possible. Any vital sign value that is judged by the investigator as 
a clinically significant change (worsening) from a baseline value will be considered an adverse 


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event, recorded on the source documentation and transcribed onto the CRF, and monitored as 
described in Section 7.1.2.
7.5.
Electrocardiography
A 12-lead ECG will be conducted as triplicate tracings taken at least 1 minute apart (with an 
upper limit of 5 minutes apart) at the time points indicated in Table 1. To determine eligibility 
based upon numerical exclusion criteria of cardiac intervals, the investigator will use the mean 
values of 3 ECGs. A qualified physician at a central diagnostic center will be responsible for 
interpreting the ECG. Any ECG finding that is judged by the investigator as a clinically 
significant change (worsening) compared with a baseline value will be considered an adverse 
event, recorded on the source documentation and transcribed onto the CRF, and monitored as 
described in Section 7.1.2.
7.6.
Physical Examinations
Physical examinations, including height (to be obtained at the screening visit only) and weight 
(screening and follow-up/ET visits only) will be performed at the time points indicated in 
Table 1. Any physical examination finding that is judged by the investigator as a clinically 
significant change (worsening) compared with a baseline value will be considered an adverse 
event, recorded on the CRF, and monitored as described in Section 7.1.2.
7.7.
Other Safety Measures and Variables: Concomitant Therapy or 
Medication
Concomitant therapy or medication usage will be monitored throughout the study. Details of 
prohibited medications are found in Section 5.3.
7.8.
Methods and Timing of Assessing, Recording, and Analyzing Safety 
Data
Methods and timing of assessing safety data are discussed in Section 3.11. Procedures for 
recording safety data are discussed in Section 13.1 and methods of analyses are discussed in 
Section 9.8.2. 
7.9.
Dermal Irritation Evaluation
Dermal irritation will be evaluated at the time points indicated in Table 1 using the scale below 
(FDA 1999):

0 = no evidence of irritation

1 = minimal erythema (barely perceptible)

2 = definite erythema, readily visible; minimal edema or minimal papular response

3 = erythema and papules

4 = definite edema

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
6 = vesicular eruption

7 = strong reaction spreading beyond test site


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8.
ASSESSMENT OF PHARMACOKINETICS /
PHARMACODYNAMICS / PHARMACOGENOMICS
8.1.
Pharmacokinetic Variables
Samples (plasma) will be analyzed for TV-45070 using an appropriate validated method.
The dates and times of study drug administration and the date and time of each pharmacokinetic 
sample must be well documented on the source documentation and transcribed onto the CRF.
Samples will be collected into K2EDTA VACUTAINER® (Becton, Dickinson and Company) 
tubes, inverted slowly 6 to 8 times to mix the contents, and placed on ice (0°C to 5°C). Blood 
samples will be centrifuged (1500 × g, approximately 10 minutes, 0°C to 5°C) within 1 hour 
after sampling. If a refrigerated centrifuge is not available, samples should be chilled before 
centrifugation. As needed, other measures should be taken to prevent samples from heating 
significantly during centrifugation. Separated plasma will be transferred in approximately equal 
portions into 2 opaque, labeled, polypropylene tubes (sets A and B).
Sample labels should include the study number, patient identification number, visit number, 
nominal collection time, set (A or B), and indication that they are pharmacokinetic samples. 
Plasma samples will be placed on ice (0°C to 5°C) in an upright position until they are frozen at 
–70°C within 1 hour of centrifugation. 
Plasma samples for all patients will be shipped from the study site to the central laboratory upon 
the Sponsor’s request and will be shipped in batch shipments to the central laboratory designated 
in the Study Laboratory Manual. Samples will be stored in an upright position at -70°C until 
assayed. The laboratory will be notified before the shipment of the samples and will be sent the
shipping information when the samples are shipped.
Set A samples will be transported, frozen with sufficient dry ice for 4 days, by next day courier 
to Teva Pharmaceutical Works P.Ltd.Co. as described in the Study Laboratory Manual. 
Set B samples will be shipped and stored as described in the Study Laboratory Manual.
Sample shipments should be sent no later in the week than Wednesday morning for next day 
delivery. Samples are not to arrive on the weekend.
Further details for sample collecting, handling, shipping, and storage are provided in the Study 
Laboratory Manual.
8.2.
Pharmacodynamic Variables
Pharmacodynamic endpoints assessed during the study are the secondary efficacy endpoints 
change from baseline in maximal intensity of patients’ brush-evoked allodynia and change from 
baseline in maximal intensity of patients’ punctate-evoked hyperalgesia.
8.3.
Pharmacogenomic Variables
It is recognized that genomic variation within the population can be an important contributory 
factor to inter-individual differences in drug response. Pharmacogenomic analyses investigate 


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the association between genetic sequence polymorphisms and/or gene expression signatures and 
clinical response to a certain therapeutic intervention. Pharmacogenomic results may help 
explain inter-individual variability and subsequently identify population subgroups that respond 
differently to the drug. Furthermore, regulatory guidance and white papers indicate that 
pharmacogenomic analyses employing DNA collected from all study participants may support 
investigation of unexpected adverse events. 
The objectives of the pharmacogenomic analyses in this study are as follows:

To genotype the underlying R1150W polymorphism in the SCN9A gene so as to 
stratify patients according to R1150W polymorphism status (homozygous minor 
allele [positive, AA], heterozygous [positive, AG], and homozygous common allele 
[negative, GG]) in the randomization

 
 
 

To genotype polymorphisms of the CYP3A4 and CYP2C19 genes as potential 
covariates in the population pharmacokinetic analysis
Individual patients will be genotyped for the R1150W polymorphism for randomization 
allocation purposes. Pharmacogenomic samples will be stored for a period of up to 15 years after
the last patient last visit in the study and then destroyed.
 
Pharmacogenomic assessment will be performed using blood samples of 12 mL total volume,
collected in 2 K3EDTA Vacutainer plastic tubes for pharmacogenomic analysis (1 sample will be 
used for the R1150W randomization test and the other for further pharmacogenomic analyses). 
Pharmacogenomic samples will be collected from all patients at the screening visit (visit 1) 
because randomization will be stratified based on R1150W polymorphism status. The samples 
may also be examined for other sequence variations in the SCN9A gene region and/or other 
genes. 
 
 
A patient’s refusal to have this blood sample taken will exclude him/her from 
participation in this study.
Pharmacogenomic samples will be sent to the central laboratory within 72 hours after collection. 
Further details for sample collecting, handling, shipping, and storage will be provided in the 
Study Laboratory Manual.
The R1150W polymorphism test will be done at the central laboratory, a Clinical Laboratory 
Improvement Amendments-certified laboratory, and the exact genotyping assay will be selected 
in discussion with the laboratory staff. The laboratory for the testing of other genetic variations 
will be selected after the start of this study (TV45070-CNS-20013) and will be performed if and 
when required. The laboratory for these other analyses will be selected according to the nature of 
the analyses.


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9.
STATISTICS
9.1.
Study Design and Randomization
This is a double-blind, randomized, placebo-controlled, parallel-group study to evaluate the 
efficacy and safety of TV-45070 treatment in patients with PHN. Patients will be randomly 
assigned to receive treatment with 4% w/w TV-45070 ointment, 8% w/w TV-45070 ointment, or 
matching placebo ointment in a 1:1:1 ratio. Randomization will be as described in Section 3.4.
9.2.
Sample Size and Power Considerations
In prior studies of gabapentin or pregabalin treatment of PHN, the difference in mean pain scores 
between active- and placebo-treated groups ranged from 1.0 (Rice et al 2001) to 1.3 (Dworkin et 
al 2003). For this decision-making, proof-of-concept study, it is reasonable to use a conservative 
estimate of 1.0. If we assume a standard deviation of 2.35, a sample size of 88 per arm (a total of 
264 patients) would be needed to provide 80% power with a 2-sided test at 5% significance level 
to detect a 1.0-point difference. Assuming an approximately 20% dropout rate, 110 patients per 
arm (a total of 330 patients) will be randomly assigned to each treatment group. During the 
study, the ultimate sample size may be adjusted on the basis of the actual dropout rate.
9.3.
Analysis Sets/Populations 
9.3.1.
Intent-to-Treat Population
The intent-to-treat (ITT) population will include all randomized patients. In this population, 
treatment will be assigned based on the treatment to which patients were randomized, regardless 
of which treatment they actually received.
9.3.2.
Safety Population
The safety population will include all randomized patients who receive at least 1 dose of study
drug. In this population, treatment will be assigned based upon the treatment patients actually 
receive, regardless of the treatment to which they were randomized. 
9.3.3.
Full Analysis Set
The full analysis set (FAS), defined as all patients in the ITT population (all patients randomly 
assigned to treatment) who receive at least 1 dose of study drug and have at least 1 post-baseline 
efficacy assessment, will be used for all efficacy analyses. Summaries will be presented by 
treatment group. The FAS will serve as the primary analysis set for efficacy analyses.
9.3.4.
Per Protocol Population
The PP population will include all subjects in the FAS who have not had major protocol 
deviations (ie, protocol violations). Protocol violations will be determined before unblinding. 
The PP Population will serve as the supportive population for efficacy analyses.


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9.3.5.
Additional Analysis Sets
The population pharmacokinetic analysis set will include all patients in the pharmacokinetic
subset who had at least 1 pharmacokinetic plasma sample analyzed for TV-45070.
9.4.
Data Handling Conventions
For all variables, only the observed data from the patients will be used in the by-visit summaries. 
Data imputation rule(s) will be detailed in the Statistical Analysis Plan.
9.5.
Study Population
The ITT population (see Section 9.3.1) will be used for all study population summaries unless 
otherwise noted. Summaries will be presented by treatment group and for all patients.
9.5.1.
Patient Disposition
Data from patients screened, patients screened but not randomized and reason not randomized, 
patients who are randomized/enrolled, patients randomized/enrolled but not treated (and reason), 
patients in the safety set and FAS, patients who complete the study, and patients who withdraw 
from the study will be summarized using descriptive statistics. Data from patients who withdraw 
from the study will also be summarized by reason for withdrawal using descriptive statistics.
9.5.2.
Demographic and Baseline Characteristics 
Patient demographic and baseline characteristics, including medical history, prior medications,
and ECG findings, will be examined to assess the comparability of the treatment groups and will 
be summarized using descriptive statistics. For continuous variables, descriptive statistics 
(number [n], mean, standard deviation, standard error, median, minimum, and maximum) will be 
provided. For categorical variables, patient counts and percentages will be provided. Categories 
for missing data will be presented if necessary.
The categorical variables of patient sex and race will be summarized using descriptive statistics 
for each variable category. Missing categories will be presented if necessary. Treatment groups 
will be compared for all categorical variables using a Pearson’s chi-square (or Fisher’s exact test 
if cell sizes are too small).
9.6.
Efficacy Analysis 
The primary, secondary, and exploratory efficacy variables and endpoints are described in 
Section 3.3.
9.6.1.
Planned Method of Analysis
The FAS (see Section 9.3.3) will serve as the primary analysis set for all efficacy analyses. The 
PP population will be the supportive population for efficacy analyses.
9.6.1.1.
Primary Efficacy Analysis
The primary efficacy variable, change from baseline to week 4 in the weekly average of the daily 
average NRS scores, will be analyzed using a Mixed Model Repeated Measures (MMRM) model
with change from baseline in the weekly average of the daily average NRS scores at weeks 2 and 


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4 as the dependent variable; visit in weeks, treatment, and treatment by visit interaction as fixed 
factors; baseline weekly average of the daily average NRS scores as covariate; and patient as 
random effect. The unstructured covariance matrix for repeated observations within patients will 
be used. The primary treatment comparison will be conducted at week 4 in this model. All tests
will be 2-sided at a significance level of 0.05. More details will be provided in the Statistical 
Analysis Plan.
9.6.1.2.
Sensitivity Analysis
Sensitivity analysis on the primary efficacy variable, while taking discontinuation reason and 
rescue medication usage into consideration, may be performed.
9.6.1.3.
Secondary Efficacy Analysis
The continuous secondary efficacy variables will be analyzed in a similar way as the primary 
efficacy variable. 
The percentages of patients with ≥30% and ≥50% improvement from baseline in weekly average 
NRS scores at week 4 will be summarized using descriptive statistics. The time to reach ≥30% 
improvement in weekly average NRS scores from baseline will also be summarized using 
descriptive statistics.
PGIC scores will be analyzed using a MMRM model with 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 will be used.
NePIQoL score will be analyzed using an analysis of covariance (ANCOVA) model with effects 
due to baseline and treatment, imputing missing data via last observation carried forward 
(LOCF).
9.6.1.4.
Exploratory Efficacy Analysis
 
 
 
 
 
 
9.7.
Multiple Comparisons and Multiplicity
This is a Phase 2 study, and there is no plan to adjust for multiplicity.


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9.8.
Safety Variables and Analysis
9.8.1.
Safety Variables
The overall safety and tolerability of topical TV-45070 (4% and 8% w/w ointment) treatment 
will be assessed throughout the study by evaluating adverse events and the following additional 
safety variables at the time points specified in Section 3.11:

clinical laboratory tests 

vital signs

physical examination 

dermal irritation

12-lead ECGs

concomitant therapy or medication usage
9.8.2.
Safety Analysis
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Each patient will be counted only once in each preferred term or system organ class 
(SOC) category for the analyses of safety. Summaries will be presented for all adverse events 
(overall and by severity), adverse events determined by the investigator to be related to study 
treatment (ie, reasonable possibility; see Section 7.1.4) (adverse events defined as related or with 
missing relationship will be summarized overall and by severity), serious adverse events, and 
adverse events causing withdrawal from the study. Summaries will be presented by treatment 
group and for all patients. Patient listings of serious adverse events and adverse events leading to 
withdrawal will be presented.
Changes in laboratory and vital signs measurement data will be summarized descriptively. All 
values will be compared with prespecified boundaries to identify potentially clinically significant 
changes or values, and such values will be listed.
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. Concomitant medications will include all medications taken while the patient is treated 
with study drug.
For continuous variables, descriptive statistics (n, mean, standard deviation, standard error, 
median, minimum, and maximum) will be provided for actual values and changes from baseline 
to each time point. For categorical variables, patient counts and percentages will be provided. 
Descriptive summaries of serious adverse events, patient withdrawals due to adverse events, and 
potentially clinically significant abnormal values (clinical laboratory or vital signs) based on 
predefined criteria will also be provided.
9.9.
Pharmacokinetic Analysis
The population pharmacokinetic analyses will be detailed in a population pharmacokinetic 
analysis plan for this study. Results will be reported separately from the main study results.


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9.10.
Pharmacodynamic Analysis
The pharmacodynamic analysis plan will be detailed in the Statistical Analysis Plan for this 
study. Exploratory analyses may be reported separately from the main study results.
9.11.
Pharmacogenomic Analysis
The objectives of the pharmacogenomic analyses in this study are provided in Section 8.3.
Exploratory analyses may be reported separately from the main study results.
9.12.
Planned Interim Analysis
No interim analysis is planned for this study.
9.13.
Reporting Deviations from the Statistical Plan
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the complete statistical plan, the clinical study report (CSR), or any 
combination of these, as appropriate, and in accordance with applicable local and regional 
requirements and regulations.


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10.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The medical experts, study monitors, auditors, IEC/IRB, and health authority inspectors (or their 
agents) will be given direct access to source data and documentation (eg, medical charts/records, 
laboratory test results, printouts, videotapes) for source data verification, provided that patient 
confidentiality is maintained in accordance with local requirements.
The investigator must maintain the original records (ie, source documents) of each patient’s data 
at all times. Examples of source documents are hospital records, office visit records, examining 
physician’s finding or notes, consultant’s written opinion or notes, laboratory reports, drug 
inventory, study drug label records, diary data, protocol required worksheets, and CRFs that are 
used as the source (see Section 3.10).
The investigator will maintain a confidential patient identification list that allows the 
unambiguous identification of each patient. All study-related documents must be kept until 
notification by the Sponsor.


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11.
QUALITY CONTROLAND QUALITYASSURANCE
11.1.
Protocol Amendments and Protocol Deviations and Violations
11.1.1.
Protocol Amendments
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the IRB, except when necessary to 
address immediate safety concerns to the patients or when the change involves only 
nonsubstantial logistics or administration. The principal investigator and the Sponsor will sign 
the protocol amendment. 
11.1.2.
Protocol Deviations
A protocol deviation is any change, divergence, or departure from the study design or procedures 
defined in the protocol.
Important protocol deviations, referred to as protocol violations, are a subset of protocol 
deviations that may significantly impact the completeness, accuracy, and/or reliability of the 
study data or that may significantly affect a patient's rights, safety, or well-being. Protocol 
violations include enrolling patients in violation of key eligibility criteria designed to ensure a 
specific subject population; failing to collect data necessary to interpret primary endpoints; 
noncompliance to study drug administration; use of prohibited medications; or any other 
deviations that may have an impact on the processes put in place for the care and safety of the 
patients or compromise the scientific value of the trial. Protocol violations will be identified and 
recorded by study site personnel on the CRF. All protocol violations will be reported to the
responsible IEC/IRB, as required.
When a protocol violation is reported, the Sponsor will determine whether to discontinue the 
patient from the study or permit the patient to continue in the study, with documented approval 
from the medical representative. The decision will be based on ensuring the safety of the patient 
and preserving the integrity of the study. 
Deviations from the inclusion/exclusion criteria of the protocol are not prospectively granted by 
the Sponsor. If study site personnel learn that a patient who did not meet protocol eligibility 
criteria was entered into a study, they must immediately inform the Sponsor of the protocol 
violation. If such patient has already completed the study or has withdrawn early, no action will 
be taken but the violation will be recorded. If such patient is still participating in the study, a 
determination will be made by the sponsor and the investigator as to whether it is in the best 
interest of the patient to continue in the study.
11.2.
Information to Study Personnel
Each investigator is responsible for giving information about the study to all staff members 
involved in the study or in any element of patient management, both before starting the study and 
during the course of the study (eg, when new staff become involved). Each investigator must 
assure that all study staff members are qualified by education, experience, and training to 
perform their specific responsibilities. These study staff members must be listed on the study site


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authorization form, which includes a clear description of each staff member’s responsibilities. 
This list must be updated throughout the study, as necessary.
The study monitor is responsible for explaining the protocol to all study staff, including each
investigator, and for ensuring they comply with the protocol. Additional information will be 
made available during the study when new staff become involved in the study and as otherwise 
agreed upon with either the investigator or the study monitor.
11.3.
Study Monitoring
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the ICF and the study is conducted according to applicable 
standard operating procedures (SOPs), the protocol, and other written instructions and regulatory
guidelines.
The study monitor is the primary association between the Sponsor and each investigator. The 
main responsibilities of the study monitor are to visit each investigator before, during, and after 
the study to ensure adherence to the protocol, that all data are correctly and completely recorded 
and reported, and that informed consent is obtained and recorded for all patients before they 
participate in the study and when changes to the consent form are warranted, in accordance with 
IEC/IRB approvals.
The study monitor(s) will contact each investigator and visit the study site at regular intervals 
throughout the study. The study monitor will be permitted to check and verify the various 
records (CRFs and other pertinent source data records, to include specific electronic source 
documentation [see Section 3.10]) relating to the study to verify adherence to the protocol and to 
ensure the completeness, consistency, and accuracy of the data being recorded. If electronic 
CRFs are used for the study, the study monitor will indicate verification by electronically 
applying source document verification (SDV) flags to the CRF and will ensure that all required 
electronic signatures are being implemented accordingly.
As part of the supervision of study progress, other Sponsor personnel may, on request, 
accompany the study monitor on visits to the study site. Each investigator and assisting staff 
must agree to cooperate with the study monitor to resolve any problems, errors, or possible 
misunderstandings concerning the findings detected in the course of these monitoring visits 
and/or provided in follow-up written communication.
11.4.
Clinical Product Complaints
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical drug supplies used in a clinical research study sponsored by 
Teva. Examples of a product complaint include but are not limited to the following: 

suspected contamination

questionable stability (eg, color change, flaking, crumbling, etc.)

defective components

missing or extra units (eg, primary container is received at the site with more or less 
than the designated number of units inside)


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
incorrect packaging or incorrect or missing labeling/labels

unexpected or unanticipated odor
Each study site will be responsible for reporting a possible clinical product complaint by 
completing the Product Complaint Form provided by Teva and emailing it to 
 within 48 hours of becoming aware of the issue.
For complaints involving a device or other retrievable item, it is required that the device (or 
item) be sent back to the sponsor for investigative testing whenever possible. For complaints 
involving a drug product, all relevant samples (eg, the remainder of the patient’s drug supply) 
should be sent back to the sponsor for investigative testing whenever possible. 
11.4.1.
Product Complaint Information Needed from the Study Site
In the event that the Product Complaint Form cannot be completed, the investigator will obtain 
the following information, as available:

study site number and principal investigator name

name, phone number, and address of the source of the complaint 

clinical protocol number

patient identifier (patient study number) and corresponding visit numbers, if 
applicable

product name and strength for open-label studies

patient number, container, and kit numbers (if applicable) for double-blind or 
open-label studies

product available for return Yes/No

product was taken or used according to protocol Yes/No

description or nature of complaint

associated serious adverse event Yes/No

clinical supplies unblinded (for blinded studies) Yes/No

date and name of person receiving the complaint 
Note: Reporting a complaint must not be delayed because not all the required information can be 
immediately obtained. Known information must be immediately reported. The sponsor will 
collaborate with the investigator to obtain any outstanding information.
11.4.2.
Handling the Study Drug at the Study Site
The investigator is responsible for retaining the product in question in a location separate from 
the investigator’s clinical study supplies. The sponsor may request that the investigator return the 
product for further evaluation and/or analysis. If this is necessary, the clinical study monitor or 
designee will provide the information needed for returning the study drug.


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If it is determined that the study site must return all of the study drug, the sponsor will provide 
the information needed to handle the return.
The integrity of the randomization code and corresponding blinded clinical supplies will be 
maintained whenever possible. A serious adverse event or the potential for a product quality 
problem existing beyond the scope of the complaint may be a reason to unblind the clinical 
supplies for an affected patient.
11.4.3.
Adverse Events or Serious Adverse Events Associated with a Product Complaint
If there is an adverse event or serious adverse event, the protocol should be followed.
11.4.4.
Documenting a Product Complaint
The investigator will record a description of the product complaint in the source documentation 
as well as any actions taken to resolve the complaint and to preserve the safety of the patient. 
Once the complaint has been investigated by the sponsor and the investigator, if necessary, an 
event closure letter may be sent to the study site where the complaint originated or to all study 
sites using the product.
11.5.
Audit and Inspection
The Sponsor may audit the study site to evaluate study conduct and compliance with protocols, 
SOPs, GCPs, and applicable regulatory requirements. The Sponsor Global Clinical Quality 
Assurance department, independent of the Global Clinical Development department, is 
responsible for determining the need for (and timing of) a study site audit.
Each investigator must accept that regulatory authorities and Sponsor representatives may 
conduct inspections to verify compliance with GCP guidelines.


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12.
ETHICS
Details of compliance with regulatory guidances and applicable laws are provided in Section 1.6.
12.1.
Informed Consent
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient of all pertinent aspects of the study, including the written information approved by the 
IEC/IRB. All written and/or oral information about the study will be provided in a language as 
nontechnical as practical and understood by the patient. The patient should be given ample time 
and opportunity to inquire about details of the study and to decide whether or not to participate in 
the study. The above should be detailed in the source documentation.
Written informed consent will be obtained from each patient before any study-specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained, according to the IEC/IRB requirements. The patient’s 
willingness to participate in the study will be documented in a consent form, which will be 
signed and personally dated by the patient and by the person who conducted the informed 
consent discussion. The investigator will keep the original consent forms, and copies will be 
given to the patients. It will also be explained to the patients that the patient is free to refuse entry 
into the study and free to withdraw from the study at any time without prejudice to future 
treatment.
12.2.
Health Authorities and Institutional Review Boards
Before this study starts, the protocol will be submitted to the FDA and to each IRB for review. 
As required, the study will not start at a given study site before the IRB and health authority 
(where applicable) for the study site give written approval or a favorable opinion.
12.3.
Confidentiality Regarding Study Patients
Each investigator must assure that the privacy of the patients, including their identity and all 
personal medical information, will be maintained at all times. In CRFs and other documents or 
image material submitted to the Sponsor, patients will be identified not by their names, but by an 
identification code (eg, identification number).
Personal medical information may be reviewed for the purpose of patient safety and/or verifying 
data in the source and transcribed onto the CRF. This review may be conducted by the study 
monitor, properly authorized persons on behalf of the Sponsor, the quality assurance unit, and/or 
regulatory authorities. Personal medical information will always be treated as confidential.
12.4.
Declaration of the End of the Clinical Study
The end of this clinical study is defined as the date of the last visit of the last study patient.
12.5.
Registration of the Clinical Study
This clinical study was registered on clinical trials registry websites according to Teva standard 
procedures.


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13.
DATA HANDLING, DATA QUALITY ASSURANCE, AND 
RECORD KEEPING
13.1.
Data Collection
Data will be collected using CRFs that are specifically designed for this study. The data collected 
on the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in 21CFR Part 11. The CDMS will be fully validated to ensure 
that it meets the scientific, regulatory, and logistical requirements of the study before it is used to 
capture data from this study. Before using the CDMS, all users will receive training on the 
system and any study-specific training. After they are trained, users will be provided with 
individual system access rights.
Data will be collected at the study site by appropriately designated and trained personnel, and 
CRFs must be completed for each screened patient who provided informed consent according to 
the data source. Patient identity should not be discernible from the data provided on the CRF. 
Data will be verified using the data source by the study monitor, and reviewed for consistency by 
Data Management using both automated logical checks and manual review. All data collected 
will be approved by the investigator at the study site. This approval acknowledges the 
investigator’s review and acceptance of the data as being complete and accurate. 
If data are processed from other sources (eg, central laboratory, bioanalytical laboratory, central 
image center, and eDiary data), the results will be sent to the study site. At the study site, the data
will be retained but not entered into the CRF unless otherwise specified in the protocol. These
data may also be sent electronically to the Sponsor (or organization performing data 
management) for direct entry into the clinical database (see Section 3.10). Laboratory test results 
will not be entered into the CRF unless otherwise noted in the protocol. All data from other 
sources will be available to the investigator(s).
For patients who enter a study but do not meet screening criteria, at a minimum, data for screen 
failure reason, demography, and adverse events from the time of informed consent will be 
entered into the CRF. 
13.2.
Data Quality Assurance
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this study. Data handling, including data quality assurance, will 
comply with international regulatory guidelines, including ICH GCP guidelines. Data 
management and control processes specific to this study, along with all steps and actions taken 
regarding data management and data quality assurance, will be described in a data management 
plan.
The CRFs received will be processed and reviewed for completeness, consistency, and the 
presence of mandatory values. Applicable terms will be coded according to the coding 
conventions for this study. Logical checks will be implemented to ensure data quality and 
accuracy. Any necessary changes will be made in the clinical database, and data review and 
validation procedures will be repeated as needed. Data from external sources will be compared 
with the information available in the CDMS. Discrepancies found will be queried.


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Data corrections in the CDMS will be made using the CDMS update function. The system 
requires a reason for each change and keeps a complete audit trail of the data values, dates and 
times of modifications, and authorized electronic approvals of the changes.
At the conclusion of the study, the CDMS and all other study data will be locked to further 
additions or corrections. Locking the study data represents the acknowledgement that all data 
have been captured and confirmed as accurate.
13.3.
Archiving of Case Report Forms and Source Documents 
13.3.1.
Investigator Responsibilities
All records related to the study (ie, source data, source documents, CRFs [see Section 3.10], data 
results from other sources [see Section 13.1], copies of protocols and protocol amendments, drug 
accountability forms, correspondence, patient identification lists, signed ICFs, and other essential 
documents) must be retained until the Sponsor notifies the institution, in writing, that records 
may be destroyed. 
If the Sponsor has not provided written notification of records destruction after 15 years from 
study completion (or earlier in the event of an institution closing), and the institution determines 
the study record retention is unduly burdensome, the institution may submit a written request to 
the Sponsor at least 60 days before the planned disposition of the study records. No study 
document or image (eg, scan, radiograph, ECG tracing) should be destroyed without prior 
written agreement between the Sponsor and the investigator. Should an investigator wish to 
assign the study records to another party or move them to another location, advance written 
notice will be given to the Sponsor.
13.3.2.
Sponsor Responsibilities
The Sponsor will be responsible for the processing and quality control of the data. Data 
management and filing will be carried out as described in the Sponsor’s SOPs for clinical 
studies.
If data management and filing of documents for this study are delegated to a contract 
organization, these functions will be carried out as described in the SOPs for clinical studies at 
that organization. These SOPs will be reviewed by the Sponsor before the start of data 
management and filing activities. The original CRFs will be archived by the Sponsor. 
Site-specific CRFs will be provided to the respective study sites for archiving.


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14.
FINANCING AND INSURANCE
A separate financial agreement will be made between each principal investigator and the Sponsor
before the study drug is delivered.
This clinical study is insured in accordance with the corresponding local legal provisions. 
The policy coverage is subject to the full policy terms, conditions, extensions, and exclusions.
Excluded from the insurance cover are, inter alia, damages to health and worsening of previous 
existing disease that would have occurred or continued if the patient had not taken part in the 
clinical study.
The policy of Clinical Trials Insurance will be provided to the study sites by the Sponsor.
For covered clinical studies (see 21CFR54), each investigator will provide the Sponsor with 
financial information required to complete Form FDA 3454. Each investigator will notify the 
Sponsor of any relevant changes during the conduct of the study and for 1 year after the study 
has been completed. 


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15.
REPORTING AND PUBLICATION OF RESULTS
The Sponsor is responsible for ensuring that the public has access to the appropriate information 
about the study by conforming to local and regional requirements for registration and posting of 
results. 
The Sponsor is responsible for preparing a CSR, in cooperation with the principal investigator. 
The final report is signed by the Sponsor and, if applicable, by the principal investigator.
When the Sponsor generates reports from the data collected in this study for presentation to 
regulatory authorities, drafts may be circulated to the principal investigator for comments and 
suggestions. An endorsement of the final report will be sought from the principal investigator.
All unpublished information given to any investigator by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor. The primary 
publication from this study will report the results of the study in accordance with the current 
“Uniform Requirements for Manuscripts Submitted to Biomedical Journals” as established by 
the International Committee of Medical Journal Editors (www.ICMJE.org). Publication of the 
results will occur in a timely manner according to applicable regulations. Authorship will be 
based on meeting all the following 4 criteria:

substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work

drafting the work or revising it critically for important intellectual content

final approval of the version to be published

agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved
The publications committee established by the Sponsor will oversee this process. Additional 
publications may follow. Policies regarding the publication of the study results are defined in the 
financial agreement.
No patent application(s) based on the results of the study may be made by the investigator nor 
may assistance be given to any third party to make such an application without the written 
authorization of the Sponsor.


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16.
REFERENCES
Davies PS, Galer BS. Review of lidocaine patch 5% studies in the treatment of postherpetic 
neuralgia. Drugs 2004;64(9):937-47.
Dubinsky RM, Kabbani H, El-Chami Z, Boutwell C, Ali H, Quality Standards Subcommittee of 
the American Academy of Neurology. Practice parameter: treatment of postherpetic neuralgia: 
an evidence-based report of the Quality Standards Subcommittee of the American Academy of 
Neurology. Neurology 2004;63(6):959-65.
Dworkin RH, Corbin AE, Young JP Jr, Sharma U, LaMoreaux L, Bockbrader H, et al. 
Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial. 
Neurology 2003;60(8):1274-83.
FDA. Skin irritation and sensitization testing of generic transdermal drug products. United States 
FDA Center for Drug Evaluation and Research (CDER)-December 1999.
Kost RG, Straus SE. Postherpetic neuralgia–pathogenesis, treatment, and prevention. NEJM 
1996;335(1):32-42.
Li K, Chen N, Yang J, Zhou M, Zhou D, Zhang Q, et al. Antiviral treatment for preventing 
postherpetic neuralgia. Cochrane Database Syst Rev 2009; Apr 15(2):CD006866.
Redfern WS Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, et al. Relationships 
between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de 
pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. 
Cardiovasc Res 2003;58(1):32-45.
Reimann F, Cox JJ, Belfer I, Diatchenko L, Zaykin DV, McHale DP, et al. Pain perception 
is altered by a nucleotide polymorphism in SCN9A. Proc Natl Acad Sci USA
2010;107(11):5148-53.
Rice AS, Maton S, Postherpetic Neuralgia Study Group. Gabapentin in postherpetic neuralgia: a 
randomised, double blind, placebo controlled study. Pain 2001;94(2):215-24.
Rowbotham MC, Petersen KL. Zoster-associated pain and neural dysfunction. Pain 2001;93:1-5.


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17.
SUMMARY OF CHANGES TO PROTOCOL
17.1.
Amendment 03 Dated 21 April 2016
The primary reason for amendment 03 is to facilitate timely enrollment of patients by broadening 
the inclusion criterion for the maximum duration of PHN and the exclusion criterion for the 
number of adequate courses of treatment with other medications for which response was 
inadequate; by allowing rescreening of patients excluded under these criteria before 
implementation of amendment 03; and by increasing the number of study sites. These changes 
are not anticipated to affect potential risks to patients or the statistical power of the study.


Placebo-Controlled Study–Postherpetic Neuralgia
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111
Original text with changes shown
New wording
Reason/Justification for change
Clinical Study Personnel Contact Information
INC Research, LLC
Role in the Study: Project Manager
INC Research, LLC
Role in the Study: Project Manager
This revision reflects a change in 
contact information for operational 
support at INC Research LLC
Synopsis: Number of Study Sites Planned
Up to approximately 5570 study sites
Up to approximately 70 study sites
The number of study sites was 
increased to improve the timely 
enrollment of patients.
Synopsis: Planned Study Period:
March 2015 (first patient randomly assigned to treatment) 
to the third quarter of late 2016 up to mid 2017 (last 
patient last visit)
March 2015 (first patient randomly assigned to treatment) 
to late 2016 up to mid 2017 (last patient last visit)
The planned study period was extended 
to allow recruitment of the needed 
number of patients.
Synopsis: Diagnosis and Criteria for Inclusion
a.
[Revision 1] Patient has chronic PHN, defined as 
pain present for more than 6 months and less than 
610 years after onset of herpes zoster skin rash 
affecting a single dermatome. Patients with more 
than 1 involved dermatome may also be included, 
provided the affected dermatomes are contiguous. 
Patients excluded under this criterion before 
implementation of Amendment 03 may be 
rescreened to determine eligibility under the revised 
criterion.
a.
[Revision 1] Patient has chronic PHN, defined 
as pain present for more than 6 months and less 
than 10 years after onset of herpes zoster skin 
rash affecting a single dermatome. Patients with 
more than 1 involved dermatome may also be 
included, provided the affected dermatomes are 
contiguous. Patients excluded under this 
criterion before implementation of Amendment 
03 may be rescreened to determine eligibility 
under the revised criterion.
This criterion was broadened to 
improve the timely enrollment of 
patients.
Synopsis: Exclusion criteria
c.
[Revision 1] Patient has a history, in the judgment of 
the investigator, of inadequate response to more than 
23 adequate courses of treatment with other 
medications used to treat neuropathic pain (eg, 
a.
[Revision 1] Patient has a history, in the 
judgment of the investigator, of inadequate 
response to more than 3 adequate courses of 
treatment with other medications used to treat 
This criterion was broadened to 
improve the timely enrollment of 
patients.


Placebo-Controlled Study–Postherpetic Neuralgia
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Study TV45070-CNS-20013
112
Original text with changes shown
New wording
Reason/Justification for change
tricyclic antidepressants, serotonin-norepinephrine 
reuptake inhibitors, anticonvulsants, topical 
lidocaine, and/or topical capsaicin). Patients 
excluded under this criterion before implementation 
of Amendment 03 may be rescreened to determine 
eligibility under the revised criterion.
neuropathic pain (eg, tricyclic antidepressants, 
serotonin-norepinephrine reuptake inhibitors, 
anticonvulsants, topical lidocaine, and/or topical 
capsaicin). Patients excluded under this criterion 
before implementation of Amendment 03 may 
be rescreened to determine eligibility under the 
revised criterion.


Placebo-Controlled Study–Postherpetic Neuralgia
Clinical Study Protocol with Amendment 03
Study TV45070-CNS-20013
113
Original text with changes shown
New wording
Reason/Justification for change
Synopsis: Sample Size Rationale
In prior studies of gabapentin or pregabalin treatment of 
PHN, the difference in mean pain scores between active-
and placebo-treated groups ranged from 1.0 (Rice et al 
2001) to 1.3 (Dworkin et al 2003). For this decision-
making, proof-of-concept study, it is reasonable to use a 
conservative estimate of 1.0. If we assume a standard 
deviation of 2.35, a sample size of up to approximately
88 per arm (a total of 264 patients) would be needed to 
provide 80% power with a 2-sided test at 5% significance 
level to detect a 1.0-point difference. Assuming an 
approximately 20% dropout rate, 110 patients per arm (a 
total of 330 patients) will be randomly assigned to each 
treatment group. During the study, the ultimate sample 
size may be adjusted on the basis of the actual dropout 
rate.
In prior studies of gabapentin or pregabalin treatment of 
PHN, the difference in mean pain scores between active-
and placebo-treated groups ranged from 1.0 (Rice et al 
2001) to 1.3 (Dworkin et al 2003). For this decision-
making, proof-of-concept study, it is reasonable to use a 
conservative estimate of 1.0. If we assume a standard 
deviation of 2.35, a sample size of up to approximately 
88 per arm (a total of 264 patients) would be needed to 
provide 80% power with a 2-sided test at 5% significance 
level to detect a 1.0-point difference. Assuming an 
approximately 20% dropout rate, 110 patients per arm (a 
total of 330 patients) will be randomly assigned to each 
treatment group. During the study, the ultimate sample 
size may be adjusted on the basis of the actual dropout 
rate.
No previous text
Amendment 03: The primary reason for amendment 03 
is to facilitate timely enrollment of patients by 
broadening the inclusion criterion for the maximum 
duration of PHN and the exclusion criterion for the 
number of adequate courses of treatment with other 
medications for which response was inadequate; by 
allowing rescreening of patients excluded under these 
criteria before implementation of amendment 03; and by 
increasing the number of study sites.
The justification for amendment 03 has 
been added.
Section 1.8.
The study is expected to start in March 2015 (first 
patient randomly assigned to treatment) and be 
completed in the third quarter oflate 2016 up to mid 
The study is expected to start in March 2015 (first 
patient randomly assigned to treatment) and be 
completed in late 2016 up to mid 2017 (last patient 
The planned study period was extended 
to allow recruitment of the needed 
number of patients.


Placebo-Controlled Study–Postherpetic Neuralgia
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Study TV45070-CNS-20013
114
Original text with changes shown
New wording
Reason/Justification for change
2017 (last patient last visit), with a duration of 
approximately 14 to 22 months.
last visit), with a duration of approximately 14 to 
22 months.
Approximately 330 patients from up to approximately 
5570 study sites are planned to be enrolled in this study. 
The study is planned to be conducted in the US.
Approximately 330 patients from up to approximately 70 
study sites are planned to be enrolled in this study. The 
study is planned to be conducted in the US.
The number of study sites was 
increased to improve the timely 
enrollment of patients.
Section 3.11.1.1.
A patient who is screened and does not meet study entry 
criteria will not be considered for screening again, except 
that patients who were excluded from enrollment under 
inclusion or exclusion criteria that have since been 
revised may be rescreened to determine their eligibility 
under these criteria as amended.
A patient who is screened and does not meet study entry 
criteria will not be considered for screening again, except 
that patients who were excluded from enrollment under 
inclusion or exclusion criteria that have since been 
revised may be rescreened to determine their eligibility 
under these criteria as amended.
Text was added to allow the rescreening 
of patients excluded under inclusion or 
exclusion criteria that have since been 
revised.
Section 4.1.
a.
[Revision 1] Patient has chronic PHN, defined as 
pain present for more than 6 months and less than 
610 years after onset of herpes zoster skin rash 
affecting a single dermatome. Patients with more 
than 1 involved dermatome may also be included, 
provided the affected dermatomes are contiguous. 
Patients excluded under this criterion before 
implementation of Amendment 03 may be 
rescreened to determine eligibility under the revised 
criterion.
a.
[Revision 1] Patient has chronic PHN, defined as 
pain present for more than 6 months and less than 
10 years after onset of herpes zoster skin rash 
affecting a single dermatome. Patients with more 
than 1 involved dermatome may also be included, 
provided the affected dermatomes are contiguous.
Patients excluded under this criterion before 
implementation of Amendment 03 may be 
rescreened to determine eligibility under the revised 
criterion.
This criterion was broadened to 
improve the timely enrollment of 
patients.
Section 4.2.
c. [Revision 1] Patient has a history, in the judgment of 
the investigator, of inadequate response to more than 
23 adequate courses of treatment with other 
medications used to treat neuropathic pain (eg, 
tricyclic antidepressants, serotonin-norepinephrine 
reuptake inhibitors, anticonvulsants, topical 
lidocaine, and/or topical capsaicin). Patients 
excluded under this criterion before implementation 
c. [Revision 1] Patient has a history, in the judgment 
of the investigator, of inadequate response to more 
than 3 adequate courses of treatment with other 
medications used to treat neuropathic pain (eg, 
tricyclic antidepressants, serotonin-norepinephrine 
reuptake inhibitors, anticonvulsants, topical 
lidocaine, and/or topical capsaicin). Patients 
excluded under this criterion before implementation 
This criterion was broadened to 
improve the timely enrollment of 
patients.


Placebo-Controlled Study–Postherpetic Neuralgia
Clinical Study Protocol with Amendment 03
Study TV45070-CNS-20013
115
Original text with changes shown
New wording
Reason/Justification for change
of Amendment 03 may be rescreened to determine 
eligibility under the revised criterion.
of Amendment 03 may be rescreened to determine 
eligibility under the revised criterion.
9.2 Sample Size and Power Considerations
Assuming an approximately 20% dropout rate, 110 
patients per arm (a total of 330 patients) will be randomly 
assigned to each treatment group. During the study, the 
ultimate sample size may be adjusted on the basis of the 
actual dropout rate.
Assuming an approximately 20% dropout rate, 110 
patients per arm (a total of 330 patients) will be randomly 
assigned to each treatment group. During the study, the 
ultimate sample size may be adjusted on the basis of the 
actual dropout rate.


Placebo-Controlled Study–Postherpetic Neuralgia
Clinical Study Protocol with Amendment 03
Study TV45070-CNS-20013
116
17.2.
Administrative Letter Dated 28 September 2015


Placebo-Controlled Study–Postherpetic Neuralgia
Clinical Study Protocol with Amendment 03
Study TV45070-CNS-20013
117
17.3.
Amendment 02 Dated 09 September 2015
The primary reason for amendment 02 is to remove the stipulation in exclusion criterion t that 
excludes patients from participating in the study if they used any of the CYP3A4 or CYP2C19 
inhibitors or substrates that were previously listed in Table 2 under Appendix A to this protocol. 
Related editorial changes have been made are as a result of this removal, including 1) 
replacement of the previous Table 2 (CYP3A4 and CYP2C19 Substrates and Inhibitors with 
Documented Clinically Significant Interactions) in Appendix A with a new Table 2 entitled 
Washout Periods for Specific Drugs, and 2) revision of any statement(s) and cross-references 
within the protocol referring to information previously provided in Table 2 of Appendix A.
An additional reason for amendment 02 is to revise inclusion criterion d to broaden the 
recruitment criterion for BMI by increasing the upper limit of the range for BMI from 32 to 34 
kg/m2.
Amendment 02 also serves to correct the list of drugs as described in Section 7.3.4.2 that are 
detected by the urine drug screen performed to detect the presence of drugs prohibited by 
protocol. Alcohol was incorrectly listed in Section 7.3.4.2 as a substance detected by the drug 
screen, and has been deleted from Section 7.3.4.2 as part of this amendment.
Time windows have been added for the timing of the dermal irritation test and for the triplicate 
ECGs to allow for natural variability in timing and to avoid unnecessary protocol deviations.
Minor editorial changes for improved text flow and clarity have been incorporated into the 
protocol text as part of this amendment.
Finally, the protocol is now presented in an updated protocol template maintained by the 
Sponsor. The change to an updated template is an administrative change per Sponsor policy, and 
is not intended to alter the clinical conduct of the study.


Placebo-Controlled Study–Postherpetic Neuralgia
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118
Original text with changes shown
New wording
Reason/Justification for change
Section 1.1.
TV-45070 is a novel, potent, voltage-dependent sodium 
channel (NaV) blocker being developed for the treatment 
of patients with various neuropathic pain indications, 
including neuropathic and nociceptive pain.
TV-45070 is a novel, potent, voltage-dependent sodium 
channel (NaV) blocker being developed for the treatment 
of patients with various neuropathic pain indications.
This change was made as an update.
Section 1.3.2.
Additionally, evaluation of topical TV-45070 has been 
evaluated is currently underway in a Phase 2 study in 
patients with osteoarthritis (OA) of the knee, and in a 
Phase 1 dose-escalation study in healthy volunteers, and a 
Phase 1 DDI study with midazolam and omeprazole. 
Final data are not yet available from these ongoing 
studies.
Additionally, topical TV-45070 has been evaluated in a 
Phase 2 study in patients with osteoarthritis (OA) of the 
knee, a Phase 1 dose-escalation study in healthy 
volunteers, and a Phase 1 drug-drug interaction study 
with midazolam and omeprazole. Final data are not yet 
available from these studies.
This change was made as an update.
The clinical conduct of all studies except for the ongoing
OA study, and the ongoing dose-escalation study, and the 
DDI study have been completed, but analysis is ongoing.
The clinical conduct of the OA study, the dose-escalation 
study, and the DDI study have been completed, but 
analysis is ongoing
This change was made as an update.
Section 1.4., 1.4.1., 1.4.2.
1.4.
Known and Potential Risks and Benefits to 
Human Subjects
1.4.1.
Risks of TV-45070
Following topical administration, […]
1.4.2.
Benefits of TV-45070
1.4.
Known and Potential Risks and Benefits to 
Human Subjects
1.4.1.
Risks of TV-45070
Following topical administration, […]
1.4.2.
Benefits of TV-45070
This change is shown as representative 
of a change based on presentation of the 
protocol in the updated template.


Placebo-Controlled Study–Postherpetic Neuralgia
Clinical Study Protocol with Amendment 03
Study TV45070-CNS-20013
119
Original text with changes shown
New wording
Reason/Justification for change
Section 1.4.1.
In vitro data using human cryopreserved hepatocytes 
have also shown that TV 45070 metabolite (M3) is an 
inhibitor of CYP3A4 and CYP2C19, which indicates a 
potential DDI risk between TV 45070 and medications 
that are primarily metabolized by CYP3A4 or CYP2C19. 
However, the preliminary results of a clinical study 
designed to assess the risk of these DDIs revealed no 
significant risk of an interaction. Therefore, certain 
medications that undergo major metabolism by CYP3A4 
and CYP2C19 are excluded as concomitant medications 
during this study (Appendix A, Table 2).
In vitro data using human cryopreserved hepatocytes 
have also shown that TV 45070 metabolite (M3) is an 
inhibitor of CYP3A4 and CYP2C19, which indicates a 
potential DDI risk between TV 45070 and medications 
that are primarily metabolized by CYP3A4 or CYP2C19. 
However, the preliminary results of a clinical study 
designed to assess the risk of these DDIs revealed no 
significant risk of an interaction.
The rationale for this change is that new 
data from a clinical study designed to 
assess the risk of DDI between 
TV-45070 and medications that are 
primarily metabolized by CYP3A4 and 
CYP2C19 revealed no significant risk 
of an interaction.
Section 2.2., 2.2.1.
2.2.
Study Objectives
2.2.1.
Primary Objective
The primary objective of this study is to […]
2.2.
Study Objectives
2.2.1.
Primary Objective
The primary objective of this study is to […]
This change is shown as representative 
of a change based on presentation of the 
protocol in the updated template 
(heading added).


Placebo-Controlled Study–Postherpetic Neuralgia
Clinical Study Protocol with Amendment 03
Study TV45070-CNS-20013
120
Original text with changes shown
New wording
Reason/Justification for change
Section 3.1. (and others, for consistency)
Appendix A3, Table 3Table 2
Appendix A, Table 2
This change was made as an update and 
correction to Appendix numbering, and 
an update to Table numbering related to 
the exclusion criterion being removed 
from the protocol
Section 3.3.4. (and others for consistency)
Skin rashes or skin irritation in the area of ointment 
application will be evaluated using a dermal irritation 
evaluation (modified Draize scale) at day 1 (at 1 hour 
[±30 minutes] after application of study drug), week 2, 
week 4, and week 8 for follow-up.
Skin rashes or skin irritation in the area of ointment 
application will be evaluated using a dermal irritation 
evaluation (modified Draize scale) at day 1 (at 1 hour 
[±30 minutes] after application of study drug), week 2, 
week 4, and week 8 for follow-up.
This change was made to allow for 
natural variability in timing and to 
avoid unnecessary protocol deviations.
Section 4.1.
d.
Patient is ≥18 years of age, with a body mass index 
(BMI) between 18 and 3234 kg/m2, inclusive, at 
screening visit.
d.
[Revision 1] Patient is ≥18 years of age, with a body 
mass index (BMI) between 18 and 34 kg/m2, inclusive, at 
screening visit.
This update was made to broaden the 
recruitment criteria.
Section 4.2. and synopsis
s.
Patient uses any non-pharmacologic pain 
management techniques […]
t.
[Criterion removed] Patient uses any CYP3A4 or 
CYP2C19 inhibitors or substrates listed in 
Appendix B.
s.
Patient uses any non-pharmacologic pain 
management techniques […]
t.
[Criterion removed]
Criteria t was removed as new data 
demonstrate that TV-45070 does not 
interact with CYP3A4 and CYP2C19 
and therefore medications metabolized 
via these pathways no longer need to be 
excluded for safety reasons.


Placebo-Controlled Study–Postherpetic Neuralgia
Clinical Study Protocol with Amendment 03
Study TV45070-CNS-20013
121
Original text with changes shown
New wording
Reason/Justification for change
Section 7.1.5.1.
Inpatient hospitalization or prolongation of existing 
hospitalization, which means that hospital inpatient 
admission and/or prolongation of hospital stay were 
required for treatment of an adverse event or that they 
occurred as a consequence of the event.
Inpatient hospitalization or prolongation of existing 
hospitalization, which means that hospital inpatient 
admission and/or prolongation of hospital stay were 
required for treatment of an adverse event or that they 
occurred as a consequence of the event.
This change is shown as representative 
of a minor editorial change for clarity.
Section 7.3.4.2.
A urine drug screen will be performed at the time points 
indicated in Table 1. The urine drug screen includes a 
means to detect the presence of drugs prohibited 
according to the protocol, including cannabinoids, 
alcohol, cocaine, amphetamines, barbiturates, 
benzodiazepine, and opiates.
A urine drug screen will be performed at the time points 
indicated in Table 1. The urine drug screen includes a 
means to detect the presence of drugs prohibited 
according to the protocol, including cannabinoids, 
cocaine, amphetamines, barbiturates, benzodiazepine, and 
opiates.
This change was made as a correction 
to the list of substances detected by the 
urine drug screen.
Section 7.5; 3.11.1; 3.11.2; 311.3.2; 311.3.3; 311.3.4 and Table 1 (footnote l) 
A 12-lead ECG will be conducted as triplicate tracings 
taken at least 1 minute apart (with an upper limit of 
5 minutes apart) at the time points indicated in Table 1.
A 12-lead ECG will be conducted as triplicate tracings 
taken at least 1 minute apart (with an upper limit of 
5 minutes apart) at the time points indicated in Table 1.
This change was made to allow for 
natural variability in timing and to 
avoid unnecessary protocol deviations.


Placebo-Controlled Study–Postherpetic Neuralgia
Clinical Study Protocol with Amendment 03
Study TV45070-CNS-20013
122
17.4.
Amendment 01 Dated 18 February 2015
The primary reason for this amendment is to update the name and contact numbers and email 
address for the Medical Monitor to the correct information. Additional reasons are to update the 
protocol wording to reflect the planned location of study sites in one country (the United States), 
and to correct a typographical error in the corporate name of the CRO providing monitoring and 
other services for Study TV45070-CNS-20013.
The revisions listed below have been made to the protocol (and protocol synopsis, as 
appropriate) and are not considered substantial by the Teva Authorized Representative.
Original text with changes shown
New wording
Reason/
Justification 
for change
TITLE PAGE
Monitor
INC Research, LLPC
Monitor
INC Research, LLC
Correcting 
typographical 
error in CRO
name 
CLINICAL STUDY PERSONNEL CONTACT INFORMATION
For medical issues, contact the 
physician listed below: 
INC Research, LLPC
Role in the Study: Medical Monitor
INC Emergency Hotline: 
For operational issues, contact the 
operational lead listed below: 
INC Research, LLPC
Role in the Study: Project Manager
For medical issues, contact the 
physician listed below: 
INC Research, LLC
Role in the Study: Medical Monitor
INC Emergency Hotline: 
For operational issues, contact the 
operational lead listed below: 
INC Research, LLC
Role in the Study: Project Manager
Updating name 
and contact 
information for 
Medical 
Monitor
Correcting 
typographical 
error in CRO 
name


Placebo-Controlled Study–Postherpetic Neuralgia
Clinical Study Protocol with Amendment 03
Study TV45070-CNS-20013
123
Original text with changes shown
New wording
Reason/
Justification 
for change
CLINICAL STUDY PERSONNEL CONTACT INFORMATION
For serious adverse events:
The serious adverse event form should be 
sent to the Sponsor’s local safety officer 
(LSO). The LSO will forward the report 
to the Sponsor’s Global Patient Safety & 
Pharmacovigilance Department. For this 
study, the e mail address for the USA 
LSO is
 
(
).
The e mail address for the LSO in Canada 
is: 
. 
In the event of difficulty transmitting the 
form, contact the Sponsor’s study 
personnel identified above for further 
instruction. 
For serious adverse events:
The serious adverse event form should be 
sent to the Sponsor’s local safety officer 
(LSO). The LSO will forward the report 
to the Sponsor’s Global Patient Safety & 
Pharmacovigilance Department. For this 
study, the e-mail address for the USA
LSO is:
 
(
). 
In the event of difficulty transmitting the 
form, contact the Sponsor’s study 
personnel identified above for further 
instruction. 
Deleting 
reference to 
Canada since 
study sites will 
not be located 
in Canada, but 
in the United 
States only 
(based on a site 
feasibility 
search that 
revealed 
insufficient 
numbers of 
patients with 
post-herpetic 
neuralgia to 
support study 
activities in 
Canada).
Section 3.10 (Other section affected by this change: Protocol Synopsis)
Approximately 330 patients from up to 
approximately 55 investigational centers 
are planned to be enrolled in the study. 
The study is planned to be conducted in 
the US and Canada.
Approximately 330 patients from up to 
approximately 55 study sites are planned 
to be enrolled in the study. The study is 
planned to be conducted in the US.
Deleting 
reference to 
Canada since 
study sites will 
not be located 
in Canada, but 
in the United 
States only (see 
above).


Placebo-Controlled Study–Postherpetic Neuralgia
Clinical Study Protocol with Amendment 03
Study TV45070-CNS-20013
124
17.5.
Administrative Letter Dated 17 December 2014


Placebo-Controlled Study–Postherpetic Neuralgia
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Study TV45070-CNS-20013
125
APPENDIX A. WASHOUT PERIODS FOR COMMON MEDICATIONS 
TAKEN BY PATIENTS WITH POSTHERPETIC 
NEURALGIA
Table 2:
Washout Periods for Specific Drugs
Name of Drug
Half-life
Recommended
Washout Period
Patches
Lidocaine
~ 6 – 12 hours (topical administration)
7 days
Anticonvulsants
Gabapentin
5 – 7 hours
7 days
Pregabalin
~ 6 hours
7 days
Antidepressants
Duloxetine
8 – 17 hours
7 days
Venlafaxine
5 – 11 hours (active metabolite)
7 days
Amitriptyline
10 – 50 hours
14 days
Nortriptyline
16 to >90 hours
21 days
Opioid Analgesics
Morphine
12 – 24 hours (ER formulation)
7 days
Oxycodone
12 – 24 hours (ER formulation)
7 days
Tramadol
6 – 18 hours
7 days
Methadone
13 – 47 hours
14 days

SAP_000.pdf: 
Statistical Analysis Plan
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Safety and Efficacy of Topically Applied TV-45070 (4% and 8% w/w Ointment) in 
Patients with Postherpetic Neuralgia
Study TV-45070-CNS-20013
NCT02365636
Date: 08 September 2015


Statistical Analysis Plan
Study TV45070-CNS-20013
TEVA BRANDED PHARMACEUTICAL PRODUCTS R&D, INC. 
STATISTICAL ANALYSIS PLAN
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety 
and Efficacy of Topically Applied TV-45070 (4% and 8% w/w Ointment) in Patients with 
Postherpetic Neuralgia
Study TV-45070-CNS-20013 Phase 2
Date: 08-Sep-2015
Version: 1.0
Prepared by:
, INC Research


Statistical Analysis Plan
Study TV45070-CNS-20013
TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................................6
PREFACE                 .......................................................................................................................8
1.
STUDY OBJECTIVES ................................................................................................9
1.1.
Primary Objective.........................................................................................................9
1.2.
Secondary Objectives ...................................................................................................9
1.3.
Exploratory Objectives ...............................................................................................10
2.
STUDY DESIGN .......................................................................................................12
2.1.
General Design and Study Schema.............................................................................12
2.2.
Primary and Secondary Measures and Endpoints ......................................................17
2.2.1.
Primary Efficacy Measure and Endpoint....................................................................17
2.2.2.
Secondary Efficacy Measures and Endpoints.............................................................17
2.2.3.
Exploratory Efficacy Measures and Endpoints ..........................................................17
2.2.4.
Safety Measures and Endpoints..................................................................................18
2.2.5.
Tolerability Measures and Endpoints.........................................................................18
2.2.6.
Pharmacokinetic Measures and Endpoints.................................................................18
2.2.7.
Pharmacodynamic Measures and Endpoints ..............................................................19
2.2.8.
Pharmacogenomic Analyses.......................................................................................19
2.3.
Sample Size and Power Considerations .....................................................................19
2.4.
Randomization and Blinding......................................................................................19
2.5.
Sequence of Planned Analyses ...................................................................................20
2.5.1.
Interim Analyses.........................................................................................................20
2.5.2.
Final Analyses and Reporting.....................................................................................20
3.
POPULATIONS /ANALYSIS SETS.........................................................................21
3.1.
Intent to Treat (ITT) Population .................................................................................21
3.2.
Safety Population........................................................................................................21
3.3.
Full Analysis Set (FAS)..............................................................................................21
3.4.
Per Protocol Population..............................................................................................21
3.5.
Pharmacokinetic Analysis Set (PK)............................................................................21
4.
GENERAL ISSUES FOR DATA ANALYSIS..........................................................22
4.1.
General........................................................................................................................22
4.2.
Specification of Baseline Values................................................................................22


Statistical Analysis Plan
Study TV45070-CNS-20013
4.3.
Multiple Comparisons and Multiplicity......................................................................22
4.4.
Handling Withdrawals and Missing Data...................................................................22
4.5.
Study Days and Visit Windows..................................................................................23
4.6.
Center..........................................................................................................................23
5.
STUDY POPULATION.............................................................................................24
5.1.
General........................................................................................................................24
5.2.
Patient Disposition......................................................................................................24
5.3.
Demographics and Baseline Characteristics...............................................................24
5.4.
Medical History ..........................................................................................................24
5.5.
Prior Medications........................................................................................................24
5.6.
Electrocardiography....................................................................................................24
5.7.
Protocol Violations.....................................................................................................25
5.8.
Childbearing Potential ................................................................................................25
6.
EFFICACY ANALYSIS ............................................................................................26
6.1.
General........................................................................................................................26
6.2.
Primary Efficacy Variable and Analysis ....................................................................26
6.2.1.
Variable Definition.....................................................................................................26
6.2.2.
Primary Analysis ........................................................................................................26
6.2.3.
Sensitivity Analysis ....................................................................................................27
6.3.
Secondary Efficacy Variables and Analysis...............................................................29
6.3.1.
Variable Definition.....................................................................................................29
6.3.2.
Secondary Efficacy Analysis......................................................................................30
6.4.
Exploratory Efficacy Analysis....................................................................................31
7.
SAFETY ANALYSIS ................................................................................................35
7.1.
General........................................................................................................................35
7.2.
Study Drug Administration.........................................................................................35
7.3.
Adverse Events ...........................................................................................................35
7.4.
Deaths .........................................................................................................................36
7.5.
Clinical Laboratory Tests ...........................................................................................36
7.6.
Vital Signs ..................................................................................................................37
7.7.
Electrocardiography....................................................................................................38
7.8.
Physical Examinations................................................................................................38
7.9.
Dermal Irritation Findings..........................................................................................38


Statistical Analysis Plan
Study TV45070-CNS-20013
7.10.
Concomitant Medications...........................................................................................38
8.
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS..............................39
9.
STATISTICAL SOFTWARE ....................................................................................40
10.
CHANGES TO PROTOCOL SPECIFIED ANALYSES ..........................................41
11.
REFERENCES ...........................................................................................................42
12.
LIST OF SUMMARIES AND LISTINGS.................................................................43
12.1.
Summary Tables .........................................................................................................43
12.2.
Individual Patient Data Listings .................................................................................46
12.3.
Graphs.........................................................................................................................48


Statistical Analysis Plan
Study TV45070-CNS-20013
LIST OF TABLES
Table 1:
Study Procedures and Assessments............................................................................13
Table 2:
Imputation Methods for Weekly Average of the Daily Average NRS Pain 
Scores..........................................................................................................................29
Table 3:
Criteria for Potentially Clinically Significant Abnormal Laboratory Values.............36
Table 4:
Criteria for Potentially Clinically Significant Vital Signs..........................................37


Statistical Analysis Plan
Study TV45070-CNS-20013
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AE
Adverse Event
ANCOVA
Analysis of Covariance
AR[1]
Autoregressive (1)
ARH[1]
Heterogeneous Autoregressive (1)
BMI
Body Mass Index
BOCF
Baseline Observation Carried Forward
CI
Confidence Interval
CRF
Case Report Form
CS
Compound Symmetry
CSH
Heterogeneous Compound Symmetry
DSIS
Daily Sleep Interference Scale
ECG
Electrocardiogram
FAS
Full Analysis Set
ICH
International Conference on Harmonization
IRT
Interactive Response Technology
ITT
Intent-to-Treat
LOCF
Last Observation Carried Forward
LS
Least Squares
MAR
Missing at Random
MCMC
Markov Chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
ML
Maximum Likelihood
MMRM
Mixed Model Repeated Measures
NePIQoL
Neuropathic Pain Impact on Quality of Life
NPSI
Neuropathic Pain Symptom Inventory 
NRS
Numerical Rating Scale
PGIC
Patient Global Impression of Change
PHN
Postherpetic Neuralgia
PP
Per Protocol
REML
Restricted Maximum Likelihood
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SOC
System Organ Class


Statistical Analysis Plan
Study TV45070-CNS-20013
TEAE
Treatment Emergent Adverse Event
WHO
World Health Organization


Statistical Analysis Plan
Study TV45070-CNS-20013
PREFACE                 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for TEVA 
Branded Pharmaceuticals Products R&D, Inc. study TV-45070-CNS-20013 , (A Phase 2, 
Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of 
Topically Applied TV-45070 (4% and 8% w/w Ointment) in Patients with Postherpetic 
Neuralgia), and was written in accordance with SOP GBP_RD_702.
This phase 2 study is being completed to assess the safety and efficacy of topically applied TV-
45070 (4% and 8% w/w Ointment) in patients with postherpetic neuralgia. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the FDA and International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH): E9 Guidance on 
Statistical Principles in Clinical Trials. All work planned and reported for this SAP will follow 
internationally accepted guidelines, published by the American Statistical Association, and the 
Royal Statistical Society, for statistical practice.
The following documents were reviewed in preparation of this SAP:

Clinical Study Protocol TV-45070-CNS-20013, issued 20 November 2014.

Case report forms (CRFs) for Study TV-45070-CNS-20013, issued 19 December 
2014.

ICH E9 Guidance on Statistical Principles for Clinical Trials.

ICH E3 Structure and Content of Clinical Study Reports.
The reader of this SAP is encouraged to also read the clinical protocol for details on the conduct 
of this study, and the operational aspects of clinical assessments and timing for completing a 
patient in this study. When differences exist in descriptions or explanations provided in the 
protocol and this SAP, the SAP prevails; the discrepancies will be explained in the CSR. 


Statistical Analysis Plan
Study TV45070-CNS-20013
1.
STUDY OBJECTIVES
1.1.
Primary Objective
The primary objective of this study is to evaluate the efficacy of 4 weeks of topical 
administration of TV-45070 (4% and 8% ointment) compared with placebo for the relief of pain  
due to postherpetic neuralgia (PHN), as assessed by the change from baseline to week 4 in the 
weekly average of the daily average Numerical Rating Scale (NRS) scores. The daily average 
NRS score is the average of the 2 NRS scores (recorded in the morning and in the evening) of 
average pain, defined as the patient-reported average pain over the prior 12 hours.
1.2.
Secondary Objectives
The secondary objectives of the study are as follows:

To evaluate the efficacy of topical TV-45070 (4% and 8% ointment) compared with 
placebo by examining the following:

Change from baseline to week 4 in the weekly average of the average pain score 
recorded in the evening

Change from baseline to week 4 in the weekly average of the average pain score 
recorded in the morning

Change from baseline to week 4 in the weekly average of the worst pain score 
recorded in the evening (worst pain is defined as the patient-reported worst pain 
intensity over the prior 24 hours)

Percentage of patients with ≥ 30% improvement from baseline in the weekly 
average of the daily average NRS scores at week 4

Percentage of patients with ≥ 50% improvement from baseline in the weekly 
average of the daily average NRS scores at week 4

Change from baseline (randomization visit) to weeks 2 and 4 in the Neuropathic 
Pain Symptom Inventory (NPSI) score

Change from baseline (randomization visit) to week 4 in the Neuropathic Pain 
Impact on Quality of Life (NePIQoL)

Patient’s global assessment of treatment as measured by the Patient Global 
Impression of Change (PGIC) scores at weeks 2 and 4

Change from baseline (randomization visit) in the Daily Sleep Interference Scale 
(DSIS) at weeks 2 and 4

Time to reach ≥ 30% improvement from baseline in the weekly average of the 
daily average NRS scores

Change from baseline (randomization visit) in maximal intensity of patients’ 
brush-evoked allodynia, as measured on 11-point NRS at weeks 2 and 4


Statistical Analysis Plan
Study TV45070-CNS-20013

Change from baseline (randomization visit) in maximal intensity of patients’ 
punctate-evoked hyperalgesia, as measured on 11-point NRS using a Medipin®
(US Neurologicals, LLC / Medipin Ltd), at weeks 2 and 4

To characterize the pharmacokinetics of TV-45070 in terms of the following. This 
will be conducted in another analysis plan.

Establishing the dose-exposure relationship of topical TV-45070 (4% and 8% 
w/w ointment under multiple-dose conditions in patients with PHN)

Estimating the apparent clearance (CL/F) and volume of distribution (V/F) of 
TV-45070 by incorporating the concentration data of this study into an enriched 
TV-45070 pharmacokinetics database and performing population 
pharmacokinetic modeling

Identifying the clinically relevant covariates (e.g. age, body weight, gender, and 
indication) affecting TV 45070 pharmacokinetics using the population 
pharmacokinetics model 

To evaluate the safety of topical TV-45070 (4% and 8% ointment) treatment 
compared with placebo, as assessed by the following at specific time points 
throughout the study based on the schedule of study procedures and assessments: 

Occurrence of adverse events (AEs) throughout the study

Clinical safety laboratory (serum chemistry, hematology, and urinalysis) test 
results

Vital signs (heart rate, respiratory rate, body temperature, and blood pressure) 
measurements

Electrocardiogram (ECG) findings

Physical examination findings

Dermal irritation findings

Concomitant medication usage throughout the study
1.3.
Exploratory Objectives
 
 
 


Statistical Analysis Plan
Study TV45070-CNS-20013

 
 
 
 


Statistical Analysis Plan
Study TV45070-CNS-20013
2.
STUDY DESIGN  
2.1.
General Design and Study Schema
This is a Phase 2, multicenter, randomized, double-blind, parallel-group, placebo-controlled 
study to evaluate the safety and efficacy of 4% and 8% w/w TV-45070 ointment compared with 
placebo ointment applied topically and twice daily to the area of PHN pain for 4 weeks (days 1 
through 28) in patients with PHN. For each patient, the duration of study participation will be 
approximately 12 weeks consisting of a 4-week screening period, a 4-week treatment period, and 
a 4-week follow-up period. There will be a total of 6 visits to the study center and 1 telephone 
contact as follows:

Visit 1: screening visit (up to 28 days before randomization/first administration of 
study drug)

Washout phone contact (approximately 1 week after the screening visit)

Visit 2: baseline visit (day –10)

Baseline pain assessment period (days -7 to -1; baseline pain score [average pain 
intensity score over this interval] obtained) 

Visit 3: randomization visit (day 1 [this is the day after day –1 and the first day of 
study drug application])

Visit 4: week 2 visit (day 15 ±1)

Visit 5: week 4 visit (day 29)

Visit 6: follow-up visit (day 57 ±3) or early termination
The study schedule is provided in Table 1, and detailed descriptions of activities at each visit are 
included in the protocol (Section 3.11). 
Visit-specific procedures and assessments are outlined in Table 1.


Statistical Analysis Plan
Study TV45070-CNS-20013
13
Table 1:
Study Procedures and Assessments
Study period
Screening
Randomization
Double-blind treatment
Follow-up / Early termination
Visit number  
Visit 1
--
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit day (window)a
Day –28b
Day –21c
Day –10c,d
Day 1d
Day 15 (±1)
Day 29e (±0)
Day 57 (±3) / Not applicable
Procedures and assessments
Screening 
visit
Washout 
phone 
contactf
Baseline 
visitg
Day of first dose
Week 2 visit
Week 4 visit
Follow-up
Early 
Termination
Informed consent
X
Inclusion and exclusion criteria
X
X
X
Xh
Medical history and demography
X
Adverse event inquiry
X
X
Xh
X
X
X
X
Prior/concomitant medication
Xi
X
X
Xh
X
X
X
X
Start of washout of prior neuropathic 
pain therapy (if needed)
X
Clinical laboratory tests (serum 
chemistry, hematology, and 
urinalysis)
X
Xh
X
X
X
X
Urine drug screen
X
Xh
X
Vital sign measurementsj
X
X
Xh
X
X
X
X
Physical examination
Xk
Xh
X
X
Xk
Xk
12-lead ECGl
X
Xh
X
X
X
X
Pregnancy test (urine)m
X
Xh
X
X
X
X
Blood sample for pharmacogenomics 
assessments
X
NPSI
X
Xh
X
X
X
DSIS
X
Xh
X
X
X
NePIQoL
X
Xh
X
X
Measure maximal intensity of 
brush-evoked allodynian
X
Xh
X
X
X
Measure of maximal intensity of 
punctate-evoked hyperalgesian
X
Xh
X
X
X
Record average daily pain intensity 
(NRS) at study site
X
Record worst daily pain intensity 
(NRS) at study site
X


Statistical Analysis Plan
Study TV45070-CNS-20013
14
Study period
Screening
Randomization
Double-blind treatment
Follow-up / Early termination
Visit number  
Visit 1
--
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit day (window)a
Day –28b
Day –21c
Day –10c,d
Day 1d
Day 15 (±1)
Day 29e (±0)
Day 57 (±3) / Not applicable
Procedures and assessments
Screening 
visit
Washout 
phone 
contactf
Baseline 
visitg
Day of first dose
Week 2 visit
Week 4 visit
Follow-up
Early 
Termination
Dispense/collect rescue medication 
(review accountability)
X
Xo
X
X (collect 
only)
X (collect 
only)
Record rescue pain medication usage 
for PHN as a concomitant medication 
(ie, not using eDiary)
X
X
Provide/review/collect patient eDiary
Xp
Xh,q
Xq
Xr
Xr
Record average daily pain intensity 
(over the previous 12 hours [NRS]) in 
the morning and evening using 
eDiarys
Xt
Xh,u
Xv
Xv
Randomization and instructions on 
application of drug
Xh
Study drug compliance check
Xh,x
X
X
X
Rescue drug compliance check
X
Xh
X
X
X
Dispense/collect study drug
Xh (dispense 
study drug only)
X
X (collect 
study drug 
only)
X (collect if 
prior to V5)
Apply study drug twice daily to area 
of PHN painy
Xz,aa
Xbb
Dermal irritation evaluation
X
Xcc,dd
X
X
X
X
Record date/time of study drug 
application using eDiary
Xaa,cc
Xbb
X (if prior to 
V5)
Record rescue pain medication usage 
for PHN via eDiaryee
Xt
Xcc (at home)
Xff
Xgg
X (if prior to 
V5)
Record worst daily pain intensity 
(NRS) in the evening using eDiary
Xt
Xcc (at home)
Xhh
X (if prior to 
V5)
Blood samples (including recording of 
sampling dates/times) for PK 
assessmentsii
Xjj
PGIC
X
X
X


Statistical Analysis Plan
Study TV45070-CNS-20013
15
a There is no day 0 for this study. Day –1 is the day before study day 1. Day 1 is the day of both randomization and the first dose (application) of study drug.
b The screening visit should occur no more than 28 days before randomization; day –28 is the earliest possible day for the screening visit.
c Variable/flexible date, depending on the need for washout and the drug(s) to be washed out.
d The baseline visit (day –10) and the randomization visit (baseline +10; day 1) must be confirmed as weekdays.
e No time window (in days) is permitted for visit 5 (day 29, week 4).
f The washout phone contact (approximately 1 week after the screening visit or day –21 at the earliest) will be the start of the washout interval (day of the phone 
contact through the day before the baseline visit) during which, if needed, the patient will discontinue medications used to treat PHN pain, including opioids 
(rescue medications [protocol-specified and provided acetaminophen only] permitted during the washout interval). The duration of the washout interval will 
vary from patient to patient depending on which (if any) medications need to be discontinued. For patients who do not need to washout medications, the other 
activities in this phone contact (review of eligibility based on laboratory test results and scheduling the baseline visit) will be performed.
g The baseline visit (day –10) will be the start of the baseline period during which baseline information regarding pain will be collected while the patient refrains 
from all PHN rescue medications.
h Performed prior to first dose of study drug.
i Includes specific query regarding past use of topical therapy such as the 5% lidocaine patch or capsaicin.
j Includes heart rate, respiration rate, body temperature, and blood pressure.
k Includes body weight (screening and follow-up/ET visits only) and height (screening visit only).
l All ECGs will be taken in triplicate and read by a central reader for the study. The central reader will be blinded (will not know the randomization assignment
of the patients).
m Only for women of child-bearing potential.
n For brush or punctate mechanical hyperalgesia. If either is not present at screening, it will not be rechecked on subsequent visits.
o Collect from patients not eligible to continue in the study.
p Provide eDiary to eligible patients and instructions on using it to record daily pain (11-point NRS), date/time of study drug applications, and rescue medication 
usage.
q Review eDiary and review eDiary data via website. Also, for patients not eligible to be randomly assigned to treatment, collect eDiary at the randomization 
visit (visit 3, day 1).
r Review eDiary, review eDiary data via website, and collect eDiary.
s The eDiary will be used to record responses to 11-point NRS each morning (0700 ±2 hours) and each evening (1900 ±2 hours) before applying the study drug.
t At home after baseline visit until randomization visit.
u At home before dosing and in the evening before dosing.
v At home through the morning of day 29.
x Note that tubes must be weighed at visit 3, to obtain a baseline weight for checking study drug compliance at visit 4 (day 15 ±1, week 2) and visit 5 (day 29, 
week 4) or ET visit. 
y Patients will apply study drug twice daily in the morning (0700 ±2 hours) and again in the evening (1900 ±2 hours). The morning applications should take 
place after recording the morning (0700 ±2 hours) responses to the 11-point NRS, and the evening applications should take place after recording the evening 
(1900 ±2 hours) responses to the 11-point NRS. On day 1, the morning dose might not be applied at 0700 ±2 hours because this first dose of study drug will be 
applied at the randomization visit. Regardless of the clock time of the first dose application at the randomization visit, the evening dose for day 1 should be 
applied at 1900 ±2 hours.


Statistical Analysis Plan
Study TV45070-CNS-20013
16
z First dose will be applied by study site staff at randomization visit (visit 3, day 1)  as per protocol section 3.4. 
aaAt visit and home on day 1; at home from day 2 onward.
bbAt home through the evening of day 28.
ccPerformed after first dose of study drug.
ddAt the randomization visit, dermal irritation will be assessed 1 hour after application of the study drug.
eeAlthough rescue medication is not allowed during the baseline period and during the 7-day period before the week 4 visit (visit 5) of the treatment period, the 
eDiary will be used to record rescue medication usage, including usage when it is prohibited per protocol.
ff At home on day 2 through the morning of day 29.
ggAt home on the morning of day 29.
hhAt home on day 2 through the evening of day 28.
ii All patients will have blood samples drawn for pharmacokinetic assessments.
jj For visit 4 (day 15 ±1, week 2), patients will go to the study center after applying study drug at home so that 2 pharmacokinetics samples can be taken, with the 
first sample taken within approximately 1 to 4 hours of the morning dose of study drug and the second taken approximately 2 hours after collection of the first 
sample. The date and time of morning dose and the date and exact time for each of the 2 pharmacokinetics samples will be recorded.
DSIS=Daily Sleep Interference Scale; ECG=electrocardiogram; eDiary=electronic diary; ET=early termination; NePIQoL=Neuropathic Pain Impact on Quality 
of Life questionnaire; NPSI=Neuropathic Pain Symptom Inventory; NRS=Numeric Rating Scale; PGIC=Patient Global Impression of Change; 
PHN=postherpetic neuralgia; PK=pharmacokinetics; V5=visit 5.


Statistical Analysis Plan
Study TV45070-CNS-20013
17
2.2.
Primary and Secondary Measures and Endpoints
2.2.1.
Primary Efficacy Measure and Endpoint
The primary efficacy endpoint for this study is the change from baseline to week 4 in the weekly 
average of the daily average NRS scores. The daily average NRS score 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.
2.2.2.
Secondary Efficacy Measures and Endpoints
The secondary efficacy endpoints for this study are as follows:

Change from baseline to weeks 1, 2, 3 and 4 in the weekly average of the average 
pain score recorded in the evening

Change from baseline to weeks 1, 2, 3 and 4 in the weekly average of the average 
pain score recorded in the morning

Change from baseline to weeks 1, 2, 3 and 4 in the weekly average of the worst pain 
score recorded in the evening (worst pain is defined as the patient-reported worst pain 
intensity over the prior 24 hours)

Percentage of patients with ≥ 30% improvement from baseline in the weekly average 
of the daily average NRS scores at week 4

Percentage of patients with ≥ 50% improvement from baseline in the weekly average 
of the daily average NRS scores at week 4

Change from baseline (randomization visit) to weeks 2 and week 4 in the NPSI score

Change from baseline (randomization visit) to week 4 in the NePIQoL score

Patients’ global assessment of treatment, as measured by PGIC scores, at weeks 2 and 
4

Change from baseline (randomization visit) in DSIS scores at weeks 2 and 4

First time to reach ≥ 30% sustained improvement from baseline  in the weekly 
average of the daily average NRS scores

Change from baseline (randomization visit) to weeks 2 and 4 in maximal intensity of 
patients’ brush-evoked allodynia, as measured on the 11-point NRS

Change from baseline (randomization visit) to weeks 2 and 4 in maximal intensity of 
patients’ punctate-evoked hyperalgesia, as measured on the 11-point NRS using a 
Medipin
2.2.3.
Exploratory Efficacy Measures and Endpoints
 
 


Statistical Analysis Plan
Study TV45070-CNS-20013
18
 
 
 
 
  
 
 
 
2.2.4.
Safety Measures and Endpoints
The safety of TV-45070 (4% and 8% ointment) will be assessed throughout the study by
evaluating AEs, clinical safety laboratory test results, vital signs measurements, ECG findings, 
physical examination results, dermal irritation findings and concomitant medication usage. Skin 
rashes or skin irritation in the area of ointment application will be evaluated using a dermal 
irritation scale (modified Draize scale) at day 1 (at 1 hour after application of study drug), week 
2, week 4, and week 8 for follow-up.
2.2.5.
Tolerability Measures and Endpoints
The tolerability of TV-45070 (4% and 8% ointment) will be assessed during the study by using 
safety endpoints that also represent patients’ experience of treatment, such as skin rashes and 
skin irritation.
2.2.6.
Pharmacokinetic Measures and Endpoints
Two blood samples will be collected from each patient following 2 weeks of treatment with 
either 4% or 8% w/w TV-45070 ointment or matching placebo ointment, to quantitate the 
concentration of TV-45070 in plasma. Plasma samples will be analyzed for TV-45070. 
Population pharmacokinetic parameters, such as CL/F and V/F will be estimated when the sparse 
data from this study are combined with enriched pharmacokinetic data from other studies with 
topical TV-45070. A summary and listing of these results may be included in this study. These 
results will also be reported separately from the main study results. 


Statistical Analysis Plan
Study TV45070-CNS-20013
19
2.2.7.
Pharmacodynamic Measures and Endpoints
Pharmacodynamic endpoints assessed during the study are the following secondary efficacy 
endpoints: change from baseline in maximal intensity of patients’ brush-evoked allodynia and 
maximal intensity of punctate-evoked hyperalgesia.
2.2.8.
Pharmacogenomic Analyses
 
 
 A pharmacogenomic blood sample may be 
used to assess the polymorphisms for CYP3A4 and CYP2C19 genes. Depending on the 
distribution of the allelic variations, these variations may be incorporated as covariates in the 
current or future population pharmacokinetic analyses. Exploratory analyses may be reported 
separately from the main study results.
2.3.
Sample Size and Power Considerations
In prior studies of gabapentin or pregabalin treatment of PHN, the difference in mean pain scores 
between active- and placebo-treated groups ranged from 1.0 to 1.3. For this study, a conservative 
estimate of 1.0 will be used. Assuming a standard deviation of 2.35, a sample size of 88 per arm 
(a total of 264 patients) would be needed to provide 80% power with a 2-sided test at 5% 
significance level to detect a 1.0-point difference. Assuming an approximately 20% dropout rate, 
110 patients per arm (a total of 330 patients) will be randomly assigned to each treatment group. 
2.4.
Randomization and Blinding
This is a randomized, double-blind, placebo-controlled study. All tubes of study drug will be 
identical, and the ointments will be indistinguishable. Patients, investigators, and all clinical 
study center staff will remain blinded to treatment assignment during the study. Eligible patients 
will be randomly assigned via interactive-response technology (IRT) in a 1:1:1 ratio to 4% w/w 
TV-45070 ointment, 8% w/w TV-45070 ointment, or placebo ointment. Randomization will be 
stratified by the R1150W underlying genotype in the SCN9A gene: homozygous minor allele 
(positive, AA), heterozygous (positive, AG), and homozygous common allele (negative, GG).
In addition, the Sponsor’s clinical personnel involved in the study will be blinded to the study 
drug identity until the database is locked for analysis and the treatment assignment revealed. A 
statistician not assigned to the study will be responsible for the randomization code, and the final 
randomization code will be maintained by the service provider. 
Patients will be randomly assigned to treatment through a qualified randomization service 
provider (eg, IRT). This system will be used to ensure a balance across treatment groups; no 
effort will be made to maintain a balance among treatment groups within a study center. 
The clinical study center will receive study drug kits, and kits will be assigned to individual 
patients by the IRT system based on the patients’ randomization assignments. The IRT system 
will record the kit numbers for all patients. Designated study center staff, who will remain 
blinded to the treatment assignments, will dispense the kits to patients based on the kit numbers 


Statistical Analysis Plan
Study TV45070-CNS-20013
20
assigned to patients by the IRT system. In case of emergency, the investigator and designated 
study center staff can call the IRT system to unblind the treatment for a specific patient.
2.5.
Sequence of Planned Analyses
2.5.1.
Interim Analyses
No interim analysis is planned for this study.
2.5.2.
Final Analyses and Reporting
All final, planned analyses identified in this SAP will be performed only after the last patient has 
completed the study. The randomization codes will not be unblinded until this SAP has been 
approved, the database is locked, and the analysis populations are determined.
Any exploratory analyses completed to support study analyses, which were not identified in this 
SAP, will be documented and reported in appendices to the CSR.


Statistical Analysis Plan
Study TV45070-CNS-20013
21
3.
POPULATIONS /ANALYSIS SETS
3.1.
Intent to Treat (ITT) Population
The ITT population will include all randomized patients. In this population, treatment will be 
assigned based upon the treatment to which patients were randomized, regardless of which 
treatment they actually received.
3.2.
Safety Population
The safety population will include all randomized patients who receive at least 1 dose of study 
medication. In this population, treatment will be assigned based upon the treatment patients 
actually receive, regardless of the treatment to which they were randomized. 
3.3.
Full Analysis Set (FAS)
The FAS, defined as all patients in the ITT population (all patients randomly assigned to a 
treatment) who receive at least 1 dose of study drug and have at least 1 post-baseline efficacy 
assessment, will be used for all efficacy analyses. Summaries will be presented by treatment 
group. The FAS will serve as the primary analysis set for efficacy analyses.
3.4.
Per Protocol Population
The per protocol analysis set (PP) will include all patients in the FAS who 1) met all inclusion 
and none of the exclusion criteria, and 2) did not use > 4 days of rescue medication in baseline 
(days –7 to –1 prior to randomization) and last 7-day window (days 22 to 28) and did not have >
6 pills of rescue medication (1950 mg/day) for any day during that time, and 3) had at least 4 
daily average NRS scores for last 7 days of treatment (days 22 to 28) and 4) had at least 70% of 
study medication compliance between visits 4 and 5.
3.5.
Pharmacokinetic Analysis Set (PK)
The population pharmacokinetic analysis set will include all patients in the pharmacokinetic 
subset who had at least 1 pharmacokinetic plasma sample analyzed for TV-45070.


Statistical Analysis Plan
Study TV45070-CNS-20013
22
4.
GENERAL ISSUES FOR DATA ANALYSIS
4.1.
General
Descriptive statistics for continuous variables include n, mean, standard deviation (SD), standard 
error of the mean (SE), median, minimum, and maximum.  If inferential statistics are computed, 
it will also include least square mean and standard error of the least square mean, 95% 
confidence interval, and p-value, unless otherwise specified. Descriptive statistics for categorical 
variables include patient counts and percentages. 
Summaries of potentially clinically significant abnormal values will include all postbaseline 
values (including scheduled, unscheduled, and early termination visits).
The last visit for efficacy and safety analyses and summaries is the last observed postbaseline 
data up to Week 4 visit.
4.2.
Specification of Baseline Values
For efficacy variables based on the weekly average of the daily average NRS scores, baseline is 
defined as the weekly average over the 7 days before randomization (day -7 to day -1). For other 
efficacy variables the baseline value is the last non-missing assessment on or before the first dose 
date if no assessment time is available. Otherwise, the baseline value is defined as the last non-
missing assessment before the first dose of study medication.
The baseline value for safety variables (i.e., clinical laboratory, vital signs, ECG, and physical 
examination) is defined as the last non-missing assessment on or before the first dose date if no 
assessment time is available. Otherwise, the baseline value is defined as the last non-missing 
assessment before the first dose of study medication.
4.3.
Multiple Comparisons and Multiplicity
This is a Phase 2 study, and there is no plan to adjust for multiplicity.
4.4.
Handling Withdrawals and Missing Data
Missing onset/stop dates of AEs and prior/concomitant mediations will not be imputed, and a 
conservative approach will be taken when assigning treatment-emergent AEs or concomitant 
medications.  
The daily average NRS score is the average of the 2 NRS scores (recorded in the morning and 
evening). At least 1 of the 2 NRS scores must be non-missing or the daily average will be 
considered missing. The weekly average NRS score is the average of the daily average over 7 
days. 
For NePIQoL and NPSI questionnaires that include multiple items/tests, the measurement value 
at each timepoint is the sum of responses of all items/tests. If the entire questionnaire is not done 
at a scheduled time point, it will be considered missing and won’t be imputed unless otherwise 
specified. Missing responses for individual items/tests will be imputed if up to 10% of the total 
items/tests for that scale are missing (up to 4 missing responses for NePIQoL, and 1 missing 


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response for NPSI). The imputed total is equal to the number of items in the scale times the sum 
of the non-missing responses divided by the number of non-missing items. If more than 10% of 
the responses are missing, then the total will be considered missing. 
4.5.
Study Days and Visit Windows
For both safety and efficacy by-visit summaries, the assessments at the scheduled visits will be 
summarized in the tables while all of the assessments including unscheduled visits will be listed. 
For patients who withdraw from the study, data at the early termination visit will be included in 
the last visit summaries.  The last visit is defined as last observed postbaseline data up to Week 4 
visit.
If there are multiple assessments at a scheduled postbaseline visit then the last non-missing value 
at that visit will be used for the by visit summary.
Study days will be numbered relative to the first day of study drug administration. The start of 
treatment (day 1) is defined as the date on which a patient applies the first dose of study drug, as 
recorded on the study drug diary. Days will be numbered relative to study start (ie, ..., –2, –1, 1, 
2, ...; with day 1 being the start of study drug and day –1 being the day before the start of study 
drug). 
4.6.
Center
The trial will be conducted in approximately 55 study centers in the United States. In order to 
include center into the model, centers will need to be combined to create approximately 15 big 
centers. Centers may be pooled according to the number of patients enrolled at each site by 
keeping the largest sites intact and pooling the remainder of the larger sites with smaller sites to 
form pooled sites. A final plan for pooling will be made and documented in Statistical Data 
Review meeting minutes prior to unblinding.  The pooled centers will be used in the efficacy
analyses as appropriate.


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5.
STUDY POPULATION 
5.1.
General
All randomized patients will be used for all study population summaries unless otherwise noted.  
Summaries will be presented by treatment group and for all patients (overall) unless otherwise 
noted. 
5.2.
Patient Disposition
Data from patients screened, patients screened but not randomized and reason not randomized 
will be summarized only for the overall group using patient counts. Patients randomized, patients 
randomized but not treated (and reason), patients in the ITT, safety, FAS, and PP populations, 
patients who complete double-blind treatment, patients who withdraw from double-blind 
treatment, patients who complete the study, and patients who withdraw from the study will be 
summarized using descriptive statistics. Data from patients who withdraw from the double-blind 
treatment and from the study will also be summarized by reason for withdrawal using descriptive 
statistics. This summary will include all patients screened into the study. The denominator for 
calculating percentages will be the number of randomized patients.
5.3.
Demographics and Baseline Characteristics
Patient demographic and baseline characteristics, including medical history, prior medications, 
and ECG findings will be examined to assess the comparability of the treatment groups and will 
be summarized using descriptive statistics by treatment group and total. For continuous 
variables, descriptive statistics (number [n], mean, standard deviation (SD), standard error (SE), 
median, minimum, and maximum) will be provided. For categorical variables, patient counts and 
percentages will be provided. Categories for missing data will be presented if necessary.
5.4.
Medical History
Patients with a medical history assessment will be summarized using descriptive statistics. 
5.5.
Prior Medications
All prior medications will be coded using the World Health Organization dictionary of medical 
codes (WHO Drug Version March 2014 enhanced B2 format) . The incidence of prior 
medications will be summarized using descriptive statistics by therapeutic class (ATC level 2) 
and preferred term. Patients are counted only once in each therapeutic class category, and only 
once in each preferred term category. Prior medications will include all medications taken prior 
to the first day of study drug.
5.6.
Electrocardiography
Electrocardiogram findings (normal, abnormal, and missing) at baseline will be summarized 
using descriptive statistics.


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5.7.
Protocol Violations 
Patients with at least 1 protocol violation for each category will be summarized using descriptive 
statistics. Patients with at least 1 major protocol violation for each category will also be 
summarized using descriptive statistics. Descriptions will be reviewed and rescue medication 
overuse will be summarized as a separate category.
5.8.
Childbearing Potential 
For female patients, information related to childbearing potential, contraception, and menopause 
will be collected at screening visit. The number of patients in each category will be reported by 
treatment group for randomized patients.


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6.
EFFICACY ANALYSIS
6.1.
General
The FAS will be used as the primary analysis for all efficacy analyses. The PP population will be 
supportive for efficacy analyses. All statistical testing will be carried out using 2-tailed tests at 
the 5% level of significance. Summaries will be presented by treatment group as 
randomized/assigned unless specified otherwise.
6.2.
Primary Efficacy Variable and Analysis
6.2.1.
Variable Definition
The NRS is a widely-used, standard one-dimensional scale from 0 to 10 for patient self-reporting 
of pain. The daily average NRS scores are the average of the 2 NRS scores (recorded in the 
morning and in the 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 must be recorded (non-missing) 
or the daily average will be considered missing. The daily average NRS scores are the average of 
evening NRS score on day x and morning NRS score on day x+1.  For example, the daily 
average NRS score on day 1 (day of first study medication) is the average of evening NRS score 
on day 1 and morning NRS score on day 2. Similarly the daily average NRS score on day 28 is 
the average of evening NRS score on day 28 and morning NRS score on day 29. The weekly 
average of the daily average is computed over the 7 days. Baseline is computed using days -7 to -
1, week 1 using days 1 to 7, week 2 using days 8 to 14, week 3 using days 15 to 21 and week 4 
using days 22 to 28. 
6.2.2.
Primary Analysis
The primary efficacy variable for this study is the change from baseline to week 4 in the weekly 
average of the daily average NRS pain scores. This variable will be analyzed using a Mixed 
Model Repeated Measures (MMRM) model with change from baseline in the weekly average of 
the daily average NRS scores at weeks 1, 2, 3 and 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. The 
unstructured covariance matrix for repeated observations within patients will be used. If the 
model does not converge, the maximum-likelihood (ML) estimation method will be used instead 
of the default restricted ML (REML) method. If the model still does not converge, then simpler 
covariance structures with less parameters will be used in the following order until the model 
does converge: heterogeneous autoregressive (1) (ARH[1]); heterogeneous compound symmetry 
(CSH); autoregressive (1) (AR[1]); and compound symmetry (CS). The primary treatment 
comparison will be conducted at week 4 in this model. 
The least square (LS) means and standard error of each treatment group, LS means differences 
including standard error, 95% confident interval (CI) and p-values, between each active group 
and the placebo group for the change from baseline to weeks 1, 2, 3 and 4 in the weekly average 
of the daily average NRS pain scores will be presented in the tables.
SAS code for primary endpoint:


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Proc mixed data=datain; 
Class treatment week patient;
Model change=base treatment center week treatment*week/ddfm=kr;
Repeated week/sub=patient type=un;
Lsmean treatment*week/pdiff cl ;
*** treatment order in the data will be placebo, 4%, 8%*********;
Estimate ‘4% vs. Placebo at week 4’ treatment -1 1 0 treatment*week  0 0 0 -1 
0 0 0 1 0 0 0 0/ cl;
Estimate ‘8% vs. Placebo at week 4’ treatment  -1 0 1 treatment*week 0 0 0 -1 
0 0 0 0 0 0 0 1/cl;
Run;
A descriptive summary of  the weekly average of the daily average NRS pain scores at baseline, 
weeks 1, 2, 3 and 4, as well as the change from baseline will be provided by treatment group.
6.2.3.
Sensitivity Analysis
Two sensitivity analyses will be performed in order to assess the robustness of the results of the 
primary analysis to changes in the assumptions and data characteristics. The first sensitivity 
analysis is a multiple imputation method to handle missing weekly average of the daily average 
NRS pain scores for week 4. Consistent with the recommendations of the National Academy of 
Sciences report (National Research Council 2010), under the assumption of missing at random 
(MAR) and taking into account of potential bias towards the active arm for patients who 
withdrew from the study due to adverse events, the following steps will be carried out in SAS 
using the MI, Mixed, and MIANALYZE procedures:

Step 1: prepare data set for MI procedure (PROC MI) 
The following auxiliary variables are to be included in the model for PROC MI:
-
Treatment (1=placebo, 2=TV45070 4%, 3=TV45070 8%)
-
R1150W genotype (1=AA, 2=GA, 3=GG)
-
All observed pain scores, screening, baseline, and weekly averages at each post 
randomization week (week 1, week 2, week 3, week 4)
The treatment will be coded to 1 (placebo) for those in the active arms withdrawn from 
study due to an adverse event or lack of efficacy.  Thus,  the missing week 4 pain scores 
will be imputed based on the observed placebo patient’s data. In order to adjust for the 
use of rescue medication at week 4, the average weekly pain intensity at week 4 will be 
set to missing for patients who used an excessive amount of rescue medication during the 
week before the multiple imputation. Excessive use of rescue medication is defined as the 
use of rescue medication on at least 4 out of 7 days of the week 4 treatment.  

Step 2: run PROC MI. The following SAS code may be used to generate the imputed data
sets:
Proc mi data=datain nimpute=5 seed=598719001 out=mi_out
   Maximum=10 minimum=0 round=0.01;
   Class treat genotype;
   Var treat genotype screening baseline week1 week2 week3 week4;
   Monotone reg;


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Run;
Note: if the missing data pattern is not monotonic, a Markov Chain Monte Carlo 
(MCMC) method will be used instead of a regression method for imputing missing data.
R1150W genotype will be used, with all 3 possible categories.

Step 3: run mixed procedure (PROC MIXED) using the data from PROC MI
The output data set MI_OUT, from the above MI procedure, will contain 5 complete data 
sets with the missing data points filled using the specified imputation methods, and 1 
additional variable, _IMPUTATION_, to indicate the order of the imputed data sets. 
Then within each data set, the primary variable, change from baseline at week 4, will be 
derived by subtracting baseline from week 4. Each data set will be analyzed using the 
ANCOVA model with the primary variable and the dependent variables, the screening 
and baseline scores as covariates, pooled study center, treatment and genotype as factors 
in the model. The following SAS code may be used to analyze the imputed data sets. 
ODS output diffs=mixed_out;
Proc mixed data=mi_out method=reml;
   By _imputation_;
   Class center armcd genotype;
   Model change4 = center armcd genotype baseline screening;
   Lsmeans armcd/diff;
Run;
ARMCD represents the treatment the patient was randomized to receive.

Step 4: calculate overall p-value and construct 95% confidence interval for the treatment 
difference.  
The output data from the above SAS code will contain the estimate of the mean 
difference and the standard error of the estimate from each of the 5 data sets. The SAS 
procedure mianalyze (PROC MIANALYZE) will be used to generate an overall p-value 
and 95% confidence interval for the treatment difference. The following SAS code may 
be used.
ODS output parameterestimates=parmest;
Proc mianalyze data=mixed_out alpha=0.05 theta0=0;
   Modeleffects estimate;
   Stderr stderr;
Run;
The second sensitivity analysis will be similar to the first one except that the baseline 
observation carried forward (BOCF) method will be used to impute the missing week 4 weekly 
average of the daily average NRS pain scores for those who discontinued the study early due to 
adverse event or lack of efficacy. Details for the week 4 imputation methods for missing weekly 
average of the daily average NRS pain scores for the two sensitivity analyses are given in 
Table 2 below. 


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Table 2:
Imputation Methods for Weekly Average of the Daily Average NRS Pain 
Scores
Double-blind
Treatment
Reason
Efficacy Analysis
Sensitivity 1
Sensitivity 2
Placebo
Discontinued due to AE or Lack of 
Efficacy
Multiple imputation
Baseline (BOCF)
Discontinued due to all other reasons
Multiple imputation
Multiple imputation
Completed study but took excessive 
rescue medication before week 4 visit
Multiple imputation
Multiple imputation
TV-45070
Discontinued due to any AE or Lack of 
Efficacy
Multiple imputation with 
treatment code set to 
placebo
Baseline (BOCF)
Discontinued due to other reasons
Multiple imputation
Multiple imputation
Completed study but took excessive 
rescue medication before week 4 visit
Multiple imputation
Multiple imputation
6.3.
Secondary Efficacy Variables and Analysis
6.3.1.
Variable Definition

Weekly average of the average pain score recorded in the evening.

Weekly average of the average pain score recorded in the morning.

Weekly average of the worst pain score recorded in the evening (worst pain is defined 
as the patient-reported worst pain intensity over the prior 24 hours).

≥ 30% improvement from baseline in the weekly average of the daily average NRS 
scores, where improvement from baseline is defined as 100*(weekly average of the 
daily average NRS scores at week 4– baseline weekly average of daily average NRS 
scores) / baseline weekly average of daily average NRS scores.

≥ 50% improvement from baseline in the weekly average of the daily average NRS 
scores, where improvement from baseline is defined as 100*(weekly average of the 
daily average NRS scores at week 4 – baseline weekly average of daily average NRS 
scores) / baseline weekly average of daily average NRS scores.

NPSI is a patient-reported questionnaire to evaluate the severity of different 
symptoms of neuropathic pain. The questionnaire contains 10 descriptors and 2 
temporal items. Descriptors are scored from 0 to 10, where 0 represents no pain and 
10 represents worst pain imaginable. The total score is the sum of the scores of the 10 
descriptors (Bouhassira, Attal, Fermanian, Alchaar, et al, 2004). The total score 
ranges from 0 to 100, where higher scores represent worse pain. If the score for one 
question is missing the total score will be computed as 10 times sum of scores of 9 
descriptors divided by 9. If more than one question is missing then the total score will 


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be missing.  The 2 temporal items will be summarized as continuous variable using 
descriptive statistics.

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 to 5, where higher scores represent greater pain-related interference in the 
quality of life (four items will have scores inverted so that higher scores reflect 
greater pain. “I involve myself with people I am close to as much as I used to despite 
the pain”,  “I can distract myself from the pain”, “I can cope with the pain”, and “I 
still enjoy my hobbies/leisure activities despite the pain.”). The total score is 
calculated as the sum of the scores for the individual questions (Poole and Nurmikko 
2009). If scores for up to 4 questions are missing then the total score will be 
computed as 41 times sum of non-missing scores divided by the number of 
non-missing questions. If responses for more than 4 questions are missing then the 
total score will be considered missing.

PGIC is a standardized self-report tool that measures the change in a patient's overall 
status rating since the start of treatment (Hurst and Bolton 2004) on 7-point scale.  
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.

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).

First time to reach ≥ 30% sustained improvement from baseline  in the weekly 
average of the daily average NRS scores will be computed in days from the date of 
first dose, where the date of first dose is day 1. Those who do not achieve ≥ 30% 
sustained improvement from baseline will be censored at date of last dose of study 
medication. Sustained improvement is defined as an improvement of  ≥30% that is 
maintained until the end of the treatment period. 

Maximal intensity of patients’ brush-evoked allodynia, as measured on the 11-point 
NRS.

Maximal intensity of patients’ punctate-evoked hyperalgesia, as measured on the 11-
point NRS using a Medipin.
6.3.2.
Secondary Efficacy Analysis
The above secondary efficacy variables will be analyzed in the similar way as the primary
analysis for the primary efficacy variable.

Change from baseline to weeks 1, 2, 3 and 4 in the weekly average of the average 
pain score recorded in the evening

Change from baseline to weeks 1, 2, 3 and 4 in the weekly average of the average 
pain score recorded in the morning


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
Change from baseline to weeks 1, 2, 3 and 4 in the weekly average of the worst pain 
score recorded in the evening (worst pain is defined as the patient-reported worst pain 
intensity over the prior 24 hours)

Change from baseline (randomization visit) to weeks 2 and 4 in the NPSI score

Change from baseline (randomization visit) in DSIS scores at weeks 2 and 4

Change from baseline (randomization visit) to weeks 2 and 4 in maximal intensity of 
patients’ brush-evoked allodynia, as measured on the 11-point NRS

Change from baseline (randomization visit) to weeks 2 and 4 in maximal intensity of 
patients’ punctate-evoked hyperalgesia using a Medipin, as measured on the 11-point 
NRS 
In addition, the following analyses will be done:

Percentage of patients with ≥ 30% improvement and ≥ 50% improvement from 
baseline in the weekly average of the daily average NRS scores at week 4 will be 
analyzed using logistic regression model with pooled study center, treatment as fixed 
factors and baseline NRS scores as covariate. 

Time to reach ≥ 30% sustained improvement from baseline  in the weekly average of 
the daily average NRS scores will be summarized using Kaplan-Meier method.

Patients’ global assessment of treatment, as measured by PGIC scores, at weeks 2 and 
4 will be analyzed using a MMRM model similar to the primary efficacy variable 
with 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 will be used.

Change from baseline (randomization visit) to week 4 in the NePIQoL score will be 
analyzed using an analysis of covariance (ANCOVA) model with pooled study 
center, treatment as fixed factors and baseline value as covariate. The missing week 4 
values will be imputed using last observation carried forward (LOCF) method.
SAS code for ANCOVA model
Proc mixed data=datain order=data;
Class center treatment;
Model change = base center treatment;
Lsmean treatment /pdiff cl ;
Run;
A descriptive summary of the secondary efficacy variables will be provided by treatment 
group for scheduled visits. Change from baseline will be provided for continuous 
variables.
6.4.
Exploratory Efficacy Analysis
 
 
 


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7.
SAFETY ANALYSIS
7.1.
General
The safety population will be used for all safety analyses.  Summaries will be presented by 
treatment group as actually received unless specified otherwise. 
7.2.
Study Drug Administration
Duration of treatment (days treated) is the number of days on treatment based on the first and last 
days of treatment with the study drug (last day of study drug – first day of study drug + 1). The 
first day of study drug and the last day of study drug will be derived from eDiary data. Total 
amount of study medication used at each visit (visits 4 and 5) and overall will be calculated as 
amount (weight in grams) of study medication dispensed minus amount of study medication 
returned.  The expected amount of study medication usage will be calculated as (duration of 
treatment in days x 2 – 1) x 2 x number of dosing cards per application x 0.6 gram for visits 4 
and 5; and duration of treatment in days x 2 x 2 x number of dosing cards per application x 0.6 
gram for overall. Study drug compliance, derived as the percentage of total amount of study 
medication used divided by the expected amount of study medication usage will be descriptively 
summarized by treatment group for the following categories: > 120%, 100% (inclusive) - 120%, 
70% (inclusive) - 100%, and < 70%. Duration of treatment (days) will also be summarized using 
descriptive statistics by treatment group.   
7.3.
Adverse Events
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product, 
regardless of whether it has a causal relationship with this treatment.
For AE recorded in this study, the study period is defined for each patient as the time period 
from signature of the ICF through the end of the follow-up period (the day 57 [±3] follow-up 
visit or when a patient is confirmed as lost to follow-up). Any AE occurring on or after the first 
application of study drug is considered a treatment-emergent adverse event (TEAE). Unless there 
is a clear evidence that the onset date of an AE is prior to the first dose date, AEs with missing or 
partial onset dates will be classified as TEAEs as the conservative approach. All AE summaries 
will be conducted for TEAEs with the exception of serious adverse event (SAE) related 
summaries.
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA version 
17.1). The incidence of AEs will be summarized using descriptive statistics by system organ 
class (SOC) and preferred term.  
Summaries will be presented for all AEs (overall, by severity and by causality), AEs determined 
by the investigator to be related to study treatment (ie, reasonable possibility; defined as related 
or with missing relationship), AEs determined by the investigator to be related to study treatment 
by severity, serious adverse event (SAEs), and AEs causing withdrawal from study. Summaries 
will be presented by treatment group and for all patients.   


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Each patient will be counted only once in each preferred term or SOC category for the analyses 
of safety. For the summaries by severity, patients are counted at the greatest severity. AEs with 
missing severity will be considered severe.
In addition, time to the  first objective application site irritation, which is defined as the number 
of days between first dose date and the start of first objective application site irritation, will be 
analyzed using Kaplan-Meier methods by treatment group.  The objective application site 
irritation is defined by AEs with preferred terms of ‘Application site erythema’, ‘Application site 
exfoliation’, ‘Application site oedema’, ‘Application site papules’ and ‘Application site rash’. 
Those who did not experience objective application site irritation will be censored at last dose 
date.
Patient listings of SAEs and AEs leading to withdrawal from treatment will be presented.
7.4.
Deaths
If any patient dies during the study all relevant information will be discussed in the patient’s 
narratives included in CSR. 
7.5.
Clinical Laboratory Tests
Summary statistics for chemistry, hematology, and urinalysis laboratory tests will be presented at 
baseline, week 2, week 4, last visit, and follow-up.  Laboratory tests results and changes from 
baseline to each visit and last visit will be summarized using descriptive statistics.  Shifts (below, 
within, and above the normal range) from baseline to each visit and last visit will be summarized 
using patient counts.  The incidence of potentially clinically significant abnormal results will be 
summarized for laboratory data using descriptive statistics with the criteria specified in Table 3. 
Table 3:
Criteria for Potentially Clinically Significant Abnormal Laboratory Values
Test
Criterion value
Serum chemistry
  Alanine aminotransferase (ALT)
3x ULN
  Aspartate aminotransferase (AST)
3x ULN
  Alkaline phosphatase
3x ULN
  Gamma-glutamyl transpeptidase (GGT)
3x ULN
  Lactate dehydrogenase (LDH)
3x ULN
  Blood urea nitrogen (BUN)
10.71 mmol/L
  Creatinine
177 mol/L
  Uric acid
Men
625 mol/L
Women
506 mol/L
  Bilirubin (total)
34.2 mol/L
Hematology
  Hematocrit
Men
<0.37 L/L
Women
<0.32 L/L
  Hemoglobin
Men
115 g/L


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Test
Criterion value
Women
95 g/L
  White blood cell (WBC) counts
3 x 109/L 
20 x 109/L
  Eosinophils
10%
  Absolute neutrophil counts (ANC)
1 x 109/L
  Platelet counts
75 x 109/L 
700 x 109/L
Urinalysis
  Blood (HGB)
2 unit increase from baseline
  Glucose
2 unit increase from baseline
  Ketones
2 unit increase from baseline
  Total protein
2 unit increase from baseline
ULN=upper limit of normal range.
Listings for potentially clinically significant abnormal laboratory data will be presented.
7.6.
Vital Signs
Summary statistics for vital signs will be presented at baseline, weeks 2, 4, last visit, and 
follow-up. Vital signs values and changes from baseline to each visit and last visit will be 
summarized using descriptive statistics. The incidence of potentially clinically significant
abnormal values will be summarized for selected vital signs using descriptive statistics. 
Table 4 specifies the criteria for identifying vital signs as potentially clinically significant
abnormal. Note that in order to be identified as potentially clinically significant abnormal, a 
value would need to meet both conditions below:  ie, have a value beyond the criterion value and 
a change of at least the magnitude specified in the change from baseline column.
Table 4:
Criteria for Potentially Clinically Significant Vital Signs
Vital Sign
Criterion value
Change relative to baseline
Pulse
120 bpm
Increase of 15
50 bpm
Decrease of 15
Systolic blood pressure
180 mm Hg
Increase of 20
90 mm Hg
Decrease of 20
Diastolic blood pressure
105 mm Hg
Increase of 15
50 mm Hg
Decrease of 15
Body temperature
≥38.3C
Change of 1.1C
A listing for potentially clinically significant abnormal vital signs will be presented.


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7.7.
Electrocardiography 
Shifts (normal and abnormal) from baseline to overall, weeks 2, 4, last visit, and follow-up will 
be summarized using patient counts.  For overall, the worst postbaseline finding (the abnormal 
finding if there are both normal and abnormal findings) for the patient will be summarized.  
Summary statistics for electrocardiogram variables will be presented at baseline, each visit, and 
last visit.  Electrocardiogram variables results and changes from baseline to each visit and last 
visit will be summarized using descriptive statistics. 
7.8.
Physical Examinations
Physical examinations, including height (to be obtained at the screening visit only) and weight 
will be performed at screening, baseline, week 2, week 4, follow-up, and early termination.   Any 
physical examination finding that is judged by the investigator as a clinically significant change 
(worsening) compared to a baseline value will be considered an adverse event and reported as 
such.
7.9.
Dermal Irritation Findings
Dermal irritation will be evaluated at baseline, week 2, week 4, follow-up, and early termination 
using the scale below:

0 = no evidence of irritation

1 = minimal erythema (barely perceptible)

2 = definite erythema, readily visible; minimal edema or minimal popular response

3 = erythema and papules

4 = definite edema

5 = erythema, edema, and papules

6 = vesicular eruption

7 = strong reaction spreading beyond test site
The frequency and percentage of patients falling into each scale at each visit and last visit will be 
descriptively summarized in the table. 
7.10.
Concomitant Medications
Concomitant medications will include all medications taken while the patient on study drug and 
are defined as any medications other than the study drug with stop dates on or after the first dose 
date. Medications with partial or missing stop dates will be assigned as concomitant medications 
unless the stop dates are apparently prior to the first dose date.
All concomitant medications will be coded using the WHO Drug Dictionary version March 2014 
enhanced B2 format. The incidence of concomitant medications will be summarized using 
descriptive statistics by therapeutic class and preferred term. Patients are counted only once in 
each therapeutic class category, and only once in each preferred term category. Concomitant 
medications will include all medications taken while the patient takes study drug.


Statistical Analysis Plan
Study TV45070-CNS-20013
39
8.
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS
The population pharmacokinetic analysis will be detailed in a separate analysis plan, and results 
will be reported separately from the main study results.  
The pharmacodyamic variables of maximal intensity of patients’ brush-evoked allodynia and 
maximal intensity of patients’ punctate-evoked hyperalgesia are detailed in section 6.3, 
Secondary Efficacy Variables and Analyses. Exploratory analyses may be reported separately 
from the main study results.


Statistical Analysis Plan
Study TV45070-CNS-20013
40
9.
STATISTICAL SOFTWARE
All data listings, summaries, and statistical analyses will be generated using SAS® version 9.3 or 
higher.


Statistical Analysis Plan
Study TV45070-CNS-20013
41
10.
CHANGES TO PROTOCOL SPECIFIED ANALYSES
Protocol Section 9.5.2, Demographics and Baseline Characteristics, states that treatment groups 
will be compared for all categorical variables using a Pearson chi-square (or Fisher’s exact test if 
cell sizes are too small). No comparisons will be done for demographic variables.
Protocol Section 9.6.1.1, Primary Efficacy Analysis, states that the MMRM model will analyze 
change from baseline in the weekly average of the daily average NRS scores at weeks 2 and 4 as 
the dependent variable. The change from baseline in the weekly average of the daily average 
NRS scores at weeks 1, 2, 3, and 4 will be used. Weeks 1 and 3 will also be included in the 
model.
Protocol Section 9.6.1.3, Secondary Efficacy Analysis, states that the time to reach ≥ 30% 
improvement in weekly average NRS scores from baseline will be summarized using descriptive 
statistics. This analysis will be reporting using Kaplan-Meier.


Statistical Analysis Plan
Study TV45070-CNS-20013
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11.
REFERENCES
Bouhassira D, Attal N, Fermanian J, Alchaar H, Gautron M, Masquelier E, Rostaing S, 
Lanteri-Minet M, Collin E, Grisart J, Boureau F. Development and validation of the Neuropathic 
Pain Symptom Inventory. Pain 2004; 108:248-257.
Hurst H, Bolton J. Assessing the clinical significance of change scores recorded on subjective
outcome measures. Journal of Manipulative Physiological Therapeutics (JMPT) 2004;27:26-35.
Poole H, Nurmikko T. Development and Preliminary Validation of the NePIQoL: A Quality-of-
Life Measure for Neuropathic Pain. Journal of Pain and Symptom Management 2009;37:233-
245.
National Research Council. The Prevention and Treatment of Missing Data in Clinical Trials. 
Panel on Handling Missing Data in Clinical Trials. Committee on National Statistics, Division of 
Behavioral and Social Sciences and Education. Washington, DC: The National Academies Press, 
2010.


Statistical Analysis Plan
Study TV45070-CNS-20013
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12.
LIST OF SUMMARIES AND LISTINGS
12.1.
Summary Tables
Summary 
number
Title
Population
15.1.1
Patient Disposition by Treatment Group
All Patients
15.1.2
Demographics by Treatment Group
Intent-to-Treat Population
15.1.3
Childbearing Potential by Treatment Group
Intent-to-Treat Population
15.1.4
General Medical History by Treatment Group
Intent-to-Treat Population
15.1.5
Prior Medications by Therapeutic Class, Preferred Term, and 
Treatment Group
Intent-to-Treat Population
15.1.6
Electrocardiogram Findings at Baseline by Treatment Group
Intent-to-Treat Population
15.1.7
Protocol Violations by Treatment Group
Intent-to-Treat Population
15.2.1.1
Summary of Change from Baseline in Weekly Average of the Daily 
Average NRS Pain Scores
Full Analysis Set
15.2.1.2
Summary of Change from Baseline in Weekly Average of the Daily 
Average NRS Pain Scores
Per Protocol Population
15.2.1.3
Sensitivity Analysis of Change from Baseline to Week 4 in  Weekly 
Average of the Daily Average NRS Pain Scores
Full Analysis Set
15.2.2.1
Summary of Change from Baseline in Weekly Average of Average 
NRS Pain Score Recorded in the Evening
Full Analysis Set
15.2.2.2
Summary of Change from Baseline in Weekly Average of Average 
NRS Pain Score Recorded in the Evening
Per Protocol Population
15.2.3.1
Summary of Change from Baseline in Weekly Average of Average 
NRS Pain Score Recorded in the Morning
Full Analysis Set
15.2.4.1
Summary of Change from Baseline in Weekly Average of Worst NRS 
Pain Score Recorded in the Evening
Full Analysis Set
15.2.5.1
Responder Rate in Weekly Average of the Daily Average NRS Pain 
Scores at Week 4
Full Analysis Set
15.2.5.2
Responder Rate in Weekly Average of the Daily Average NRS Pain 
Scores at Week 4
Per Protocol Population
15.2.6.1
Summary of Change from Baseline in Neuropathic Pain Symptom 
Inventory (NPSI)
Full Analysis Set
15.2.7.1
Summary of Change from Baseline to Week 4 in Neuropathic Pain 
Impact on Quality of Life (NePIQoL)
Full Analysis Set
15.2.8.1
Summary of PGIC Scores after 2 Weeks and 4 Weeks of Study Drug 
Treatment
Full Analysis Set
15.2.8.2
Summary of PGIC Scores after 2 Weeks and 4 Weeks of Study Drug 
Treatment
Per Protocol Population


Statistical Analysis Plan
Study TV45070-CNS-20013
44
Summary 
number
Title
Population
15.2.9.1
Summary of Change from Baseline in Daily Sleep Interference Scale 
(DSIS)
Full Analysis Set
15.2.9.2
Summary of Change from Baseline in Daily Sleep Interference Scale 
(DSIS)
Per Protocol Population
15.2.10.1
First Time to Reach 30% or More Sustained Improvement in Weekly 
Average of the Daily Average NRS Pain Scores
Full Analysis Set
15.2.11.1
Summary of Change from Baseline in Maximal Intensity of Brush-
Evoked Allodynia as Measured on 11-point NRS
Full Analysis Set
15.2.12.1
Summary of Change from Baseline in Maximal Intensity of  Punctate-
Evoked Hyperalgesia as Measured on 11-point NRS
Full Analysis Set
15.2.13.1
Full Analysis Set
15.2.13.2
Per Protocol Population
15.2.13.3
Full Analysis Set
15.2.13.4
Full Analysis Set
15.2.13.5
Full Analysis Set
15.2.13.6
Full Analysis Set
15.2.13.7
Per Protocol Population
15.2.13.8
Full Analysis Set
15.2.13.9
Full Analysis Set
15.2.13.10
Full Analysis Set
15.2.13.11
Full Analysis Set
15.2.13.12
Full Analysis Set
15.2.13.13
Full Analysis Set
15.2.13.14
Full Analysis Set


Statistical Analysis Plan
Study TV45070-CNS-20013
45
Summary 
number
Title
Population
15.2.14
Full Analysis Set
15.2.15.1
 
Full Analysis Set
15.2.15.2
 
Full Analysis Set
15.2.15.3
 
 
Full Analysis Set
15.2.15.4
 
 
Full Analysis Set
15.2.16
Association of CYP3A4 and CYP2C19 with Response Variables
Full Analysis Set
15.3.1.1
Study Drug Exposure by Treatment Group
Safety Analysis Set
15.3.1.2
Study Drug Compliance by Treatment Group
Safety Analysis Set
15.3.1.3
Pharmacokinetic Plasma Concentrations
Safety Analysis Set
15.3.2
Treatment Emergent Adverse Events by System Organ Class, Preferred 
Term, and Treatment Group
Safety Analysis Set
15.3.3
Treatment Emergent Adverse Events by System Organ Class, Preferred 
Term, Severity, and Treatment Group
Safety Analysis Set
15.3.4
Treatment-Related Adverse Events by System Organ Class, Preferred 
Term, and Treatment Group
Safety Analysis Set
15.3.5
Treatment-Related Adverse Events by System Organ Class, Preferred 
Term, Severity, and Treatment Group
Safety Analysis Set
15.3.6
Treatment Emergent Adverse Events by System Organ Class, Preferred 
Term, Causality, and Treatment Group
Safety Analysis Set
15.3.7
Treatment Emergent Serious Adverse Events by System Organ Class, 
Preferred Term, and Treatment Group
Safety Analysis Set
15.3.8
Treatment Emergent Adverse Events Causing Discontinuation From 
the Study by System Organ Class, Preferred Term, and Treatment 
Group
Safety Analysis Set
15.3.9
Treatment Emergent Non-Serious Adverse Events by System Organ 
Class, Preferred Term, and Treatment Group
Safety Analysis Set
15.3.10
Serum Chemistry Laboratory Tests Results and Changes From 
Baseline to Each Visit by Treatment Group
Safety Analysis Set
15.3.11
Hematology Laboratory Tests Results and Changes From Baseline to 
Each Visit by Treatment Group
Safety Analysis Set
15.3.12
Urinalysis Laboratory Tests Results and Changes From Baseline to 
Each Visit by Treatment Group
Safety Analysis Set
15.3.13
Serum Chemistry Laboratory Tests Results Shifts From Baseline to 
Each Visit by Treatment Group
Safety Analysis Set


Statistical Analysis Plan
Study TV45070-CNS-20013
46
Summary 
number
Title
Population
15.3.14
Hematology Laboratory Tests Results Shifts From Baseline to Each 
Visit by Treatment Group
Safety Analysis Set
15.3.15
Urinalysis Laboratory Tests Results Shifts From Baseline to Each Visit 
by Treatment Group
Safety Analysis Set
15.3.16
Serum Chemistry Laboratory Tests Potentially Clinically Significant 
Abnormal Results by Treatment Group 
Safety Analysis Set
15.3.17
Hematology Laboratory Tests Potentially Clinically Significant 
Abnormal Results by Treatment Group 
Safety Analysis Set
15.3.18
Urinalysis Laboratory Tests Potentially Clinically Significant 
Abnormal Results by Treatment Group 
Safety Analysis Set
15.3.19
Vital Signs Values and Changes From Baseline to Each Visit by 
Treatment Group
Safety Analysis Set
15.3.20
Vital Signs Potentially Clinically Significant Abnormal Values by 
Treatment Group
Safety Analysis Set
15.3.21
Electrocardiogram Findings Shifts From Baseline to Overall and Each 
Visit by Treatment Group
Safety Analysis Set
15.3.22
Electrocardiogram Variables Results and Changes From Baseline to 
Each Visit by Treatment Group
Safety Analysis Set
15.3.23
Dermal Irritation Finding at Each Visit by Treatment Group
Safety Analysis Set
15.3.24
Summary of Time (days) to First Application Site Skin Irritation by 
Treatment Group
Safety Analysis Set
15.3.25
Concomitant Medications by Therapeutic Class and Treatment Group
Safety Analysis Set
12.2.
Individual Patient Data Listings
Listing 
Number
Title
Population
16.2.1.1
Patient Disposition by Treatment Group
Intent-to-Treat Population
16.2.1.2
Patients Who Did Not Meet Screening Criteria
16.2.2
Protocol Violations by Treatment Group
Intent-to-Treat Population
16.2.4.1
Demographics by Treatment Group
Intent-to-Treat Population
16.2.4.2
Childbearing Potential by Treatment Group (Females Only)
Intent-to-Treat Population
16.2.4.3
Telephone Contact and Patient Continuation at Washout Period by 
Treatment Group
Intent-to-Treat Population
16.2.4.4
Medical History by Treatment Group
Intent-to-Treat Population
16.2.5.1
Study Drug Record by Treatment Group
Intent-to-Treat Population
16.2.5.2
Study Drug Accountability by Treatment Group
Intent-to-Treat Population
16.2.5.3
Rescue Drug Accountability by Treatment Group
Intent-to-Treat Population
16.2.5.4
Rescue Drug Record by Treatment Group
Intent-to-Treat Population
16.2.6.1
Numerical Rating Scale (NRS) Pain Scores by Treatment Group
Intent-to-Treat Population


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Listing 
Number
Title
Population
16.2.6.2
Neuropathic Pain Symptom Inventory (NPSI) by Treatment Group
Intent-to-Treat Population
16.2.6.3
Neuropathic Pain Impact on Quality of Life (NePIQoL) by Treatment 
Group
Intent-to-Treat Population
16.2.6.4
Patient Global Impression of Change (PGIC) by Treatment Group
Intent-to-Treat Population
16.2.6.5
Daily Sleep Interference Scale (DSIS) by Treatment Group
Intent-to-Treat Population
16.2.6.6
Brush-Evoked Allodynia and Punctate-Evoked Hyperalgesia by 
Treatment Group
Intent-to-Treat Population
16.2.6.7
Intent-to-Treat Population
16.2.6.8
Genetic Variables by Treatment Group
Intent-to-Treat Population
16.2.7.1
Adverse Events by Treatment Group
Intent-to-Treat Population
16.2.7.2
Deaths by Treatment Group
Intent-to-Treat Population
16.2.7.3
Serious Adverse Events by Treatment Group
Intent-to-Treat Population
16.2.7.4
Adverse Events Causing Discontinuation From the Study by Treatment 
Group
Intent-to-Treat Population
16.2.8.1
Laboratory Reference Ranges
16.2.8.2
Serum Chemistry Laboratory Tests Results by Treatment Group
Intent-to-Treat Population
16.2.8.3
Hematology and Coagulation Laboratory Tests Results by Treatment 
Group
Intent-to-Treat Population
16.2.8.4
Urinalysis Laboratory Tests Results by Treatment Group
Intent-to-Treat Population
16.2.8.5
Urine Drug Screen Results by Treatment Group
Intent-to-Treat Population
16.2.8.6
Pregnancy Test Results by Treatment Group (Females Only)
Intent-to-Treat Population
16.2.8.7
Serum Chemistry Laboratory Tests Potentially Clinically Significant
Abnormal Results by Treatment Group
Intent-to-Treat Population
16.2.8.8
Hematology Laboratory Tests Potentially Clinically Significant
Abnormal Results by Treatment Group
Intent-to-Treat Population
16.2.8.9
Urinalysis Laboratory Tests Potentially Clinically Significant
Abnormal Results by Treatment Group
Intent-to-Treat Population
16.2.8.10
Treatment Schedule
Intent-to-Treat Population
16.2.8.11
Vital Signs Values by Treatment Group
Intent-to-Treat Population
16.2.8.12
Vital Signs Potentially Clinically Significant Abnormal Values by 
Treatment Group
Intent-to-Treat Population
16.2.8.13
Electrocardiogram Findings by Treatment Group
Intent-to-Treat Population
16.2.8.14
Electrocardiogram Variable Results by Treatment Group
Intent-to-Treat Population
16.2.8.15
Dermal Irritation Evaluation by Treatment Group
Intent-to-Treat Population
16.2.8.16
Prior and Concomitant Medications by Treatment Group
Intent-to-Treat Population
16.2.8.17
Pharmacokinetic Plasma Concentrations
Intent-to-Treat Population


Statistical Analysis Plan
Study TV45070-CNS-20013
48
Listing 
Number
Title
Population
16.2.8.18
Adverse Events for Patients Who Did Not Meet Screening Criteria
12.3.
Graphs
Graph 
Number
Title
Population
17.1.1
Mean Weekly Average of the Daily Average NRS Pain Scores versus 
Week by Treatment Group 
Full Analysis Set
17.1.2
Mean Weekly Average of the Daily Average NRS Pain Scores versus 
Week by Treatment Group
Per Protocol Population
17.1.3
 
 
 
Full Analysis Set
17.1.4
 
 
 
Full Analysis Set
17.2
Mean Weekly Average of Average NRS Pain Score Recorded in the 
Evening versus Week by Treatment Group   
Full Analysis Set
17.3
Mean Weekly Average of Average NRS Pain Score Recorded in the 
Morning versus Week by Treatment Group
Full Analysis Set
17.4
Mean Weekly Average of the Worst NRS Pain Score Recorded in the 
Evening versus Week by Treatment Group
Full Analysis Set
17.5.1
Responder Rate versus Percent of Improvement from Baseline in 
Weekly Average of the Daily Average NRS Pain Score at Week 4
Full Analysis Set
17.5.2
Responder Rate versus Percent of Improvement from Baseline in 
Weekly Average of the Daily Average NRS Pain Score at Week 4
Per Protocol Population
17.5.3
 
Full Analysis Set
17.5.4
 
Per Protocol Population
17.6
Kaplan-Meier Plot of First Time to Reach 30% or More Sustained 
Improvement from Baseline in Weekly Average of the Daily Average 
NRS Pain Score
Full Analysis Set
17.7
Box Plot of PGIC Scores after 2 Weeks and 4 Weeks of Study Drug 
Treatment
Full Analysis Set