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

Study Overview
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Brief Summary
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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

Official Title
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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.

Conditions
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Postherpetic Neuralgia

Intervention / Treatment
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* Drug: TV-45070
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has chronic Postherpetic Neuralgia (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. Patient is ≥18 years of age, with a body mass index (BMI) between 18 and 34 kg/m2, inclusive, at the screening visit. If the patient is a woman and is 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 for the duration of the study, including follow-up. If the patient is a man and is capable of producing offspring, the patient must agree to use an acceptable method of contraception, unless the partner cannot become pregnant for the duration of the study, including follow-up. Patient must sign the written Informed Consent Form (ICF) for the study and be willing to comply with all study procedures and restrictions. Patient must be judged by the investigator to be medically healthy (except for PHN) and able to participate in the study Other criteria apply, please contact the investigator for more information Exclusion Criteria: Patient has any other severe pain that might confound assessment or self-evaluation of pain due to PHN. Patient has PHN affecting the face (trigeminal nerve distribution). 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). 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. Patient has been treated with topical capsaicin at any time in the past 6 months for neuropathic pain. Patient has a history of fibromyalgia. Other criteria apply, please contact the investigator for more information

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TV-45070 4%<br>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. | Drug: TV-45070<br>* TV-45070 is an ointment applied topically twice daily to area of pain.<br>* Other names: XEN402;|
| Experimental: TV-45070 8%<br>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. | Drug: TV-45070<br>* TV-45070 is an ointment applied topically twice daily to area of pain.<br>* Other names: XEN402;|
| Placebo Comparator: Placebo<br>Placebo ointment applied topically twice daily to the area of postherpetic neuralgia (PHN) pain during the treatment period from days 1 through 28. | Drug: Placebo<br>* The matching placebo ointment contained only the excipients of the active treatment; also applied topically twice daily to area of pain.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 4 in the Weekly Average of the Daily Average Numeric Rating Scale (NRS) Pain Scores Using a Mixed Model for Repeated Measures | The primary efficacy endpoint was the change from baseline to week 4 in the weekly average of the daily average NRS scores. The NRS is a widely-used, standard one-dimensional 11-point scale from 0=no pain to 10=worst pain imaginable as reported by patients. The daily average NRS scores is the average of the 2 NRS scores (recorded in the morning and evening) of average pain, defined as the patient-reported average pain intensity over the prior 12 hours. At least 1 of the 2 daily scores had to be recorded (non-missing) or the daily average was considered missing. Negative change from baseline values indicate a lessening of pain. The Mixed Model Repeated Measures (MMRM) model with change from baseline in the weekly average of the daily average NRS scores at week 4 as the dependent variable; week, pooled study center, treatment, and treatment by visit interaction as fixed factors, baseline weekly average of the daily average NRS scores as covariate; and patient as a random effect. | Baseline (day -7 to day -1), Week 4 (day 22 to day 28) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 4 in the Weekly Average of the Average Numeric Rating Scale (NRS) Pain Scores Recorded in the Evening Using a Mixed Model for Repeated Measures | The NRS is a widely-used, standard one-dimensional 11-point scale from 0=no pain to 10=worst pain imaginable as reported by patients. The NRS pain scores recorded in the evening is defined as the patient-reported average pain intensity over the prior 12 hours. Negative change from baseline values indicate a lessening of pain. The Mixed Model Repeated Measures (MMRM) model with change from baseline in the weekly average of the evening NRS scores at week 4 as the dependent variable; week, pooled study center, treatment, and treatment by visit interaction as fixed factors, baseline weekly average of the evening NRS scores as covariate; and patient as a random effect. | Baseline (day -7 to day -1), Week 4 (day 22 to day 28) | 
| Change From Baseline to Week 4 in the Weekly Average of the Average Numeric Rating Scale (NRS) Pain Scores Recorded in the Morning Using a Mixed Model for Repeated Measures | The NRS is a widely-used, standard one-dimensional 11-point scale from 0=no pain to 10=worst pain imaginable as reported by patients. The NRS pain scores recorded in the morning is defined as the patient-reported average pain intensity over the prior 12 hours. Negative change from baseline values indicate a lessening of pain. The Mixed Model Repeated Measures (MMRM) model with change from baseline in the weekly average of the evening NRS scores at week 4 as the dependent variable; week, pooled study center, treatment, and treatment by visit interaction as fixed factors, baseline weekly average of morning NRS scores as covariate; and patient as a random effect. | Baseline (day -7 to day -1), Week 4 (day 22 to day 28) | 
| Change From Baseline to Week 4 in the Weekly Average of the Worst Numeric Rating Scale (NRS) Pain Scores Recorded in the Evening Using a Mixed Model for Repeated Measures | The NRS is a widely-used, standard one-dimensional 11-point scale from 0=no pain to 10=worst pain imaginable as reported by patients. The worst pain is defined as the patient-reported worst pain intensity over the prior 24 hours. Negative change from baseline values indicate a lessening of pain. The Mixed Model Repeated Measures (MMRM) model with change from baseline in the weekly average of the worst pain NRS scores at week 4 as the dependent variable; week, pooled study center, treatment, and treatment by visit interaction as fixed factors, baseline weekly average of the evening NRS scores as covariate; and patient as a random effect. | Baseline (day -7 to day -1), Week 4 (day 22 to day 28) | 
| Percentage of Participants With >=30% and >=50% Improvement From Baseline in the Weekly Average of the Daily Average Numeric Rating Scale (NRS) Pain Scores at Week 4 Using a Mixed Model for Repeated Measures | The NRS is a 11-point scale from 0=no pain to 10=worst pain imaginable as reported by patients. The daily average NRS scores is the average of the 2 NRS scores (recorded in the morning and evening) of average pain, defined as the patient-reported average pain intensity over the prior 12 hours. Percent improvement is calculated as 100 × (the weekly average of the daily average NRS pain score at week 4 - weekly average of the daily average NRS pain scores at baseline /weekly average of the daily average NRS pain scores at baseline. Patients missing a week 4 average are considered non-responders (<50% improvement or <30% improvement). The Mixed Model Repeated Measures (MMRM) model with change from baseline in the weekly average of the daily average NRS scores at week 4 as the dependent variable; week, pooled study center, treatment, and treatment by visit interaction as fixed factors, baseline weekly average of the daily average NRS scores as covariate; and patient as a random effect. | Baseline (day -7 to day -1), Week 4 (day 22 to day 28) | 
| Change From Baseline to Weeks 2 and 4 in the Neuropathic Pain Symptom Inventory (NPSI) Total Score Using a Mixed Model for Repeated Measures (MMRM) | NPSI is a patient-reported questionnaire to evaluate the severity of different symptoms of neuropathic pain. The questionnaire contains 10 descriptors representing 5 distinct dimensions of pain: burning pain, deep pain, paroxysmal pain, evoked pain, and paresthesia/dysesthesia, plus 2 temporal items. Descriptors are scored from 0 through 10, where higher scores represent worse pain. The total score is the sum of the scores of the 10 descriptors (Bouhassira et al 2004). The total score ranges from 0 (no pain) through 100 (worst pain imaginable). If the score for one question was missing the total score was computed as 10 times sum of scores of 9 descriptors divided by 9. If more than one question was missing then the total score was missing. Negative change from baseline scores indicated less pain. The MMRM used pooled study center, week, treatment, and treatment by week interaction as fixed factors and patient as a random factor. | Baseline (day 1 prior to dosing), Weeks 2 (day 15) and Week 4 (day 29) | 
| Change From Baseline to Week 4 in the Neuropathic Pain Impact on Quality of Life (NePIQoL) Total Score | NePIQoL is a questionnaire that contains 41 items to evaluate quality of life in patients with neuropathic pain. Each question has responses ranging from strongly agree or always to strongly disagree or never. Questions are scored on a 5-point scale from 1 through 5, where higher scores represent greater pain-related interference in quality of life. Total range is 41 (great quality of life) to 205 (worst quality of life). Negative change from baseline scores indicated an improving quality of life. | Baseline (day 1), Week 4 (day 29) | 
| Participants' Global Assess of Treatment as Measured by the Patient Global Impression of Change (PGIC) at Weeks 2 and 4 Using a Mixed Model for Repeated Measures (MMRM) | PGIC is a standardized self-report tool that measures the change in a patient's overall status rating since the start of treatment on 7-point scale (Hurst and Bolton 2004). The 7-point scale is defined as: 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse. The MMRM used pooled study center, week, treatment, and treatment by week interaction as fixed factors and patient as a random factor. | Weeks 2 (day 15) and Week 4 (day 29) | 
| Change From Baseline to Weeks 2 and 4 in the Daily Sleep Interference Scale (DSIS) Using a Mixed Model for Repeated Measures | DSIS is an 11-point scale that asks the patient to select the number that best describes how much your pain has interfered with your sleep during the past 24 hours. Response options range from 0 (Did not interfere with sleep) to 10 (Completely interfered with sleep/unable to sleep due to pain). Negative change from baseline scores indicate improvement (lessening) of how much pain interfered with sleep. The MMRM used pooled study center, week, treatment, and treatment by week interaction as fixed factors and patient as a random factor. | Baseline (day 1 prior to dosing), Weeks 2 (day 15) and Week 4 (day 29) | 
| Kaplan-Meier Estimates for First Time to Reach 30% or More Sustained Improvement in Weekly Average of the Daily Average NRS Pain Scores | Percent improvement is calculated as 100*(the weekly average of the daily average NRS pain score - weekly average of the daily average NRS pain scores at baseline [days -7 to -1])/weekly average of the daily average NRS pain scores at baseline. Patients who do not reach >= 30% improvement are censored at their last non-missing weekly average. Patients who reach >= 30% improvement, but the improvement is not sustained through the end of the treatment period are censored at their last non-missing weekly average. For patients who reach >= 30% improvement that is sustained through the end through the end of the of the treatment, the time >= 30% improvement is first reached is used. | Baseline (days -7 to -1), Week 1 (days 1-7), Week 2 (day 8-14), Week 3 (days 15-21), Week 4 (days 22-29) | 
| Change From Baseline to Weeks 2 and 4 in Maximal Intensity of Brush-Evoked Allodynia as Measured on an 11-point Numeric Rating Scale (NRS) Using a Mixed Model for Repeated Measures (MMRM) | Allodynia refers to central pain sensitization (increased response of neurons) following normally non-painful, often repetitive, stimulation. In this case, pain evoked by innocuous brush is measured on an 11-point NRS where 0=no pain and 11=worst pain imaginable as reported by patients Negative change from baseline scores indicate improvement (lessening) of pain. | Baseline (day 1 prior to dosing), Weeks 2 (day 15) and Week 4 (day 29) | 
| Change From Baseline to Weeks 2 and 4 in Maximal Intensity of Punctate-Evoked Hyperalgesia as Measured on an 11-point Numeric Rating Scale (NRS) Using a Mixed Model for Repeated Measures (MMRM) | Hyperalgesia refers to increased pain from a stimulus that normally provokes pain. In this case, pain is evoked by punctate skin stimulation using a Medipin® and is measured on an 11-point NRS where 0=no pain and 11=worst pain imaginable as reported by patients. Negative change from baseline scores indicate improvement (lessening) of pain. The MMRM used pooled study center, week, treatment, and treatment by week interaction as fixed factors and patient as a random factor. The unstructured covariance matrix for repeated observations within patients was used. | Baseline (day 1 prior to dosing), Weeks 2 (day 15) and Week 4 (day 29) | 
| Participants With Treatment-Emergent Adverse Events | An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes. | day 1 up to day 57 |