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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.