Dose Response Study of EMA401 in Patients With Post-herpetic Neuralgia (PHN)

Study Overview
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Brief Summary
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This study was designed to characterize dose response, and evaluate safety and efficacy of three different doses of EMA401 compared to placebo in patients with post-herpetic neuralgia (PHN).

Detailed Description
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This was an interventional, randomized, parallel, placebo-controlled, dose ranging, double-blind treatment study consisting of 3 periods i.e. Screening, Treatment, and Treatment withdrawal. The study was planned in two cohorts. The initial cohort had three treatment arms i.e. Placebo b.i.d., EMA401 25 mg b.i.d., or EMA401 100 mg b.i.d. Following an unblinded safety review by an independent DMC, the second cohort was to have been initiated with an additional treatment arm i.e. EMA401 300 mg b.i.d.. Due to the premature study termination, the second cohort was not initiated. At the end of treatment period the 25mg BID and 100mg BID arms were re-randomized (1:1) to the same treatment or placebo. Placebo arm stayed on placebo. The planned duration of treatment period was 12 weeks and 1 week of treatment withdrawal at the end of treatment period. The study was terminated early due to pre-clinical toxicity data that became available after start of trial. Novartis implemented a Urgent Safety Measure (USM) which instructed sites to discontinue study treatment immediately and to have all patients return for additional laboratory assessments (full hematology including coagulation and clinical chemistry panel). Safety data from the USM was presented as a separate outcome measure table and not included in the Adverse Event section.

Official Title
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A Double-blind, Placebo-controlled, Randomized Dose Ranging Trial to Determine the Safety and Efficacy of Three Dose Levels of EMA401 in Reducing 24-hour Average Pain Intensity Score in Patients With Post-herpetic Neuralgia

Conditions
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Post-herpetic Neuralgia

Intervention / Treatment
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* Drug: EMA401
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At the time of Screening, must have had documented diagnosis of PHN (ICD-10 code B02.29), defined as pain in the region of the rash persisting for more than 6 months after onset of herpes zoster rash. Assessed as suffering from moderate to severe neuropathic pain across the Screening epoch (NRS ≥ 4). Patients must have had documented past and/or ongoing inadequate treatment response (having insufficient pain relief with treatment or inability to tolerate) to at least 2 different prescribed therapies commonly used to treat and considered effective by the Investigator for the treatment of PHN. Patient must have been willing to complete daily eDiary Exclusion Criteria: History or had current diagnosis of electrocardiogram (ECG) abnormalities indicating significant risk of safety for patients participating in the study Had a major depressive episode within 6 months prior to Screening and/or a history of diagnosed recurrent major depressive disorder according to Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V) diagnostic criteria Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant. Had evidence of significant renal insufficiency or pre-existing liver condition Had platelets ≤ 100 x 10^9/L, or neutrophil count < 1.2 x 10^9/L (or equivalent), hemoglobin ≤ 100 g/L for women or hemoglobin ≤ 110 g/L for men. Patients who had a known diagnosis of diabetes and are stable on medication with a hemoglobin A1c > 8%. Those who did not have a known diagnosis of diabetes with a hemoglobin A1c > 7%.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EMA401 25mg BID<br>Ema401 25 mg was administered orally twice a day | Drug: EMA401<br>* EMA401<br>|
| Experimental: EMA401 100mg BID<br>Ema401 100 mg was administered orally twice a day | Drug: EMA401<br>* EMA401<br>|
| Placebo Comparator: Placebo BID<br>Matching placebo capsules administered orally twice a day | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-response in Change in Weekly Mean of the 24-hour Average Pain Score, Using an 11-point Numeric Rating Scale (NRS), From Baseline to Week 12 | Since the 300 mg b.i.d. dose of EMA401 could not be initiated in the study due to premature study termination, the dose-response characterization was not performed. Specifically, only the trend test deduced from the set of candidate models was performed but the dose response estimation was not conducted. | Baseline up to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Weekly Mean 24-hour Average Pain Score Using the 11 Point Numerical Rating Scale (NRS) From Baseline to Week 12 | The NRS is an 11-point scale ranging from zero (no pain) to ten (pain as bad as you can imagine) for self-reporting of pain by patients. The following parameters were evaluated using the 11-point NRS: 24-hour Average Pain Score and 24-hour Worst Pain Score Patients evaluated their average pain and worst pain during the past 24 hours in the evening prior to sleep by touching the appropriate corresponding number between zero and ten on a eDiary device. | Baseline up to Week 12 | 
| Change in Brief Pain Inventory-Short Form Interference (BPI-SF) Mean Total Score From Baseline to Week 12 | The BPI-SF is a validated, self-administered (at clinic) questionnaire that assesses pain severity and its mpact on daily functions. Patients were asked to complete the 7-item pain interference scale that assessed the degree to which pain interfered with walking and other physical activity, work, mood, relations with others and sleep using a zero to ten numeric rating scale (NRS) with zero being does not interfere and ten being completely interferes. A reduction in mean indicates improvement | Baseline up to Week 12 | 
| Change in Weekly Mean of the 24-hour Worst Pain Score, Using an 11-point NRS, From Baseline to Week 12 | The NRS is an 11-point scale ranging from zero (no pain) to ten (pain as bad as you can imagine) for self-reporting of pain by patients. The following parameters were evaluated using the 11-point NRS: 24-hour Average Pain Score and 24-hour Worst Pain Score Patients evaluated their average pain and worst pain during the past 24 hours in the evening prior to sleep by touching the appropriate corresponding number between zero and ten on a eDiary device. | Baseline up to Week 12 | 
| Number of Participants Per Patient Global Impression of Change Category at Week 12 | The Patient Global Impression of Change (PGIC) is a patient-reported instrument that measures change in overall status on a scale ranging from one (very much improved) to seven (very much worse). The PGIC is based on the validated Clinical Global Impression of Change scale. The PGIC was to be completed by patients using the electronic tablet at the site | Baseline up to Week 12 | 
| Percentage of Patients Achieving at Least 30% Pain Reduction at Week 12 on NRS 11 Point Scale | The NRS is an 11-point scale ranging from zero (no pain) to ten (pain as bad as you can imagine) for self-reporting of pain by patients. The number of patients with observed response, i.e. a decrease of 30% /50% units in weekly mean of the 24-hour average pain score NRS. Logistic regression model with region, treatment, sex, use of PHN medications (yes/no) as factors and age and baseline NRS as covariates. An odds ratio >1 = higher chance of a clinically important improvement. | Baseline up to Week 12 | 
| Percentage of Patients Achieving at Least 50% Pain Reduction at Week 12 on NRS 11 Point Scale | The NRS is an 11-point scale ranging from zero (no pain) to ten (pain as bad as you can imagine) for self-reporting of pain by patients. The number of patients with observed response, i.e. a decrease of 50% units in weekly mean of the 24-hour average pain score NRS. Logistic regression model with region, treatment, sex, use of PHN medications (yes/no) as factors and age and baseline NRS as covariates. An odds ratio >1 = higher chance of a clinically important improvement. | Baseline up to Week 12 | 
| Mean Change in Insomnia Severity Index (ISI) From Baseline to Week 12 | Patients were asked to complete the ISI using five-point Likert-style scale as a measure of perceived sleep difficulties. Scores ranged from zero to 28, with a cut-off score of eight suggesting the presence of sub-threshold insomnia. The questionnaire assessed the severity of insomnia, satisfaction with current sleep pattern, sleep interference, noticeability of sleeping problem to others and concern about sleeping problems. | Baseline up to Week 12 | 
| Change in Neuropathic Pain Symptom Inventory (NPSI) From Baseline to Week 12 | The Neuropathic Pain Symptom Inventory (NPSI) is a 12 item patient reported outcome measure that contains 10 descriptors representing 5 dimensions of pain (burning pain, deep/pressing pain, paroxysmal pain, evoked pain and paraesthesia/dysesthesia) and 2 temporal items designed to assess pain duration and the number of pain paroxysms. The sum of the responses to the 10 questions (all except temporal questions) was regarded as the total score and was divided by 10 (10 questions). The range of the total score and of the 5 dimensional scores is 0 to 10. Lower values represent better outcomes. | Baseline up to Week 12 | 
| Plasma Pharmacokinetics (PK) Concentrations at Week 8 and 12 | Due to the premature termination of the study, the number of patients and observations providing PK data was much smaller than planned, and no PK model was developed. As a consequence, no PK parameters (Cmax, Tmax, AUC) were derived for this study. Only, summary statistics of the plasma concentrations were calculated | Week 8, Week 12 | 
| Exposure-response (Decrease in Pain Intensity) Via Evaluation of Effect of EMA401 Exposure on Efficacy Variables (e.g. Change From Baseline of Pain Score), Via Descriptive Pharmacokinetics/ Pharmacodynamics (PK/PD) | Due to the premature termination of the study, the number of patients providing data for PKPD analysis data was much smaller than planned and no model to correlate drug exposure (PK) with the change in the pain score (PD) was developed | Baseline, Week 8, Week 12 | 
| Treatment Emergent Adverse Events During Urgent Safety Measure (USM) Follow-Up | Participants were instructed to stop taking drug immediately upon termination of study and asked to come in for two unscheduled visits for follow up safety assessments | Approximately from 3 weeks after end of study up to 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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post-herpetic neuralgia, neuropathic pain, angiotensin II type 2 receptor antagonist, dose ranging