Safety and Efficacy of EMA401 in Patients With Painful Diabetic Neuropathy (PDN)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate safety and efficacy of EMA401 compared to placebo in patients with painful diabetic neuropathy (PDN).

Detailed Description
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This was an interventional, randomized, parallel, placebo-controlled, double-blind treatment study consisting of 3 periods i.e. Screening, Treatment, and Treatment withdrawal. Patients were planned to be randomized in a 1:1 ratio to Placebo b.i.d. or EMA401 100 mg b.i.d.. Concomitant use of pregabalin or duloxetine at stable doses was allowed. Based on historical data, it was planned that the study would enroll approximately 50% of patients who were on stable doses of concomitant pregabalin or duloxetine in the study. At the end of treatment period the 100mg b.i.d. arm was 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 Trial to Determine the Safety and Efficacy of EMA401 in Reducing 24-hour Average Pain Intensity Score in Patients With Painful Diabetic Neuropathy (EMPADINE)

Conditions
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Painful Diabetic Neuropathy

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 Type I OR Type II diabetes mellitus (DM) with painful distal symmetrical sensorimotor neuropathy (ICD-10 code G63.2) of more than 6 months duration with any one or more of the following: Neuropathic symptoms (e.g. numbness, non-painful paresthesias or tingling, non-painful sensory distortions or misinterpretations, etc.) Decreased distal sensation (e.g. decreased vibration, pinprick sensation, light touch, etc.) Been assessed as suffering from moderate to severe neuropathic pain across the Screening epoch (NRS ≥ 4). A score of ≥4 on the Douleur Neuropathique en 4 Questions (DN4) questionnaire at Screening. Exclusion Criteria: Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they were using highly effective methods of contraception during dosing and for 3 days after stopping of study medication. Highly effective contraception methods included: Total abstinence (when this was is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal were not acceptable methods of contraception. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman had been confirmed by follow up hormone level assessment. Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should have been the sole partner for that subject. Placement of an intrauterine device (IUD) or intrauterine system (IUS). History or current diagnosis of electrocardiogram (ECG) abnormalities indicating significant risk of safety for patients participating in the study. 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. 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. Participants whose glycemic control had been unstable within 3 months immediately prior to screening (e.g., ketoacidosis requiring hospitalization, any recent episode of hypoglycemia requiring assistance through medical intervention, uncontrolled hyperglycemia) Patients who had any differential diagnosis of PDN including but not limited to other neuropathies (e.g. Vitamin B12 deficiency, Chronic Inflammatory Demyelinating Polyneuropathy), polyradiculopathies, central disorders (e.g. demyelinating disease), or rheumatological disease (e.g., foot arthritis, plantar fasciitis). Patient was unwilling or unable to complete daily eDiary.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EMA401<br>During the treatment epoch, patients will receive EMA401 for 12 weeks. During the treatment withdrawal epoch, patients will receive EMA401 or matching placebo for 1 week. | Drug: EMA401<br>* capsules, oral<br>Drug: Placebo<br>* Placebo to EMA401 capsules, oral<br>|
| Placebo Comparator: Placebo<br>Participants will receive matching placebo to EMA401 during both the treatment and treatment withdrawal epochs for a total of 13 weeks. | Drug: Placebo<br>* Placebo to EMA401 capsules, oral<br>|

What is the study measuring?
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Primary 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 scale with zero being does not interfere and ten being completely interferes. The BPI total score is the sum of the 7 items. Each item ranges from 0 to 10, thus the total score ranges from 0 to 70. Lower values indicate a better outcome. | 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% 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. 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. The scale consists of 7 items. The sum of seven items represents the total score. Each of the 7 items is scored using a range from 0 to 4, thus the total score values ranges from zero to 28. 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 (Prior dose, 1-3 hours, 4-6 hours), Week 12 (Prior dose, 1-3 hours, 4-6 hours) | 
| Percentage of Patients Who Required Rescue Medication in Double-blind Treatment Period | Patients were allowed to take acetaminophen/paracetamol up to a maximum of 3 g daily (divided into 4 times/day) for unacceptable pain due to any reason during the study. This medication use was to be recorded in eDiary prior to use. Percentages of patients presented are those who required rescue meds within 7 days prior to visit. | Baseline and weekly up to 12 weeks, once during double-blind period | 
| Percentage of Patients Who Required Rescue Medication in Treatment Withdrawal Period | Patients were allowed to take acetaminophen/paracetamol up to a maximum of 3 g daily (divided into 4 times/day) for unacceptable pain due to any reason during the study. This medication use was to be recorded in eDiary prior to use. Percentages of patients presented are those who required rescue meds within 7 days prior to visit. | Week 12 to Week 13 (planned duration subject to varibility in visit scheduling) | 
| Time to First Rescue Medication Intake | Patients were allowed to take acetaminophen/paracetamol up to a maximum of 3 g daily (divided into 4 times/day) for unacceptable pain due to any reason during the study. This medication use was to be recorded in eDiary prior to use. Patients who did not take any rescue medication were censored at the last date of double-blind treatment period. | Baseline up to day 92 | 
| 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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Painful diabetic neuropathy, Neuropathic pain, Angiotensin II type 2 receptor antagonist, adult, EMA401, diabetic neuropathy