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

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

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

Eligibility Criteria:
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.