Clinical trial NCT03297294: Safety and Efficacy of EMA401 in Patients With Painful Diabetic Neuropathy (PDN)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Painful Diabetic Neuropathy
Keywords: Painful diabetic neuropathy
Neuropathic pain
Angiotensin II type 2 receptor antagonist
adult
EMA401
diabetic neuropathy
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2017-09-29
Enrollment: 142
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Primary outcomes:
measure: Change in Weekly Mean 24-hour Average Pain Score Using the 11 Point Numerical Rating Scale (NRS) From Baseline to Week 12
timeFrame: Baseline up to Week 12
Secondary outcomes:
measure: Change in Neuropathic Pain Symptom Inventory (NPSI) From Baseline to Week 12
timeFrame: Baseline up to Week 12
measure: Change in Brief Pain Inventory-Short Form Interference (BPI-SF) Mean Total Score From Baseline to Week 12
timeFrame: Baseline up to Week 12
measure: Change in Weekly Mean of the 24-hour Worst Pain Score, Using an 11-point NRS, From Baseline to Week 12
timeFrame: Baseline up to Week 12
measure: Number of Participants Per Patient Global Impression of Change Category at Week 12
timeFrame: Baseline up to Week 12
measure: Percentage of Patients Achieving at Least 30% Pain Reduction at Week 12 on NRS 11 Point Scale
timeFrame: Baseline up to Week 12
measure: Percentage of Patients Achieving at Least 50% Pain Reduction at Week 12 on NRS 11 Point Scale
timeFrame: Baseline up to Week 12
measure: Mean Change in Insomnia Severity Index (ISI) From Baseline to Week 12
timeFrame: Baseline up to Week 12
measure: Plasma Pharmacokinetics (PK) Concentrations at Week 8 and 12
timeFrame: Week 8 (Prior dose, 1-3 hours, 4-6 hours), Week 12 (Prior dose, 1-3 hours, 4-6 hours)
measure: Percentage of Patients Who Required Rescue Medication in Double-blind Treatment Period
timeFrame: Baseline and weekly up to 12 weeks, once during double-blind period
measure: Percentage of Patients Who Required Rescue Medication in Treatment Withdrawal Period
timeFrame: Week 12 to Week 13 (planned duration subject to varibility in visit scheduling)
measure: Time to First Rescue Medication Intake
timeFrame: Baseline up to day 92
measure: Treatment Emergent Adverse Events During Urgent Safety Measure (USM) Follow-Up
timeFrame: Approximately from 3 weeks after end of study up to 16 weeks
Other outcomes:
Locations:
city: Broadmeadow
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Orange
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Adelaide
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Heidelberg Heights
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Graz
country: Austria
facility: Novartis Investigative Site
city: Klagenfurt
country: Austria
facility: Novartis Investigative Site
city: Wien
country: Austria
facility: Novartis Investigative Site
city: Edegem
country: Belgium
facility: Novartis Investigative Site
city: Liege
country: Belgium
facility: Novartis Investigative Site
city: Pellenberg
country: Belgium
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
state: Sofia-Grad
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Ontario
country: Canada
facility: Novartis Investigative Site
state: CAN
city: Thornhill
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Laval
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Aarhus
country: Denmark
facility: Novartis Investigative Site
city: Gentofte
country: Denmark
facility: Novartis Investigative Site
city: Odense C
country: Denmark
facility: Novartis Investigative Site
city: Tampere
country: Finland
facility: Novartis Investigative Site
city: Boulogne Billancourt
country: France
facility: Novartis Investigative Site
city: Bielefeld
country: Germany
facility: Novartis Investigative Site
city: Duesseldorf
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Halle (Saale)
country: Germany
facility: Novartis Investigative Site
city: Kassel
country: Germany
facility: Novartis Investigative Site
city: Kiel
country: Germany
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Wiesbaden
country: Germany
facility: Novartis Investigative Site
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
state: HUN
city: Esztergom
country: Hungary
facility: Novartis Investigative Site
state: HUN
city: Szeged
country: Hungary
facility: Novartis Investigative Site
state: HUN
city: Balatonfured
country: Hungary
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Kistarcsa
country: Hungary
facility: Novartis Investigative Site
city: Pecs
country: Hungary
facility: Novartis Investigative Site
city: Szeged
country: Hungary
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Krakow
country: Poland
facility: Novartis Investigative Site
state: POL
city: Bialystok
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Caldas da Rainha
country: Portugal
facility: Novartis Investigative Site
city: Lisboa
country: Portugal
facility: Novartis Investigative Site
city: Matosinhos
country: Portugal
facility: Novartis Investigative Site
city: Porto
country: Portugal
facility: Novartis Investigative Site
city: Viana do Castelo
country: Portugal
facility: Novartis Investigative Site
city: Vila Nova de Gaia
country: Portugal
facility: Novartis Investigative Site
city: Lucenec
country: Slovakia
facility: Novartis Investigative Site
state: Slovak Republic
city: Bratislava
country: Slovakia
facility: Novartis Investigative Site
city: Bratislava
country: Slovakia
facility: Novartis Investigative Site
city: Presov
country: Slovakia
facility: Novartis Investigative Site
city: Presov
country: Slovakia
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Bradford
country: United Kingdom
facility: Novartis Investigative Site
state: West Yorkshire
city: Bath
country: United Kingdom
facility: Novartis Investigative Site
city: Bournemouth
country: United Kingdom
facility: Novartis Investigative Site
city: Edinburgh
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Middlesborough
country: United Kingdom
facility: Novartis Investigative Site
city: Oldham
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Rice ASC, Dworkin RH, Finnerup NB, Attal N, Anand P, Freeman R, Piaia A, Callegari F, Doerr C, Mondal S, Narayanan N, Ecochard L, Flossbach Y, Pandhi S. Efficacy and safety of EMA401 in peripheral neuropathic pain: results of 2 randomised, double-blind, phase 2 studies in patients with postherpetic neuralgia and painful diabetic neuropathy. Pain. 2021 Oct 1;162(10):2578-2589. doi: 10.1097/j.pain.0000000000002252.