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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03297294
Registration number
NCT03297294
Ethics application status
Date submitted
26/09/2017
Date registered
29/09/2017
Date last updated
8/10/2021
Titles & IDs
Public title
Safety and Efficacy of EMA401 in Patients With Painful Diabetic Neuropathy (PDN)
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Scientific 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)
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Secondary ID [1]
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2016-000281-39
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Secondary ID [2]
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CEMA401A2202
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Universal Trial Number (UTN)
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Trial acronym
EMPADINE
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Painful Diabetic Neuropathy
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Condition category
Condition code
Neurological
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Other neurological disorders
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Metabolic and Endocrine
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Diabetes
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - EMA401
Treatment: Drugs - Placebo
Experimental: EMA401 - 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.
Placebo Comparator: Placebo - Participants will receive matching placebo to EMA401 during both the treatment and treatment withdrawal epochs for a total of 13 weeks.
Treatment: Drugs: EMA401
capsules, oral
Treatment: Drugs: Placebo
Placebo to EMA401 capsules, oral
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Change in Weekly Mean 24-hour Average Pain Score Using the 11 Point Numerical Rating Scale (NRS) From Baseline to Week 12
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Assessment method [1]
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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.
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Timepoint [1]
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Baseline up to Week 12
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Secondary outcome [1]
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Change in Neuropathic Pain Symptom Inventory (NPSI) From Baseline to Week 12
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Assessment method [1]
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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.
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Timepoint [1]
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Baseline up to Week 12
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Secondary outcome [2]
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Change in Brief Pain Inventory-Short Form Interference (BPI-SF) Mean Total Score From Baseline to Week 12
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Assessment method [2]
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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.
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Timepoint [2]
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Baseline up to Week 12
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Secondary outcome [3]
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Change in Weekly Mean of the 24-hour Worst Pain Score, Using an 11-point NRS, From Baseline to Week 12
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Assessment method [3]
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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.
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Timepoint [3]
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Baseline up to Week 12
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Secondary outcome [4]
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Number of Participants Per Patient Global Impression of Change Category at Week 12
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Assessment method [4]
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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
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Timepoint [4]
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Baseline up to Week 12
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Secondary outcome [5]
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Percentage of Patients Achieving at Least 30% Pain Reduction at Week 12 on NRS 11 Point Scale
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Assessment method [5]
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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.
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Timepoint [5]
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Baseline up to Week 12
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Secondary outcome [6]
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Percentage of Patients Achieving at Least 50% Pain Reduction at Week 12 on NRS 11 Point Scale
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Assessment method [6]
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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.
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Timepoint [6]
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Baseline up to Week 12
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Secondary outcome [7]
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Mean Change in Insomnia Severity Index (ISI) From Baseline to Week 12
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Assessment method [7]
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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.
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Timepoint [7]
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Baseline up to Week 12
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Secondary outcome [8]
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Plasma Pharmacokinetics (PK) Concentrations at Week 8 and 12
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Assessment method [8]
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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
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Timepoint [8]
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Week 8 (Prior dose, 1-3 hours, 4-6 hours), Week 12 (Prior dose, 1-3 hours, 4-6 hours)
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Secondary outcome [9]
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Percentage of Patients Who Required Rescue Medication in Double-blind Treatment Period
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Assessment method [9]
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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.
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Timepoint [9]
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Baseline and weekly up to 12 weeks, once during double-blind period
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Secondary outcome [10]
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Percentage of Patients Who Required Rescue Medication in Treatment Withdrawal Period
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Assessment method [10]
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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.
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Timepoint [10]
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Week 12 to Week 13 (planned duration subject to varibility in visit scheduling)
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Secondary outcome [11]
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Time to First Rescue Medication Intake
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Assessment method [11]
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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.
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Timepoint [11]
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Baseline up to day 92
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Secondary outcome [12]
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Treatment Emergent Adverse Events During Urgent Safety Measure (USM) Follow-Up
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Assessment method [12]
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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
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Timepoint [12]
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Approximately from 3 weeks after end of study up to 16 weeks
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Eligibility
Key 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.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Terminated
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
14/03/2018
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
25/03/2019
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Sample size
Target
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Accrual to date
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Final
142
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Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
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Recruitment hospital [1]
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Novartis Investigative Site - Broadmeadow
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Recruitment hospital [2]
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Novartis Investigative Site - Orange
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Recruitment hospital [3]
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Novartis Investigative Site - Adelaide
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Recruitment hospital [4]
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Novartis Investigative Site - Heidelberg Heights
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Recruitment postcode(s) [1]
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2292 - Broadmeadow
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Recruitment postcode(s) [2]
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2800 - Orange
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Recruitment postcode(s) [3]
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5000 - Adelaide
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Recruitment postcode(s) [4]
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3081 - Heidelberg Heights
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Recruitment outside Australia
Country [1]
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Austria
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Graz
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Austria
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Klagenfurt
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Austria
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Wien
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Belgium
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Edegem
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Belgium
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Liege
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Belgium
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Pellenberg
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Bulgaria
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Sofia-Grad
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Bulgaria
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Sofia
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Canada
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CAN
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Canada
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Ontario
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Canada
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Denmark
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Aarhus
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Denmark
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Gentofte
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Odense C
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Tampere
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France
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Boulogne Billancourt
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Bielefeld
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Germany
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Duesseldorf
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Germany
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Essen
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Germany
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Kassel
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Germany
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Kiel
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Germany
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Leipzig
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Germany
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Wiesbaden
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HUN
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Hungary
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Balatonfured
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Hungary
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Budapest
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Szeged
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Norway
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Oslo
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Bialystok
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Lisboa
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Matosinhos
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Portugal
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Porto
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Portugal
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Viana do Castelo
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Portugal
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Vila Nova de Gaia
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Presov
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Madrid
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Bath
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Bournemouth
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London
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Middlesborough
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United Kingdom
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Oldham
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Novartis Pharmaceuticals
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Address
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Country
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Ethics approval
Ethics application status
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Summary
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).
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03297294
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Novartis Pharmaceuticals
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Address
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Novartis Pharmaceuticals
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03297294
Download to PDF