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NCT03297294: EMPADINE

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

Terminated Phase 2 Results posted Last updated 8 October 2021
What this trial tests

Phase 2 trial testing EMA401 in Painful Diabetic Neuropathy in 142 participants. Terminated before completion.

Timeline
14 March 2018
Primary endpoint
25 March 2019
25 March 2019

Quick facts

Lead sponsorNovartis Pharmaceuticals
PhasePhase 2
StatusTerminated
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingtriple
Primary purposetreatment
Enrollment142
Start date14 March 2018
Primary completion25 March 2019
Estimated completion25 March 2019
Sites64 locations across Denmark, France, Finland, Slovakia, Belgium, Austria, United Kingdom, Germany

Drugs / interventions tested

Conditions studied

Sponsor

Novartis Pharmaceuticals — full company profile →

Who can join

18 and older, any sex, with Painful Diabetic Neuropathy. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change in Weekly Mean 24-hour Average Pain Score Using the 11 Point Numerical Rating Scale (NRS) From Baseline to Week 12 Primary · Baseline up 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.

Week 4
GroupValue95% CI
EMA401 100mg BID DB-1.0± 0.21
Placebo BID DB-0.8± 0.18
Week 8
GroupValue95% CI
EMA401 100mg BID DB-1.7± 0.29
Placebo BID DB-1.1± 0.26
Week 12
GroupValue95% CI
EMA401 100mg BID DB-1.9± 0.31
Placebo BID DB-1.3± 0.27
Change in Neuropathic Pain Symptom Inventory (NPSI) From Baseline to Week 12 Secondary · Baseline up 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.

Week 4
GroupValue95% CI
EMA401 100mg BID DB-1.2± 0.19
Placebo BID DB-1.0± 0.18
Week 8
GroupValue95% CI
EMA401 100mg BID DB-1.3± 0.25
Placebo BID DB-0.9± 0.22
Week 12
GroupValue95% CI
EMA401 100mg BID DB-1.6± 0.32
Placebo BID DB-1.1± 0.26
Change in Brief Pain Inventory-Short Form Interference (BPI-SF) Mean Total Score From Baseline to Week 12 Secondary · Baseline up 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.

GroupValue95% CI
EMA401 100mg BID DB-12.03± 13.336
Placebo BID DB-10.83± 14.602
Change in Weekly Mean of the 24-hour Worst Pain Score, Using an 11-point NRS, From Baseline to Week 12 Secondary · Baseline up 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.

GroupValue95% CI
EMA401 100mg BID DB-1.63± 1.837
Placebo BID DB-1.28± 1.577
Number of Participants Per Patient Global Impression of Change Category at Week 12 Secondary · Baseline up to 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

Very much improved
GroupValue95% CI
EMA401 100mg BID DB4
Placebo BID DB2
Much improved
GroupValue95% CI
EMA401 100mg BID DB7
Placebo BID DB11
Minimally improved
GroupValue95% CI
EMA401 100mg BID DB17
Placebo BID DB18
No change
GroupValue95% CI
EMA401 100mg BID DB18
Placebo BID DB14
Minimally worse
GroupValue95% CI
EMA401 100mg BID DB3
Placebo BID DB2
Much worse
GroupValue95% CI
EMA401 100mg BID DB0
Placebo BID DB0
Very much worse
GroupValue95% CI
EMA401 100mg BID DB0
Placebo BID DB0
Missing
GroupValue95% CI
EMA401 100mg BID DB21
Placebo BID DB20
Percentage of Patients Achieving at Least 30% Pain Reduction at Week 12 on NRS 11 Point Scale Secondary · Baseline up 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 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.

Week 4 - at least 30% pain reduction
GroupValue95% CI
EMA401 100mg BID DB34.0
Placebo BID DB24.7
Week 12 - at least 30% pain reduction
GroupValue95% CI
EMA401 100mg BID DB52.7
Placebo BID DB40.4
Percentage of Patients Achieving at Least 50% Pain Reduction at Week 12 on NRS 11 Point Scale Secondary · Baseline up 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 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.

GroupValue95% CI
EMA401 100mg BID DB31.4
Placebo BID DB14.1
Mean Change in Insomnia Severity Index (ISI) From Baseline to Week 12 Secondary · Baseline up 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.

GroupValue95% CI
EMA401 100mg BID DB-4.00± 4.854
Placebo BID DB-1.03± 6.312
Plasma Pharmacokinetics (PK) Concentrations at Week 8 and 12 Secondary · Week 8 (Prior dose, 1-3 hours, 4-6 hours), Week 12 (Prior dose, 1-3 hours, 4-6 hours)

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
GroupValue95% CI
EMA401 100mg BID DB30.5± 126.6
Week 8 1-3 hours
GroupValue95% CI
EMA401 100mg BID DB205.1± 212.8
Week 8 4-6 hours
GroupValue95% CI
EMA401 100mg BID DB72.8± 115.2
Week 12 Prior dose
GroupValue95% CI
EMA401 100mg BID DB29.5± 209.3
Week 12 1-3 hours
GroupValue95% CI
EMA401 100mg BID DB118.4± 278.3
Week 12 4-6 hours
GroupValue95% CI
EMA401 100mg BID DB89.8± 117.0
Percentage of Patients Who Required Rescue Medication in Double-blind Treatment Period Secondary · Baseline and weekly up to 12 weeks, once during double-blind 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 1
GroupValue95% CI
EMA401 100mg BID DB13.0
Placebo BID DB10.6
Week 2
GroupValue95% CI
EMA401 100mg BID DB7.7
Placebo BID DB9.5
Week 4
GroupValue95% CI
EMA401 100mg BID DB8.6
Placebo BID DB7.0
Week 6
GroupValue95% CI
EMA401 100mg BID DB7.8
Placebo BID DB7.5
Week 8
GroupValue95% CI
EMA401 100mg BID DB9.3
Placebo BID DB9.5
Week 10
GroupValue95% CI
EMA401 100mg BID DB5.3
Placebo BID DB13.2
Week 12
GroupValue95% CI
EMA401 100mg BID DB2.9
Placebo BID DB8.6
At least once during double-blind period
GroupValue95% CI
EMA401 100mg BID DB20.0
Placebo BID DB19.4
Percentage of Patients Who Required Rescue Medication in Treatment Withdrawal Period Secondary · Week 12 to Week 13 (planned duration subject to varibility in visit scheduling)

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.

GroupValue95% CI
EMA401 100mg BID -> EMA401 100mg BID TW14.3
EMA401 100mg BID -> Placebo BID TW8.3
Placebo BID -> Placebo BID TW7.4
Time to First Rescue Medication Intake Secondary · Baseline up to day 92

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.

GroupValue95% CI
EMA401 100mg BID DB44.02 – 90
Placebo BID DB56.52 – 92

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events were collected from first dose of study treatment until end of study treatment plus 21 days post treatment, up to maximum duration of 111 days. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

EMA401 100mg BID DB
Serious: 5/69 (7%)
Deaths: 0/69
Placebo BID DB
Serious: 3/66 (5%)
Deaths: 0/66
EMA401 100mg BID -> EMA401 100mg BID TW
Serious: 0/14 (0%)
Deaths: 0/14
EMA401 100mg BID -> Placebo BID TW
Serious: 0/12 (0%)
Deaths: 0/12
Placebo BID -> Placebo BID TW
Serious: 0/26 (0%)
Deaths: 0/26

Serious adverse events (7 terms)

ReactionSystemEMA401 100mg BID DBPlacebo BID DBEMA401 100mg BID -> EMA401…EMA401 100mg BID -> Placeb…Placebo BID -> Placebo BID…
Cholecystitis acuteHepatobiliary disorders
Acute coronary syndromeCardiac disorders
Product intoleranceGeneral disorders
CholelithiasisHepatobiliary disorders
ErysipelasInfections and infestations
Localised infectionInfections and infestations
Chronic obstructive pulmonary diseaseRespiratory, thoracic and mediastinal disorders
Other adverse events (8 terms — click to expand)

ReactionSystemEMA401 100mg BID DBPlacebo BID DBEMA401 100mg BID -> EMA401…EMA401 100mg BID -> Placeb…Placebo BID -> Placebo BID…
NasopharyngitisInfections and infestations
Lipase increasedInvestigations
Abdominal pain upperGastrointestinal disorders
NauseaGastrointestinal disorders
Gamma-glutamyltransferase increasedInvestigations
HeadacheNervous system disorders
HypertensionVascular disorders
PalpitationsCardiac disorders

Most-reported serious reactions: Cholecystitis acute, Acute coronary syndrome, Product intolerance, Cholelithiasis, Erysipelas, Localised infection, Chronic obstructive pulmonary disease.

Data from ClinicalTrials.gov NCT03297294 adverse events section.

Sponsor's own description

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

Publications & conference data

7 peer-reviewed publications reference this trial (live from Europe PMC):

  1. The Angiotensin AT<sub>2</sub> Receptor: From a Binding Site to a Novel Therapeutic Target.
    Steckelings UM, Widdop RE, Sturrock ED, Lubbe L, et al · · 2022 · cited 66× · PMID 36180112 · DOI 10.1124/pharmrev.120.000281
  2. Diabetic neuropathy: cutting-edge research and future directions.
    Yang Y, Zhao B, Wang Y, Lan H, et al · · 2025 · cited 61× · PMID 40274830 · DOI 10.1038/s41392-025-02175-1
  3. Pharmacotherapeutic Options for Managing Neuropathic Pain: A Systematic Review and Meta-Analysis.
    Di Stefano G, Di Lionardo A, Di Pietro G, Cruccu G, et al · · 2021 · cited 21× · PMID 33986899 · DOI 10.1155/2021/6656863
  4. Diagnosis and Management of Neuropathic Pain in Spine Diseases.
    Bielewicz J, Kamieniak M, Szymoniuk M, Litak J, et al · · 2023 · cited 15× · PMID 36835916 · DOI 10.3390/jcm12041380
  5. Update on Treating Painful Diabetic Peripheral Neuropathy: A Review of Current US Guidelines with a Focus on the Most Recently Approved Management Options.
    Mallick-Searle T, Adler JA. · · 2024 · cited 9× · PMID 38505500 · DOI 10.2147/jpr.s442595
  6. Nonopioid analgesics discovery and the Valley of Death: EMA401 from concept to clinical trial.
    Smith MT. · · 2022 · cited 5× · PMID 35984369 · DOI 10.1097/j.pain.0000000000002675
  7. Emerging Therapeutic Modalities and Pharmacotherapies in Neuropathic Pain Management: A Systematic Review and Meta-Analysis of Parallel Randomized Controlled Trials.
    Kontor EK, Wellan C, Maaz HM, Muhammad DG, et al · · 2024 · cited 2× · PMID 39748928 · DOI 10.1155/prm/6782574

Verify or expand the search:

Other trials of EMA401

Trials testing the same drug.

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Other Novartis Pharmaceuticals trials

Trials by the same sponsor.

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Drug Landscape aggregates and links these public records for informational use only. Always verify against the primary source before clinical or regulatory decisions. Canonical URL: https://druglandscape.com/trial/NCT03297294.

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