Dose Response Study of EMA401 in Patients With Post-herpetic Neuralgia (PHN)

Post-herpetic Neuralgia Clinical Trial

— EMPHENE  

Official title:

A Double-blind, Placebo-controlled, Randomized Dose Ranging Trial to Determine the Safety and Efficacy of Three Dose Levels of EMA401 in Reducing 24-hour Average Pain Intensity Score in Patients With Post-herpetic Neuralgia

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03094195
• Other study ID #: CEMA401A2201
• Status: Terminated
• Phase: Phase 2
• Start date: June 27, 2017
• Est. completion date: March 7, 2019

Study information

• Verified date: October 2021
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study was designed to characterize dose response, and evaluate safety and efficacy of three different doses of EMA401 compared to placebo in patients with post-herpetic neuralgia (PHN).

Description:

This was an interventional, randomized, parallel, placebo-controlled, dose ranging, double-blind treatment study consisting of 3 periods i.e. Screening, Treatment, and Treatment withdrawal. The study was planned in two cohorts. The initial cohort had three treatment arms i.e. Placebo b.i.d., EMA401 25 mg b.i.d., or EMA401 100 mg b.i.d. Following an unblinded safety review by an independent DMC, the second cohort was to have been initiated with an additional treatment arm i.e. EMA401 300 mg b.i.d.. Due to the premature study termination, the second cohort was not initiated. At the end of treatment period the 25mg BID and 100mg BID arms were 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 130
• Est. completion date: March 7, 2019
• Est. primary completion date: March 7, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• At the time of Screening, must have had documented diagnosis of PHN (ICD-10 code B02.29), defined as pain in the region of the rash persisting for more than 6 months after onset of herpes zoster rash.
• Assessed as suffering from moderate to severe neuropathic pain across the Screening epoch (NRS = 4).
• Patients must have had documented past and/or ongoing inadequate treatment response (having insufficient pain relief with treatment or inability to tolerate) to at least 2 different prescribed therapies commonly used to treat and considered effective by the Investigator for the treatment of PHN.
• Patient must have been willing to complete daily eDiary

Exclusion Criteria:

• History or had current diagnosis of electrocardiogram (ECG) abnormalities indicating significant risk of safety for patients participating in the study
• Had a 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
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant.
• 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.
• Patients who had a known diagnosis of diabetes and are stable on medication with a hemoglobin A1c > 8%. Those who did not have a known diagnosis of diabetes with a hemoglobin A1c > 7%.

Related Conditions & MeSH terms

• Neuralgia
• Neuralgia, Postherpetic
• Post-herpetic Neuralgia

Intervention

Drug:
• EMA401
EMA401
• Placebo
Placebo

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Melbourne	Victoria
Austria	Novartis Investigative Site	Klagenfurt
Austria	Novartis Investigative Site	Vienna
Belgium	Novartis Investigative Site	Pellenberg
Canada	Novartis Investigative Site	Levis	Quebec
Canada	Novartis Investigative Site	Ontario	CAN
Canada	Novartis Investigative Site	Quebec
Czechia	Novartis Investigative Site	Brno
Czechia	Novartis Investigative Site	Chocen
Czechia	Novartis Investigative Site	Plzen-Bory
Czechia	Novartis Investigative Site	Praha 10
Denmark	Novartis Investigative Site	Odense C
France	Novartis Investigative Site	Boulogne Billancourt
France	Novartis Investigative Site	Clermont-Ferrand
France	Novartis Investigative Site	LILLE Cédex
France	Novartis Investigative Site	Nice
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Erlangen
Germany	Novartis Investigative Site	Essen	Nordrhein Westfalen
Germany	Novartis Investigative Site	Haar
Germany	Novartis Investigative Site	Kiel
Germany	Novartis Investigative Site	Kiel
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Wiesbaden
Hungary	Novartis Investigative Site	Esztergom	HUN
Hungary	Novartis Investigative Site	Kistarcsa
Hungary	Novartis Investigative Site	Szeged
Italy	Novartis Investigative Site	Rome
Japan	Novartis Investigative Site	Kasukabe-shi	Tokyo
Japan	Novartis Investigative Site	Kawaguchi-city	Saitama
Japan	Novartis Investigative Site	Nishinomiya	Hyogo
Japan	Novartis Investigative Site	Oita
Japan	Novartis Investigative Site	Sakai	Osaka
Japan	Novartis Investigative Site	Setagaya ku	Tokyo
Japan	Novartis Investigative Site	Shizuoka-shi	Shizuoka
Japan	Novartis Investigative Site	Yokohama	Kanagawa
Japan	Novartis Investigative Site	Yokohama	Kanagawa
Japan	Novartis Investigative Site	Yokohama-shi	Kanagawa
Korea, Republic of	Novartis Investigative Site	Seongnam-si	Gyeonggi-do
Norway	Novartis Investigative Site	Oslo
Poland	Novartis Investigative Site	Olsztyn
Poland	Novartis Investigative Site	Warszawa
Portugal	Novartis Investigative Site	Almada
Portugal	Novartis Investigative Site	Aveiro
Portugal	Novartis Investigative Site	Leiria
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Porto
Slovakia	Novartis Investigative Site	Banska Bystrica
Slovakia	Novartis Investigative Site	Dubnica nad Vahom	SVK
Slovakia	Novartis Investigative Site	Presov
Slovakia	Novartis Investigative Site	Spisska Nova Ves
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	L Hospitalet De Llobregat	Barcelona
Taiwan	Novartis Investigative Site	Tainan
United Kingdom	Novartis Investigative Site	Darlington	Durham
United Kingdom	Novartis Investigative Site	Liverpool
United Kingdom	Novartis Investigative Site	London	GBR

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Australia,  Austria,  Belgium,  Canada,  Czechia,  Denmark,  France,  Germany,  Hungary,  Italy,  Japan,  Korea, Republic of,  Norway,  Poland,  Portugal,  Slovakia,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose-response in Change in Weekly Mean of the 24-hour Average Pain Score, Using an 11-point Numeric Rating Scale (NRS), From Baseline to Week 12	Since the 300 mg b.i.d. dose of EMA401 could not be initiated in the study due to premature study termination, the dose-response characterization was not performed. Specifically, only the trend test deduced from the set of candidate models was performed but the dose response estimation was not conducted.	Baseline up to Week 12
Secondary	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	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 numeric rating scale (NRS) with zero being "does not interfere" and ten being "completely interferes". A reduction in mean indicates improvement	Baseline up to Week 12
Secondary	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
Secondary	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
Secondary	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% /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
Secondary	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
Secondary	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. Scores ranged from zero to 28, with a cut-off score of eight suggesting the presence of sub-threshold insomnia. 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.	Baseline up to Week 12
Secondary	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
Secondary	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, Week 12
Secondary	Exposure-response (Decrease in Pain Intensity) Via Evaluation of Effect of EMA401 Exposure on Efficacy Variables (e.g. Change From Baseline of Pain Score), Via Descriptive Pharmacokinetics/ Pharmacodynamics (PK/PD)	Due to the premature termination of the study, the number of patients providing data for PKPD analysis data was much smaller than planned and no model to correlate drug exposure (PK) with the change in the pain score (PD) was developed	Baseline, Week 8, Week 12
Secondary	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

External Links

•   A Plain Language Trial Summary is available on novartisclinicaltrials.com