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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03297294
• Collaborator: (none)
• Enrollment: 142
• Locations: 64
• Arms: 2
• Actual Duration (Months): 12.4
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Painful Diabetic Neuropathy	Drug: EMA401; Drug: Placebo	Phase 2

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 142 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: Mar 14, 2018
• Actual Primary Completion Date: Mar 25, 2019
• Actual Study Completion Date: Mar 25, 2019

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: EMA401; capsules, oral; Drug: Placebo; Placebo to EMA401 capsules, oral
Placebo Comparator: Placebo Participants will receive matching placebo to EMA401 during both the treatment and treatment withdrawal epochs for a total of 13 weeks.	Drug: Placebo; Placebo to EMA401 capsules, oral

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

1. Change in Neuropathic Pain Symptom Inventory (NPSI) From Baseline to Week 12 [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.

2. Change in Brief Pain Inventory-Short Form Interference (BPI-SF) Mean Total Score From Baseline to Week 12 [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.

3. Change in Weekly Mean of the 24-hour Worst Pain Score, Using an 11-point NRS, From Baseline to Week 12 [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.

4. Number of Participants Per Patient Global Impression of Change Category at Week 12 [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

5. Percentage of Patients Achieving at Least 30% Pain Reduction at Week 12 on NRS 11 Point Scale [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.

6. Percentage of Patients Achieving at Least 50% Pain Reduction at Week 12 on NRS 11 Point Scale [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.

7. Mean Change in Insomnia Severity Index (ISI) From Baseline to Week 12 [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.

8. Plasma Pharmacokinetics (PK) Concentrations at Week 8 and 12 [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

9. Percentage of Patients Who Required Rescue Medication in Double-blind Treatment Period [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.

10. Percentage of Patients Who Required Rescue Medication in Treatment Withdrawal Period [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.

11. Time to First Rescue Medication Intake [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.

12. Treatment Emergent Adverse Events During Urgent Safety Measure (USM) Follow-Up [Approximately from 3 weeks after end of study up to 16 weeks]

    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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Broadmeadow	New South Wales	Australia	2292
2	Novartis Investigative Site	Orange	New South Wales	Australia	2800
3	Novartis Investigative Site	Adelaide	South Australia	Australia	5000
4	Novartis Investigative Site	Heidelberg Heights	Victoria	Australia	3081
5	Novartis Investigative Site	Graz		Austria	A-8036
6	Novartis Investigative Site	Klagenfurt		Austria	9020
7	Novartis Investigative Site	Wien		Austria	A-1090
8	Novartis Investigative Site	Edegem		Belgium	2650
9	Novartis Investigative Site	Liege		Belgium	4000
10	Novartis Investigative Site	Pellenberg		Belgium	3212
11	Novartis Investigative Site	Sofia	Sofia-Grad	Bulgaria	1336
12	Novartis Investigative Site	Sofia		Bulgaria	1000
13	Novartis Investigative Site	Sofia		Bulgaria	1407
14	Novartis Investigative Site	Sofia		Bulgaria	1431
15	Novartis Investigative Site	Ontario	CAN	Canada	L4J 1W3
16	Novartis Investigative Site	Thornhill	Ontario	Canada	L4J 8L7
17	Novartis Investigative Site	Toronto	Ontario	Canada	M4G 3E8
18	Novartis Investigative Site	Laval	Quebec	Canada	H7T 2P5
19	Novartis Investigative Site	Aarhus		Denmark	8000
20	Novartis Investigative Site	Gentofte		Denmark	DK 2820
21	Novartis Investigative Site	Odense C		Denmark	DK 5000
22	Novartis Investigative Site	Tampere		Finland	FIN-33520
23	Novartis Investigative Site	Boulogne Billancourt		France	92104
24	Novartis Investigative Site	Bielefeld		Germany	D 33647
25	Novartis Investigative Site	Duesseldorf		Germany	40225
26	Novartis Investigative Site	Essen		Germany	45147
27	Novartis Investigative Site	Halle (Saale)		Germany	06120
28	Novartis Investigative Site	Kassel		Germany
29	Novartis Investigative Site	Kiel		Germany	24119
30	Novartis Investigative Site	Leipzig		Germany	04109
31	Novartis Investigative Site	Wiesbaden		Germany	65191
32	Novartis Investigative Site	Debrecen	HUN	Hungary	4032
33	Novartis Investigative Site	Esztergom	HUN	Hungary	2500
34	Novartis Investigative Site	Szeged	HUN	Hungary	6720
35	Novartis Investigative Site	Balatonfured		Hungary	8230
36	Novartis Investigative Site	Budapest		Hungary	1085
37	Novartis Investigative Site	Budapest		Hungary	1089
38	Novartis Investigative Site	Kistarcsa		Hungary	2143
39	Novartis Investigative Site	Pecs		Hungary	7632
40	Novartis Investigative Site	Szeged		Hungary	6725
41	Novartis Investigative Site	Oslo		Norway	0450
42	Novartis Investigative Site	Krakow	POL	Poland	31 505
43	Novartis Investigative Site	Bialystok		Poland	15-351
44	Novartis Investigative Site	Warszawa		Poland	00 144
45	Novartis Investigative Site	Caldas da Rainha		Portugal	2500 176
46	Novartis Investigative Site	Lisboa		Portugal	1250 203
47	Novartis Investigative Site	Matosinhos		Portugal	4454 509
48	Novartis Investigative Site	Porto		Portugal	4200 319
49	Novartis Investigative Site	Viana do Castelo		Portugal	4901858
50	Novartis Investigative Site	Vila Nova de Gaia		Portugal	4434 502
51	Novartis Investigative Site	Lucenec	Slovak Republic	Slovakia	98401
52	Novartis Investigative Site	Bratislava		Slovakia	83305
53	Novartis Investigative Site	Bratislava		Slovakia	85101
54	Novartis Investigative Site	Presov		Slovakia	080 01
55	Novartis Investigative Site	Presov		Slovakia	08001
56	Novartis Investigative Site	Sevilla	Andalucia	Spain	41014
57	Novartis Investigative Site	Madrid		Spain	28222
58	Novartis Investigative Site	Bradford	West Yorkshire	United Kingdom	BD9 6RJ
59	Novartis Investigative Site	Bath		United Kingdom	BA1 3NG
60	Novartis Investigative Site	Bournemouth		United Kingdom	BH7 7DW
61	Novartis Investigative Site	Edinburgh		United Kingdom	EH4 2XU
62	Novartis Investigative Site	London		United Kingdom	SE1 7EH
63	Novartis Investigative Site	Middlesborough		United Kingdom	TS4 3BW
64	Novartis Investigative Site	Oldham		United Kingdom	OL1 2JH

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Sep 15, 2017
• Statistical Analysis Plan - Jun 18, 2019

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03297294
• Other Study ID Numbers: CEMA401A2202; 2016-000281-39
• First Posted: Sep 29, 2017
• Last Update Posted: Oct 8, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Painful diabetic neuropathy; Neuropathic pain; Angiotensin II type 2 receptor antagonist; adult; EMA401; diabetic neuropathy
• Additional relevant MeSH terms: Peripheral Nervous System Diseases; Diabetic Neuropathies; Pain

Study Results

Participant Flow

Pre-assignment Detail	Three hundred six patients were screened and 137 randomized

Arm/Group Title	EMA401 100mg BID DB	Placebo BID DB	EMA401 100mg BID -> EMA401 100mg BID TW	EMA401 100mg BID -> Placebo BID TW	Placebo BID -> Placebo BID TW
Arm/Group Description	Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period	Matching placebo capsules administered orally twice a day during double blind (DB) treatment period	Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of DB treatment period (week 12)	Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of DB treatment period (week 12)	Participants on placebo remained on placebo at end of DB treatment period (week 12)
Period Title: Double-Blind Treatment Period (DB)
STARTED	70	67	0	0	0
COMPLETED	32	30	0	0	0
NOT COMPLETED	38	37	0	0	0
Period Title: Double-Blind Treatment Period (DB)
STARTED	0	0	14	12	27
COMPLETED	0	0	14	11	27
NOT COMPLETED	0	0	0	1	0

Baseline Characteristics

Arm/Group Title	EMA401 100mg BID DB	Placebo BID DB	Total
Arm/Group Description	Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period	Matching placebo capsules administered orally twice a day during double blind (DB) treatment period	Total of all reporting groups
Overall Participants	70	67	137
Age, Customized (Count of Participants)
18 - 64 years	34 48.6%	33 49.3%	67 48.9%
65 - 84 years	36 51.4%	33 49.3%	69 50.4%
≥ 85 years	0 0%	1 1.5%	1 0.7%
Sex: Female, Male (Count of Participants)
Female	20 28.6%	24 35.8%	44 32.1%
Male	50 71.4%	43 64.2%	93 67.9%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	70 100%	63 94%	133 97.1%
Asian	0 0%	1 1.5%	1 0.7%
Other	0 0%	3 4.5%	3 2.2%
Body mass index (kg/m^2) [Median (Full Range) ]
Median (Full Range) [kg/m^2]	30.8	30.2	30.6

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	EMA401 100mg BID DB	Placebo BID DB
Arm/Group Description	Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period	Matching placebo capsules administered orally twice a day during double blind (DB) treatment period
Measure Participants	70	67
Week 4	-1.0 (0.21)	-0.8 (0.18)
Week 8	-1.7 (0.29)	-1.1 (0.26)
Week 12	-1.9 (0.31)	-1.3 (0.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EMA401 100mg BID DB, Placebo BID DB
	Comments
	Type of Statistical Test	Superiority
	Comments	at week 12
Statistical Test of Hypothesis	p-Value	0.101
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	least squares mean
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -1.4 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.39
	Estimation Comments

2. Secondary Outcome

Title	Change in Neuropathic Pain Symptom Inventory (NPSI) From Baseline to Week 12
Description	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.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	EMA401 100mg BID DB	Placebo BID DB
Arm/Group Description	Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period	Matching placebo capsules administered orally twice a day during double blind (DB) treatment period
Measure Participants	70	67
Week 4	-1.2 (0.19)	-1.0 (0.18)
Week 8	-1.3 (0.25)	-0.9 (0.22)
Week 12	-1.6 (0.32)	-1.1 (0.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EMA401 100mg BID DB, Placebo BID DB
	Comments	At week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.168
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -1.3 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.38
	Estimation Comments

3. Secondary Outcome

Title	Change in Brief Pain Inventory-Short Form Interference (BPI-SF) Mean Total Score From Baseline to Week 12
Description	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.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	EMA401 100mg BID DB	Placebo BID DB
Arm/Group Description	Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period	Matching placebo capsules administered orally twice a day during double blind (DB) treatment period
Measure Participants	70	67
Mean (Standard Deviation) [scores on a scale]	-12.03 (13.336)	-10.83 (14.602)

4. Secondary Outcome

Title	Change in Weekly Mean of the 24-hour Worst Pain Score, Using an 11-point NRS, From Baseline to Week 12
Description	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.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	EMA401 100mg BID DB	Placebo BID DB
Arm/Group Description	Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period	Matching placebo capsules administered orally twice a day during double blind (DB) treatment period
Measure Participants	70	67
Mean (Standard Deviation) [scores on numeric rating scale]	-1.63 (1.837)	-1.28 (1.577)

5. Secondary Outcome

Title	Number of Participants Per Patient Global Impression of Change Category at Week 12
Description	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
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	EMA401 100mg BID DB	Placebo BID DB
Arm/Group Description	Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period	Matching placebo capsules administered orally twice a day during double blind (DB) treatment period
Measure Participants	70	67
Very much improved	4 5.7%	2 3%
Much improved	7 10%	11 16.4%
Minimally improved	17 24.3%	18 26.9%
No change	18 25.7%	14 20.9%
Minimally worse	3 4.3%	2 3%
Much worse	0 0%	0 0%
Very much worse	0 0%	0 0%
Missing	21 30%	20 29.9%

6. Secondary Outcome

Title	Percentage of Patients Achieving at Least 30% Pain Reduction at Week 12 on NRS 11 Point Scale
Description	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.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	EMA401 100mg BID DB	Placebo BID DB
Arm/Group Description	Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period	Matching placebo capsules administered orally twice a day during double blind (DB) treatment period
Measure Participants	70	67
Week 4 - at least 30% pain reduction	34.0 48.6%	24.7 36.9%
Week 12 - at least 30% pain reduction	52.7 75.3%	40.4 60.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EMA401 100mg BID DB, Placebo BID DB
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.255
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.6
	Confidence Interval	(2-Sided) 95%; 0.7 to 3.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Percentage of Patients Achieving at Least 50% Pain Reduction at Week 12 on NRS 11 Point Scale
Description	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.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	EMA401 100mg BID DB	Placebo BID DB
Arm/Group Description	Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period	Matching placebo capsules administered orally twice a day during double blind (DB) treatment period
Measure Participants	70	67
Number [% of participants - model adjusted rate]	31.4 44.9%	14.1 21%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EMA401 100mg BID DB, Placebo BID DB
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.100
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.8
	Confidence Interval	(2-Sided) 95%; 0.8 to 9.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Mean Change in Insomnia Severity Index (ISI) From Baseline to Week 12
Description	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.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	EMA401 100mg BID DB	Placebo BID DB
Arm/Group Description	Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period	Matching placebo capsules administered orally twice a day during double blind (DB) treatment period
Measure Participants	70	67
Mean (Standard Deviation) [scores on a scale]	-4.00 (4.854)	-1.03 (6.312)

9. Secondary Outcome

Title	Plasma Pharmacokinetics (PK) Concentrations at Week 8 and 12
Description	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
Time Frame	Week 8 (Prior dose, 1-3 hours, 4-6 hours), Week 12 (Prior dose, 1-3 hours, 4-6 hours)

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	EMA401 100mg BID DB
Arm/Group Description	Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period
Measure Participants	32
Week 8 Prior dose	30.5 (126.6)
Week 8 1-3 hours	205.1 (212.8)
Week 8 4-6 hours	72.8 (115.2)
Week 12 Prior dose	29.5 (209.3)
Week 12 1-3 hours	118.4 (278.3)
Week 12 4-6 hours	89.8 (117.0)

10. Secondary Outcome

Title	Percentage of Patients Who Required Rescue Medication in Double-blind Treatment Period
Description	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.
Time Frame	Baseline and weekly up to 12 weeks, once during double-blind period

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	EMA401 100mg BID DB	Placebo BID DB
Arm/Group Description	Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period	Matching placebo capsules administered orally twice a day during double blind (DB) treatment period
Measure Participants	70	67
Week 1	13.0 18.6%	10.6 15.8%
Week 2	7.7 11%	9.5 14.2%
Week 4	8.6 12.3%	7.0 10.4%
Week 6	7.8 11.1%	7.5 11.2%
Week 8	9.3 13.3%	9.5 14.2%
Week 10	5.3 7.6%	13.2 19.7%
Week 12	2.9 4.1%	8.6 12.8%
At least once during double-blind period	20.0 28.6%	19.4 29%

11. Secondary Outcome

Title	Percentage of Patients Who Required Rescue Medication in Treatment Withdrawal Period
Description	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.
Time Frame	Week 12 to Week 13 (planned duration subject to varibility in visit scheduling)

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	EMA401 100mg BID -> EMA401 100mg BID TW	EMA401 100mg BID -> Placebo BID TW	Placebo BID -> Placebo BID TW
Arm/Group Description	Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of DB treatment period (week 12)	Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of DB treatment period (week 12)	Participants on placebo remained on placebo at end of DB treatment period (week 12)
Measure Participants	35	35	67
Number [Percentage of participants]	14.3 20.4%	8.3 12.4%	7.4 5.4%

12. Secondary Outcome

Title	Time to First Rescue Medication Intake
Description	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.
Time Frame	Baseline up to day 92

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	EMA401 100mg BID DB	Placebo BID DB
Arm/Group Description	Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period	Matching placebo capsules administered orally twice a day during double blind (DB) treatment period
Measure Participants	70	67
Median (Full Range) [days]	44.0	56.5

13. Secondary Outcome

Title	Treatment Emergent Adverse Events During Urgent Safety Measure (USM) Follow-Up
Description	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
Time Frame	Approximately from 3 weeks after end of study up to 16 weeks

Outcome Measure Data

Analysis Population Description

The Overall Number of Participants Analyzed reflects the Safety population, regardless of whether they completed the study

Arm/Group Title	EMA401 100mg BID -> EMA401 100mg BID TW	EMA401 100mg BID -> Placebo BID TW	Placebo BID -> Placebo BID TW
Arm/Group Description	Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of DB treatment period (week 12)	Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of DB treatment period (week 12)	Participants on placebo remained on placebo at end of DB treatment period (week 12)
Measure Participants	34	35	66
Peritoneal adhesions	1 1.4%	0 0%	0 0%
Cholelithiasis	1 1.4%	0 0%	0 0%
Liver abscess	1 1.4%	0 0%	0 0%
Blood creatinine increased	0 0%	0 0%	1 0.7%

Adverse Events

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
Adverse Event Reporting Description	Any sign or symptom that occurs during the study treatment plus the 21 days post treatment are reported in adverse event (AE) section. Upon termination of study, participants were instructed to attend two unscheduled visits for follow-up safety assessments for Urgent Safety Measure (USM) follow-up. Adverse events collected during USM are not included in this AE section but reported in secondary outcome measure 13 entitled Treatment Emergent Adverse Events During Urgent Safety Measure Follow-up
Arm/Group Title	EMA401 100mg BID DB		Placebo BID DB		EMA401 100mg BID -> EMA401 100mg BID TW		EMA401 100mg BID -> Placebo BID TW		Placebo BID -> Placebo BID TW
Arm/Group Description	Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period		Matching placebo capsules administered orally twice a day during double blind (DB) treatment period		Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of DB treatment period (week 12)		Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of DB treatment period (week 12)		Participants on placebo remained on placebo at end of DB treatment period (week 12)
All Cause Mortality
	EMA401 100mg BID DB		Placebo BID DB		EMA401 100mg BID -> EMA401 100mg BID TW		EMA401 100mg BID -> Placebo BID TW		Placebo BID -> Placebo BID TW
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/69 (0%)		0/66 (0%)		0/14 (0%)		0/12 (0%)		0/26 (0%)
Serious Adverse Events
	EMA401 100mg BID DB		Placebo BID DB		EMA401 100mg BID -> EMA401 100mg BID TW		EMA401 100mg BID -> Placebo BID TW		Placebo BID -> Placebo BID TW
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/69 (7.2%)		3/66 (4.5%)		0/14 (0%)		0/12 (0%)		0/26 (0%)
Cardiac disorders
Acute coronary syndrome	0/69 (0%)		1/66 (1.5%)		0/14 (0%)		0/12 (0%)		0/26 (0%)
General disorders
Product intolerance	1/69 (1.4%)		0/66 (0%)		0/14 (0%)		0/12 (0%)		0/26 (0%)
Hepatobiliary disorders
Cholecystitis acute	2/69 (2.9%)		0/66 (0%)		0/14 (0%)		0/12 (0%)		0/26 (0%)
Cholelithiasis	1/69 (1.4%)		0/66 (0%)		0/14 (0%)		0/12 (0%)		0/26 (0%)
Infections and infestations
Erysipelas	0/69 (0%)		1/66 (1.5%)		0/14 (0%)		0/12 (0%)		0/26 (0%)
Localised infection	1/69 (1.4%)		0/66 (0%)		0/14 (0%)		0/12 (0%)		0/26 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/69 (0%)		1/66 (1.5%)		0/14 (0%)		0/12 (0%)		0/26 (0%)
Other (Not Including Serious) Adverse Events
	EMA401 100mg BID DB		Placebo BID DB		EMA401 100mg BID -> EMA401 100mg BID TW		EMA401 100mg BID -> Placebo BID TW		Placebo BID -> Placebo BID TW
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/69 (33.3%)		10/66 (15.2%)		1/14 (7.1%)		2/12 (16.7%)		0/26 (0%)
Cardiac disorders
Palpitations	0/69 (0%)		1/66 (1.5%)		0/14 (0%)		1/12 (8.3%)		0/26 (0%)
Gastrointestinal disorders
Abdominal pain upper	5/69 (7.2%)		0/66 (0%)		0/14 (0%)		0/12 (0%)		0/26 (0%)
Nausea	4/69 (5.8%)		1/66 (1.5%)		0/14 (0%)		0/12 (0%)		0/26 (0%)
Infections and infestations
Nasopharyngitis	4/69 (5.8%)		6/66 (9.1%)		0/14 (0%)		0/12 (0%)		0/26 (0%)
Investigations
Gamma-glutamyltransferase increased	4/69 (5.8%)		1/66 (1.5%)		0/14 (0%)		0/12 (0%)		0/26 (0%)
Lipase increased	6/69 (8.7%)		0/66 (0%)		1/14 (7.1%)		0/12 (0%)		0/26 (0%)
Nervous system disorders
Headache	4/69 (5.8%)		4/66 (6.1%)		0/14 (0%)		0/12 (0%)		0/26 (0%)
Vascular disorders
Hypertension	1/69 (1.4%)		2/66 (3%)		0/14 (0%)		1/12 (8.3%)		0/26 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.