DS-5565 Phase III Study for Post-herpetic Neuralgia

• Sponsor: Daiichi Sankyo Co., Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02318719
• Collaborator: SRL Medisearch Inc. (Industry), Quintiles, Inc. (Industry)
• Enrollment: 765
• Location: 1
• Arms: 4
• Actual Duration (Months): 28.7
• Patients Per Site Per Month: 26.6

Study Details

Study Description

Brief Summary

Investigate the efficacy and safety of DS-5565 in subjects with Post-Herpetic Neuralgia (PHN) in comparison to placebo

Condition or Disease	Intervention/Treatment	Phase
Post-Herpetic Neuralgia	Drug: Placebo; Drug: DS-5565	N/A

Detailed Description

[Double Blind Phase] The primary objective is to compare change in the Average Daily Pain Score (ADPS) from baseline to Week 14 in Asian subjects with PHN receiving DS-5565 versus placebo.

[Open Extension Phase] The objective is to assess the long-term safety and efficacy of DS-5565 in subjects with PHN.

Study Design

• Study Type: Interventional
• Actual Enrollment: 765 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Official Title: An Asian, Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled 14-Week Study of DS-5565 in Patients With Post-herpetic Neuralgia Followed by a 52-Week Open-label Extension
• Actual Study Start Date: Jan 1, 2015
• Actual Primary Completion Date: May 25, 2017
• Actual Study Completion Date: May 25, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo (14-weeks)	Drug: Placebo; Placebo
Experimental: DS-5565 15 mg Group DS-5565 15 mg, oral administration, Treatment period; 2-weeks titration and 12-weeks fixed dose	Drug: DS-5565; Other Names: Mirogabalin
Experimental: DS-5565 20 mg Group DS-5565 20 mg, oral administration, Treatment period; 1-week titration and 13-weeks fixed dose	Drug: DS-5565; Other Names: Mirogabalin
Experimental: DS-5565 30 mg Group DS-5565 30 mg, oral administration, Treatment period; 2-weeks titration and 12-weeks fixed dose	Drug: DS-5565; Other Names: Mirogabalin

Outcome Measures

Primary Outcome Measures

1. Change in the Average Daily Pain Score (ADPS) From Baseline to Week 14 Following Oral Administration of DS-5565 in Asian Participants With Post-herpetic Neuralgia [Baseline to Week 14]

   Each participant recorded a pain score in the electronic patient diary once daily from the day after the screening visit (Visit 1) to the end of treatment/early termination visit (Visit 10). Prior to taking the study drug each morning, the participant selected the number that best described his or her pain over the past 24 hours on a scale of 0 (no pain) to 10 (worst possible pain). Higher ADPS scores indicated worse outcome. ADPS was the weekly average pain score based on the pain scores from the electronic patient diaries (Pain diary). In this outcome, the change from baseline in ADPS is being reported with negative values representing improvements in average daily pain. The larger the negative value (ie. improvement), the greater the improvement in average daily pain.

Secondary Outcome Measures

1. Change in Visual Analog Scale (VAS) Pain From Baseline (Week 14) to Week 66 Following Administration of DS-5565 in Asian Participants With Post-herpetic Neuralgia [From baseline (Week 14) to Week 66]

   Visual Analog Scale (VAS) pain is a 10-point assessment tool to measure pain levels, where 0 is defined as 'no pain' and 10 is defined as 'worst possible pain'. Higher VAS pain scores indicate worse outcome. In this outcome, the change from baseline in VAS pain is being reported with negative values representing improvements in pain intensity. The larger the negative value (ie. improvement), the greater the improvement in pain intensity.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• PHN defined as pain present for more than 3 months after herpes zoster skin rash at screening

• At screening, a pain scale of ≥ 40 mm

Exclusion Criteria:

• Previous use of neurolytic block

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medical Corporation Fujigaki Clinic	Oita		Japan	870-0942

Sponsors and Collaborators

• Daiichi Sankyo Co., Ltd.
• SRL Medisearch Inc.
• Quintiles, Inc.

Investigators

• Study Director: Global Clinical Leader, Daichii Sankyo

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 18, 2016

More Information

Publications

None provided.

• Responsible Party: Daiichi Sankyo Co., Ltd.
• ClinicalTrials.gov Identifier: NCT02318719
• Other Study ID Numbers: DS5565-A-J304
• First Posted: Dec 17, 2014
• Last Update Posted: Nov 2, 2020
• Last Verified: Oct 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Daiichi Sankyo Co., Ltd.: Post-Herpetic Neuralgia; Developmental Phase III
• Additional relevant MeSH terms: Neuralgia; Neuralgia, Postherpetic

Study Results

Participant Flow

Recruitment Details	A total of 765 participants who met all inclusion and no exclusion criteria were enrolled in the study; 763 participants received treatment in the double-blind phase. A total of 239 participants received treatment in the open-label extension phase.
Pre-assignment Detail	This study included a double-blind phase where participants received DS-5565 (15 mg, 20 mg, or 30 mg) or placebo and an open-label extension phase where participants received DS-5565 (starting dose 5 mg).

Arm/Group Title	Placebo	DS-5565 15 mg/Day	DS-5565 20 mg/Day	DS-5565 30 mg/Day	DS-5565 Open-label Extension
Arm/Group Description	Participants who received placebo for 14 weeks.	Participants received oral administrations of DS-5565 15 mg/day with a 2 week titration (5 mg/day during 1st week and 10 mg/day during 2nd week) followed by 12 weeks fixed dose (15 mg/day).	Participants received oral administrations of DS-5565 20 mg/day with a 1 week titration (5 mg BID) followed by 13 weeks fixed dose (10 mg BID).	Participants received oral administrations of DS-5565 30 mg/day with a 2 week titration (5 mg BID during 1st week and 10 mg BID during 2nd week) followed by 12 weeks fixed dose (15 mg BID).	Participants who received 5 mg BID for the first 2 weeks and 10 mg BID for the second 2 weeks (i.e., Week 3 and 4). At Week 5, the dosage escalated to 15 mg BID if there were no concerns in safety. For the subsequent visits, the dosage may have changed to either 10 mg BID or 15 mg BID depending on safety findings.
Period Title: Double-blind Phase
STARTED	304	153	153	155	0
Did Not Receive Treatment	1	1	0	0	0
COMPLETED	266	137	128	140	0
NOT COMPLETED	38	16	25	15	0
Period Title: Double-blind Phase
STARTED	0	0	0	0	239
COMPLETED	0	0	0	0	184
NOT COMPLETED	0	0	0	0	55

Baseline Characteristics

Arm/Group Title	Placebo	DS-5565 15 mg	DS-5565 20 mg	DS-5565 30 mg	Total
Arm/Group Description	Participants who received placebo for 14 weeks.	Participants who received oral administration of DS-5565 15 mg with a 2 week titration and 12 weeks fixed dose treatment period.	Participants who received oral administration of DS-5565 20 mg with a 1 week titration and 13 weeks fixed dose treatment period.	Participants who received oral administration of DS-5565 30 mg with a 2 week titration and 12 weeks fixed dose treatment period.	Total of all reporting groups
Overall Participants	304	153	153	155	765
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	102 33.6%	47 30.7%	39 25.5%	64 41.3%	252 32.9%
>=65 years	202 66.4%	106 69.3%	114 74.5%	91 58.7%	513 67.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66.2 (10.13)	66.6 (8.97)	68.9 (9.19)	64.5 (10.74)	66.5 (9.94)
Sex: Female, Male (Count of Participants)
Female	127 41.8%	56 36.6%	62 40.5%	59 38.1%	304 39.7%
Male	177 58.2%	97 63.4%	91 59.5%	96 61.9%	461 60.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	304 100%	153 100%	153 100%	155 100%	765 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Japan	304 100%	153 100%	153 100%	155 100%	765 100%

Outcome Measures

1. Primary Outcome

Title	Change in the Average Daily Pain Score (ADPS) From Baseline to Week 14 Following Oral Administration of DS-5565 in Asian Participants With Post-herpetic Neuralgia
Description	Each participant recorded a pain score in the electronic patient diary once daily from the day after the screening visit (Visit 1) to the end of treatment/early termination visit (Visit 10). Prior to taking the study drug each morning, the participant selected the number that best described his or her pain over the past 24 hours on a scale of 0 (no pain) to 10 (worst possible pain). Higher ADPS scores indicated worse outcome. ADPS was the weekly average pain score based on the pain scores from the electronic patient diaries (Pain diary). In this outcome, the change from baseline in ADPS is being reported with negative values representing improvements in average daily pain. The larger the negative value (ie. improvement), the greater the improvement in average daily pain.
Time Frame	Baseline to Week 14

Outcome Measure Data

Analysis Population Description

Average daily pain score (ADPS) was assessed in the modified Intent-to-Treat Analysis Set.

Arm/Group Title	Placebo	DS-5565 15 mg/Day	DS-5565 20 mg/Day	DS-5565 30 mg/Day
Arm/Group Description	Participants who received placebo for 14 weeks.	Participants received oral administrations of DS-5565 15 mg/day with a 2 week titration (5 mg/day during 1st week and 10 mg/day during 2nd week) followed by 12 weeks fixed dose (15 mg/day).	Participants received oral administrations of DS-5565 20 mg/day with a 1 week titration (5 mg BID) followed by 13 weeks fixed dose (10 mg BID).	Participants received oral administrations of DS-5565 30 mg/day with a 2 week titration (5 mg BID during 1st week and 10 mg BID during 2nd week) followed by 12 weeks fixed dose (15 mg BID).
Measure Participants	303	152	153	155
Week 1	-0.10 (0.743)	-0.39 (0.787)	-0.54 (0.783)	-0.46 (0.693)
Week 2	-0.33 (0.902)	-0.72 (1.036)	-1.06 (0.998)	-0.95 (1.003)
Week 3	-0.48 (1.030)	-0.96 (1.195)	-1.16 (1.122)	-1.20 (1.188)
Week 4	-0.64 (1.163)	-1.08 (1.283)	-1.24 (1.192)	-1.33 (1.236)
Week 5	-0.74 (1.215)	-1.17 (1.351)	-1.36 (1.233)	-1.49 (1.275)
Week 6	-0.81 (1.329)	-1.29 (1.412)	-1.44 (1.337)	-1.55 (1.277)
Week 7	-0.96 (1.399)	-1.32 (1.409)	-1.45 (1.382)	-1.67 (1.346)
Week 8	-1.03 (1.466)	-1.39 (1.509)	-1.40 (1.455)	-1.62 (1.375)
Week 9	-1.09 (1.478)	-1.44 (1.574)	-1.42 (1.480)	-1.72 (1.431)
Week 10	-1.15 (1.547)	-1.49 (1.632)	-1.51 (1.564)	-1.81 (1.486)
Week 11	-1.22 (1.601)	-1.53 (1.647)	-1.60 (1.576)	-1.84 (1.473)
Week 12	-1.21 (1.614)	-1.59 (1.727)	-1.63 (1.624)	-1.89 (1.519)
Week 13	-1.25 (1.665)	-1.63 (1.769)	-1.68 (1.643)	-1.95 (1.486)
Week 14	-1.31 (1.710)	-1.67 (1.717)	-1.73 (1.715)	-1.96 (1.501)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, DS-5565 15 mg/Day
	Comments	Placebo vs DS-5565 15 mg/day at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0170
	Comments	DS-5565 20 mg and 30 mg vs placebo were tested at level of 0.025. If both were significant, 15 mg was tested at 0.05. If neither were significant, 15 mg was no longer tested. If either 20 mg or 30 mg was significant, 15 mg was tested at 0.025.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Difference of least square mean
	Estimated Value	-0.41
	Confidence Interval	(2-Sided) 95%; -0.74 to -0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, DS-5565 20 mg/Day
	Comments	Placebo vs DS-5565 20 mg/day at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0058
	Comments	DS-5565 20 mg and 30 mg vs placebo were tested at level of 0.025. If both were significant, 15 mg was tested at 0.05. If neither were significant, 15 mg was no longer tested. If either 20 mg or 30 mg was significant, 15 mg was tested at 0.025.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Difference of least square means
	Estimated Value	-0.47
	Confidence Interval	(2-Sided) 95%; -0.81 to -0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, DS-5565 30 mg/Day
	Comments	Placebo vs DS-5565 30 mg/day at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	DS-5565 20 mg and 30 mg vs placebo were tested at level of 0.025. If both were significant, 15 mg was tested at 0.05. If neither were significant, 15 mg was no longer tested. If either 20 mg or 30 mg was significant, 15 mg was tested at 0.025.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Difference of least square means
	Estimated Value	-0.77
	Confidence Interval	(2-Sided) 95%; -1.10 to -0.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Visual Analog Scale (VAS) Pain From Baseline (Week 14) to Week 66 Following Administration of DS-5565 in Asian Participants With Post-herpetic Neuralgia
Description	Visual Analog Scale (VAS) pain is a 10-point assessment tool to measure pain levels, where 0 is defined as 'no pain' and 10 is defined as 'worst possible pain'. Higher VAS pain scores indicate worse outcome. In this outcome, the change from baseline in VAS pain is being reported with negative values representing improvements in pain intensity. The larger the negative value (ie. improvement), the greater the improvement in pain intensity.
Time Frame	From baseline (Week 14) to Week 66

Outcome Measure Data

Analysis Population Description

Visual analog scale (VAS) was assessed in the modified Intent-to-Treat Analysis Set.

Arm/Group Title	DS-5565 Open-label Extension
Arm/Group Description	Participants who received 5 mg BID for the first 2 weeks and 10 mg BID for the second 2 weeks (i.e., Week 3 and 4). At Week 5, the dosage escalated to 15 mg BID if there were no concerns in safety. For the subsequent visits, the dosage may have changed to either 10 mg BID or 15 mg BID depending on safety findings.
Measure Participants	237
Week 16	-0.70 (9.530)
Week 18	4.60 (9.850)
Week 22	-8.30 (12.070)
Week 26	-8.60 (12.030)
Week 30	-8.70 (13.670)
Week 34	-10.00 (14.260)
Week 38	-10.40 (14.450)
Week 42	-11.20 (13.930)
Week 46	-12.00 (13.890)
Week 50	-12.60 (14.530)
Week 54	-12.50 (14.760)
Week 58	-12.90 (15.250)
Week 62	-14.00 (16.790)
Week 66	-14.70 (15.270)

Adverse Events

Time Frame	Adverse events (AEs) were collected from after the participant signed the informed consent form and up to 7 days after the last dose of the study drug (the post-treatment follow-up visit [Visit 11]), up to 2 years 5 months.
Adverse Event Reporting Description	Treatment-emergent AEs were defined as any AEs that appeared after the first administration of study treatment or that worsened relative to the pre-treatment state. Safety data were reported from participants in the Safety Analysis Set who had available safety data; 2 participants in the DS-5565 open-label extension data did not have available safety data and were not included in the analysis.
Arm/Group Title	Placebo		DS-5565 15 mg/Day		DS-5565 20 mg/Day		DS-5565 30 mg/Day		DS-5565 Open-label Extension
Arm/Group Description	Participants who received placebo for 14 weeks.		Participants received oral administrations of DS-5565 15 mg/day with a 2 week titration (5 mg/day during 1st week and 10 mg/day during 2nd week) followed by 12 weeks fixed dose (15 mg/day).		Participants received oral administrations of DS-5565 20 mg/day with a 1 week titration (5 mg BID) followed by 13 weeks fixed dose (10 mg BID).		Participants received oral administrations of DS-5565 30 mg/day with a 2 week titration (5 mg BID during 1st week and 10 mg BID during 2nd week) followed by 12 weeks fixed dose (15 mg BID).		Participants who received 5 mg BID for the first 2 weeks and 10 mg BID for the second 2 weeks (i.e., Week 3 and 4). At Week 5, the dosage escalated to 15 mg BID if there were no concerns in safety. For the subsequent visits, the dosage may have changed to either 10 mg BID or 15 mg BID depending on safety findings.
All Cause Mortality
	Placebo		DS-5565 15 mg/Day		DS-5565 20 mg/Day		DS-5565 30 mg/Day		DS-5565 Open-label Extension
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Serious Adverse Events
	Placebo		DS-5565 15 mg/Day		DS-5565 20 mg/Day		DS-5565 30 mg/Day		DS-5565 Open-label Extension
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		20/237 (8.4%)
Cardiac disorders
Acute myocardial infarction	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Atrial fibrillation	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Myocardial ischaemia	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Gastrointestinal disorders
Constipation	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Gastric ulcer haemorrhage	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Infections and infestations
Cellulitis	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Pneumonia	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Injury, poisoning and procedural complications
Femur fracture	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Laceration	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Lower limb fracture	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Road traffic accident	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Metabolism and nutrition disorders
Hyperglycaemia	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Gastric cancer	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Hepatocellular carcinoma	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Nervous system disorders
Transient ischaemic attack	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Psychiatric disorders
Dissociative disorder	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Reproductive system and breast disorders
Uterine fibrosis	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Surgical and medical procedures
Large intestinal polypectomy	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Nasal polypectomy	0/303 (0%)		0/152 (0%)		0/153 (0%)		0/155 (0%)		1/237 (0.4%)
Other (Not Including Serious) Adverse Events
	Placebo		DS-5565 15 mg/Day		DS-5565 20 mg/Day		DS-5565 30 mg/Day		DS-5565 Open-label Extension
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	45/303 (14.9%)		44/152 (28.9%)		53/153 (34.6%)		72/155 (46.5%)		99/237 (41.8%)
General disorders
Oedema	2/303 (0.7%)		2/152 (1.3%)		6/153 (3.9%)		11/155 (7.1%)		14/237 (5.9%)
Infections and infestations
Nasopharyngitis	26/303 (8.6%)		13/152 (8.6%)		16/153 (10.5%)		20/155 (12.9%)		39/237 (16.5%)
Investigations
Weight increased	1/303 (0.3%)		7/152 (4.6%)		8/153 (5.2%)		8/155 (5.2%)		22/237 (9.3%)
Nervous system disorders
Somnolence	11/303 (3.6%)		20/152 (13.2%)		26/153 (17%)		37/155 (23.9%)		36/237 (15.2%)
Dizziness	10/303 (3.3%)		10/152 (6.6%)		15/153 (9.8%)		24/155 (15.5%)		26/237 (11%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.