DS-5565 Phase III Study for Diabetic Peripheral Neuropathic Pain

• Sponsor: Daiichi Sankyo Co., Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02318706
• Collaborator: CMIC Co, Ltd. Japan (Industry), Quintiles, Inc. (Industry), Quintiles Malaysia Sdn. Bhd. (Other)
• Enrollment: 854
• Location: 1
• Arms: 4
• Actual Duration (Months): 29.9
• Patients Per Site Per Month: 28.6

Study Details

Study Description

Brief Summary

Investigate the efficacy and safety of DS-5565 in subjects with Diabetic Peripheral Neuropathic Pain (DPNP) in comparison to placebo

Condition or Disease	Intervention/Treatment	Phase
Diabetic Peripheral Neuropathic Pain	Drug: DS-5565; Drug: placebo	Phase 3

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 DPNP 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 DPNP.

Study Design

• Study Type: Interventional
• Actual Enrollment: 854 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 Diabetic Peripheral Neuropathic Pain Followed by a 52-Week Open-label Extension
• Actual Study Start Date: Jan 1, 2015
• Actual Primary Completion Date: Jun 29, 2017
• Actual Study Completion Date: Jun 29, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: placebo placebo group (14 weeks)	Drug: placebo
Experimental: DS-5565 15mg 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 Administration of DS-5565 in Participants With Diabetic Peripheral Neuropathic Pain [Baseline to Week 14 (post-dose 1 [15 mg QD] and post-dose 2 [20 mg and 30 mg])]

   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 From Baseline (Week 14) to Week 66 Following Administration of DS-5565 in Participants With Diabetic Peripheral Neuropathic Pain [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:

• Type 1 or type 2 diabetes mellitus at screening

• Painful distal symmetric polyneuropathy

• At screening, a pain scale of ≥ 40 mm

Exclusion Criteria:

• HbA1c (National Glycohemoglobin Standardization Program) > 10.0%

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Saiki Central Hospital	Oita		Japan	876-0851

Sponsors and Collaborators

• Daiichi Sankyo Co., Ltd.
• CMIC Co, Ltd. Japan
• Quintiles, Inc.
• Quintiles Malaysia Sdn. Bhd.

Investigators

• Study Director: Global Clinical Leader, Daiichi Sankyo, Inc.

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: NCT02318706
• Other Study ID Numbers: DS5565-A-J303
• 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
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Daiichi Sankyo Co., Ltd.: Diabetic Peripheral Neuropathic Pain
• Additional relevant MeSH terms: Neuralgia; Diabetic Neuropathies

Study Results

Participant Flow

Recruitment Details	A total of 854 participants who met all inclusion and no exclusion criteria were enrolled; 834 were randomized to treatment in the double-blind phase. Twenty participants were excluded by the sponsor due to a serious Good Clinical Practice violation (inform consent form-related). A total of 214 participants enrolled in the open-label extension.
Pre-assignment Detail	Participants were randomized to DS-5565 (15, 20, or 30 mg) or placebo in the double-blind (DB) phase and open-label DS-5565 in the long-term (LT) phase. Patients who complete the DB phase may not enroll in the LT phase. DB phase determine significant difference vs placebo (~750 target cases). LT phase confirm long-term safety (~180 target cases).

Arm/Group Title	Placebo	DS-5565 15mg QD	DS-5565 20 mg (10 mg BID)	DS-5565 30 mg (15 mg BID)	DS-5565 Open-label Extension
Arm/Group Description	Participants who received an oral dose of placebo twice daily (BID) for 14 weeks.	Participants who received an oral dose of DS-5565 15 mg every day (QD). During the titration period, DS-5565 was administered orally at a daily dose of 5 mg (5 mg QD) during the first week and followed by 10 mg (10 mg QD) during the second week. During the fixed-dose period, a daily dose of 15 mg (15 mg QD) was administered orally for 12 weeks.	Participants who received an oral dose of DS-5565 20 mg (10 mg BID). During the titration period, DS-5565 was administered orally at a daily dose of 10 mg (5 mg BID) for 1 week. During the fixed-dose period, a daily dose of 20 mg (10 mg BID) was administered orally for 13 weeks.	Participants who received an oral dose of DS-5565 30 mg (15 mg BID). During the titration period, DS-5565 was administered orally at a daily dose of 10 mg (5 mg BID) for the first week followed by 20 mg (10 mg BID) during the second week. During the fixed-dose period, a daily dose of 30 mg (15 mg BID) was administered orally for 12 weeks.	Participants who received an oral dose of DS-5565 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 was 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	334	166	168	166	0
COMPLETED	309	154	150	142	0
NOT COMPLETED	25	12	18	24	0
Period Title: Double-blind Phase
STARTED	0	0	0	0	214
COMPLETED	0	0	0	0	172
NOT COMPLETED	0	0	0	0	42

Baseline Characteristics

Arm/Group Title	Placebo	DS-5565 15mg QD	DS-5565 20 mg (10 mg BID)	DS-5565 30 mg (15 mg BID)	Total
Arm/Group Description	Participants who received an oral dose of placebo twice daily (BID) for 14 weeks.	Participants who received an oral dose of DS-5565 15 mg QD. During the titration period, DS-5565 was administered orally at a daily dose of 5 mg (5 mg QD) during the first week and followed by 10 mg (10 mg QD) during the second week. During the fixed-dose period, a daily dose of 15 mg (15 mg QD) was administered orally for 12 weeks.	Participants who received an oral dose of DS-5565 20 mg (10 mg BID). During the titration period, DS-5565 was administered orally at a daily dose of 10 mg (5 mg BID) for 1 week. During the fixed-dose period, a daily dose of 20 mg (10 mg BID) was administered orally for 13 weeks.	Participants who received an oral dose of DS-5565 30 mg (15 mg BID). During the titration period, DS-5565 was administered orally at a daily dose of 10 mg (5 mg BID) for the first week followed by 20 mg (10 mg BID) during the second week. During the fixed-dose period, a daily dose of 30 mg (15 mg BID) was administered orally for 12 weeks.	Total of all reporting groups
Overall Participants	334	166	168	166	834
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	198 59.3%	99 59.6%	102 60.7%	98 59%	497 59.6%
>=65 years	136 40.7%	67 40.4%	66 39.3%	68 41%	337 40.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.0 (10.5)	61.9 (8.4)	61.2 (10.1)	61.8 (9.4)	61.4 (9.8)
Sex: Female, Male (Count of Participants)
Female	93 27.8%	53 31.9%	47 28%	36 21.7%	229 27.5%
Male	241 72.2%	113 68.1%	121 72%	130 78.3%	605 72.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	334 100%	166 100%	168 100%	166 100%	834 100%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	334 100%	166 100%	168 100%	166 100%	834 100%
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%

Outcome Measures

1. Primary Outcome

Title	Change in the Average Daily Pain Score (ADPS) From Baseline to Week 14 Following Administration of DS-5565 in Participants With Diabetic Peripheral Neuropathic Pain
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 (post-dose 1 [15 mg QD] and post-dose 2 [20 mg and 30 mg])

Outcome Measure Data

Analysis Population Description

ADPS was assessed in the Modified-Intent-to-Treat Analysis Set.

Arm/Group Title	Placebo	DS-5565 15mg QD	DS-5565 20 mg (10 mg BID)	DS-5565 30 mg (15 mg BID)
Arm/Group Description	Participants who received an oral dose of placebo twice daily (BID) for 14 weeks.	Participants who received an oral dose of DS-5565 15 mg every day (QD). During the titration period, DS-5565 was administered orally at a daily dose of 5 mg (5 mg QD) during the first week and followed by 10 mg (10 mg QD) during the second week. During the fixed-dose period, a daily dose of 15 mg (15 mg QD) was administered orally for 12 weeks.	Participants who received an oral dose of DS-5565 20 mg (10 mg BID). During the titration period, DS-5565 was administered orally at a daily dose of 10 mg (5 mg BID) for 1 week. During the fixed-dose period, a daily dose of 20 mg (10 mg BID) was administered orally for 13 weeks.	Participants who received an oral dose of DS-5565 30 mg (15 mg BID). During the titration period, DS-5565 was administered orally at a daily dose of 10 mg (5 mg BID) for the first week followed by 20 mg (10 mg BID) during the second week. During the fixed-dose period, a daily dose of 30 mg (15 mg BID) was administered orally for 12 weeks.
Measure Participants	330	164	165	165
Week 1	-0.26 (0.79)	-0.39 (0.67)	-0.40 (0.85)	-0.60 (1.01)
Week 2	-0.46 (0.96)	-0.60 (0.90)	-0.72 (1.12)	-1.00 (1.27)
Week 3	-0.57 (1.08)	-0.78 (1.02)	-0.84 (1.22)	-1.33 (1.49)
Week 4	-0.70 (1.12)	-0.87 (1.13)	-0.94 (1.38)	-1.43 (1.63)
Week 5	-0.84 (1.17)	-0.97 (1.20)	-1.06 (1.50)	-1.48 (1.68)
Week 6	-0.92 (1.25)	-1.01 (1.32)	-1.13 (1.52)	-1.58 (1.73)
Week 7	-1.03 (1.31)	-1.06 (1.40)	-1.13 (1.59)	-1.57 (1.72)
Week 8	-1.09 (1.39)	-1.07 (1.49)	-1.26 (1.59)	-1.53 (1.79)
Week 9	-1.16 (1.42)	-1.13 (1.49)	-1.27 (1.56)	-1.63 (1.76)
Week 10	-1.18 (1.44)	-1.19 (1.56)	-1.33 (1.65)	-1.67 (1.83)
Week 11	-1.25 (1.46)	-1.23 (1.57)	-1.36 (1.64)	-1.69 (1.80)
Week 12	-1.28 (1.50)	-1.24 (1.60)	-1.36 (1.67)	-1.82 (1.84)
Week 13	-1.32 (1.55)	-1.27 (1.63)	-1.43 (1.72)	-1.85 (1.93)
Week 14	-1.37 (1.60)	-1.34 (1.74)	-1.47 (1.69)	-1.88 (1.88)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, DS-5565 15mg QD
	Comments	Week 14 change from baseline
	Type of Statistical Test	Superiority
	Comments	DS-5565 20 mg and 30 mg are tested against placebo at significance level of 0.025, respectively. If both arms are statistically significant, DS-5565 15 mg arm will be tested at level of 0.05. If neither of the arms is statistically significant, DS-5565 15 mg arm is no longer tested. If either DS-5565 20 mg or DS-5565 30 mg is statistically significant, DS-5565 15 mg arm is tested at level of 0.025.
Statistical Test of Hypothesis	p-Value	0.8773
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95%; -0.35 to 0.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, DS-5565 20 mg (10 mg BID)
	Comments	Week 14 change from baseline
	Type of Statistical Test	Superiority
	Comments	DS-5565 20 mg and 30 mg are tested against placebo at significance level of 0.025, respectively. If both arms are statistically significant, DS-5565 15 mg arm will be tested at level of 0.05. If neither of the arms is statistically significant, DS-5565 15 mg arm is no longer tested. If either DS-5565 20 mg or DS-5565 30 mg is statistically significant, DS-5565 15 mg arm is tested at level of 0.025.
Statistical Test of Hypothesis	p-Value	0.3494
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.48 to 0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, DS-5565 30 mg (15 mg BID)
	Comments	Week 14 change from baseline
	Type of Statistical Test	Superiority
	Comments	DS-5565 20 mg and 30 mg are tested against placebo at significance level of 0.025, respectively. If both arms are statistically significant, DS-5565 15 mg arm will be tested at level of 0.05. If neither of the arms is statistically significant, DS-5565 15 mg arm is no longer tested. If either DS-5565 20 mg or DS-5565 30 mg is statistically significant, DS-5565 15 mg arm is tested at level of 0.025.
Statistical Test of Hypothesis	p-Value	0.0027
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	-0.50
	Confidence Interval	(2-Sided) 95%; -0.82 to -0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Visual Analog Scale From Baseline (Week 14) to Week 66 Following Administration of DS-5565 in Participants With Diabetic Peripheral Neuropathic Pain
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 was assessed in all enrolled participants.

Arm/Group Title	DS-5565 Open-label Extension
Arm/Group Description	Participants who received an oral dose of DS-5565 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 was 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	214
Week 16	-0.90 (9.190)
Week 18	-4.00 (11.140)
Week 22	-7.00 (12.690)
Week 26	-6.20 (11.430)
Week 30	-7.20 (12.620)
Week 34	-7.80 (13.260)
Week 38	-7.30 (15.230)
Week 42	-8.00 (14.420)
Week 46	-8.10 (15.780)
Week 50	-7.80 (15.100)
Week 54	-9.20 (14.360)
Week 58	-8.80 (14.940)
Week 62	-10.00 (15.390)
Week 66	-10.80 (13.950)

Adverse Events

Time Frame	Adverse events were collected after the participant signed the informed consent up to 7 days after the last dose of the study drug (the post-treatment follow-up visit [Visit 11]), up to 2 years 6 months.
Adverse Event Reporting Description	A total of 824 participants were included in the Safety Analysis Set. An adverse event was defined as any unfavorable and unintended sign (including an abnormal laboratory value or abnormal vital sign), symptom, or disease that developed, regardless of relationship to the study drug.
Arm/Group Title	Placebo		DS-5565 15mg QD		DS-5565 20 mg (10 mg BID)		DS-5565 30 mg (15 mg BID)		DS-5565 Open-label Extension
Arm/Group Description	Participants who received an oral dose of placebo twice daily (BID) for 14 weeks.		Participants who received an oral dose of DS-5565 15 mg every day (QD). During the titration period, DS-5565 was administered orally at a daily dose of 5 mg (5 mg QD) during the first week and followed by 10 mg (10 mg QD) during the second week. During the fixed-dose period, a daily dose of 15 mg (15 mg QD) was administered orally for 12 weeks.		Participants who received an oral dose of DS-5565 20 mg (10 mg BID). During the titration period, DS-5565 was administered orally at a daily dose of 10 mg (5 mg BID) for 1 week. During the fixed-dose period, a daily dose of 20 mg (10 mg BID) was administered orally for 13 weeks.		Participants who received an oral dose of DS-5565 30 mg (15 mg BID). During the titration period, DS-5565 was administered orally at a daily dose of 10 mg (5 mg BID) for the first week followed by 20 mg (10 mg BID) during the second week. During the fixed-dose period, a daily dose of 30 mg (15 mg BID) was administered orally for 12 weeks.		Participants who received an oral dose of DS-5565 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 was 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 15mg QD		DS-5565 20 mg (10 mg BID)		DS-5565 30 mg (15 mg BID)		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	0/330 (0%)		0/164 (0%)		2/165 (1.2%)		0/165 (0%)		1/214 (0.5%)
Serious Adverse Events
	Placebo		DS-5565 15mg QD		DS-5565 20 mg (10 mg BID)		DS-5565 30 mg (15 mg BID)		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	11/330 (3.3%)		4/164 (2.4%)		8/165 (4.8%)		11/165 (6.7%)		24/214 (11.2%)
Cardiac disorders
Acute myocardial infarction	1/330 (0.3%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		0/214 (0%)
Angina pectoris	1/330 (0.3%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		0/214 (0%)
Atrioventricular block second degree	0/330 (0%)		0/164 (0%)		0/165 (0%)		1/165 (0.6%)		0/214 (0%)
Coronary artery disease	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Myocardial infarction	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Eye disorders
Diplopia	0/330 (0%)		0/164 (0%)		1/165 (0.6%)		1/165 (0.6%)		0/214 (0%)
Cataract	1/330 (0.3%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Diabetic retinopathy	0/330 (0%)		1/164 (0.6%)		0/165 (0%)		0/165 (0%)		0/214 (0%)
Glaucoma	0/330 (0%)		1/164 (0.6%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Vitreous haemorrhage	0/330 (0%)		1/164 (0.6%)		0/165 (0%)		0/165 (0%)		0/214 (0%)
Macular oedema	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Retinal detachment	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Gastrointestinal disorders
Duodenal ulcer perforation	1/330 (0.3%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		0/214 (0%)
Diverticulum intestinal haemorrhagic	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Gastrooesophageal reflux disease	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Pancreatitis acute	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
General disorders
Death	0/330 (0%)		0/164 (0%)		1/165 (0.6%)		0/165 (0%)		0/214 (0%)
Drowning	0/330 (0%)		0/164 (0%)		1/165 (0.6%)		0/165 (0%)		1/214 (0.5%)
Oedema	0/330 (0%)		0/164 (0%)		1/165 (0.6%)		0/165 (0%)		0/214 (0%)
Hepatobiliary disorders
Cholangitis	1/330 (0.3%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		0/214 (0%)
Infections and infestations
Bronchitis	0/330 (0%)		0/164 (0%)		1/165 (0.6%)		0/165 (0%)		0/214 (0%)
Perinephric abscess	1/330 (0.3%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		0/214 (0%)
Pyelonephritis acute	0/330 (0%)		0/164 (0%)		0/165 (0%)		1/165 (0.6%)		0/214 (0%)
Subcutaneous abscess	0/330 (0%)		0/164 (0%)		0/165 (0%)		1/165 (0.6%)		0/214 (0%)
Urinary tract infection	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Injury, poisoning and procedural complications
Burns third degree	0/330 (0%)		0/164 (0%)		0/165 (0%)		1/165 (0.6%)		0/214 (0%)
Comminuted fracture	1/330 (0.3%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		0/214 (0%)
Hand fracture	0/330 (0%)		0/164 (0%)		0/165 (0%)		1/165 (0.6%)		1/214 (0.5%)
Humerus fracture	0/330 (0%)		1/164 (0.6%)		0/165 (0%)		0/165 (0%)		0/214 (0%)
Clavicle fracture	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Femoral neck fracture	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Fractured sacrum	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Ligament rupture	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Lower limb fracture	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Rib fracture	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Road traffic accident	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Ulnar nerve injury	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Investigations
Alanine aminotransferase increased	0/330 (0%)		0/164 (0%)		0/165 (0%)		1/165 (0.6%)		0/214 (0%)
Aspartate aminotransferase increased	0/330 (0%)		0/164 (0%)		0/165 (0%)		1/165 (0.6%)		1/214 (0.5%)
Metabolism and nutrition disorders
Diabetes mellitus	0/330 (0%)		0/164 (0%)		0/165 (0%)		1/165 (0.6%)		0/214 (0%)
Diabetic ketoacidosis	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatocellular carcinoma	1/330 (0.3%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		0/214 (0%)
Lung neoplasm malignant	0/330 (0%)		0/164 (0%)		0/165 (0%)		1/165 (0.6%)		0/214 (0%)
Colon cancer	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Pancreatic carcinoma	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Nervous system disorders
Cerebal infarction	1/330 (0.3%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		0/214 (0%)
Lacunar infarction	0/330 (0%)		0/164 (0%)		0/165 (0%)		1/165 (0.6%)		0/214 (0%)
Loss of consciousness	0/330 (0%)		0/164 (0%)		1/165 (0.6%)		0/165 (0%)		0/214 (0%)
Subarachnoid haemorrhage	0/330 (0%)		0/164 (0%)		0/165 (0%)		1/165 (0.6%)		0/214 (0%)
VIIth nerve paralysis	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/330 (0%)		0/164 (0%)		1/165 (0.6%)		0/165 (0%)		0/214 (0%)
Ovarian cyst	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		2/214 (0.9%)
Respiratory, thoracic and mediastinal disorders
Lung disorder	1/330 (0.3%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		0/214 (0%)
Pneumothorax	0/330 (0%)		0/164 (0%)		1/165 (0.6%)		0/165 (0%)		0/214 (0%)
Skin and subcutaneous tissue disorders
Diabetic foot	1/330 (0.3%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		0/214 (0%)
Vascular disorders
Peripheral arterial occlusion	0/330 (0%)		0/164 (0%)		0/165 (0%)		0/165 (0%)		1/214 (0.5%)
Other (Not Including Serious) Adverse Events
	Placebo		DS-5565 15mg QD		DS-5565 20 mg (10 mg BID)		DS-5565 30 mg (15 mg BID)		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	101/330 (30.6%)		60/164 (36.6%)		62/165 (37.6%)		84/165 (50.9%)		141/214 (65.9%)
Eye disorders
Diabetic retinopathy	16/330 (4.8%)		7/164 (4.3%)		3/165 (1.8%)		6/165 (3.6%)		25/214 (11.7%)
Gastrointestinal disorders
Diarrhoea	6/330 (1.8%)		2/164 (1.2%)		2/165 (1.2%)		1/165 (0.6%)		18/214 (8.4%)
Constipation	8/330 (2.4%)		3/164 (1.8%)		3/165 (1.8%)		5/165 (3%)		12/214 (5.6%)
General disorders
Oedema peripheral	4/330 (1.2%)		8/164 (4.9%)		4/165 (2.4%)		14/165 (8.5%)		24/214 (11.2%)
Oedema	0/330 (0%)		2/164 (1.2%)		1/165 (0.6%)		2/165 (1.2%)		13/214 (6.1%)
Infections and infestations
Nasopharyngitis	42/330 (12.7%)		22/164 (13.4%)		24/165 (14.5%)		27/165 (16.4%)		58/214 (27.1%)
Injury, poisoning and procedural complications
Contusion	6/330 (1.8%)		2/164 (1.2%)		3/165 (1.8%)		9/165 (5.5%)		9/214 (4.2%)
Investigations
Weight increased	2/330 (0.6%)		4/164 (2.4%)		5/165 (3%)		11/165 (6.7%)		17/214 (7.9%)
Metabolism and nutrition disorders
Diabetes mellitus	3/330 (0.9%)		1/164 (0.6%)		1/165 (0.6%)		3/165 (1.8%)		12/214 (5.6%)
Hypoglycaemia	11/330 (3.3%)		2/164 (1.2%)		4/165 (2.4%)		1/165 (0.6%)		12/214 (5.6%)
Musculoskeletal and connective tissue disorders
Back pain	7/330 (2.1%)		4/164 (2.4%)		4/165 (2.4%)		4/165 (2.4%)		11/214 (5.1%)
Nervous system disorders
Somnolence	13/330 (3.9%)		14/164 (8.5%)		20/165 (12.1%)		24/165 (14.5%)		20/214 (9.3%)
Dizziness	7/330 (2.1%)		8/164 (4.9%)		14/165 (8.5%)		18/165 (10.9%)		16/214 (7.5%)

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.