Asian Phase 2 Study for Treatment of Pain Associated With Diabetic Peripheral Neuropathy

• Sponsor: Daiichi Sankyo Co., Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01504412
• Collaborator: (none)
• Enrollment: 450
• Locations: 3
• Arms: 5
• Duration (Months): 17
• Patients Per Site: 150
• Patients Per Site Per Month: 8.8

Study Details

Study Description

Brief Summary

The purpose of this study is to investigate the effectiveness and safety of DS-5565, compared to placebo, in subjects with pain associated with diabetic peripheral neuropathy.

Condition or Disease	Intervention/Treatment	Phase
Pain; Diabetic Peripheral Neuropathy	Drug: DS-5565; Drug: DS-5565; Drug: DS-5565; Drug: Placebo; Drug: Pregabalin capsules	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 450 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: An Asian, Phase 2, Multicenter, Randomized, Double-blind, Placebo- and Pregabalin-controlled, Dose-finding Study of DS-5565 in Patients With Pain Associated With Diabetic Peripheral Neuropathy
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: Jun 1, 2013
• Actual Study Completion Date: Jun 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: DS-5565 Low Dose DS-5565 10mg/day, administered in 2 doses. Treatment period: 1 week titration and 6 weeks of fixed dose.	Drug: DS-5565; Oral tablets administered twice daily
Experimental: DS-5565 Middle Dose DS-5565 20mg/day, administered in 2 doses. Treatment period: 1 week titration and 6 weeks of fixed dose.	Drug: DS-5565; Oral tablets administered twice daily
Experimental: DS-5565 High Dose DS-5565 30mg/day, administered in 2 doses. Treatment period: 1 week titration and 6 weeks of fixed dose.	Drug: DS-5565; Oral tablets administered twice daily
Placebo Comparator: Placebo DS-5565 placebo oral tablets and pregabalin placebo oral capsules administered 2 times per day.	Drug: Placebo; DS-5565 placebo oral tablets and pregabalin placebo oral capsules administered 2 times per day
Active Comparator: Pregabalin Pregabalin capsules 300mg/day administered in 2 doses	Drug: Pregabalin capsules; Pregabalin oral capsules 150 mg administered twice a day

Outcome Measures

Primary Outcome Measures

1. Mean Change in Average Daily Pain Score From Baseline Among Participants Who Received DS5565 for Pain Associated With Diabetic Peripheral Neuropathy [Baseline to Week 7 postdose]

   The mean change in average daily pain score (ADPS) was measured using a 11-point numeric rating scale (NRS; 0 [no pain] to 10 [worst possible pain]. The rating averaged over a 7-day period and was based on entries in patients' daily pain diaries. Greater mean changes (improvements) in ADPS indicated better outcomes. A minimally meaningful effect was a mean decrease of at least 1.0 point [scale of 0 to 10] versus placebo.

Secondary Outcome Measures

1. Mean Change in Short Form-McGill Pain Questionnaire From Baseline Among Participants Who Received DS5565 for Pain Associated With Diabetic Peripheral Neuropathy [at Week 7 postdose]

   The Short Form-McGill Pain Questionnaire (SF-MPQ) Visual Analog Scale (VAS) is reported. For VAS, participants rated pain intensity on a 100 mm-long horizontal line, where 0 mm = no pain and 100 mm = worst possible pain. Greater mean changes (improvements) in SF-MPQ indicated better outcomes.

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

• Painful distal symmetric polyneuropathy

• Average daily pain score is great than or equal to 4

Exclusion Criteria:

• HbA1c greater than 9.0

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Tokyo		Japan
2		Seoul		Korea, Republic of
3		Taipei		Taiwan

Sponsors and Collaborators

• Daiichi Sankyo Co., Ltd.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Daiichi Sankyo Co., Ltd.
• ClinicalTrials.gov Identifier: NCT01504412
• Other Study ID Numbers: DS5565-A-J202
• First Posted: Jan 5, 2012
• Last Update Posted: Mar 18, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Daiichi Sankyo Co., Ltd.: Pain; Diabetic Peripheral Neuropathy
• Additional relevant MeSH terms: Peripheral Nervous System Diseases; Diabetic Neuropathies; Pregabalin

Study Results

Participant Flow

Recruitment Details	Participants who met all inclusion criteria and none of the exclusion criteria were enrolled and randomized to treatment.
Pre-assignment Detail	Enrolled participants were equally randomized (1:1:1:1:1) to placebo, pregabalin, or one of three different doses of DS-5565 in a double-blind fashion. After randomization, participants received one-half the fixed dose for the first week, and subsequently received the fixed dose for 6 weeks. All participants were followed for an additional week.

Arm/Group Title	Placebo	Pregabalin	DS-5565 10 mg/Day	DS-5565 20 mg/Day	DS-5565 30 mg/Day
Arm/Group Description	DS-5565 placebo oral tablets and pregabalin placebo oral capsules administered 2 times per day.	Pregabalin capsules 300 mg/day administered in 2 doses	DS-5565 10 mg/day, administered in 2 doses (5 mg twice daily).	DS-5565 20 mg/day, administered in 2 doses (10 mg twice daily).	DS-5565 30mg/day, administered in 2 doses (15 mg twice daily).
Period Title: Overall Study
STARTED	89	87	90	94	90
COMPLETED	84	75	86	75	77
NOT COMPLETED	5	12	4	19	13

Baseline Characteristics

Arm/Group Title	Placebo	Pregabalin	DS-5565 10 mg/Day	DS-5565 20 mg/Day	DS-5565 30 mg/Day	Total
Arm/Group Description	DS-5565 placebo oral tablets and pregabalin placebo oral capsules administered 2 times per day.	Pregabalin capsules 300 mg/day administered in 2 doses	DS-5565 10 mg/day, administered in 2 doses (5 mg twice daily).	DS-5565 20 mg/day, administered in 2 doses (10 mg twice daily).	DS-5565 30mg/day, administered in 2 doses (15 mg twice daily).	Total of all reporting groups
Overall Participants	89	87	90	94	90	450
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	64 71.9%	61 70.1%	56 62.2%	60 63.8%	69 76.7%	310 68.9%
>=65 years	25 28.1%	26 29.9%	34 37.8%	34 36.2%	21 23.3%	140 31.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.3 (9.79)	60.1 (8.74)	60.5 (9.77)	60.9 (9.32)	59.0 (10.06)	59.8 (9.55)
Sex: Female, Male (Count of Participants)
Female	27 30.3%	25 28.7%	31 34.4%	36 38.3%	41 45.6%	160 35.6%
Male	62 69.7%	62 71.3%	59 65.6%	58 61.7%	49 54.4%	290 64.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	89 100%	87 100%	90 100%	94 100%	90 100%	450 100%
Unknown or Not Reported	0 0%	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%	0 0%
Asian	89 100%	87 100%	90 100%	94 100%	90 100%	450 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Mean Change in Average Daily Pain Score From Baseline Among Participants Who Received DS5565 for Pain Associated With Diabetic Peripheral Neuropathy
Description	The mean change in average daily pain score (ADPS) was measured using a 11-point numeric rating scale (NRS; 0 [no pain] to 10 [worst possible pain]. The rating averaged over a 7-day period and was based on entries in patients' daily pain diaries. Greater mean changes (improvements) in ADPS indicated better outcomes. A minimally meaningful effect was a mean decrease of at least 1.0 point [scale of 0 to 10] versus placebo.
Time Frame	Baseline to Week 7 postdose

Outcome Measure Data

Analysis Population Description

Mean change in ADPS was assessed in the Full Analysis Set.

Arm/Group Title	Placebo	Pregabalin	DS-5565 10 mg/Day	DS-5565 20 mg/Day	DS-5565 30 mg/Day
Arm/Group Description	DS-5565 placebo oral tablets and pregabalin placebo oral capsules administered 2 times per day.	Pregabalin capsules 300 mg/day administered in 2 doses	DS-5565 10 mg/day, administered in 2 doses (5 mg twice daily).	DS-5565 20 mg/day, administered in 2 doses (10 mg twice daily).	DS-5565 30mg/day, administered in 2 doses (15 mg twice daily).
Measure Participants	88	85	90	93	90
Baseline to Week 1	-0.59 (1.13)	-0.71 (1.29)	-0.69 (0.90)	-0.88 (1.32)	-0.60 (1.01)
Baseline to Week 2	-0.86 (1.36)	-0.92 (1.33)	-1.16 (1.06)	-1.21 (1.56)	-1.06 (1.28)
Baseline to Week 3	-1.05 (1.38)	-1.06 (1.29)	-1.32 (1.15)	-1.50 (1.68)	-1.35 (1.52)
Baseline to Week 4	-1.12 (1.47)	-1.29 (1.48)	-1.50 (1.22)	-1.65 (1.68)	-1.56 (1.53)
Baseline to Week 5	-1.28 (1.62)	-1.44 (1.56)	-1.62 (1.32)	-1.68 (1.80)	-1.47 (1.61)
Baseline to Week 6	-1.41 (1.68)	-1.40 (1.51)	-1.79 (1.31)	-1.78 (1.68)	-1.68 (1.50)
Baseline to Week 7	-1.50 (1.77)	-1.55 (1.77)	-1.82 (1.36)	-1.91 (1.77)	-1.75 (1.68)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, DS-5565 10 mg/Day
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1995
	Comments	Dunnett method was used for adjustment of multiple testing.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	-0.42
	Confidence Interval	(2-Sided) 95%; -0.99 to 0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, DS-5565 20 mg/Day
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2886
	Comments	Dunnett method was used for adjustment of multiple testing.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	-0.37
	Confidence Interval	(2-Sided) 95%; -0.93 to 0.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, DS-5565 30 mg/Day
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4704
	Comments	Dunnett method was used for adjustment of multiple testing.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	-0.30
	Confidence Interval	(2-Sided) 95%; -0.87 to 0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Mean Change in Short Form-McGill Pain Questionnaire From Baseline Among Participants Who Received DS5565 for Pain Associated With Diabetic Peripheral Neuropathy
Description	The Short Form-McGill Pain Questionnaire (SF-MPQ) Visual Analog Scale (VAS) is reported. For VAS, participants rated pain intensity on a 100 mm-long horizontal line, where 0 mm = no pain and 100 mm = worst possible pain. Greater mean changes (improvements) in SF-MPQ indicated better outcomes.
Time Frame	at Week 7 postdose

Outcome Measure Data

Analysis Population Description

Mean change in SF-MPQ VAS was assessed in the Full Analysis Set.

Arm/Group Title	Placebo	Pregabalin	DS-5565 10 mg/Day	DS-5565 20 mg/Day	DS-5565 30 mg/Day
Arm/Group Description	DS-5565 placebo oral tablets and pregabalin placebo oral capsules administered 2 times per day.	Pregabalin capsules 300 mg/day administered in 2 doses	DS-5565 10 mg/day, administered in 2 doses (5 mg twice daily).	DS-5565 20 mg/day, administered in 2 doses (10 mg twice daily).	DS-5565 30mg/day, administered in 2 doses (15 mg twice daily).
Measure Participants	88	85	90	93	90
Mean (Standard Error) [units on a scale]	-16.7 (2.03)	-17.2 (2.06)	-21.9 (2.01)	-22.1 (1.97)	-24.2 (2.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, DS-5565 10 mg/Day
	Comments	This analysis assessed placebo vs DS-5565 10 mg/day for the visual analog scale.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0691
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-5.2
	Confidence Interval	(2-Sided) 95%; -10.8 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, DS-5565 20 mg/Day
	Comments	This analysis assessed placebo vs DS-5565 20 mg/day for the visual analog scale.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0577
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-5.4
	Confidence Interval	(2-Sided) 95%; -10.9 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, DS-5565 30 mg/Day
	Comments	This analysis assessed placebo vs DS-5565 30 mg/day for the visual analog scale.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0093
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-7.4
	Confidence Interval	(2-Sided) 95%; -13.0 to -1.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse event data were collected from the time the Informed Consent Form was signed to 7 days after the last dose of study medication, approximately 18 months.
Adverse Event Reporting Description	Adverse events that appeared for the first time during treatment, or that worsened relative to the pre-treatment state, were analyzed. Additionally, 3 participants who had major violations of GCP were excluded from the Safety Analysis Set (1 participant each in the placebo, pregabalin, and in the 20-mg/day group).
Arm/Group Title	Placebo		Pregabalin		DS-5565 10 mg/Day		DS-5565 20 mg/Day		DS-5565 30 mg/Day
Arm/Group Description	DS-5565 placebo oral tablets and pregabalin placebo oral capsules administered 2 times per day.		Pregabalin capsules 300 mg/day administered in 2 doses		DS-5565 10 mg/day, administered in 2 doses (5 mg twice daily). Treatment period: 1 week titration and 6 weeks of fixed dose.		DS-5565 20 mg/day, administered in 2 doses (10 mg twice daily). Treatment period: 1 week titration and 6 weeks of fixed dose.		DS-5565 30mg/day, administered in 2 doses (15 mg twice daily). Treatment period: 1 week titration and 6 weeks of fixed dose.
All Cause Mortality
	Placebo		Pregabalin		DS-5565 10 mg/Day		DS-5565 20 mg/Day		DS-5565 30 mg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/88 (0%)		0/86 (0%)		0/90 (0%)		1/93 (1.1%)		0/90 (0%)
Serious Adverse Events
	Placebo		Pregabalin		DS-5565 10 mg/Day		DS-5565 20 mg/Day		DS-5565 30 mg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/88 (3.4%)		2/86 (2.3%)		1/90 (1.1%)		4/93 (4.3%)		2/90 (2.2%)
Eye disorders
Diabetic retinopathy	0/88 (0%)		0/86 (0%)		0/90 (0%)		1/93 (1.1%)		0/90 (0%)
Vitreous haemorrhage	0/88 (0%)		0/86 (0%)		1/90 (1.1%)		0/93 (0%)		0/90 (0%)
Infections and infestations
Pneumonia	0/88 (0%)		1/86 (1.2%)		0/90 (0%)		1/93 (1.1%)		0/90 (0%)
Bronchitis	0/88 (0%)		0/86 (0%)		0/90 (0%)		0/93 (0%)		1/90 (1.1%)
Gastroenteritis	0/88 (0%)		0/86 (0%)		0/90 (0%)		1/93 (1.1%)		0/90 (0%)
Osteomyelitis	0/88 (0%)		1/86 (1.2%)		0/90 (0%)		0/93 (0%)		0/90 (0%)
Urinary tract infection	1/88 (1.1%)		0/86 (0%)		0/90 (0%)		0/93 (0%)		0/90 (0%)
Injury, poisoning and procedural complications
Thermal burn	1/88 (1.1%)		0/86 (0%)		0/90 (0%)		0/93 (0%)		0/90 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to lymph node	1/88 (1.1%)		0/86 (0%)		0/90 (0%)		0/93 (0%)		0/90 (0%)
Nervous system disorders
Brain stem infarction	0/88 (0%)		1/86 (1.2%)		0/90 (0%)		0/93 (0%)		0/90 (0%)
Cognitive disorder	0/88 (0%)		0/86 (0%)		0/90 (0%)		0/93 (0%)		1/90 (1.1%)
Psychiatric disorders
Completed suicide	0/88 (0%)		0/86 (0%)		0/90 (0%)		1/93 (1.1%)		0/90 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Pregabalin		DS-5565 10 mg/Day		DS-5565 20 mg/Day		DS-5565 30 mg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/88 (14.8%)		28/86 (32.6%)		18/90 (20%)		38/93 (40.9%)		42/90 (46.7%)
Gastrointestinal disorders
Vomiting	1/88 (1.1%)		5/86 (5.8%)		1/90 (1.1%)		3/93 (3.2%)		2/90 (2.2%)
General disorders
Oedema peripheral	1/88 (1.1%)		5/86 (5.8%)		3/90 (3.3%)		3/93 (3.2%)		7/90 (7.8%)
Gait disturbance	1/88 (1.1%)		4/86 (4.7%)		1/90 (1.1%)		7/93 (7.5%)		2/90 (2.2%)
Infections and infestations
Nasopharyngitis	3/88 (3.4%)		2/86 (2.3%)		7/90 (7.8%)		13/93 (14%)		3/90 (3.3%)
Investigations
Weight increased	0/88 (0%)		2/86 (2.3%)		1/90 (1.1%)		2/93 (2.2%)		5/90 (5.6%)
Nervous system disorders
Somnolence	5/88 (5.7%)		12/86 (14%)		8/90 (8.9%)		13/93 (14%)		19/90 (21.1%)
Dizziness	3/88 (3.4%)		9/86 (10.5%)		5/90 (5.6%)		10/93 (10.8%)		15/90 (16.7%)
Headache	2/88 (2.3%)		5/86 (5.8%)		2/90 (2.2%)		4/93 (4.3%)		3/90 (3.3%)

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.