Safety Study of DS-5565 for Treatment of Fibromyalgia Pain in Subjects With Chronic Kidney Disease

• Sponsor: Daiichi Sankyo, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02496884
• Collaborator: Syneos Health (Other)
• Enrollment: 56
• Locations: 39
• Arms: 4
• Actual Duration (Months): 24.3
• Patients Per Site: 1.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

DS-5565 (mirogabalin) is being studied as treatment for fibromyalgia (FM) pain. Because it is excreted through the kidneys, people who have reduced kidney function will not process the drug as well as with those with normal kidney function, so the dose must be reduced. This study will test two reduced dose levels for both moderately reduced and severely reduced kidney function. The study will test the hypothesis that the drug will be safe and well-tolerated in people who have both fibromyalgia and chronic kidney disease.

Condition or Disease	Intervention/Treatment	Phase
Fibromyalgia	Drug: DS-5565; Drug: Placebo	Phase 3

Detailed Description

The main objective of the trial is to determine the safety and tolerability of subjects with FM and moderate to severe renal dysfunction during 13 weeks of renally-adjusted dosing of DS-5565 compared to placebo, followed by a short-term (4-week) safety follow-up.

This trial is conducted in accordance with the ethical principles of Good Clinical Practice, according to the International Council for Harmonisation (ICH) Harmonised Tripartite Guidelines. An independent Data Safety Monitoring Board (DSMB) is created to further protect the rights, safety, and well-being of subjects who participate in this study by monitoring their progress and results. The independent DSMB is composed of qualified scientists who are not investigators in the study and not otherwise directly associated with the sponsor.

Additional protection is provided by special monitoring of liver enzyme elevations and liver dysfunction performed by a Hepatic Adjudication Committee (HAC), comprised of three qualified hepatologists who are not investigators in the study and not otherwise directly associated with the sponsor. The HAC completes assessments on an ongoing basis. Adjudication of hepatic events is based on evaluation of electronic case report forms (eCRFs) and source documents, as available, including but not limited to hospital discharge summaries, diagnostic imaging, histopathology, consultation, and laboratory reports.

Study Design

• Study Type: Interventional
• Actual Enrollment: 56 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled Safety Study of DS-5565 for Treatment of Pain Due to Fibromyalgia in Subjects With Chronic Kidney Disease
• Actual Study Start Date: Jun 26, 2015
• Actual Primary Completion Date: Jul 6, 2017
• Actual Study Completion Date: Jul 6, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: M-CKD DS-5565 7.5 mg BID Patients with moderate chronic kidney disease (M-CKD) randomized to receive DS-5565 BID during the treatment period.	Drug: DS-5565; DS-5565 7.5 mg tablet for oral use; Other Names: Experimental drug Mirogabalin SUB60040
Experimental: S-CKD DS-5565 7.5 mg QD Fibromyalgia patients with severe chronic kidney disease (S-CKD) randomized to receive a DS-5565 7.5 mg tablet once per day (QD), and a placebo tablet (no drug) QD, for a total of 7.5 mg DS-5565	Drug: DS-5565; DS-5565 7.5 mg tablet for oral use; Other Names: Experimental drug Mirogabalin SUB60040 ; Drug: Placebo; Placebo tablet for oral use to match DS-5565 7.5 mg tablet; Other Names: No drug Placebo comparator
Placebo Comparator: M-CKD Placebo Patients with M-CKD randomized to receive placebo twice daily (BID) during the treatment period.	Drug: Placebo; Placebo tablet for oral use to match DS-5565 7.5 mg tablet; Other Names: No drug Placebo comparator
Placebo Comparator: S-CKD Placebo Patients with S-CKD randomized to receive placebo once daily (QD) during the treatment period.	Drug: Placebo; Placebo tablet for oral use to match DS-5565 7.5 mg tablet; Other Names: No drug Placebo comparator

Outcome Measures

Primary Outcome Measures

1. Number of Participants Experiencing a Treatment Emergent Adverse Event (TEAE) [Baseline up to 30 days after last dose, up to 25 months]

   A TEAE is any adverse event that emerges on or after the first dosing of double blind study medication and during study treatment up to 4 weeks after the last dose of double blind study medication (having been absent prior to treatment) or worsens relative to the pre-double blind treatment state. Relationship of TEAEs to study drug is assessed by the investigator. Clinically significant changes from baseline in clinical laboratory evaluations, neurological examinations, and electrocardiograms are reported as TEAEs.

2. Patients Answering Yes to Any Question on the Columbia-Suicide Severity Rating Scale (C-SSRS) [Screening up to Week 13 postdose]

   The C-SSRS is described as a scale developed at Columbia University that has 2-6 questions each in categories of Suicidal Ideation, Intensity of Ideation, Suicidal Behavior, and Actual Attempts. Four constructs were measured. Severity of Suicidal ideation is rated on a 5-point ordinal scale. Intensity of ideation is comprised of 5 items (frequency, duration, controllability, deterrents, and reason for ideation), each rated on a 5-point ordinal scale. Suicidal behavior is rated on a nominal scale that includes actual, aborted, and interrupted attempts; preparatory behavior; and non-suicidal self-injurious behavior. Lethality, assesses actual attempts; actual lethality is rated on a 6-point ordinal scale, and if actual lethality is 0, potential lethality of attempts is rated on a 3-point ordinal scale.The higher the C-SSRS score, the higher the suicide risk (ie. worse outcome).

Secondary Outcome Measures

1. Mean Weekly Average of Individual Daily Pain Scores (ADPS) [Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11, Week 12, and Week 13 postdose]

   Each day participants will rate their worst pain over the last 24 hours on a scale from 0-10, where 0=no pain and 10=worst pain imaginable. Each week individual pain scores will be averaged, and the mean weekly score for the treatment group will be calculated. Higher ADPS scores indicate worse outcome.

2. Number of Participants With Different Scale Ranges of the Patient Global Impression of Change (PGIC) Scale at Week 13 [Week 13 postdose]

   The PGIC is a validated outcome measure for treatment of pain in the acute pain setting. At the end of treatment, participants will rate their overall status on a scale of 1-7, where 1=very much improved and 7=very much worse using the standard PGIC questionnaire. Higher scores indicate worse outcome.

Eligibility Criteria

Criteria

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

Abbreviations: alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine clearance [(CrCL) determined by the central laboratory using the Cockcroft-Gault equation], upper limit of normal (ULN), Columbia-Suicide Severity Rating Scale (C-SSRS)

Inclusion Criteria:

• Age ≥ 18 years

• Able to give written informed consent

• Able to complete patient-reported questionnaires per the Investigator's judgment

• Estimated CrCl between 15-59 mL/min from serum creatinine by the central laboratory using the Cockcroft-Gault equation

• Fibromyalgia meeting American College of Rheumatology criteria for FM:

• Widespread pain index (WPI) ≥ 7 and symptom severity (SS) scale score ≥ 5 or WPI 3 to 6 and SS scale score ≥ 9,

• Pain in at least 11 of 18 specific tender point sites,

• Symptoms have been present at a similar level for at least 3 months, and

• The subject does not have a disorder that would otherwise explain the pain

• Average Daily Pain Score of ≥ 4 on the 11-point numeric rating scale (NRS) over the 7 days prior to randomization (based on completion of at least 4 daily pain assessments during the 7-day baseline period prior to randomization)

• Women of child bearing potential (WOCBP) must be using adequate methods of contraception to avoid pregnancy during the study and for 4 weeks after study completion.

Exclusion Criteria:

• Need for ongoing use of concomitant chronic pain medications or any new non-pharmacological pain management techniques that may confound assessments of efficacy and/or safety, including neurolytic treatments (destruction of nerves by chemicals, heat, cold) or surgery, intrathecal pumps, spinal cord stimulators or psychological support within the previous year. Also excluded: topical capsaicin within 6 months; or systemic corticosteroids within 3 months of baseline period.

• Unable to undergo pre-study washout of prohibited concomitant medications

• Subjects with recent history (i.e., within 1 year prior to screening) of alcohol abuse or illicit drug use (cocaine, heroin, marijuana [including medical, prescribed], etc.)

• Use of any selective serotonin reuptake inhibitor (SSRI), unless the subject has been on a stable dose for ≥ 90 days prior to screening and is not anticipated to need any dose adjustment during the course of the study

• Subjects with severe or uncontrolled depression that, in the judgment of the Investigator, makes the subject inappropriate for entry into the study

• Significant neurological or psychiatric disorder unrelated to neuropathic pain

• Other severe pain (eg, sciatica, rheumatoid arthritis) that might impair the assessment of neuropathic pain

• CrCl ≥ 60 mL/min estimated from serum creatinine by the central laboratory using the Cockcroft-Gault equation.

• Subjects who are on hemodialysis or who require hemodialysis before the follow-up assessment; acute renal failure; history of kidney transplant

• Any history of a malignancy other than basal cell carcinoma within the past 5 years

• Clinically significant unstable neurologic, ophthalmologic, hepatobiliary, respiratory, or hematologic illness or unstable cardiovascular disease (eg, severe hypotension, uncontrolled cardiac arrhythmia, or myocardial infarction) within 12 months prior to screening

• Pregnancy or breast feeding or intent to become pregnant during the study period

• Known hypersensitivity to α2δ ligands or other components of the study medications. Note: Prior exposure to DS-5565 is allowed, as long as hypersensitivity to DS-5565 was not observed.

• Clinically significant ECG abnormalities at the Screening Visit

• Subjects who are at risk of suicide, as defined by their responses to the C-SSRS or in the opinion of the Investigator. Note: Subjects answering "yes" to any of the questions about active suicidal ideation/intent/behaviors that occurred within the past 12 months must be excluded (C-SSRS Suicide Ideation section - Questions 3, 4, or 5; C-SSRS Suicidal Behavior section - any of the suicide behaviors questions). Such subjects should be referred immediately to a mental health professional for appropriate evaluation.

• Subjects who are unlikely to comply with the protocol (eg, uncooperative attitude, inability to return for subsequent visits, and/or otherwise considered by the Investigator to be unlikely to complete the study)

• Subject is currently enrolled in, or it has been fewer than 30 days since ending, another investigational device or drug study or is receiving another investigational agent.

• Subjects who are employees or immediate family of employees of the study site, Sponsor, or contract research organization (CRO)

• Screening laboratory values outside the limits listed in the table below:

• Hematology

• Hemoglobin < 8 g/dL

• Platelet count < 100,000/mm3

• Absolute neutrophil count < 1,500/mm3

• Blood chemistry

• AST > 2.0 × ULN

• ALT > 2.0 × ULN

• Alkaline phosphatase > 1.5 × ULN

• Total bilirubin > 1.2 × ULN (If a subject has total bilirubin >ULN: unconjugated and conjugated bilirubin fractions should be analyzed and only subject documented to have Gilbert's syndrome may be enrolled)

• Creatine kinase > 3.0 × ULN

• Calculated CrCl ≥ 60 mL/min

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Phoenix	Arizona	United States	85018
2		Colton	California	United States	92324
3		Los Angeles	California	United States	90033
4		Santa Ana	California	United States	92705
5		Colorado Springs	Colorado	United States	80918
6		Brooksville	Florida	United States	34601
7		DeBary	Florida	United States	32713
8		Hialeah	Florida	United States	33013
9		Kissimmee	Florida	United States	34744
10		Miami	Florida	United States	33144
11		Grand Blanc	Michigan	United States	48439
12		High Point	North Carolina	United States	27262
13		Cincinnati	Ohio	United States	45224
14		Wyomissing	Pennsylvania	United States	19610
15		Greer	South Carolina	United States	29651
16		Rapid City	South Dakota	United States	57702
17		Knoxville	Tennessee	United States	37919
18		Houston	Texas	United States	77098
19		Plano	Texas	United States	75093
20		Bellevue	Washington	United States	98007
21		Charleston	West Virginia	United States	25304
22		Morgantown	West Virginia	United States	26505
23		Plovdiv		Bulgaria
24		Sevlievo		Bulgaria
25		Sofia		Bulgaria
26		Stara Zagora		Bulgaria
27		Varna		Bulgaria
28		Prague		Czechia
29		Ricany		Czechia
30		Budapest		Hungary
31		Nyiregyhaza		Hungary
32		Elblag		Poland
33		Kraków		Poland
34		Cluj-napoca		Romania
35		Johannesburg		South Africa
36		Pretoria		South Africa
37		Barcelona		Spain
38		Santiago de Compostela		Spain
39		Valencia		Spain

Sponsors and Collaborators

• Daiichi Sankyo, Inc.
• Syneos Health

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 14, 2017

More Information

Publications

None provided.

• Responsible Party: Daiichi Sankyo, Inc.
• ClinicalTrials.gov Identifier: NCT02496884
• Other Study ID Numbers: DS5565-A-U307; 2014-003972-21
• First Posted: Jul 14, 2015
• Last Update Posted: Nov 24, 2020
• Last Verified: Nov 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Daiichi Sankyo, Inc.: chronic kidney disease; . α2δ ligands; mirogabalin; pain relief; kidney metabolism
• Additional relevant MeSH terms: Fibromyalgia; Myofascial Pain Syndromes; Kidney Diseases; Renal Insufficiency, Chronic

Study Results

Participant Flow

Recruitment Details	A total of 56 participants who met all inclusion and no exclusion criteria were randomized to treatment in four countries: Bulgaria, Romania, Spain, and the United States.
Pre-assignment Detail	Eligible participants were randomized 2:1 to receive either DS-5565 7.5 mg QD or placebo for participants with CrCl 15 to 29 mL/min, or 2:1 to receive treatment with DS-5565 7.5 mg BID or placebo for participants with CrCl 30 to 59 mL/min over a 13-week double-blind treatment period.

Arm/Group Title	M-CKD Placebo	M-CKD DS-5565 7.5 mg BID	S-CKD Placebo	S-CKD DS-5565 7.5 mg QD
Arm/Group Description	Patients with moderate chronic kidney disease (M-CKD) randomized to receive placebo twice daily (BID) during the treatment period.	Patients with moderate chronic kidney disease (M-CKD) randomized to receive DS-5565 7.5 mg BID during the treatment period.	Patients with severe chronic kidney disease (S-CKD) randomized to receive placebo once daily (QD) during the treatment period.	Patients with severe chronic kidney disease (S-CKD) randomized to receive a DS-5565 7.5 mg tablet once per day (QD).
Period Title: Overall Study
STARTED	17	34	1	4
Safety Analysis Set	17	34	1	4
Modified Intent to Treat Set (mITT)	17	34	1	4
Pharmacokinetic (PK) Analysis Set	0	33	0	4
Completed Treatment Per Protocol	16	27	1	3
COMPLETED	15	31	1	4
NOT COMPLETED	2	3	0	0

Baseline Characteristics

Arm/Group Title	M-CKD Placebo	M-CKD DS-5565 7.5 mg BID	S-CKD Placebo	S-CKD DS-5565 7.5 mg QD	Total
Arm/Group Description	Patients with moderate chronic kidney disease (M-CKD) randomized to receive placebo twice daily (BID) during the treatment period.	Patients with moderate chronic kidney disease (M-CKD) randomized to receive DS-5565 7.5 mg BID during the treatment period.	Patients with severe chronic kidney disease (S-CKD) randomized to receive placebo once daily (QD) during the treatment period.	Patients with severe chronic kidney disease (S-CKD) randomized to receive a DS-5565 7.5 mg tablet once per day (QD).	Total of all reporting groups
Overall Participants	17	34	1	4	56
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	8 47.1%	12 35.3%	1 100%	1 25%	22 39.3%
>=65 years	9 52.9%	22 64.7%	0 0%	3 75%	34 60.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.4 (11.39)	68.4 (13.92)	53.0	74.0 (12.25)	67.3 (13.14)
Sex: Female, Male (Count of Participants)
Female	16 94.1%	28 82.4%	1 100%	0 0%	45 80.4%
Male	1 5.9%	6 17.6%	0 0%	4 100%	11 19.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	2 11.8%	2 5.9%	0 0%	1 25%	5 8.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 5.9%	3 8.8%	1 100%	1 25%	6 10.7%
White	14 82.4%	29 85.3%	0 0%	2 50%	45 80.4%
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%
Baseline Average Daily Pain Score (ADPS) (Count of Participants)
ADPS less than 7	8 47.1%	9 26.5%	1 100%	2 50%	20 35.7%
ADPS 7 or more	9 52.9%	25 73.5%	0 0%	2 50%	36 64.3%
Baseline Average Daily Pain Score (ADPS) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	6.99 (1.35)	7.21 (0.96)	5.70	6.53 (0.82)	7.07 (1.09)

Outcome Measures

1. Primary Outcome

Title	Number of Participants Experiencing a Treatment Emergent Adverse Event (TEAE)
Description	A TEAE is any adverse event that emerges on or after the first dosing of double blind study medication and during study treatment up to 4 weeks after the last dose of double blind study medication (having been absent prior to treatment) or worsens relative to the pre-double blind treatment state. Relationship of TEAEs to study drug is assessed by the investigator. Clinically significant changes from baseline in clinical laboratory evaluations, neurological examinations, and electrocardiograms are reported as TEAEs.
Time Frame	Baseline up to 30 days after last dose, up to 25 months

Outcome Measure Data

Analysis Population Description

Safety events were assessed in the Safety Analysis Set.

Arm/Group Title	M-CKD Placebo	M-CKD DS-5565 7.5 mg BID	S-CKD Placebo	S-CKD DS-5565 7.5 mg QD
Arm/Group Description	Patients with moderate chronic kidney disease (M-CKD) randomized to receive placebo twice daily (BID) during the treatment period.	Patients with moderate chronic kidney disease (M-CKD) randomized to receive DS-5565 7.5 mg BID during the treatment period.	Patients with severe chronic kidney disease (S-CKD) randomized to receive placebo once daily (QD) during the treatment period.	Patients with severe chronic kidney disease (S-CKD) randomized to receive a DS-5565 7.5 mg tablet once per day (QD).
Measure Participants	17	34	1	4
At least 1 TEAE	8 47.1%	16 47.1%	0 0%	3 75%
Drug-related TEAEs	1 5.9%	9 26.5%	0 0%	0 0%
Serious TEAE	0 0%	1 2.9%	0 0%	0 0%
Drug-related serious TEAE	0 0%	0 0%	0 0%	0 0%

2. Primary Outcome

Title	Patients Answering Yes to Any Question on the Columbia-Suicide Severity Rating Scale (C-SSRS)
Description	The C-SSRS is described as a scale developed at Columbia University that has 2-6 questions each in categories of Suicidal Ideation, Intensity of Ideation, Suicidal Behavior, and Actual Attempts. Four constructs were measured. Severity of Suicidal ideation is rated on a 5-point ordinal scale. Intensity of ideation is comprised of 5 items (frequency, duration, controllability, deterrents, and reason for ideation), each rated on a 5-point ordinal scale. Suicidal behavior is rated on a nominal scale that includes actual, aborted, and interrupted attempts; preparatory behavior; and non-suicidal self-injurious behavior. Lethality, assesses actual attempts; actual lethality is rated on a 6-point ordinal scale, and if actual lethality is 0, potential lethality of attempts is rated on a 3-point ordinal scale.The higher the C-SSRS score, the higher the suicide risk (ie. worse outcome).
Time Frame	Screening up to Week 13 postdose

Outcome Measure Data

Analysis Population Description

The C-SSRS score was assessed in the Safety Analysis Set.

Arm/Group Title	M-CKD Placebo	M-CKD DS-5565 7.5 mg BID	S-CKD Placebo	S-CKD DS-5565 7.5 mg QD
Arm/Group Description	Patients with moderate chronic kidney disease (M-CKD) randomized to receive placebo twice daily (BID) during the treatment period.	Patients with moderate chronic kidney disease (M-CKD) randomized to receive DS-5565 7.5 mg BID during the treatment period.	Patients with severe chronic kidney disease (S-CKD) randomized to receive placebo once daily (QD) during the treatment period.	Patients with severe chronic kidney disease (S-CKD) randomized to receive a DS-5565 7.5 mg tablet once per day (QD).
Measure Participants	17	34	1	4
Screening	0 0%	0 0%	0 0%	0 0%
Baseline	0 0%	0 0%	0 0%	0 0%
Week 13	0 0%	0 0%	0 0%	0 0%

3. Secondary Outcome

Title	Mean Weekly Average of Individual Daily Pain Scores (ADPS)
Description	Each day participants will rate their worst pain over the last 24 hours on a scale from 0-10, where 0=no pain and 10=worst pain imaginable. Each week individual pain scores will be averaged, and the mean weekly score for the treatment group will be calculated. Higher ADPS scores indicate worse outcome.
Time Frame	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11, Week 12, and Week 13 postdose

Outcome Measure Data

Analysis Population Description

Average daily pain scores were assessed in the modified Intent-to-Treat (mITT) Analysis Set.

Arm/Group Title	M-CKD Placebo	M-CKD DS-5565 7.5 mg BID	S-CKD Placebo	S-CKD DS-5565 7.5 mg QD
Arm/Group Description	Patients with moderate chronic kidney disease (M-CKD) randomized to receive placebo twice daily (BID) during the treatment period.	Patients with moderate chronic kidney disease (M-CKD) randomized to receive DS-5565 7.5 mg BID during the treatment period.	Patients with severe chronic kidney disease (S-CKD) randomized to receive placebo once daily (QD) during the treatment period.	Patients with severe chronic kidney disease (S-CKD) randomized to receive a DS-5565 7.5 mg tablet once per day (QD).
Measure Participants	17	34	1	4
Baseline	6.99 (1.35)	7.21 (0.96)	5.70	6.53 (0.82)
Week 1	6.26 (1.53)	6.10 (1.63)	2.0	6.88 (0.15)
Week 2	6.03 (1.68)	5.73 (2.06)	1.70	6.60 (0.80)
Week 3	5.77 (1.72)	5.55 (1.94)	1.70	6.80 (0.40)
Week 4	5.41 (1.91)	5.43 (1.99)	1.30	6.75 (0.50)
Week 5	5.45 (1.65)	5.46 (2.08)	0.70	6.90 (0.99)
Week 6	5.16 (1.75)	5.16 (2.18)	1.4	6.43 (1.91)
Week 7	5.03 (2.10)	5.09 (2.14)	1.20	6.67 (1.53)
Week 8	5.15 (2.03)	5.04 (2.23)	1.00	6.73 (1.52)
Week 9	5.09 (1.82)	4.81 (2.24)	1.00	6.47 (1.91)
Week 10	4.86 (2.06)	4.97 (2.20)	0.90	6.53 (1.75)
Week 11	4.28 (1.99)	4.80 (2.31)	0.70	6.73 (1.12)
Week 12	4.17 (2.16)	4.69 (2.20)	0.80	6.63 (2.27)
Week 13	4.28 (2.45)	4.15 (1.84)	1.00	6.80 (2.23)

4. Secondary Outcome

Title	Number of Participants With Different Scale Ranges of the Patient Global Impression of Change (PGIC) Scale at Week 13
Description	The PGIC is a validated outcome measure for treatment of pain in the acute pain setting. At the end of treatment, participants will rate their overall status on a scale of 1-7, where 1=very much improved and 7=very much worse using the standard PGIC questionnaire. Higher scores indicate worse outcome.
Time Frame	Week 13 postdose

Outcome Measure Data

Analysis Population Description

Patient Global Impression of Change (PGIC) scores were assessed in the modified Intent-to-Treat (mITT) Analysis Set.

Arm/Group Title	M-CKD Placebo	M-CKD DS-5565 7.5 mg BID	S-CKD Placebo	S-CKD DS-5565 7.5 mg QD
Arm/Group Description	Patients with moderate chronic kidney disease (M-CKD) randomized to receive placebo twice daily (BID) during the treatment period.	Patients with moderate chronic kidney disease (M-CKD) randomized to receive DS-5565 7.5 mg BID during the treatment period.	Patients with severe chronic kidney disease (S-CKD) randomized to receive placebo once daily (QD) during the treatment period.	Patients with severe chronic kidney disease (S-CKD) randomized to receive a DS-5565 7.5 mg tablet once per day (QD).
Measure Participants	17	34	1	4
Score 1-3; Improved	12 70.6%	20 58.8%	1 100%	1 25%
Score 4; No change	3 17.6%	8 23.5%	0 0%	3 75%
Score 5-7; Worsened	1 5.9%	0 0%	0 0%	0 0%
Missing	1 5.9%	6 17.6%	0 0%	0 0%

Adverse Events

Time Frame	Treatment-emergent adverse events (TEAEs) were collected from baseline up to 30 days after last dose, up to 25 months.
Adverse Event Reporting Description	A TEAE was any adverse event that emerged on or after the first dosing of double-blind study medication and during study treatment up to 4 weeks after the last dose of double-blind study medication (having been absent prior to treatment) or worsened relative to the pre-double-blind treatment state.
Arm/Group Title	M-CKD Placebo		M-CKD DS-5565 7.5 mg BID		S-CKD Placebo		S-CKD DS-5565 7.5 mg QD
Arm/Group Description	Patients with moderate chronic kidney disease (M-CKD) randomized to receive placebo twice daily (BID) during the treatment period.		Patients with moderate chronic kidney disease (M-CKD) randomized to receive DS-5565 7.5 mg BID during the treatment period.		Patients with severe chronic kidney disease (S-CKD) randomized to receive placebo once daily (QD) during the treatment period.		Patients with severe chronic kidney disease (S-CKD) randomized to receive a DS-5565 7.5 mg tablet once per day (QD).
All Cause Mortality
	M-CKD Placebo		M-CKD DS-5565 7.5 mg BID		S-CKD Placebo		S-CKD DS-5565 7.5 mg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/34 (0%)		0/1 (0%)		0/4 (0%)
Serious Adverse Events
	M-CKD Placebo		M-CKD DS-5565 7.5 mg BID		S-CKD Placebo		S-CKD DS-5565 7.5 mg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		1/34 (2.9%)		0/1 (0%)		0/4 (0%)
Nervous system disorders
Transient ischaemic attack	0/17 (0%)		1/34 (2.9%)		0/1 (0%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	M-CKD Placebo		M-CKD DS-5565 7.5 mg BID		S-CKD Placebo		S-CKD DS-5565 7.5 mg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/17 (47.1%)		16/34 (47.1%)		0/1 (0%)		3/4 (75%)
Blood and lymphatic system disorders
Iron deficiency anemia	1/17 (5.9%)		0/34 (0%)		0/1 (0%)		0/4 (0%)
Neutrophilia	1/17 (5.9%)		0/34 (0%)		0/1 (0%)		0/4 (0%)
Eye disorders
Dry eye	1/17 (5.9%)		0/34 (0%)		0/1 (0%)		0/4 (0%)
Gastrointestinal disorders
Gastrooesophageal reflux disease	1/17 (5.9%)		1/34 (2.9%)		0/1 (0%)		0/4 (0%)
Nausea	1/17 (5.9%)		0/34 (0%)		0/1 (0%)		0/4 (0%)
General disorders
Drug withdrawal syndrome	0/17 (0%)		2/34 (5.9%)		0/1 (0%)		0/4 (0%)
Oedema peripheral	0/17 (0%)		2/34 (5.9%)		0/1 (0%)		0/4 (0%)
Infections and infestations
Nasopharyngitis	1/17 (5.9%)		3/34 (8.8%)		0/1 (0%)		1/4 (25%)
Upper respiratory tract infection	1/17 (5.9%)		1/34 (2.9%)		0/1 (0%)		0/4 (0%)
Urinary tract infection	1/17 (5.9%)		1/34 (2.9%)		0/1 (0%)		0/4 (0%)
Injury, poisoning and procedural complications
Ligament sprain	1/17 (5.9%)		0/34 (0%)		0/1 (0%)		0/4 (0%)
Investigations
Weight increased	0/17 (0%)		2/34 (5.9%)		0/1 (0%)		0/4 (0%)
Creatinine renal decreased	1/17 (5.9%)		0/34 (0%)		0/1 (0%)		0/4 (0%)
Metabolism and nutrition disorders
Gout	0/17 (0%)		2/34 (5.9%)		0/1 (0%)		0/4 (0%)
Hyperuricaemia	3/17 (17.6%)		0/34 (0%)		0/1 (0%)		0/4 (0%)
Musculoskeletal and connective tissue disorders
Back pain	2/17 (11.8%)		0/34 (0%)		0/1 (0%)		0/4 (0%)
Nervous system disorders
Dizziness	0/17 (0%)		3/34 (8.8%)		0/1 (0%)		1/4 (25%)
Headache	0/17 (0%)		2/34 (5.9%)		0/1 (0%)		1/4 (25%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/17 (5.9%)		0/34 (0%)		0/1 (0%)		0/4 (0%)
Skin and subcutaneous tissue disorders
Skin lesion	1/17 (5.9%)		0/34 (0%)		0/1 (0%)		0/4 (0%)

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.