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

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.

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