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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Randomized, Double-blind, Placebo-controlled Safety Study of DS-5565 for Treatment of Pain Due to Fibromyalgia in Subjects With Chronic Kidney Disease

Conditions
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Fibromyalgia

Intervention / Treatment
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* Drug: DS-5565
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: M-CKD DS-5565 7.5 mg BID<br>Patients with moderate chronic kidney disease (M-CKD) randomized to receive DS-5565 BID during the treatment period. | Drug: DS-5565<br>* DS-5565 7.5 mg tablet for oral use<br>* Other names: SUB60040;|
| Experimental: S-CKD DS-5565 7.5 mg QD<br>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<br>* DS-5565 7.5 mg tablet for oral use<br>* Other names: SUB60040;Drug: Placebo<br>* Placebo tablet for oral use to match DS-5565 7.5 mg tablet<br>* Other names: Placebo comparator;|
| Placebo Comparator: M-CKD Placebo<br>Patients with M-CKD randomized to receive placebo twice daily (BID) during the treatment period. | Drug: Placebo<br>* Placebo tablet for oral use to match DS-5565 7.5 mg tablet<br>* Other names: Placebo comparator;|
| Placebo Comparator: S-CKD Placebo<br>Patients with S-CKD randomized to receive placebo once daily (QD) during the treatment period. | Drug: Placebo<br>* Placebo tablet for oral use to match DS-5565 7.5 mg tablet<br>* Other names: Placebo comparator;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing a Treatment Emergent Adverse Event (TEAE) | 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. | Baseline up to 30 days after last dose, up to 25 months | 
| Patients Answering Yes to Any Question on the Columbia-Suicide Severity Rating Scale (C-SSRS) | 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). | Screening up to Week 13 postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Weekly Average of Individual Daily Pain Scores (ADPS) | 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. | 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 | 
| Number of Participants With Different Scale Ranges of the Patient Global Impression of Change (PGIC) Scale at Week 13 | 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. | Week 13 postdose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic kidney disease, . α2δ ligands, mirogabalin, pain relief, kidney metabolism