A Study to Assess the Analgesic Efficacy and Safety of ASP0819 in Patients With Fibromyalgia

Study Overview
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Brief Summary
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This study assessed analgesic efficacy of ASP0819 relative to placebo as well as the safety and tolerability. This study assessed treatment differences in physical function as well as the improvements in overall subject status (e.g., fibromyalgia symptoms and global functioning) of ASP0819 relative to placebo.

Official Title
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A Phase 2a, Randomized, Double-Blind Placebo-controlled, Parallel-group Study to Assess the Analgesic Efficacy and Safety of ASP0819 in Patients With Fibromyalgia

Conditions
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Fibromyalgia

Intervention / Treatment
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* Drug: ASP0819
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has a body mass index (BMI) ≤ 45 kg/m2. Female subject must either: Be of nonchildbearing potential: postmenopausal (defined as at least 1 year without any menses) prior to Screening, or documented surgically sterile (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy). Or, if of childbearing potential: agree not to try to become pregnant during the study and for 28 days after the final study drug administration, have a negative blood pregnancy test at Screening and negative urine test on Day 1, and if heterosexually active, agree to consistently use 1 form of highly effective birth control starting at Screening and throughout the study period and for 28 days after the final study drug administration. Female subject must agree not to breastfeed at Screening and throughout the study period, and for 28 days after the final study drug administration. Female subject must not donate ova starting at Screening, throughout the study period, and for 28 days after the final study drug administration Male subject must not donate sperm starting at Screening and throughout the study period, and for 28 days after the final study drug administration. Male subject with a partner of child-bearing potential, or a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom throughout the study period and for 28 days after the final study drug administration. Subject meets the American College of Rheumatology (ACR) 1990 fibromyalgia diagnostic criteria at Screening: Widespread pain for at least 3 months, defined as the presence of all of the following: pain on right and left sides of the body, pain above and below the waist, and pain in the axial skeleton (cervical spine or anterior chest or thoracic spine or low back) must be present. Pain in at least 11 of 18 tender point sites on digital palpation. Digital palpation should be performed with an approximate force of 4 kg. Subject meets the ACR 2010 fibromyalgia diagnostic criteria at Screening: Widespread pain index (WPI) ≥ 7 and Symptom severity (SS) scale score ≥ 5 or WPI 3-6 and SS scale score ≥ 9. Symptoms have been present at a similar level for at least 3 months. The subject does not have a disorder that would otherwise explain the pain. Subject has a pain score ≥ 4 on the revised fibromyalgia impact questionnaire revised (FIQR) pain item at Screening. Subject is compliant with daily pain recordings during the Baseline Diary Run-In period, as defined by the completion of a minimum of 5 of 7 daily average pain ratings and agrees to complete daily diaries throughout the duration of the study. Subject has a mean daily average pain score ≥ 4 and ≤ 9 on an 11-point 0 to 10 NRS as recorded in the subject e-diary during the Baseline Diary Run-In period, and meeting pre-specified criteria for daily average pain scores. Subject agrees to use only acetaminophen as rescue medication for fibromyalgia pain throughout the course of the trial (up to 1000 mg per dose and not to exceed 3000 mg/day). Subject agrees not to initiate or change any non-pharmacologic interventions (including normal daily exercise routines, chiropractic care, physical therapy, psychotherapy, and massage therapy) during the course of the study. Non-pharmacologic interventions must be stable for a minimum of 30 days prior to Screening. The subject agrees to maintain usual level of activity for the duration of the study. Subject is capable of completing study assessments and procedures. Subject agrees not to participate in another interventional study from Screening through the End of Study (EOS) visit. Exclusion Criteria: Subject has received an investigational therapy within 28 days or 5 half-lives, whichever is longer, prior to Screening. Subject has had no meaningful improvement, from 2 or more prior treatments (commercially available) for fibromyalgia (in at least 2 pharmacologic classes). Subject has had known hypersensitivity or intolerance to the use of acetaminophen or associated formulation components; known hypersensitivity to the formulation components of ASP0819. Subject has pain due to diabetic peripheral neuropathy, post-herpetic neuralgia, traumatic injury, prior surgery, complex regional pain syndrome, or other source of pain that would confound or interfere with the assessment of the subject's fibromyalgia pain or require excluded therapies during the subject's study participation. Subject has infectious or inflammatory arthritis (e.g., rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and gout), autoimmune disease (e.g., systemic lupus erythematosus), or other widespread rheumatic disease other than fibromyalgia. Subject has a current, untreated moderate or severe major depressive disorder as assessed by the Mini-International Neuropsychiatric Interview (M.I.N.I.). Subject with current, treated major depressive disorder can be included provided that it is without clinically significant changes in symptoms while on the same dose of a protocol allowed antidepressant for greater than 60 days prior to Screening. Subject has initiated any non-pharmacologic interventions for the treatment of fibromyalgia or depression within 30 days prior to Screening or during the Screening period. Subject has a history of any psychotic and/or bipolar disorder as assessed by the M.I.N.I. Subject has a Hospital Anxiety and Depression Scale (HADS) score > 14 on the Depression subscale at Screening or at the time of Visit 3 (Randomization). Subject has a history of suicide attempt or suicidal behavior within the last 12 months, or has suicidal ideation within the last 12 months (a response of yes to questions 4 or 5 on the suicidal ideation portion of the Columbia-Suicide Severity Rating Scale (C-SSRS)), or who is at significant risk to commit suicide at the time of Visit 3 (Randomization). Subject has clinically significant abnormalities in clinical chemistry, hematology, or urinalysis, or a serum creatinine > 1.5 times the Upper limit of normal (ULN) at Screening. These assessments may be repeated once, after a reasonable time period (but within the Screening period). Subject has aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 1.5 times the upper limit of the reference range at Screening. These assessments may be repeated once, after a reasonable time period (but within the Screening period). Subject has a positive test for hepatitis B surface antigen (HBsAg), hepatitis A virus antibodies (immunoglobulin M) (anti-HAV [IgM]) or hepatitis C virus antibodies (anti-HCV) at Screening or has history of a positive test for human immunodeficiency virus type 1(HIV-1) and/or type 2 (HIV-2). Subject has a resting systolic blood pressure (SBP) > 180 mmHg or < 90 mmHg, and/or a sitting diastolic blood pressure (DBP) > 100 mmHg at Screening. These assessments may be repeated once, after a reasonable time period (but within the Screening period). Subject has a clinically significant abnormality on 12-lead Electrocardiogram (ECG) at Screening or Visit 3 (Randomization). If the ECG is abnormal, an additional ECG can be carried out. If this also gives an abnormal result, the subject must be excluded. Subject has a history of myocardial infarction (within 6 months of Screening), unexplained syncope, cardiac arrest, unexplained cardiac arrhythmias or torsade de pointes, structural heart disease or a family history of Long time from electrocardiogram Q wave to the end of the T wave (QT) Syndrome. Subject has evidence of any clinically significant, uncontrolled cardiovascular, gastrointestinal, endocrinologic (low thyroid stimulating hormone [TSH], but euthyroid is allowed), hematologic, hepatic, immunologic, infectious, metabolic, urologic, pulmonary (including obstructive sleep apnea not controlled by a Continuous positive airway pressure (CPAP) device) neurologic, dermatologic, psychiatric, renal and/or other major disease (exclusive of fibromyalgia). Subject has planned surgery during the study participation. Subject has an active malignancy or a history of malignancy (except for treated nonmelanoma skin cancer) within 5 years of Screening. Subject has a positive drug or alcohol test at Screening, Baseline Diary Run-In or prior to Randomization. However, a positive test for tetrahydrocannabinol (THC) and/or opioids is allowed at the Screening visit, but must be confirmed negative prior to Baseline Diary Run-In and Randomization. Subject has a current or recent (within 12 months of Screening) history of a substance use disorder including cannabinoid and/or alcohol abuse disorder. Subject has used opioids for pain for more than 4 days during the week preceding the Screening visit. Subject is currently using protocol specified prohibited medications and is unable to wash-out. Subject has filed or is awaiting judgment on a disability claim or has any pending worker's compensation litigation or related monetary settlements. Subject is an employee of the Astellas Group, the Contract Research Organization (CRO) involved, or the investigator site personnel directly affiliated with this study and/or their immediate families (spouse, parent, child, or sibling, whether biological or legally adopted).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASP0819<br>Participants received ASP019 15 mg capsules, orally, once daily in the morning, with or without food for 8 weeks. | Drug: ASP0819<br>* Oral capsule<br>|
| Placebo Comparator: Placebo<br>Participants received ASP019 matching placebo capsules, orally, once daily in the morning, with or without food for 8 weeks. | Drug: Placebo<br>* Oral capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 8 in Mean Daily Average Pain Score Assessed by NRS | The change from baseline to Week 8 in mean daily average pain score is assessed by NRS. The NRS is a generic instrument for the assessment of pain, consisting of a single question that asks participants to record their daily average pain on an 11-point scale, where 0 anchors no pain and 10 pain as bad as you can imagine. A negative change indicates a reduction/improvement from baseline (i.e. a favorable outcome). | Baseline and week 8 | 
| Number of Participants With Adverse Events | TEAE was defined as any AE which started, or worsened, after the first dose of study drug through 30 days after the last dose of study drug. AE was considered serious if: resulted in death, was life- threatening, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly or birth defect, required inpatient hospitalization or led to prolongation of hospitalization, other medically important events. | From first dose of study drug until end of study (up to Day 85) | 
| Number of Participants With Suicidal Ideation and Suicidal Behavior at Week 2 | C-SSRS was used for suicide assessment. Participants were asked detailed questions regarding suicidal ideation, behaviors, intensity of ideation, and attempts. Suicidal ideation: A yes answer to any one of the following five questions from suicidal ideation section on the C-SSRS. 1. Wish to be dead 2. Non-specific active suicidal thoughts 3. Active suicidal ideation with any methods (not plan) without intent to act 4. Active suicidal ideation with some intent to act, without specific plan 5. Active suicidal ideation with specific plan and intent. Suicidal behavior: yes answer to any one of the following five questions from suicidal behavior section on the C-SSRS. 6. Preparatory acts or behavior 7. Aborted attempt 8. Interrupted attempt 9. Actual attempt 10. Completed suicide. | Week 2 | 
| Number of Participants With Suicidal Ideation and Suicidal Behavior at Week 4 | C-SSRS was used for suicide assessment. Participants were asked detailed questions regarding suicidal ideation, behaviors, intensity of ideation, and attempts. Suicidal ideation: A yes answer to any one of the following five questions from suicidal ideation section on the C-SSRS. 1. Wish to be dead 2. Non-specific active suicidal thoughts 3. Active suicidal ideation with any methods (not plan) without intent to act 4. Active suicidal ideation with some intent to act, without specific plan 5. Active suicidal ideation with specific plan and intent. Suicidal behavior: yes answer to any one of the following five questions from suicidal behavior section on the C-SSRS. 6. Preparatory acts or behavior 7. Aborted attempt 8. Interrupted attempt 9. Actual attempt 10. Completed suicide. | Week 4 | 
| Number of Participants With Suicidal Ideation and Suicidal Behavior at Week 8 | C-SSRS was used for suicide assessment. Participants were asked detailed questions regarding suicidal ideation, behaviors, intensity of ideation, and attempts. Suicidal ideation: A yes answer to any one of the following five questions from suicidal ideation section on the C-SSRS. 1. Wish to be dead 2. Non-specific active suicidal thoughts 3. Active suicidal ideation with any methods (not plan) without intent to act 4. Active suicidal ideation with some intent to act, without specific plan 5. Active suicidal ideation with specific plan and intent. Suicidal behavior: yes answer to any one of the following five questions from suicidal behavior section on the C-SSRS. 6. Preparatory acts or behavior 7. Aborted attempt 8. Interrupted attempt 9. Actual attempt 10. Completed suicide. | Week 8 | 
| Number of Participants With Suicidal Ideation and Suicidal Behavior at Week 10 | C-SSRS was used for suicide assessment. Participants were asked detailed questions regarding suicidal ideation, behaviors, intensity of ideation, and attempts. Suicidal ideation: A yes answer to any one of the following five questions from suicidal ideation section on the C-SSRS. 1. Wish to be dead 2. Non-specific active suicidal thoughts 3. Active suicidal ideation with any methods (not plan) without intent to act 4. Active suicidal ideation with some intent to act, without specific plan 5. Active suicidal ideation with specific plan and intent Suicidal behavior: yes answer to any one of the following five questions from suicidal behavior section on the C-SSRS. 6. Preparatory acts or behavior 7. Aborted attempt 8. Interrupted attempt 9. Actual attempt 10. Completed suicide. | Week 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Greater Than or Equal to (≥)30 % Reduction From Baseline to Week 8 in Mean Daily Average Pain Score Assessed by NRS | The mean daily average pain score is assessed by NRS. The NRS is a generic instrument for the assessment of pain, consisting of a single question that asks participants to record their daily average pain on an 11-point scale, where 0 anchors no pain and 10 pain as bad as you can imagine. | Baseline and week 8 | 
| Percentage of Participants Achieving ≥ 30 % Reduction From Baseline to End of Treatment (EOT) in Mean Daily Average Pain Score Assessed by NRS | The mean daily average pain score is assessed by NRS.The NRS is a generic instrument for the assessment of pain, consisting of a single question that asks participants to record their daily average pain on an 11-point scale, where 0 anchors no pain and 10 pain as bad as you can imagine. | Baseline and EOT (Up to week 8) | 
| Percentage of Participants Achieving ≥ 50 % Reduction From Baseline to Week 8 in Mean Daily Average Pain Score Assessed by NRS | The mean daily average pain score is assessed by NRS. The NRS is a generic instrument for the assessment of pain, consisting of a single question that asks participants to record their daily average pain on an 11-point scale, where 0 anchors no pain and 10 pain as bad as you can imagine. | Baseline and week 8 | 
| Percentage of Participants Achieving ≥ 50 % Reduction From Baseline to EOT in Mean Daily Average Pain Score Assessed by NRS | The mean daily average pain score is assessed by NRS. The NRS is a generic instrument for the assessment of pain, consisting of a single question that asks participants to record their daily average pain on an 11-point scale, where 0 anchors no pain and 10 pain as bad as you can imagine. | Baseline and EOT (Up to week 8) | 
| Change From Baseline in the Fibromyalgia Impact Questionnaire Revised (FIQR) FIQR Function, Symptoms, and Overall Impact Subscales | The 21-item FIQR contains 3 domains: activities of daily living, overall impact, and symptoms. Participants answer each question on an 11-point NRS, with anchors appropriate to each question. The range of function subscale scores will be 0 to 90, with a lower score indicting better (higher) function. The range of overall impact subscale scores will be 0 to 20, with a lower score indicating better (lower) impact. The range of symptoms subscale scores will be 0 to 100, with a lower score indicating a better (lower) level of symptoms. A negative change indicates a reduction/improvement from baseline (i.e. a favorable outcome). | Baseline and weeks 2, 4, 8 | 
| Change From Baseline in the Fibromyalgia Impact Questionnaire Revised (FIQR) FIQR Function, Symptoms, and Overall Impact Subscales | The 21-item FIQR contains 3 domains: activities of daily living, overall impact, and symptoms. Participants answer each question on an 11-point NRS, with anchors appropriate to each question. The range of function subscale scores will be 0 to 90, with a lower score indicting better (higher) function. The range of overall impact subscale scores will be 0 to 20, with a lower score indicating better (lower) impact. The range of symptoms subscale scores will be 0 to 100, with a lower score indicating a better (lower) level of symptoms. A negative change indicates a reduction/improvement from baseline (i.e. a favorable outcome). | Baseline and EOT (Up to week 8) | 
| Percentage of Participants With Overall Participant Improvement Assessed by Patient Global Impression of Change (PGIC) | The PGIC is a self-administered 7-point Likert scale that asks participants to evaluate their fibromyalgia relative to baseline. PGIC score ranges from 1 to 7, where 1 anchors Very Much Improved and 7 anchors Very Much Worse. | Weeks 2, 4, and EOT (Up to week 8) | 
| Percentage of Participants With Overall Participant Improvement Assessed by Patient Global Impression of Change (PGIC) | The PGIC is a self-administered 7-point Likert scale that asks participants to evaluate their fibromyalgia relative to baseline. PGIC score ranges from 1 to 7, where 1 anchors Very Much Improved and 7 anchors Very Much Worse. | Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ASP0819, Fibromyalgia