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| Name | Class |
|---|---|
| University of California, Los Angeles | OTHER |
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The goal of this clinical trial is to evaluate the safety, tolerability and preliminary efficacy of ASA-001 in two adults diagnosed with ADSS1 deficient myopathy. The main questions it aims to answer are:
Participants will:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Multiple ascending dose-escalation of ASA-001 | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| adenylosuccinic acid | Drug | ASA-001 will be administered as a sterile solution (500-2500 mg/day) by sub-cutaneous infusion pump. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Incidence and severity of all adverse events (AEs), treatment emergent adverse events (TAEs) and serious adverse events (SAEs). | AEs are classified as to seriousness, expectedness, and potential relationship to the investigational product. Seriousness (SAE) criteria:
Severity criteria:
Expectedness criteria:
Causality criteria:
| Screening through to the last assessment at 10 months. |
| Observed and changes from baseline in vital signs. | Vital signs (including blood pressure (BP; mmHg), heart rate (HR; beats per minute), respiratory rate (RR; breaths per minute), and oral/tympanic/axillary temperature are measured at all visits. Height is measured at baseline only (cm); weight is measured at each visit (Kg). | Screening through to the last assessment at 10 months. |
| Observed and changes from baseline in 12-lead electrocardiogram (ECG). | A standard 12-lead ECG will be recorded per Schedule of Events after 5 mins rest. The ECG has little or no risk. Skin may become red or itchy in the areas where the stickers with ECG electrodes are placed. The gel that is used may cause mild skin irritation/abrasion, along with the sticky pads used to attach the electrodes. | Screening through to the last assessment at 10 months. |
| Observed and changes from baseline in physical examination. | A physical exam will be given at screening and per schedule of events to assess general appearance, HEENT (head, eyes, ear, nose and throat), cardiovascular, respiratory (chest), gastrointestinal (abdomen), dermatological, extremities, neurological (mental status, cranial nerves, motor examination, sensory examination, coordination, reflexes, gait), musculoskeletal and lymphatics. |
| Measure | Description | Time Frame |
|---|---|---|
| Plasma pharmacokinetic (PK) concentration of ASA-001. | Singles doses of ASA-001 will be administered on Day 1 and Day 14 and samples will be taken at baseline (time 0), 0.5, 1, 2, 4, 6, 8 h post dose. The results from Day 1 samples are required prior to dose escalation on Day 14. The multiple dose escalation phase will commence on Day 29 and conclude on Day 85 - plasma samples will be taken pre-dose (time 0) and at 1, 2 and 4 h post-dosing. |
| Measure | Description | Time Frame |
|---|---|---|
| Plasma metabolomic assay (exploratory) | Targeted purine metabolites (inosine, hypoxanthine, xanthine, uric acid, adenosine, adenine) will be measured in plasma using ultra-high performance liquid chromatography (uHPLC). | Screening through to last assessment at 10 months. |
Inclusion criteria:
Exclusion criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Perry B Shieh, M.D., Ph.D. | UCLA Medical Centre | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California Los Angeles (UCLA) | Los Angeles | California | 90095 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37375769 | Background | Rybalka E, Kourakis S, Bonsett CA, Moghadaszadeh B, Beggs AH, Timpani CA. Adenylosuccinic Acid: An Orphan Drug with Untapped Potential. Pharmaceuticals (Basel). 2023 May 31;16(6):822. doi: 10.3390/ph16060822. | |
| 39593137 | Background | Rybalka E, Park HJ, Nalini A, Baskar D, Polavarapu K, Durmus H, Xia Y, Wan L, Shieh PB, Moghadaszadeh B, Beggs AH, Mack DL, Smith AST, Hanna-Rose W, Jinnah HA, Timpani CA, Shen M, Upadhyay J, Brault JJ, Hall MD, Baweja N, Kakkar P. Current insights in ultra-rare adenylosuccinate synthetase 1 myopathy - meeting report on the First Clinical and Scientific Conference. 3 June 2024, National Centre for Advancing Translational Science, Rockville, Maryland, the United States of America. Orphanet J Rare Dis. 2024 Nov 26;19(1):438. doi: 10.1186/s13023-024-03429-x. |
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| ID | Term |
|---|---|
| C012168 | adenylosuccinate |
| C014308 | adenosine 5'-phosphorothioate |
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| Screening through to the last assessment at 10 months. |
| Observed and changes from baseline in hematology, comprehensive metabolic panel (CMP), hepatic tests, renal function, and serology. | Laboratory analyte samples will be collected throughout the study per Schedule of Events. Hematology (complete blood count with auto-differential), comprehensive metabolic panel (CMP) including HbA1C, with hepatic tests (to include serum transaminases, , total bilirubin and alkaline phosphatase), renal function to include creatinine, Cystatin C, urinalysis, uric acid, INR, APTT; Serology will include HIV-1, hepatitis B and C at screening. | Screening through to last assessment at 10 months. |
| Observed and changes from baseline in pulmonary function. | Forced Vital Capacity (FVC), Maximal Inspiratory Pressure (MIP) and Maximal Expiratory Pressure will be measured by spirometry to assess the strength of respiratory muscles, with MIP indicating the maximum pressure generated during a forceful inhalation against a closed airway, and MEP indicating the maximum pressure generated during a forceful exhalation against a closed airway monitor. | Screening through to the last assessment at 10 months. |
| Observed and changes from baseline in cardiac function. | A standard trans-thoracic echocardiogram will be recorded and read at selected study visits per Schedule of Events. Assessments include standard assessments of the anatomy (veins and atria, atrioventricular segment, ventricles, conotruncus, great arteries) as well as left ventricular and valvular function (including measurements of the left ventricular ejection fraction (LVEF)). | Screening through to the last assessment at 10 months. |
| Observed and changes from baseline in injection site monitoring. | Injection site(s) will be examined at each visit. | Screening through to the last assessment at 10 months. |
| Day 1 through to Day 85 (visit 8). |
| Observed and changes from baseline in serum creatinine concentration (preliminary efficacy). | Serum creatinine will be assessed within the clinical chemistry assessment, since prior clinical experience with ASA showed normalisation (from below normal range) of this measure. | Screening through to the last assessment at 10 months. |
| Change from baseline in Ten meter walk/run time (10MWT) (preliminary efficacy). | The time required for the participant to run or walk (fastest way to cover the distance safely) 10 meters (on a safe walkway) from a standing position will be measured (sec or min) | Screening through to the last assessment at 10 months. |
| Change from baseline in Timed Up-and-Go (TUG) (preliminary efficacy). | The time taken to stand from a chair, walk three metres, turn around and return and sit in the chair will be measured (sec or min). | Screening through to the last assessment at 10 months. |
| Change from baseline in Jamar grip strength dynamometry (preliminary efficacy). | Squeeze and grip strength will be measured using a hand held dynamometer (Kg). | Screening through to the last assessment at 10 months |
| Change from baseline in nerve conduction study with repetitive nerve stimulation test (preliminary efficacy). | The speed at which electrical signals travel through peripheral nerves will be assessed to identify nerve damage or dysfunction (meters/sec). | Screening through to the last assessment at 10 months |
| Change from baseline in clinical muscle histopathology on core needle muscle biopsy (preliminary efficacy). | Muscle core needle biopsy will be sampled at baseline and at the end of treatment (day 239) and clinical histopathology scoring will measured to assess preliminary efficacy. | Screening and at the end of treatment at Day 239. |
| Changes from baseline in muscle protein abundance and phosphorylation on core needle biopsy (preliminary efficacy). | Quantitative proteomics (including of phosphorylated proteins) will be used to measure muscle protein abundance and phosphorylation (preliminary efficacy). | Screening and at the end of treatment at Day 239. |
| Change from baseline in Quality Of Life (QOL)/patient reported outcomes measure (preliminary efficacy). | Patient reported outcomes will be assessed using Neuro-QOL Item Bank v.10 - Upper Extremity Function (Fine Motor, ADL) - Short Form (PROMIS Health Organization, National Institute for Neurological Disorders and Stroke (NINDS), 2008-13). | Screening through to the last assessment at 10 months |
| Changes from baseline in muscle metabolomics on core needle biopsy (preliminary efficacy). | Semi-quantitative metabolomics will be used to measure relative changes in muscle metabolite levels from baseline. | Screening and at the end of treatment at Day 239. |
| Change from baseline in muscle transcriptomic signature on core needle biopsy (preliminary efficacy). | RNA sequencing will be used to assess the muscle transcriptomic signature in response to treatment. | Screening and at the end of treatment at Day 239. |