Treatment of adolescent and adult congenital and juvenile onset myotonic dystrophy MedDRA version: 19.1 Level: PT Classification code 10068871 Term: Myotonic dystrophy System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Interventions
Product Name: Tideglusib
Pharmaceutical Form: Powder for oral suspension
INN or Proposed INN: Tideglusib
Other descriptive name: 4-Benzyl-2-naphthalen-1-yl-1,2,4- thiadiazolidine-3,5-dione
Concentrati
Sponsors
AMO Pharma Ltd.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Subjects under study must be adolescent or adults with a diagnosis of congenital or juvenile-onset type 1 myotonic dystrophy (DM-1). For the purposes of this study, the following definitions apply: Congenital: in addition to the genetic confirmation of DM-1, one or more of the following signs or symptoms was evident within the first week after birth: a) Hypotonia b) Generalized weakness c) Respiratory insufficiency d) Feeding difficulties e) Clubfoot or another musculoskeletal deformity Childhood/juvenile-onset: in addition to the genetic confirmation of DM-1, at least 2 signs or symptoms (not caused by another, unrelated condition) were evident prior to 12 years of age that can be clearly assigned to DM-1, for example: a) Muscle weakness b) Myotonia (delayed muscle relaxation) c) Difficulty using hands, including fine motor problems d) Excessive daytime sleepiness e) Problems with upper or lower gastrointestinal functioning f) Problems with concentration or focusing (including symptoms of attention-deficit/hyperactivity disorder) g) Learning difficulties (including dyslexia) 2. Diagnosis must be genetically confirmed 3. Subjects must be male or female aged 12 years to 45 years (the first 3 subjects in Cohort 1 must be =18 years) 4. Subjects must have a Clinical Global Impression – Severity (CGI-S) score of 4 or greater at Screening and Run-in (V2) 5. Subjects must be ambulatory and able to complete the 10 metre walk/run test (splints allowed) 6. Subject’s legally authorised representative (LAR) must provide written informed consent and there must be written consent or assent (as age applicable and developmentally appropriate) by the subject before any study-related procedures are conducted 7. Subject’s caregiver must be willing and able to support subject’s participation for duration of study and if different from the LAR, must consent to this in writing Are the trial subjects under 18? yes Number of subjects for this age range: 8 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 8 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Non-ambulatory (full time) wheel chair user 2. Receiving stimulant medication 3. Receiving other medications/therapies not stable (changed) within 4 weeks prior to Run-in (V2) 4. Medical illness or other concern which would cause investigator to conclude subjects will not be able to perform the study procedures or assessments or would confound interpretation of data obtained during assessment 5. Current enrolment in a clinical trial of an investigational drug or enrolment in a clinical trial of an investigational drug in the last 6 months 6. Women of child bearing potential who are pregnant, lactating or not willing to use a protocol-defined acceptable* contraception method if sexually active and not surgically sterile 7. Men, if engaged in sexual relations with a female of child-bearing potential, not using an acceptable contraceptive method if not surgically sterile 8. Gastrointestinal disease which may interfere with the absorption, distribution, metabolism or excretion of the study medication and impact the interpretability of the study results 9. Current clinically significant (as determined by the investigator) cardiovascular, renal, hepatic, endocrine or respiratory disease 10. Clinically significant heart disease (in the opinion of the investigator) or second or third degree heart block, atrial flutter, atrial fibrillation, ventricular arrhythmias, or is receiving medication for treatment of a cardiac arrhythmia 11. Average QTcF value of >450msec at screening 12. Kidney disease requiring ongoing treatment 13. A history of chronic liver disease with current out of range value for ALT, clinically relevant hepatic steatosis or other clinical manifestations of ongoing liver disease 14. Current ALT value > 2X the upper limit of the normal reference range at Screening or Run-in (V2) (may repeat to confirm) 15. Current total bilirubin value greater than the upper limit of the normal reference range at Screening or Run-in (V2) (unless due to Gilbert’s syndrome) (may repeat to confirm) 16. HbA1c values greater than 6% or 42.0mmol/mol at Screening (may repeat to confirm) 17. TSH values outside of the normal reference range at Screening or Run-in (V2) (may repeat to confirm) 18. Serum creatinine >150 umol/L and creatinine clearance = 60 mL/m (according to Cockcroft-Gault formula) at Screening (may repeat to confirm) 19. Clinical history of hepatitis, previous or current positive serological evidence for hepatitis B or C 20. Serological evidence of Hepatitis A at Screening or in the 6 months preceding Screening 21. A history of significant drug allergy (such as Steven-Johnson syndrome, anaphylaxis) 22. A history of alcohol or substance use disorders 23. Current malignancy or any history of malignancy except for surgically-cured skin cancer or pilomatricoma (benign tumor of the hair follicle that is associated with DM-1). 24. Severe arthritis or other medical condition (besides DM-1) that would significantly impact ambulation 25. Use within 4 weeks prior to baseline (V3) of strong CYP3A4 inhibitors e.g. clarithyromycin, telithromycin, ketoconazole, itarconazole, posaconazole, nefazadone, indinavir, ritonavir 26. Concurrent use of drugs metabolised by CYP3A4 with a narrow therapeutic window e.g. warfarin and digitoxin 27. Judged clinically to be at risk of suicide (suicidal ideation, severe depression, or other factors) over the last three months, as assessed by the Investigator. 28. Hypersensitivity to tideglusib or any components of i
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To investigate the safety and tolerability between baseline and end-of-treatment of tideglusib in adolescent and adult subjects with congenital or juvenile-onset myotonic dystrophy;Secondary Objective: To investigate the blood pharmacokinetics of tideglusib in adolescent and adult subjects with congenital or juvenile-onset myotonic dystrophy. To investigate differences in outcomes reflective of efficacy, between baseline and end-of treatment, with tideglusib in adolescent and adult subjects with congenital or juvenile-onset myotonic dystrophy.;Primary end point(s): Incidence of adverse events (AE), including Serious adverse events (SAE). The incidence of abnormal findings in objective assessments (e.g. laboratory values, ECGs, and vital signs, weight, physical examination, urinalysis) during the course of the study will also be assessed.;Timepoint(s) of evaluation of this end point: AEs will be evaluated between baseline and Follow-up Visit, while SAEs will be evaluated between screening and the last clinic visit or until resolution, whenever possible. The incidence of abnormal findings in objective assessments (e.g. laboratory values, ECGs, and vital signs, weight, physical examination, urinalysis) during the course of the study will also be assessed. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Blood pharmacokinetics (PK) of tideglusib • 10 metre walk/run test (self-selected and fastest velocity) • Computerised handgrip myometer measure of grip strength and muscle relaxation time • Respiratory Forced vital capacity (FVC) • Clinical Global Impressions– Severity and –Improvement (CGI-S and CGI-I) • Actigraphy (measure daily averages of: number of bouts of activity, number of steps taken and energy expenditure ) • Nine Hole Peg Test (NHPT) • Dual-energy X-ray absorptiometry (DXA) whole body scan of lean muscle mass (g) legs, arms, and total • Top 3 Concerns VAS (caregiver-completed and where possible, subject-completed also) • OSU Autism Rating Scale (OARS) • OSU Autism CGI • Clinician-completed Domain Specific Cause for Concern VAS: Myotonic Dystrophy • Peabody Picture Vocabulary Test • Biomarker - lymphocyte GSK3ß levels and activity ;Timepoint(s) of evaluation of this end point: Throughout study: Grip strength, Actigraphy (except for screening). Screening, run-in, baseline, week 6, EOT: 10 metre walk/run and Pulmonary function tests [(FVC) and at follow up] Screening, run-in, baseline, week 2, 8, EOT: Nine Hole Peg Test Screening, run-in, baseline, EOT, follow up: CGI-S Baseline, weeks 2, 4, 6, 8, 10, EOT, follow up: CGI-I Run-in, baseline, week 6, EOT, follow up: Clinician-completed Domain Specific Cause for Concern VAS: Myotonic Dystrophy and Top 3 Concerns Run-in, baseline and EOT: OSU CGI-S Baseline, week 6, EOT: OSU CGI-I Run-in, baseline, EOT: OSU Autism Rating Scale (and week 6), Peabody Picture Vocabulary Test Week 2, end of trial: PK samples Run-in, baseline, week 2, EOT: biomarker and RNA sample Baseline and EOT: DXA | — |
Countries
United Kingdom
Contacts
Public ContactGeneral enquiries
AMO Pharma Ltd
Outcome results
None listed