A clinical trial to investigate how safe and effective tideglusib is, as treatment for adolescents and adults with myotonic dystrophy diagnosed before they were 12 years old.

• Register: EUCTR
• Last refreshed on: 10 September 2018
• Main ID: EUCTR2016-000067-16-GB
• Date of registration: 13/05/2016
• Prospective Registration: No
• Primary sponsor: AMO Pharma Ltd.
• Public title: A clinical trial to investigate how safe and effective tideglusib is, as treatment for adolescents and adults with myotonic dystrophy diagnosed before they were 12 years old.
• Scientific title: A Single-Blind, Phase 2 Study To Evaluate The Safety And Efficacy Of Tideglusib 400 mg Or 1000 mg For The Treatment Of Adolescent And Adult Congenital And Juvenile-Onset Myotonic Dystrophy
• Date of first enrolment: 20/04/2016
• Target sample size: 16
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-000067-16
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: no Open: no Single blind: yes Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

United Kingdom

Contacts

• Name: General enquiries
• Affiliation: AMO Pharma Ltd

• Name: General enquiries
• Affiliation: AMO Pharma Ltd

Key inclusion & exclusion 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:
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

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

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

Intervention(s)

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
Concentration unit: mg milligram(s)
Concentration type: up to
Concentration number: 1000-
Pharmaceutical form of the placebo: Powder for oral suspension
Route of administration of the placebo: Oral use

Primary Outcome(s)

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.

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.

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 Outcome(s)

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

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

Secondary ID(s)

AMO-02-MD-2-001

Source(s) of Monetary Support

AMO Pharma Ltd