Study of Tideglusib in Adolescent and Adult Patients With Myotonic Dystrophy

AMO Pharma Limited16 enrolled

Overview

The purpose of this study is to determine whether Tideglusib is safe and efficacious in the treatment of adolescents and adults with congenital and juvenile-onset Myotonic Dystrophy. The pharmacokinetics of tideglusib and its primary metabolite will also be investigated.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Enrollment

Conditions

Myotonic Dystrophy 1

Interventions

TideglusibDRUG

Tideglusib for oral suspension,

Eligibility

Sex: ALLMin age: 12 YearsMax age: 45 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Adolescents or adults with diagnosis of congenital or juvenile-onset type 1 myotonic dystrophy (DM-1) * Diagnosis must be genetically confirmed * Subjects must be male or female aged 12 years to 45 years * Subjects must have a Clinical Global Impression - Severity (CGI-S) score of 4 or greater at Screening and Run-in (V2) * Subjects must be ambulatory and able to complete the 10 metre walk/run test (splints allowed) * Subject's legally authorized 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 Exclusion Criteria: * Non-ambulatory (full time) wheel chair user * Receiving stimulant medication * Receiving other medications/therapies not stable (changed) within 4 weeks prior to Run-in (V2) * 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. * 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 * 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. * Gastrointestinal disease which may interfere with the absorption, distribution, metabolism or excretion of the study medication and impact the interpretability of the study results * Current clinically significant (as determined by the investigator) cardiovascular, renal, hepatic, endocrine or respiratory disease * 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 * A history of chronic liver disease with current out of range values for Alanine transaminase (ALT), clinically relevant hepatic steatosis or other clinical manifestations of ongoing liver disease * A history of significant drug allergy (such as Steven-Johnson syndrome, anaphylaxis) * A history of alcohol or substance use disorders

Locations (1)

Newcastle-upon-Tyne Hospitals NHS Trust

Newcastle upon Tyne, Tyne and Wear, United Kingdom

Outcomes

Primary Outcomes

Safety (Adverse Events)

Incidence of Adverse events (AEs), including serious adverse events (SAEs), between baseline to end of study.

Time frame: 12 weeks

Secondary Outcomes

Plasma Concentration of Tideglusib

Pharmacokinetic samples were collected to determine Tideglusib plasma concentration

Time frame: 12 weeks

Blood Pharmacokinetics of Tideglusib

Pharmacokinetic samples were collected to determine time of the maximum plasma concentration and terminal elimination half-life of tideglusib

Time frame: 12 weeks

Area Under the Plasma Concentration vs. Time Curve of Tideglusib

Pharmacokinetic samples were collected to determine area under the plasma concentration vs. time curve from 0 to 12 h and area under the plasma concentration vs. time curve from 0 to 24 h of tideglusib

Time frame: 12 weeks

10 Metre Walk/Run Test

The 10-metre walk/run test is a performance measure used to assess walking speed in metres per second over a short distance and was used as an assessment of functional mobility. Time taken to complete the 10m walk/run test at fastest and preferred speed is measured.

Time frame: 12 weeks

Computerised Handgrip Myometer Measure of Grip Strength and Muscle Relaxation Time

Handgrip myometry is used as a measure of myotonia and muscle strength for the dominant hand

Time frame: 12 weeks

Respiratory Forced Vital Capacity (FVC)

FVC is a measure of lung function (the total amount of air exhaled during a Forced Expiratory Volume is measured using a spirometer)

Data from ClinicalTrials.gov

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Time frame: 12 weeks

Dual-energy X-ray Absorptiometry (DXA)

DXA utilises two low energy X-ray beams, with different energy levels, which are aimed at the subject's bones. The DXA scan is more typically used to measure bone mineral density, however it can also be used to measure total lean muscle mass

Time frame: 12 weeks

Clinical Global Impressions- Severity (CGI-S)

The CGI-S is a 7-point Likert type scale that requires the clinician to rate the severity of the subject's illness at the time of assessment, relative to the clinician's past experience with subjects who have the same diagnosis. Considering total clinical experience, a subject is assessed on severity of illness at the time of rating 1, normal, not at all ill; 2, borderline ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill. Change in CGI-S was observed in only 1 subject. Consequently statistical analysis was not conducted.

Time frame: 12 weeks

Clinical Global Impressions- Improvement (CGI-I)

The CGI-I requires the clinician to rate how much the subject's illness has improved or worsened relative to a baseline state. A seven point Likert type scale is used from 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse.

Time frame: 12 weeks

Actigraphy (3-minute Bouts of Activity)

Actigraphy is a non-invasive method of monitoring physical activity via an actigraph device. The actigraph device was worn on the waist during waking hours, according to the device's instruction manual.

Time frame: 12 weeks

Actigraphy (>10-minute Bouts of Activity)

Time frame: 12 weeks

Actigraphy (Steps)

Time frame: 12 weeks

Nine Hole Peg Test (NHPT)

Measure of fine manual dexterity. Time to taken to complete the NHPT (dominant hand) is recorded.

Time frame: 12 weeks

Top 3 Concerns Visual Analogue Scale (VAS) Score

The Top 3 concerns VAS allows caregivers to identify their main three causes of concern, related to the subject's myotonic dystrophy, rather than these being pre-specified within a scale and then rating how these concerns have changed at specific time-points during the study. Subjects, where possible, and caregivers were asked to rate three causes for concern by drawing a vertical mark on a 10 cm long visual analogue scale with anchors of "not at all severe" at the left end (0 cm) and "very severe" at the right end (10 cm). A score for each concern was to be determined by measuring the number of centimeters on the 10 cm VAS line from the anchor point on the left side of the line. A total VAS score for each subject was calculated as the sum of the scores for the 3 concerns (minimum = 0 cm, maximum = 30 cm). A higher score represents a worse outcome.

Time frame: 12 weeks

Ohio State University (OSU) Autism Rating Scale (OARS)

The OARS-4 contains the autism signs and symptoms in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. These were to be rated with the degree of impairment the subject experiences for the given symptom. The symptoms were to be elicited in a semi-structured interview with the subject's primary caregiver. The assessor was to take both frequency/duration and degree of impairment into account and how much the item interferes with relationships, learning, and/or activities of daily living. The scores for this assessment were from 0 (Never or Rarely; Not a Problem) to 3 (Very Often; A Severe Problem): a score for each symptom of social impairment, communication impairment and restricted patterns were averaged to provide a total impairment score. A higher score represents a worse outcome (minimum = 0, maximum 3).

Time frame: 12 weeks

Ohio State University (OSU) Autism Clinical Global Impression (CGI)

The OSU Autism CGI scale contains separate subscales for symptom severity and for global improvement. These are rated in a similar way to the National Institute of Mental Health (NIMH) CGI Severity scale, but it is focused on autism spectrum symptoms. OSU Autism CGI-severity and OSU Autism CGI-improvement scores use a seven point Likert rating scale from 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse.

Time frame: 12 weeks

Clinician-completed Domain Specific Cause for Concern Visual Analogue Scale (VAS): Myotonic Dystrophy

The Clinician-completed Domain Specific Causes for Concern is a Visual Analogue Scale completed by the clinician that scores the severity of concerns of domains that are clinically relevant in myotonic dystrophy. The severity of the clinician's concern is scored by using a 10 cm visual analogue scale (VAS), with anchors of "not at all severe" at the left end (0 cm) and "very severe" at the right end (10 cm). The clinician is asked to make a vertical line indicating his/her level of concern in each domain, using a time frame of the past week for reference. A score is to be determined by measuring the number of centimeters on the 10 cm VAS line from the anchor point on the left side of the line. A total VAS score for each subject was calculated as the sum of the scores for the 17 domains (minimum = 0, maximum = 170 cm). A higher score represents a worse outcome.

Time frame: 12 weeks

Peabody Picture Vocabulary Test (PPVT)

The PPVT-4 scale is a norm-referenced instrument for measuring the receptive (hearing) vocabulary of children and adults. It contains training items and 228 test items, each consisting of four full-colour pictures as response options on a page. For each item, the examiner says a word, and the examinee responds by selecting the picture that best illustrates that word's meaning. Each administration of the test produces a raw score (number of test items answered correctly), which can be converted to a standard score (using age-based norms) with a mean of 100 and a standard deviation of 15. Higher scores mean a better performance/receptive vocabulary.

Time frame: 12 weeks

Biomarker - Lymphocyte GSK3β Levels and Activity

Total levels of GSK3β protein was determined via x-MAP technology in a Luminex 200 platform using the AKT Pathway Total Multispecies 7-Plex Panel from ThermoFisher Scientific.

Time frame: 12 weeks