SMT C11005

Principal Investigator: Russell Butterfield
Keywords: DMD , Duchenne Muscular Dystrophy , study Department: Pediatric Administration
IRB Number: 00089711 Co Investigator: Nicholas Johnson
Specialty: Neurology, Neurology, Neurology
Sub Specialties: Neuromuscular Diseases, Movement Disorders, Muscular Dystrophy
Recruitment Status: Not yet recruiting

Contact Information

Bryant Gordon
bryant.gordon@genetics.utah.edu
801-585-5052

Brief Summary

Primary Objectives
• To investigate changes in leg MRI in paediatric patient with DMD, following treatment with SMT C1100(Cohort 1 and 2)
• To investigate the relationships between changes in leg MRI with plasma concentrations of SMT C1100 and its metabolites in paediatric subjects with DMD, following treatment with SMT C1100 (Cohort 1 and 2)
To assess the safety and tolerablility of SMT and its metabolites in paediatric patients with DMD
 
 
Secondary Objectives
• To investigate changes in utrophin expression and muscle fibre regeneration in muscle, in paediatric subjects with DMD, following treatment with SMT C1100( Cohort 1 and 2)
•  To investigate the relationships between changes in utrophin expression and fibre regeneration in muscle and safety parameters with plasma concentrations of SMT C1100 and its metabolites in paediatric subjects with DMD, following treatment with SMT C1100 (Cohorts 1 and 2)
To investigate changes in pulmonary functions tests in paediatric subjects with DMD, following treatment with SMT C1100 
To investigate the relationship between pulmonary function test with plasma concentrations of SMT C100 and it metabolites in peadiatric subjects with DMD, following treatment with SMT C1100
 
Exploratory Objectives
• To investigate changes in functional measures, in paediatric patients with DMD, following treatment with SMT C1100, including the relationship between functional measures and exposure
• To investigate changes in paediatric outcomes data collection instrument (PODCI) scores in paediatric patients with DMD, following treatment with SMT C1100, including the relationship between PODCI scores and exposure
• To investigate changes in blood biomarkers in paediatric patients with DMD, following treatment with SMT C1100, including the relationship between blood biomarkers and exposure
To investigate changes in cardiac MRI tests in peadiactric subjects with DMD following treatment with SMT C1100 (Cohort 3)
To investigate the relationships between changes in cardiac MRI with plasma concentrations of SMT C1100 and its metabolites in paediatric subjects with DMD following treatment with SMT C1100 (Cohort 3)

Detailed Description

This study will specifically investigate if the expected changes in utrophin have also had a demonstrable effect on leg muscles (determined by magnetic resonance imaging [MRI]). In order to detect whether daily dosing with SMT C1100 modulates the effect of utrophin with corresponding reduction in fibre regeneration within a muscle biopsy, the levels of utrophin protein at the myofibre membrane will be calculated for all fibres found in a biopsy section. In parallel the quantity of regenerating fibres will also be calculated using markers of regeneration namely myosin protein intensity and myofibre cross sectional area. Pharmacokinetic sampling will occur throughout the study and the profiles compared against the MRI, utrophin and fibre regeneration measures, functional measures and safety results to identify and characterise any relationship that might exist. These analyses will provide further information on the impact of blood concentrations of SMT C1100 on both positive and negative outcomes of dosing against the MRI utrophin muscle expression. In order to determine if an effect has occurred, relating to utrophin or fibre regeneration, muscle biopsies will be performed at baseline, Week 24 and Week 48. In light of their young age, the subjects they will only be required to undergo two biopsies – baseline and one post-dose time point. Further investigations will also determine if the expected changes translate into clinical improvements or at least prevent deterioration in walk distance and other functional tests when compared to natural history data, where available. Finally, blood biomarkers will be reviewed in order to provide further information on potentially beneficial changes resulting from SMT C1100 treatment at the cellular level. Objectives Primary Objective •To investigate changes in leg MRI in paediatric subjects with DMD, following treatment with SMT C1100 Secondary Objectives •To investigate changes in utrophin expression and muscle fibre regeneration in muscle, in paediatric subjects with DMD, following treatment with SMT C1100 •To investigate the relationships between changes in MRI, utrophin expression and fibre regeneration in leg muscle, functional measures and safety parameters with plasma concentrations of SMT C1100 and its metabolites in paediatric subjects with DMD, following treatment with SMT C1100 Exploratory Objectives •To investigate changes in functional measures, in paediatric subjects with DMD, following treatment with SMT C1100 •To investigate changes in blood biomarkers in paediatric subjects with DMD, following treatment with SMT C1100, including the relationship between blood biomarkers and exposure

Inclusion Criteria

Criterion Number

Criterion

Cohort 1

Cohort 2

Cohort 3

1

Be able to provide written informed consent/assent as per local requirements.

ü

ü

ü

2

Be male

ü

ü

ü

3

Be aged ≥5 years to <10 years of age (from 5th birthday to 10th birthday)

ü

ü

 NA

4

Have phenotypic evidence of dystrophinopathy based on the onset of characteristic clinical symptoms or signs (e.g., proximal muscle weakness, waddling gait, and Gowers' manoeuvre), an elevated serum creatinine kinase level, and ongoing difficulty with walking

ü

ü

ü

5

Have prior confirmation of the DMD diagnosis through:

Documentation of the presence of a mutation in the dystrophin gene as determined by gene sequencing from a laboratory certified by the College of American Pathologists, the Clinical Laboratory Improvement Act/Amendment or an equivalent organisation.

Or

          Documentation of the absence of dystrophin in the muscle (via biopsy)

ü

ü

ü

6

Be willing and able to comply with two muscle biopsy procedures

ü

ü

 NA

7

Be able to undergo MRI examination

ü

ü

ü

8

Patients must have used stable systemic corticosteroids (prednisone, prednisolone or deflazacort) for a minimum of 6 months immediately prior to the start of the Treatment Phase, with no significant change in dosage or dosing regimen (not related to body weight change) and a reasonable expectation that dosage and dosing regimen will not change significantly for the duration of the study

ü

ü

ü

9

Have the ability to walk at least 300 meters unassisted during the screening 6MWD and be below the protocol-specified threshold for 80%-predicted 6MWD

ü

ü

 NA

10

Have results of two 6MWD by Baseline determined as valid. The results of the second 6MWD (baseline) must be within 20% of the first 6MWD (screening)

ü

ü

 NA

11

Have cardiac ECHO measurements showing an ejection fraction of 55% and fractional shortening of 28%

ü

ü

 NA

12

Confirmed screening laboratory values within the central laboratory ranges (haematology, renal and serum electrolyte parameters and serum chemistry parameters) or considered not clinically significant in the opinion of the Investigator. Variations in specific parameters expected in a DMD population (e.g., AST, ALT, alkaline phosphatase, lactate dehydrogenase and CPK) classed by the Investigator as not clinically significant will not exclude the patient

ü

ü

ü

13

Be willing and able to comply with scheduled visits, drug administration plan, study procedures, laboratory tests and study restrictions

ü

ü

ü

14

Have taken part in a prior SMT C1100 study

 NA

 NA

ü

Exclusion Criteria

 

  1. Have uncontrolled clinical symptoms and signs of CHF (American College of Cardiology/American Heart Association Stage C or Stage D).
  2. Have abnormal GLDH or coagulation times at baseline (>1.5xULN)
  3. Have an abnormal ECG e.g., a QTcF >500ms, left bundle-branch block or any other major conduction defect.
  4. Use beta blockers (however, if during the course of the study they are clinically indicated they can be initiated).
  5. Use herbal supplements and be unwilling to stop these for the duration of the study.
  6. Have a known hypersensitivity to any of the ingredients or excipients of the IMP. (i.e., microfluidised oral suspension (F3; Cohort 1): Poloxamer 188, Methylparaben, Propylparaben, Hydroxypropylmethyl cellulose, Glycerol, Non crystallising sorbitol [70%], Xanthan gum, Strawberry cream flavour [PHS-132963]; Powder for oral suspension (F6; Cohort 2): hypromellose acetate succinate)
  7. Have been exposed to another investigational drug or DMD interventional agent within 3 months prior to start of the Treatment Phase. Prior exposure to SMT C1100 or participation in an approved deflazacort access program (e.g., FOR-DMD or ACCESS DMD clinical trials) within this period would not exclude the patient (provided they have been on stable treatment for 6 months).
  8. Have a history of major surgical procedure within 12 weeks prior to the start of the Treatment Phase (Week 1).
  9. Be undertaking ongoing immunosuppressive therapy (other than corticosteroids).
  10. Have an expectation of a major surgical procedure (e.g., scoliosis surgery) during the 12-month Treatment Phase of the study.
  11. Require daytime ventilator assistance.
  12. Have a prior or ongoing medical condition (e.g., concomitant illness, psychiatric condition, behavioural disorder, alcoholism, drug abuse), medical history, ECG findings, or laboratory abnormality that, in the Investigator's opinion, could adversely affect the safety of the patient, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results.
  13. Be dairy or lactose intolerant or have any other dietary restrictions that might interfere with the conduct of the study.
  14. Be a smoker, use other tobacco or nicotine products or be exposed to daily passive smoking (including parent/legal guardian, siblings) so as to minimise environmental factors causing CYP1A induction.
  15. Be using an approved DMD medication or anticipates using one during the duration of the study e.g., ataluren, idebenone, drisapersen, Exondys51. Patients who are taking part in the FOR-DMD and ACCESS DMD studies will be allowed to take part.
  16. Be using an inhibitor of CYP1A1 or CYP1A2.
  17. Be using an inducer of CYP1A1 or CYP1A2.
  18. Be using a substrate of CYP1A1, CYP1A2 or CYP2B6.
  19. All prescription, OTC, and herbal products that are known CYP2B6 sensitive substrates (e.g., buproprion, efavirenz) will be excluded 14 days prior to study conduct (beginning at screening) through 14 days after study conduct completion. Please note, this is not an exhaustive list of CYP2B6 substrates and a discussion with the Medical Monitor may be warranted.
  20. Be using drugs that have serotonergic, norepinephrinergic or dopaminergic activity (e.g., selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, tryptophan, dextromethorphan, meperidine, bupropion, nortriptyline, desipramine, doxepin, amoxapine, rasagiline, selegiline), or treatments used in attention deficit hyperactivity disorder such as Methylphenidate, and phenethylamine (PEA).
  21. Use of substrates of BRCP (e.g., omeprazole, rabeprazole, fluvastatin, methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan).

Criterion Number

Criterion

Cohort 1

Cohort 2

Cohort 3

1

Have physical exam findings that in the investigator’s opinion should be exclusionary e.g., lower limb injury that may affect 6MWD performance

ü

ü

ü

2

Have any change (initiation, change in type of drug, dose modification, schedule modification, interruption, discontinuation or reinitiation) in prophylaxis/treatment for congestive heart failure (CHF) within 3 months prior to the start of study treatment

ü

ü

ü

3

Have uncontrolled clinical symptoms and signs of CHF (American College of Cardiology/American Heart Association Stage C or Stage D)

ü

ü

ü

4

Have abnormal GLDH at baseline (>1.5 x ULN)

ü

ü

ü

5

Have abnormal coagulation times at baseline (>1.5 x ULN)

 

ü

ü

6

Have an abnormal ECG e.g., a QTcF >500 ms, left bundle-branch block or any other major conduction defect

ü

ü

ü

7

Use beta blockers (however, if during the course of the study they are clinically indicated they can be initiated)

ü

ü

 NA

8

Use herbal supplements and be unwilling to stop these for the duration of the study

ü

ü

ü

8

Have a known hypersensitivity to any of the ingredients or excipients of the IMP. microfluidised oral suspension (F3): Poloxamer 188, Methylparaben, Propylparaben, Hydroxypropylmethyl cellulose, Glycerol, Non crystallising sorbitol [70%], Xanthan gum, Strawberry cream flavour [PHS-132963]

ü

 NA

ü

10

Have a known hypersensitivity to any of the ingredients or excipients of the IMP. Powder for oral suspension (F6): hypromellose acetate succinate

 NA

ü

 NA

11

Have been exposed to another investigational drug or DMD interventional agent within 3 months prior to start of the Treatment Phase. Prior exposure to SMT C1100 or participation in an approved deflazacort access program (e.g., FOR-DMD or ACCESS DMD clinical trials) within this period would not exclude the patient (provided they have been on stable treatment for 6 months)

ü

ü

ü

12

Have a history of major surgical procedure within 12 weeks prior to the start of the Treatment Phase (Week 1)

ü

ü

ü

13

Be undertaking ongoing immunosuppressive therapy (other than corticosteroids)

ü

ü

ü

14

Have an expectation of a major surgical procedure (e.g., scoliosis surgery) during the 12-month Treatment Phase of the study

ü

ü

ü

15

Require daytime ventilator assistance

ü

ü

ü

16

Have a prior or ongoing medical condition (e.g., concomitant illness, psychiatric condition, behavioural disorder, alcoholism, drug abuse), medical history, ECG findings, or laboratory abnormality that, in the Investigator's opinion, could adversely affect the safety of the patient, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results

ü

ü

ü

17

Be dairy or lactose intolerant or have any other dietary restrictions that might interfere with the conduct of the study

ü

ü

ü

18

Be a smoker, use other tobacco or nicotine products or be exposed to daily passive smoking (including parent/legal guardian, siblings) so as to minimise environmental factors causing CYP1A induction

ü

ü

ü

19

Be using an approved DMD medication or anticipates using one during the duration of the study e.g., ataluren, idebenone, drisapersen, Exondys51. Patients who are taking part in the FOR-DMD and ACCESS DMD studies will be allowed to take part

ü

ü

ü

20

Be using an inducer of CYP1A1 or CYP1A2

ü

ü

ü

21

Be using a substrate of CYP2B6

ü

ü

ü

22

All prescription, OTC, and herbal products that are known CYP2B6 sensitive substrates (e.g., buproprion, efavirenz) will be excluded 14 days prior to study conduct (beginning at screening) through 14 days after study conduct completion. Please note, this is not an exhaustive list of CYP2B6 substrates and a discussion with the Medical Monitor may be warranted

ü

ü

ü

23

Be using drugs that have serotonergic, norepinephrinergic or dopaminergic activity (e.g., selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, tryptophan, dextromethorphan, meperidine, bupropion, nortriptyline, desipramine, doxepin, amoxapine, rasagiline, selegiline), or treatments used in attention deficit hyperactivity disorder such as Methylphenidate, and phenethylamine (PEA)

ü

ü

ü

24

Use of substrates of BRCP (e.g., omeprazole, rabeprazole, fluvastatin, methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan)

ü

ü

ü