| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Duchenne muscular dystrophy (DMD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| A progressive, lethal muscle wasting disease, characterised by a generalised weakness and progressive loss of muscle strength; cardiac and respiratory difficulties present, leading to death |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10013801 |
| E.1.2 | Term | Duchenne muscular dystrophy |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary purpose of this study (part A) is to investigate how the body handles 2 formulations of SMT C1100 with respect to levels of parent compound and its breakdown products in healthy adult male volunteers.
The primary purpose in Part B is to determine how the body handles the multiple dose of SMT C1100 and its breakdown products, following oral administration of up to 3 different dose levels of the formulation of SMT C1100 selected from Part A, in DMD (Duchenne Muscular Dystrophy) children. |
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| E.2.2 | Secondary objectives of the trial |
The secondary research objectives are as follow:
Part A
1) To determine the safety and tolerability of SMT C1100 and its breakdown products with either 1 or 2 different oral (via the mouth) formulations of SMT C1100 in healthy adult subjects.
2) To explore the effect of intake of food in comparison to a fasting condition (without food) in how the body handles SMT C1100 and its breakdown products for either 1 or 2 different oral formulations of SMT C1100 in healthy adult subjects.
3) To compare the differences in levels of SMT C1100 between the morning and evening doses.
Part B
1) To determine the safety and tolerability of SMC C1100 and its breakdown products in children with DMD.
2) To investigate the variations in how the body handles SMT C1100 when is given as a morning dose compared with the situation when it is given as an evening dose.
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part A:
1. Males of any ethnic origin aged 18 to 55 years inclusive and with body weight of 60 to 85 kg inclusive and a body mass index (BMI) of 18.5 to 30 kg/m2 inclusive.
2. In good health, as determined by a medical history, physical examination, 12-lead ECG and clinical laboratory evaluations (congenital non-haemolytic hyperbilirubinaemia, Gilbert’s syndrome, is acceptable).
3. Subjects who are non-smokers and do not use other tobacco or nicotine products for at least 60 days preceding screening and are willing and able to refrain from smoking, tobacco, and nicotine products until after completion of the follow up visit.
4. Willing and able to give written informed consent to participate in the study and to abide by the study restrictions.
Part B:
1. Male children aged 5 to 9 years inclusive of any ethnic origin with a genetic diagnosis of DMD.
2. The subject is willing to give verbal or written age appropriate assent to participate. A parent/legal guardian must date and sign a written consent on behalf of the subject, according to ICH and local regulations. This person must understand the contents of the consent, requirements of the study and have had an opportunity to review questions with a medically trained member of the site study team. For safety reasons, the subject’s parent/legal guardian must have a good understanding of the English language, in which the consent/assent forms are available, and understand the requirements for reporting of any AE to the Investigator.
3. The subject has 3 months or more stable systemic (subjects using an intermittent regimen of steroid are allowed to be enrolled) corticosteroid therapy prior to Screening. Dose modifications for body weight are permitted.
4. The subject has a North Star Ambulatory Assessment (NSAA) score; a historical NSAA score maybe provided if performed within 30 days prior to the Screening visit. The subject should have a minimum NSAA score of 17.
5. The subject and parent are willing for the subject to adhere to a balanced diet from 1 week prior to dosing until the end of the follow-up period.
6. Subjects must agree to not have sexual intercourse during the study treatment phases and until the end of their participation in the study |
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| E.4 | Principal exclusion criteria |
Part A:
1. Not willing, or partners not willing, to use appropriate contraception, or not willing to avoid donating sperm from time of first dose until 3 months after final dose
2. Received any prescribed systemic or topical medication within 14 days of first dose unless in the opinion of the Investigator it will not interfere with the study procedures or compromise safety
3. Used any non-prescribed systemic or topical medication (including herbal remedies) within 7 days of the first dose (with the exception of vitamin/mineral supplements) unless in the opinion of the Investigator it will not interfere with the study procedures or compromise safety
4. Received any medications, including St John’s Wort, known to chronically alter drug absorption or elimination processes within 30 days of first dose unless in the opinion of the Investigator it will not interfere with the study procedures or compromise safety
5. Still participating or has participated in a clinical study involving administration of an investigational drug in the past 3 months
6. Has donated any blood, plasma or platelets in the 3 months prior to screening or who have made donations on more than two occasions within the 12 months preceding first dose
7. Significant history of drug allergy as determined by the Investigator, or any clinically significant allergic disease (excluding non-active hay fever) as determined by the Investigator
8. Known hypersensitivity to the excipients of the study drug or potential reconstitution vehicle
9. Subject is dairy or lactose intolerant, has an allergy to egg or nuts or any other dietary restrictions that might interfere with the study conduct
10. Supine blood pressure and/or supine pulse rate higher than 150/90 mmHg and 110 beats per minute (bpm), or lower than 90/40 mmHg and/or 40 bpm, after 5 minutes rest, confirmed by a repeat assessment
11. Consumes more than 28 units of alcohol per week or has a significant history of alcoholism or drug/chemical abuse as determined by the Investigator
12. Positive urine drug, alcohol or cotinine result at screening or admission to the clinical unit
13. History of, any clinically significant neurological, gastrointestinal, renal, hepatic, cardiovascular, psychiatric, respiratory, metabolic, endocrine, haematological or other major disorders as determined by the Investigator
14. Clinically significant illness within 4 weeks of start of dose
15. Known to have serum hepatitis, or tests positive for hepatitis B surface antigen, hepatitis C antibody or human immunodeficiency virus (HIV) I or II tests at screening
16. Abnormality in the 12-lead ECG that, in the opinion of the investigator, increases the risk of participating in the study
17. Subjects who, in the opinion of the Investigator, should not participate in the study
18. Vegans or medical dietary restrictions
19. Cannot communicate reliably with the Investigator
20. Unlikely to co-operate with the study requirements
Part B:
1. Enrolment or participation in any therapeutic clinical trial within prior 3 months or 5 times the half-life (whichever is longer)
2. Known hypersensitivity to the excipients of the study drug or potential reconstitution vehicle or a previous history of drug allergy
3. Subject or parent/legal guardian is unwilling for the subject to adhere to a balanced diet from 1 week prior to dosing until the end of the follow-up period.4. Subject is dairy or lactose intolerant, has an allergy to egg or nuts or any other dietary restrictions that might interfere with the conduct of the study
5. Subject unable to refrain from eating cruciferous vegetables and barbecued meat for the duration of the study
6. Use of prohibited medication
7. Subject has intermittent/continuous difficulties in swallowing
8. Subject is non ambulatory
9. Any clinically significant acute illness within 4 weeks of the start of dose administration
10. Any comorbidity, in the opinion of the Investigator, increases the risk of participating in the study
11. Symptomatic cardiomyopathy in the opinion of the Investigator prohibits participation in this study
12. Abnormality in the 12-lead ECG at the Screening visit that, in the opinion of the Investigator, is clinically significant
13. Any clinically significant medical condition, other than DMD, that in the opinion of the Investigator may increase the risk of participating in the study or interfere with the interpretation of safety or efficacy evaluations
14. The subject smokes, uses other tobacco or nicotine products or has exposure to daily passive smoking
15. Subjects with respiratory insufficiency requiring mechanical ventilation during the study
16-18. Subjects using an inhibitor, inducer or substrate of CYP1A1, CYP1A2 or CYP2B6
19. All prescription, OTC & herbal products that are known CYP2B6 sensitive substrates as well as CYP2B6 inhibitors or inducers will be excluded 14 days prior to study through to 14 days after study completion |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A:
To determine the multiple dose PK of SMT C1100 and its dihydrodiol (DHD) metabolites at 2 dose levels following oral administration with up to 2 different formulations of SMT C1100
Part B:
To determine the multiple dose PK of SMT C1100 and its 2 DHD metabolites, following oral administration of up to 3 ascending dose regimens of the formulation of SMT C1100 selected from Part A.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A:
Blood samples will be collected for 24 hours after the first am dose on Days 1, 3, 4 and 5 of each treatment period
A trough sample will be collected on Day 2 (pre am dose) and on Day 6 (24 hours after morning dose on Day 5).
Urine samples will be collected over a 24 hour period after am dose on Days 1, 3, 4 and 5.
Part B:
Blood samples will be collected for 24 hours after the am dose on Days 1 and 7.
Urine samples will be collected for 24 hours after the morning dose on Days 1 and 7.
|
|
| E.5.2 | Secondary end point(s) |
Part A:
• To determine the safety and tolerability of SMT C1100 and its DHD metabolites with either 1 or 2 different oral formulations of SMT C1100 in healthy adult subjects.
• To explore the effect of intake of food in comparison to a fasting condition on the PK of SMT C1100 and its 2 DHD metabolites for either 1 or 2 different oral formulations of SMT C1100 in healthy adult subjects.
• To investigate the diurnal variation in PK from morning versus evening dose administration of SMT C1100 and its 2 DHD metabolites, for up to 2 different oral formulations of SMT C1100 in healthy adult subjects.
Part B:
• To determine the diurnal variability, safety and tolerability of SMT C1100 and its DHD metabolites with a selected formulation of SMT C1100 in DMD paediatric subjects.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A:
AEs continuous.
Blood samples for serum chemistry & haematology Day -1, prior to am dose on Days 2-5 & am Day 6. Urine samples for urinalysis: screening & Days -1 & 6.
Vital signs: Days 1-5: pre am dose, 2, 4 & 6 hours post am dose and pre pm dose, 2 & 4 hours post pm dose.
12-lead ECGs in triplicate: Days 1, 3, 4 & 5: pre dose, 2 4 & 6 hours post dose. Continuous ECG on Days 1, 4 & 5 from 30 to 60 minutes prior to dose until 6 hours postdose. This may be extended as required for safety.
Part B:
AEs continuous.
On Days 1 & 7 blood & urine samples prior to the am dose for serum chemistry, haematology & urinalysis.
12-lead ECG in triplicate on Days 1, 2 & 7: prior to am dose & 0.5, 2, 4 & 6 hours after the am dose & prior to pm dose & 0.5, 2 & 4 after pm dose |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Trial to study the safety & PK of 2 new formulations in healthy volunteers & 1 in DMD boys |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 19 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 19 |
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