Duchenne Muscular Dystrophy
Conditions
Brief summary
The objective of this study is to evaluate the safety and pharmacokinetic of TAS-205 in patients with Duchenne Muscular Dystrophy.
Detailed description
Duchenne Muscular Dystrophy (DMD) is the most common fatal genetic disorder diagnosed in childhood, affecting approximately 1 in every 3500 lives male births. DMD patients suffer from a relentless decline in muscle strength that impairs the ability of walking and breathing, resulting in their lives with wheelchairs and loss of upper body function. The objective of this study is to evaluate the safety and pharmacokinetic of TAS-205 after single and multiple doses in DMD patients. It is also evaluated if TAS-205 affects the urinary excretion of pharmacodynamic (PD) marker in DMD patients.
Interventions
DRUGTAS-205
* Single-dose phase: 3 steps (low dose, middle dose or high dose group), 5 patients/step, single oral administration after meals * Multiple-dose phase: 3 steps (low dose, middle dose or high dose group), 5 patients/step (the same patients between single- and multiple-dose phases), repeated oral administration for 7 days, BID after meals
DRUGPlacebo
* Single-dose phase: 3steps (low dose, middle dose or high dose group), 2 patients/step, single oral administration after meals * Multiple-dose phase: 3 steps (low dose, middle dose or high dose group), 2 patients/step (the same patients between single- and multiple-dose phases), repeated oral administration for 7 days, BID after meals
Sponsors
Taiho Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
5 Years to 15 Years
Healthy volunteers
No
Inclusion criteria
* Able to give an informed consent. If applicable, able to give an informed assent. * Male and \>= 5 years and \< 16 years of age. * Bodyweight of \>= 15.0 kg and \< 75.0 kg. * Phenotypic evidence of DMD. * Able to take tablets. * If taking oral glucocorticosteroids no significant change in total daily dosage or dosing regimen after enrollment. * Confirmed the urinary PD marker over its criteria. * Able to follow the study protocol.
Exclusion criteria
* Current diagnosis or history of any drug allergy. * A forced vital capacity (FVC) \< 50% of predicted value. * A left ventricular ejection fraction (EF) \< 50% or fractional shortening (FS) \< 25% based on echocardiogram (ECHO). * Ongoing immunosuppressive therapy (other than corticosteroids). * With severe disease such as hepatic disease, kidney disease and others. * With any systemic allergic disease or any chronic inflammatory disease. * Treated with any other investigational agents within 90 days. * Positive reaction in hepatitis B surface antigen (HbsAg), hepatitis C antibody test (HCV), or human immunodeficiency virus (HIV) test.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events | From the first administration day to the end of the observation period (ie. single-dose phase: 8 days, multiple-doses phase: 14 days) | Source Vocabulary Name for Table Default: CTCAE (4.03) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak Plasma Concentration (Cmax) of TAS-205 | Single-dose phase: immediately before dosing, 0, 0.5, 1, 2, 4, 8, 24, 48 hours post-dose, Multiple-dose phase: Days 1 and 7, immediately before morning dose, 0.5, 1, 2, 4, and 8 hours post-dose and Day 4, immediately before morning dose. | Due to inspection missing, some data were not analyzed. |
| Area Under the Plasma Concentration Versus Time Curve (AUC) of TAS-205 | Administration period (ie. single-dose phase: from single administration day to 48 hours after the administration, multiple-dose phase: from the first administration day to 8 hours after the last administration) | Due to inspection missing, some data were not analyzed. |
| The Urinary Excretion of PD Marker | Single-dose: Day -1 before administration, 0-24 hr post-dose, and 24-48 hr post-dose, Multiple-doses: Day -1 before administration, 0 hr after administration on Day 1 and 4 to the following day (Day 2 and 5), and 0-24 hr after administration on Day 7. | Ratio of prostaglandin E2 metabolite / creatinine Due to inspection missing, some data were not analyzed. |
Countries
Japan
Participant flow
Pre-assignment details
Two participants in 21 participants of Single-dose phase discontinued after Single-dose phase. So, 19 participants moved to Multiple-dose phase. And new two participants enrolled in Multiple-dose phase.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo: ・Single-dose phase: 3steps (low dose, middle dose or high dose group), 2 patients/step, single oral administration after meals
・Multiple-dose phase: 3 steps (low dose, middle dose or high dose group), 2 patients/step (the same patients between single- and multiple-dose phases), repeated oral administration for 7 days, BID after meals | 6 |
| TAS-205 Low Dose TAS-205: ・Single-dose phase: 3 steps (low dose, middle dose or high dose group), 5 patients/step, single oral administration after meals
・Multiple-dose phase: 3 steps (low dose, middle dose or high dose group), 5 patients/step (the same patients between single- and multiple-dose phases), repeated oral administration for 7 days, BID after meals | 6 |
| TAS-205 Middle Dose TAS-205: ・Single-dose phase: 3 steps (low dose, middle dose or high dose group), 5 patients/step, single oral administration after meals
・Multiple-dose phase: 3 steps (low dose, middle dose or high dose group), 5 patients/step (the same patients between single- and multiple-dose phases), repeated oral administration for 7 days, BID after meals | 5 |
| TAS-205 High Dose TAS-205: ・Single-dose phase: 3 steps (low dose, middle dose or high dose group), 5 patients/step, single oral administration after meals
・Multiple-dose phase: 3 steps (low dose, middle dose or high dose group), 5 patients/step (the same patients between single- and multiple-dose phases), repeated oral administration for 7 days, BID after meals | 6 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Multiple-dose Phase | Protocol Violation | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | TAS-205 Middle Dose | TAS-205 High Dose | Total | Placebo | TAS-205 Low Dose |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 5 Participants | 6 Participants | 23 Participants | 6 Participants | 6 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Japan | 5 participants | 6 participants | 23 participants | 6 participants | 6 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 23 Participants | 6 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 4 |
| other Total, other adverse events | 0 / 6 | 3 / 5 | 1 / 5 | 1 / 5 | 0 / 5 | 1 / 5 | 3 / 5 | 1 / 4 |
| serious Total, serious adverse events | 0 / 6 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 4 |
Outcome results
Primary
Incidence of Adverse Events
Source Vocabulary Name for Table Default: CTCAE (4.03)
Time frame: From the first administration day to the end of the observation period (ie. single-dose phase: 8 days, multiple-doses phase: 14 days)
Population: About repeated-dose period, one participants of placebo group and one of TAS-205 high dose group were excluded from analysis population, due to significant deviation from the protocol.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Incidence of Adverse Events | Single-dose Period | 0 participants |
| Placebo | Incidence of Adverse Events | Repeated-dose Period | 0 participants |
| TAS-205 Low Dose | Incidence of Adverse Events | Repeated-dose Period | 1 participants |
| TAS-205 Low Dose | Incidence of Adverse Events | Single-dose Period | 3 participants |
| TAS-205 Middle Dose | Incidence of Adverse Events | Single-dose Period | 1 participants |
| TAS-205 Middle Dose | Incidence of Adverse Events | Repeated-dose Period | 3 participants |
| TAS-205 High Dose | Incidence of Adverse Events | Single-dose Period | 1 participants |
| TAS-205 High Dose | Incidence of Adverse Events | Repeated-dose Period | 1 participants |
Secondary
Area Under the Plasma Concentration Versus Time Curve (AUC) of TAS-205
Due to inspection missing, some data were not analyzed.
Time frame: Administration period (ie. single-dose phase: from single administration day to 48 hours after the administration, multiple-dose phase: from the first administration day to 8 hours after the last administration)
Population: About repeated-dose period, one paticipant of TAS-205 high dose group was excluded from analysis population, due to significant deviation from the protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Area Under the Plasma Concentration Versus Time Curve (AUC) of TAS-205 | Single-dose Period | 2604 ng*hr/mL | Standard Deviation 851 |
| Placebo | Area Under the Plasma Concentration Versus Time Curve (AUC) of TAS-205 | Repeated-dose Period (Day 7) | 2642 ng*hr/mL | Standard Deviation 673 |
| Placebo | Area Under the Plasma Concentration Versus Time Curve (AUC) of TAS-205 | Repeated-dose Period (Day 1) | 2525 ng*hr/mL | Standard Deviation 1208 |
| TAS-205 Low Dose | Area Under the Plasma Concentration Versus Time Curve (AUC) of TAS-205 | Single-dose Period | 5776 ng*hr/mL | Standard Deviation 2951 |
| TAS-205 Low Dose | Area Under the Plasma Concentration Versus Time Curve (AUC) of TAS-205 | Repeated-dose Period (Day 1) | 5281 ng*hr/mL | Standard Deviation 2553 |
| TAS-205 Low Dose | Area Under the Plasma Concentration Versus Time Curve (AUC) of TAS-205 | Repeated-dose Period (Day 7) | 6087 ng*hr/mL | Standard Deviation 2561 |
| TAS-205 Middle Dose | Area Under the Plasma Concentration Versus Time Curve (AUC) of TAS-205 | Single-dose Period | 9118 ng*hr/mL | Standard Deviation 3334 |
| TAS-205 Middle Dose | Area Under the Plasma Concentration Versus Time Curve (AUC) of TAS-205 | Repeated-dose Period (Day 7) | 9452 ng*hr/mL | Standard Deviation 4405 |
| TAS-205 Middle Dose | Area Under the Plasma Concentration Versus Time Curve (AUC) of TAS-205 | Repeated-dose Period (Day 1) | 6391 ng*hr/mL | Standard Deviation 4731 |
Secondary
Peak Plasma Concentration (Cmax) of TAS-205
Due to inspection missing, some data were not analyzed.
Time frame: Single-dose phase: immediately before dosing, 0, 0.5, 1, 2, 4, 8, 24, 48 hours post-dose, Multiple-dose phase: Days 1 and 7, immediately before morning dose, 0.5, 1, 2, 4, and 8 hours post-dose and Day 4, immediately before morning dose.
Population: About repeated-dose period, one participants of TAS-205 high dose group was excluded from analysis population, due to significant deviation from the protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Peak Plasma Concentration (Cmax) of TAS-205 | Repeated-dose Period (Day 1) | 1004 ng/mL | Standard Deviation 656 |
| Placebo | Peak Plasma Concentration (Cmax) of TAS-205 | Single-dose Period | 839 ng/mL | Standard Deviation 383 |
| Placebo | Peak Plasma Concentration (Cmax) of TAS-205 | Repeated-dose Period (Day 7) | 891 ng/mL | Standard Deviation 297 |
| TAS-205 Low Dose | Peak Plasma Concentration (Cmax) of TAS-205 | Repeated-dose Period (Day 1) | 1894 ng/mL | Standard Deviation 691 |
| TAS-205 Low Dose | Peak Plasma Concentration (Cmax) of TAS-205 | Single-dose Period | 1847 ng/mL | Standard Deviation 996 |
| TAS-205 Low Dose | Peak Plasma Concentration (Cmax) of TAS-205 | Repeated-dose Period (Day 7) | 2322 ng/mL | Standard Deviation 776 |
| TAS-205 Middle Dose | Peak Plasma Concentration (Cmax) of TAS-205 | Single-dose Period | 3202 ng/mL | Standard Deviation 1493 |
| TAS-205 Middle Dose | Peak Plasma Concentration (Cmax) of TAS-205 | Repeated-dose Period (Day 7) | 4660 ng/mL | Standard Deviation 3671 |
| TAS-205 Middle Dose | Peak Plasma Concentration (Cmax) of TAS-205 | Repeated-dose Period (Day 1) | 2635 ng/mL | Standard Deviation 2813 |
Secondary
The Urinary Excretion of PD Marker
Ratio of prostaglandin E2 metabolite / creatinine Due to inspection missing, some data were not analyzed.
Time frame: Single-dose: Day -1 before administration, 0-24 hr post-dose, and 24-48 hr post-dose, Multiple-doses: Day -1 before administration, 0 hr after administration on Day 1 and 4 to the following day (Day 2 and 5), and 0-24 hr after administration on Day 7.
Population: About repeated-dose period, one participants of placebo group and one of TAS-205 high dose group were excluded from analysis population, due to significant deviation from the protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | The Urinary Excretion of PD Marker | Single-dose Period | 1.05 ratio | Standard Deviation 0.14 |
| Placebo | The Urinary Excretion of PD Marker | Repeated-dose Period (Day 7) | 1.22 ratio | Standard Deviation 0.46 |
| Placebo | The Urinary Excretion of PD Marker | Repeated-dose Period (Day 1) | 1.22 ratio | Standard Deviation 0.34 |
| TAS-205 Low Dose | The Urinary Excretion of PD Marker | Single-dose Period | 0.92 ratio | Standard Deviation 0.28 |
| TAS-205 Low Dose | The Urinary Excretion of PD Marker | Repeated-dose Period (Day 7) | 1.27 ratio | Standard Deviation 0.35 |
| TAS-205 Low Dose | The Urinary Excretion of PD Marker | Repeated-dose Period (Day 1) | 1.23 ratio | Standard Deviation 0.33 |
| TAS-205 Middle Dose | The Urinary Excretion of PD Marker | Repeated-dose Period (Day 1) | 1.07 ratio | Standard Deviation 0.26 |
| TAS-205 Middle Dose | The Urinary Excretion of PD Marker | Single-dose Period | 1.13 ratio | Standard Deviation 0.31 |
| TAS-205 Middle Dose | The Urinary Excretion of PD Marker | Repeated-dose Period (Day 7) | 1.27 ratio | Standard Deviation 0.21 |
| TAS-205 High Dose | The Urinary Excretion of PD Marker | Single-dose Period | 1.26 ratio | Standard Deviation 0.46 |
| TAS-205 High Dose | The Urinary Excretion of PD Marker | Repeated-dose Period (Day 7) | 0.76 ratio | Standard Deviation 0.17 |
| TAS-205 High Dose | The Urinary Excretion of PD Marker | Repeated-dose Period (Day 1) | 1.26 ratio | Standard Deviation 0.34 |