ADHD
Conditions
Brief summary
The purpose of this study is to assess bioequivalence of 2 capsule strengths.
Detailed description
This will be a randomised, open-label, two-period, single dose, crossover bioequivalence study in healthy subjects under fasting conditions to assess bioequivalence of 1 x 60 mg capsule methylphenidate compared to 2 x 30 mg capsules methylphenidate. Pharmacokinetics and safety will be assessed.
Interventions
DRUGSPD544
two 30mg capsules, single oral dose
DRUGMethylphenidate hydrochloride
one 60mg capsule, single oral dose
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy subjects, aged 18-55 years inclusive at the time of consent. 2. Subject must be willing to comply with applicable contraceptive requirements of the protocol and be: * Male, or * Non-pregnant, non-lactating female who must be \>90 days post-partum or nulliparous. 3. Body Mass Index (BMI) between 18.5 and 30.0kg/m² inclusive. This inclusion criterion will only be assessed at the Screening visit. 4. Satisfactory medical assessment with no clinically significant or relevant abnormalities in medical history, physical examination, vital signs, ECG, and clinical laboratory evaluation (haematology, biochemistry, urinalysis) as assessed by the Investigator. 5. Ability to provide written, personally signed and dated informed consent to participate in the study. 6. An understanding, ability and willingness to fully comply with study procedures and restrictions. 7. Ability to swallow all investigational medicinal products (IMPs).
Exclusion criteria
1. Current or recurrent disease (e.g., cardiovascular, renal, liver, gastrointestinal, malignancy or other conditions) that could affect the action, absorption, or disposition of the IMPs, or could affect clinical or laboratory assessments. 2. Current or relevant history of physical or psychiatric illness, any medical disorder that may require treatment or make the subject unlikely to fully comply with the requirements of the study or complete the study, or any condition that presents undue risk from the IMPs or study procedures. 3. Current use of any medication (including prescription, over-the-counter \[OTC\], herbal, or homeopathic preparations) with the exception of hormone replacement therapy or hormonal contraceptives and/or an occasional dose of nonsteroidal anti-inflammatory (NSAID), or paracetamol (current use is defined as use within 14 days of first dose of IMP). 4. History of hypertension or a resting sitting systolic blood pressure \>139mmHg or diastolic blood pressure \>89mmHg. 5. History of seizure (other than infantile febrile seizures), any tic disorder, or a current diagnosis and/or family history of Tourette's Disorder. 6. Known history of symptomatic cardiovascular disease, advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, transient ischaemic attack or stroke, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. 7. Family history of sudden cardiac death or ventricular arrhythmia. 8. Known cerebrovascular disorders such as cerebral aneurysm, vascular abnormalities including vasculitis or history of stroke. 9. Diagnosis of glaucoma. 10. Diagnosis of phaeochromocytoma. 11. Current abnormal thyroid function, as defined as abnormal screening thyroid stimulating hormone (TSH) and thyroxine (T4). 12. Current marked anxiety, tension and/or agitation. 13. History of alcohol or other substance abuse within the last year. 14. A positive screen for alcohol or drugs of abuse at Screening or Day -1 of Treatment Period 1. 15. Male subjects who consume more than 3 units of alcohol per day. Female subjects who consume more than 2 units of alcohol per day. 16. A positive human immunodeficiency virus (HIV) antibody screen, Hepatitis B surface antigen (HBsAg), or Hepatitis C virus (HCV) antibody screen. 17. Use of tobacco in any form (e.g., smoking or chewing) or other nicotine-containing products in any form (e.g., gum, patch) within 30 days prior to the Screening visit. 18. Routine consumption of more than 300mg of caffeine per day or subjects who experience caffeine withdrawal headaches or have a history of caffeine withdrawal headaches. 19. Donation of blood or blood products (e.g., plasma or platelets) within 90 days prior to the first dose of IMP.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Steady-state Plasma Concentration-time Curve (AUC 0-t) for Methylphenidate Hydrochloride (MPH) Using Two Different Formulations (Equasym XL and Metadate CD) | predose and 0.5, 1.0, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20 and 24 hours post-dose | AUC 0-t is the area under the plasma concentration versus time curve from time 0 to the time of last quantifiable concentration. AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure how much and how long a drug stays in a body. |
| Maximum Plasma Concentration (Cmax) for MPH Using Two Different Formulations (Equasym XL and Metadate CD) | predose and 0.5, 1.0, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20 and 24 hours post-dose | Cmax is a term that refers to the maximum (or peak) concentration that a drug achieves in the body after the drug has been administrated. |
| Time of Maximum Plasma Concentration (Tmax) for MPH Using Two Different Formulations (Equasym XL and Metadate CD) | predose and 0.5, 1.0, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20 and 24 hours post-dose | Tmax is the time after administration of a drug when the maximum plasma concentration in the body is reached. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Equasym XL First, Then Metadate CD Subjects received a single oral dose of 60 mg of Equasym XL (SPD544, Methylphenidate HCl given as two 30 mg capsules), then a 7-day washout period, then subjects received a single oral dose of 60 mg of Metadate CD (Methylphenidate HCl given as one 60 mg capsule) | 14 |
| Metadate CD First, Then Equasym XL Subjects received a single oral dose of 60 mg of Metadate CD (Methylphenidate HCl given as one 60 mg capsule), then a 7-day washout period, then subjects received a single oral dose of 60 mg of Equasym XL (SPD544, Methylphenidate HCl given as two 30 mg capsules) | 14 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Equasym XL First, Then Metadate CD | Metadate CD First, Then Equasym XL | Total |
|---|---|---|---|
| Age, Customized 18 to 55 years | 14 Participants | 14 Participants | 28 Participants |
| Age, Customized | 30.8 years STANDARD_DEVIATION 10.12 | 29.5 years STANDARD_DEVIATION 8.61 | 30.1 years STANDARD_DEVIATION 9.24 |
| Region of Enrollment United Kingdom | 14 Participants | 14 Participants | 28 Participants |
| Sex: Female, Male Female | 4 Participants | 7 Participants | 11 Participants |
| Sex: Female, Male Male | 10 Participants | 7 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 28 | 6 / 27 |
| serious Total, serious adverse events | 0 / 28 | 0 / 27 |
Outcome results
Primary
Area Under the Steady-state Plasma Concentration-time Curve (AUC 0-t) for Methylphenidate Hydrochloride (MPH) Using Two Different Formulations (Equasym XL and Metadate CD)
AUC 0-t is the area under the plasma concentration versus time curve from time 0 to the time of last quantifiable concentration. AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure how much and how long a drug stays in a body.
Time frame: predose and 0.5, 1.0, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20 and 24 hours post-dose
Population: Pharmacokinetic analysis set (PK) defined as all subjects in the safety analysis set who had evaluable plasma concentration-time profiles for MPH through 24 hours post-dosing in both treatment periods. Subjects who vomited or experienced significant diarrhea between dosing and 10 hours post-dose were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Equasym XL | Area Under the Steady-state Plasma Concentration-time Curve (AUC 0-t) for Methylphenidate Hydrochloride (MPH) Using Two Different Formulations (Equasym XL and Metadate CD) | 133 ng*h/ml |
| Metadate CD | Area Under the Steady-state Plasma Concentration-time Curve (AUC 0-t) for Methylphenidate Hydrochloride (MPH) Using Two Different Formulations (Equasym XL and Metadate CD) | 127 ng*h/ml |
90% CI: [0.915, 0.993]Mixed Models Analysis
Primary
Maximum Plasma Concentration (Cmax) for MPH Using Two Different Formulations (Equasym XL and Metadate CD)
Cmax is a term that refers to the maximum (or peak) concentration that a drug achieves in the body after the drug has been administrated.
Time frame: predose and 0.5, 1.0, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20 and 24 hours post-dose
Population: PK set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Equasym XL | Maximum Plasma Concentration (Cmax) for MPH Using Two Different Formulations (Equasym XL and Metadate CD) | 14.9 ng/ml |
| Metadate CD | Maximum Plasma Concentration (Cmax) for MPH Using Two Different Formulations (Equasym XL and Metadate CD) | 14.7 ng/ml |
90% CI: [0.931, 1.05]Mixed Models Analysis
Primary
Time of Maximum Plasma Concentration (Tmax) for MPH Using Two Different Formulations (Equasym XL and Metadate CD)
Tmax is the time after administration of a drug when the maximum plasma concentration in the body is reached.
Time frame: predose and 0.5, 1.0, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20 and 24 hours post-dose
Population: PK set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Equasym XL | Time of Maximum Plasma Concentration (Tmax) for MPH Using Two Different Formulations (Equasym XL and Metadate CD) | 5.0 hours |
| Metadate CD | Time of Maximum Plasma Concentration (Tmax) for MPH Using Two Different Formulations (Equasym XL and Metadate CD) | 5.0 hours |
90% CI: [-0.15, 0.492]Wilcoxon (Hodges-Lehmann)