Attention-Deficit/Hyperactivity Disorder
Conditions
Keywords
ADHD
Brief summary
The primary objective of this study is to evaluate the maintenance of efficacy, as measured by Adult ADHD Rating Scale with Prompts (Adult ADHD-RS with prompts) and Clinical Global Impression - Severity (CGI-S) scores, through a randomized withdrawal design when subjects with ADHD have been on stable treatment with commercial SPD489 for a minimum of 6 months and are maintained on their screening dose of commercial SPD489.
Interventions
1 capsule (either 30, 50, or 70mg strength) per day for 6 weeks.
DRUGPlacebo
1 capsule (identical to drug capsules) per day for 4 weeks during the double blind period.
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Subject must be 18-55 years of age, inclusive at the time of consent. 2. Female subjects must have a negative serum beta Human Chorionic Gonadotropin (HCG) pregnancy test at Screening and a negative urine pregnancy test at baseline and agree to comply with any applicable contraceptive requirements of the protocol. 3. Subject has a documented diagnosis of ADHD or meets DSM-IV-TR™ with adult prompts criteria by history for a primary diagnosis of ADHD prior to treatment. 4. Subject has a Baseline score of \<22 using the Adult ADHD-RS with prompts and CGI-S score ≤3. 5. Subject has been on stable treatment with commercial SPD489 (30, 50, or 70mg) for a minimum of at least 6 months preceding the Screening Visit with acceptable tolerability.Prior treatment with commercial SPD489 in the 6 months preceding the Screening Visit must be documented by prescription records, prescribing physician notes, or pharmacy records. Those subjects whose primary care physician (PCP) is someone other than the Principal Investigator (PI) will be required to provide the above documentation to the site. 6. Subject must have a minimum level of intellectual functioning, as determined by the Investigator. 7. Subject is willing and able to comply with all the testing and requirements defined in this protocol. 8. Subject is able to swallow a capsule. 9. Subject must be able to provide written, personally signed and dated informed consent to participate in the study, in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E627 and applicable regulations, before completing any study-related procedures.
Exclusion criteria
1. Subject has a current comorbid psychiatric disorder that is either controlled with medications prohibited in this study or is uncontrolled and associated with significant symptoms. Prohibited disorders include those associated with diagnoses including but not limited to any severe comorbid Axis II disorder or severe Axis I disorder (such as Post Traumatic Stress Disorder \[PTSD\], psychosis, bipolar illness, pervasive developmental disorder, severe obsessive compulsive disorder, severe depressive or severe anxiety disorder). Other symptomatic manifestations (such as agitated states)that contraindicate treatment with SPD489 or confound efficacy or safety assessments in the opinion of the examining physician are also prohibited. Comorbid psychiatric diagnoses will be established by the psychiatric evaluation that includes the Structured Clinical Interview for DSM-IV-TR™ disorders (SCID-I). 2. Subject is currently considered a suicide risk, has previously made a suicide attempt or has a prior history of, or is currently demonstrating suicidal ideation. 3. The subject has a body mass index (BMI) of \<18.5 or ≥40. 4. Subject has a concurrent chronic or acute illness (such as severe allergic rhinitis or an infectious process requiring antibiotics), disability, or other condition that might confound the results of safety assessments administered in the study or that might increase risk to the subject. Similarly, the subject will be excluded if he or she has any additional condition(s) that in the Investigator's opinion would prohibit the subject from completing the study or would not be in the best interest of the subject. This would include any significant illness or unstable medical condition that could lead to difficulty complying with the protocol. Mild, stable asthma is not exclusionary. 5. Subject has a history of seizures (other than infantile febrile seizures), any tic disorder, or a current diagnosis and/or a known family history of Tourette's Disorder. 6. Subject has known history of symptomatic cardiovascular disease, advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, transient ischemic attack or stroke or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. 7. Subject has a known family history of sudden cardiac death or ventricular arrhythmia. 8. Subject has any clinically significant ECG or clinically significant laboratory abnormality at Screening. 9. Subject has current abnormal thyroid function, as defined as abnormal Screening thyroid stimulating hormone (TSH) and thyroxine (T4). Treatment with a stable dose of thyroid medication for at least 3 months is permitted. 10. Subject has a history of moderate to severe hypertension or has a resting sitting systolic blood pressure \>139mmHg or diastolic blood pressure \>89mmHg. Subjects with well-controlled mild or moderate hypertension on a single antihypertensive agent are allowed. 11. Subject is taking any medication that is excluded (Please refer to Table 2). 12. Subject has a documented allergy, hypersensitivity, or intolerance to amphetamines. 13. Subject has a recent history (within the past 6 months) of suspected substance abuse or dependence disorder (excluding nicotine) in accordance with DSM-IV-TR™ criteria. 14. Subject has a positive urine drug result at Screening (with the exception of subject's current stimulant therapy). 15. Subject has taken an investigational compound that has a central nervous system(CNS) effect or taken part in a clinical trial for ADHD 6 months prior to the Screening Visit. 16. Subject has taken part in an investigational trial within the 30 days prior to the Screening Visit. 17. Subject has glaucoma. 18. Subject is taking other medications that have CNS effects or affect performance, such as chronic use of sedating antihistamines and decongestant sympathomimetics (7 days prior to Screening). Stable use of bronchodilator inhalers is not exclusionary. 19. Subject is female and pregnant or lactating. 20. Subjects who have previously been enrolled into this study and subsequently withdrawn. 21. Subject is not well controlled on SPD489 with acceptable tolerability (Adult ADHD-RS with prompts score ≥22).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Treatment Failures at up to 6 Weeks | Up to 6 weeks | Treatment failure defined as \> or equal to 50% increase in the ADHD-RS with adult prompts total score and a \> or equal to 2 point increase in the CGI-S score. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS) With Adult Prompts Total Score at up to 6 Weeks | Up to 6 weeks | The ADHD-RS consists of 18 items scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms) with total score ranging from 0 to 54. |
| Assessment of Clinical Global Impression-Severity of Illness (CGI-S) at up to 6 Weeks | Up to 6 weeks | CGI-S assesses the severity of the subject's condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill) |
Countries
United States
Participant flow
Pre-assignment details
Subjects had been on stable treatment with commercial SPD489 (30, 50, or 70 mg/day) for at least 6 months. They then entered a 3-week open-label treatment phase on SPD489 (30, 50, or 70 mg/day). They then entered a 6-week double-blind randomized withdrawal phase where they were assigned to either SPD489 or placebo treatment group.
Participants by arm
| Arm | Count |
|---|---|
| SPD489 Subjects receive SPD489 at 30, 50, or 70 mg/day. | 122 |
| Total | 122 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind Randomized Withdrawal Phase | Adverse Event | 0 | 1 |
| Double-blind Randomized Withdrawal Phase | Moved out of state | 1 | 0 |
| Double-blind Randomized Withdrawal Phase | Protocol Violation | 0 | 1 |
| Double-blind Randomized Withdrawal Phase | Relapse criteria met | 5 | 45 |
| Open-label Treatment Phase | Adverse Event | 1 | 0 |
| Open-label Treatment Phase | Lost to Follow-up | 1 | 0 |
| Open-label Treatment Phase | Out of country for business | 1 | 0 |
| Open-label Treatment Phase | Protocol Violation | 3 | 0 |
| Open-label Treatment Phase | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | SPD489 |
|---|---|
| Age, Continuous | 35.4 years STANDARD_DEVIATION 11.16 |
| Age, Customized Between 18 and 55 years | 122 Participants |
| Region of Enrollment United States | 122 Participants |
| Sex: Female, Male Female | 68 Participants |
| Sex: Female, Male Male | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 56 | 6 / 60 |
| serious Total, serious adverse events | 0 / 56 | 1 / 60 |
Outcome results
Primary
Percent of Treatment Failures at up to 6 Weeks
Treatment failure defined as \> or equal to 50% increase in the ADHD-RS with adult prompts total score and a \> or equal to 2 point increase in the CGI-S score.
Time frame: Up to 6 weeks
Population: Full Analysis Set (FAS) defined as all subjects who were randomized and received at least 1 dose of investigational product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SPD489 | Percent of Treatment Failures at up to 6 Weeks | 8.9 Percent of participants |
| Placebo | Percent of Treatment Failures at up to 6 Weeks | 75.0 Percent of participants |
p-value: <0.0001Chi-squared
Secondary
Assessment of Clinical Global Impression-Severity of Illness (CGI-S) at up to 6 Weeks
CGI-S assesses the severity of the subject's condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill)
Time frame: Up to 6 weeks
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SPD489 | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) at up to 6 Weeks | Mildly ill | 17.9 Percent of Participants |
| SPD489 | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) at up to 6 Weeks | Markedly ill | 7.1 Percent of Participants |
| SPD489 | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) at up to 6 Weeks | Borderline mentally ill | 35.7 Percent of Participants |
| SPD489 | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) at up to 6 Weeks | Severely ill | 0 Percent of Participants |
| SPD489 | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) at up to 6 Weeks | Moderately ill | 7.1 Percent of Participants |
| SPD489 | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) at up to 6 Weeks | Among the most extremely ill | 0 Percent of Participants |
| SPD489 | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) at up to 6 Weeks | Normal, not at all ill | 32.1 Percent of Participants |
| Placebo | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) at up to 6 Weeks | Among the most extremely ill | 0 Percent of Participants |
| Placebo | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) at up to 6 Weeks | Normal, not at all ill | 5.0 Percent of Participants |
| Placebo | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) at up to 6 Weeks | Borderline mentally ill | 11.7 Percent of Participants |
| Placebo | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) at up to 6 Weeks | Mildly ill | 11.7 Percent of Participants |
| Placebo | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) at up to 6 Weeks | Moderately ill | 33.3 Percent of Participants |
| Placebo | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) at up to 6 Weeks | Markedly ill | 35.0 Percent of Participants |
| Placebo | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) at up to 6 Weeks | Severely ill | 3.3 Percent of Participants |
p-value: <0.0001Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS) With Adult Prompts Total Score at up to 6 Weeks
The ADHD-RS consists of 18 items scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms) with total score ranging from 0 to 54.
Time frame: Up to 6 weeks
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SPD489 | Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS) With Adult Prompts Total Score at up to 6 Weeks | 1.6 Units on a scale | Standard Error 1.39 |
| Placebo | Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS) With Adult Prompts Total Score at up to 6 Weeks | 16.8 Units on a scale | Standard Error 1.35 |
p-value: <0.000195% CI: [-19.1, -11.4]ANCOVA