Attention-Deficit/Hyperactivity Disorder (ADHD)
Conditions
Brief summary
The purpose of this study is to investigate the safety and efficacy of an investigational treatment for Attention Deficit Hyperactivity Disorder (ADHD) when compared to placebo.
Interventions
DRUGMK0249
MK-0249, 10 mg per day was taken orally daily. If patients were unable to tolerate 10 mg per day, they were allowed to titrate down to 5 mg per day.
DRUGConcerta (methylphenidate)
Titration of Concerta began with two 18-mg capsules (36 mg) for 3 consecutive days, followed by three 18-mg capsules (54 mg) for another 3 consecutive days, ending with four 18-mg capsules (72 mg) for the remainder of the treatment period. If patients were unable to tolerate 72 mg per day, they were allowed to titrate down to 54 mg per day. Concerta was taken orally once daily.
DRUGPlacebo
For 4 of the 6 treatment sequences, patients had one 4-week treatment period with placebo of MK-0249 (tablets) and placebo of Concerta (capsules). For patients assigned to active treatments of MK-0249 or Concerta, in order to preserve the blind, placebo of the non-active component was provided, ie, if MK was assigned (tablets), then placebo of Concerta (capsules) was also provided. Each patient was to dose with tablets and capsules, either active or placebo. Placebo was taken orally once daily.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Patient is between 18 and 55 years of age (inclusive) * Patient is an adult with a current DSM-IV diagnosis of ADHD of inattentive or combined subtype, as assessed via a structured interview using the ACDS and AISRS * Females of child-bearing potential must use acceptable methods of birth control during the study and for 1 month post-therapy
Exclusion criteria
* Patient has a history of a neurological disorder resulting in ongoing impairment * Patient has a lifetime history of a psychotic disorder, bipolar disorder, or post-traumatic stress disorder * Patient has evidence of ongoing depression * Patient is sensitive or allergic to methylphenidate * Patient has glaucoma * Patient has a previous history of narrowing or blockage of the GI tract * Patient has a history of a sleep disorder (e.g., insomnia, sleep apnea, nightmares, or night terrors) within 6 months prior to screening * Patient has a history of a cardiovascular disorder within 6 months prior to screening * Patient has moderate or severe persistent asthma * Patient has a history of substance abuse or dependence not in sustained full remission for at least one year according to DSM-IV * Patient has taken part in a research study within the past 30 days of signing informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in the Adult Attention Deficit Hyperactivity Disorder Investigator Symptom Rating Scale (AISRS) Total Score After 4 Weeks of Treatment | after 4 weeks of treatment | The AISRS total score consists of 18 items from the original Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS) which were derived based on Diagnostic and Statistical Manual-4 (DSM-IV) criteria for ADHD. The ADHD-RS include 9 items that address symptoms of inattention and 9 items that address symptoms of impulsivity and hyperactivity. Each item is rated from 0 to 3. The AISRS total score can range from 0 to 54. A higher score corresponds to a worse severity of ADHD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in the AISRS Inattentive Subscale Score After 4 Weeks of Treatment | after 4 weeks of treatment | The AISRS inattentive subscale score consists of 9 items from the original ADHD-RS which address inattention. Each item is rated from 0 to 3. The AISRS inattentive subscale score can range from 0 to 27. A higher score corresponds to a worse severity of ADHD inattentiveness. Data not reported due to failure of primary hypothesis and program termination. |
| >/= 30% AISRS Total Score Responder Rate After 4 Weeks of Treatment; | after 4 weeks of treatment | The AISRS total score consists of 18 items from the original ADHD-RS which were derived based on DSM-IV criteria for ADHD. The ADHD-RS include 9 items that address symptoms of inattention and 9 items that address symptoms of impulsivity and hyperactivity. Each item is rated from 0 to 3. The AISRS total score can range from 0 to 54. A higher score corresponds to a worse severity of ADHD. Data not reported due to failure of primary hypothesis and program termination. |
| >/=1-point Improvement in the CGI-S Score | 4 weeks of treatment | The Clinical Global Impression - Severity of Illness Scale (CGI-S) is administered by a trained investigator who rates the severity of a patient's illness at the time of assessment, relative to the investigator's past experience with patients who have an ADHD diagnosis. The scores range from 1 to 7. Higher numbers correspond to more severe illness. Data not reported due to failure of primary hypothesis and program termination. |
| Mean Change From Baseline in the Conners' Adult ADHD Rating Scale - Observer Screening Version (CAARS-O:SV) Total ADHD Symptom Score. | 4 weeks of treatment | Conners' Adult ADHD Rating Scale - Observer Screening version (CAARS-O: SV) evaluates DSM-IV-oriented inattention, impulsivity and hyperactivity as well as measures of self-concept. It is a 30-item scale administered by a trained investigator or rater with cue questions. Each item is scored from 0 to 3 with higher scores corresponding to worse symptoms. The total score can range from 0 to 90. Data not reported due to failure of primary hypothesis and program termination. |
| Mean Change From Baseline in the Clinical Global Impressions-severity of Illness Scale(CGI-S) Score | 4 weeks of treatment | The Clinical Global Impression - Severity of Illness Scale (CGI-S) is administered by a trained investigator who rates the severity of a patient's illness at the time of assessment, relative to the investigator's past experience with patients who have an ADHD diagnosis. The scores range from 1 to 7. Higher numbers correspond to more severe illness. Data not reported due to failure of primary hypothesis and program termination. |
| Mean Change From Baseline in the AISRS Hyperactive/Impulsive Subscale Score | 4 weeks of treatment | The Adult Attention Deficit Hyperactivity Disorder Investigator Symptom Rating Scale (AISRS) hyperactive/impulsive subscale score consists of 9 items from the original Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS) which address hyperactivity and impulsivity. Each item is rated from 0 to 3. The AISRS hyperactive/impulsive subscale score can range from 0 to 27. A higher score corresponds to a worse severity of ADHD hyperactivity/impulsivity. Data not reported due to failure of primary hypothesis and program termination |
Other
| Measure | Time frame | Description |
|---|---|---|
| Baseline AISRS | Baseline | Baseline values for all treatment groups are equal because the constrained longitudinal data analysis (cLDA) model was used (Liang and Zeger, 2000, Sankhyā: The Indian Journal of Statistics, Series B 62, 134-148). |
Participant flow
Recruitment details
First Patient Dosed: 16 AUG 2007; Last Patient Last Treatment: 04 APR 2008. Six U.S. study centers.
Pre-assignment details
Pre-Treatment consisted of 2 visits: Screening Visit1 & Baseline Randomization Visit2. Patients continuing after Visit1 entered a 1-wk placebo Run-in period. At Visit2, patients were assessed using the protocol eligibility criteria. Then, if deemed eligible, patients were randomized at Visit2 to one of six 2-period cross-over treatment sequences.
Participants by arm
| Arm | Count |
|---|---|
| MK-0249 Then Placebo These participants received MK-0249 during Treatment Period 1 and placebo during Treatment Period 2 | 14 |
| Placebo Then MK-0249 These participants received placebo during Treatment Period 1 and MK-0249 during Treatment Period 2 | 13 |
| MK-0249 Then Concerta These participants received MK-0249 during Treatment Period 1 and Concerta during Treatment Period 2 | 7 |
| Concerta Then MK-0249 These participants received Concerta during Treatment Period 1 and MK-0249 during Treatment Period 2 | 7 |
| Concerta Then Placebo These participants received Concerta during Treatment Period 1 and placebo during Treatment Period 2 | 16 |
| Placebo Then Concerta These participants received placebo during Treatment Period 1 and Concerta during Treatment Period 2 | 15 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Treatment Period 1 | Adverse Event | 2 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period 1 | DC due to AE but continuing | 0 | 0 | 0 | 1 | 2 | 2 |
| Treatment Period 1 | DC due to no efficacy but Continuing | 0 | 1 | 0 | 0 | 0 | 0 |
| Treatment Period 1 | Lack of Efficacy | 1 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period 1 | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 1 |
| Treatment Period 1 | Protocol Violation | 0 | 0 | 0 | 1 | 0 | 0 |
| Treatment Period 1 | Withdrawal by Subject | 1 | 1 | 0 | 0 | 0 | 0 |
| Treatment Period 2 | Adverse Event | 0 | 1 | 0 | 2 | 0 | 0 |
| Treatment Period 2 | Lack of Efficacy | 0 | 0 | 0 | 0 | 0 | 1 |
| Treatment Period 2 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 |
| Treatment Washout | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 | 0 |
| Treatment Washout | Protocol Violation | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | MK-0249 Then Placebo | Placebo Then MK-0249 | MK-0249 Then Concerta | Concerta Then MK-0249 | Concerta Then Placebo | Placebo Then Concerta | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 39.6 years STANDARD_DEVIATION 9.2 | 36.9 years STANDARD_DEVIATION 11 | 39.3 years STANDARD_DEVIATION 7.5 | 39.0 years STANDARD_DEVIATION 12.3 | 39.8 years STANDARD_DEVIATION 11.1 | 36.5 years STANDARD_DEVIATION 13.3 | 38.4 years STANDARD_DEVIATION 10.8 |
| Sex: Female, Male Female | 6 Participants | 4 Participants | 2 Participants | 5 Participants | 3 Participants | 7 Participants | 27 Participants |
| Sex: Female, Male Male | 8 Participants | 9 Participants | 5 Participants | 2 Participants | 13 Participants | 8 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 27 / 37 | 33 / 44 | 33 / 54 |
| serious Total, serious adverse events | 0 / 37 | 0 / 44 | 0 / 54 |
Outcome results
Primary
Mean Change From Baseline in the Adult Attention Deficit Hyperactivity Disorder Investigator Symptom Rating Scale (AISRS) Total Score After 4 Weeks of Treatment
The AISRS total score consists of 18 items from the original Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS) which were derived based on Diagnostic and Statistical Manual-4 (DSM-IV) criteria for ADHD. The ADHD-RS include 9 items that address symptoms of inattention and 9 items that address symptoms of impulsivity and hyperactivity. Each item is rated from 0 to 3. The AISRS total score can range from 0 to 54. A higher score corresponds to a worse severity of ADHD.
Time frame: after 4 weeks of treatment
Population: Full Analysis Set (FAS): The FAS included all randomized patients who received at least one dose of study medication. Patients with at least one assessment (baseline or post-randomization) were included in the FAS. Missing data were handled using the data as observed (DAO) approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-0249 | Mean Change From Baseline in the Adult Attention Deficit Hyperactivity Disorder Investigator Symptom Rating Scale (AISRS) Total Score After 4 Weeks of Treatment | -9.8 score on scale |
| Concerta | Mean Change From Baseline in the Adult Attention Deficit Hyperactivity Disorder Investigator Symptom Rating Scale (AISRS) Total Score After 4 Weeks of Treatment | -15.3 score on scale |
| Placebo | Mean Change From Baseline in the Adult Attention Deficit Hyperactivity Disorder Investigator Symptom Rating Scale (AISRS) Total Score After 4 Weeks of Treatment | -7.6 score on scale |
p-value: 0.341Mixed Models Analysis
p-value: 0.001Mixed Models Analysis
Secondary
>/=1-point Improvement in the CGI-S Score
The Clinical Global Impression - Severity of Illness Scale (CGI-S) is administered by a trained investigator who rates the severity of a patient's illness at the time of assessment, relative to the investigator's past experience with patients who have an ADHD diagnosis. The scores range from 1 to 7. Higher numbers correspond to more severe illness. Data not reported due to failure of primary hypothesis and program termination.
Time frame: 4 weeks of treatment
Secondary
>/= 30% AISRS Total Score Responder Rate After 4 Weeks of Treatment;
The AISRS total score consists of 18 items from the original ADHD-RS which were derived based on DSM-IV criteria for ADHD. The ADHD-RS include 9 items that address symptoms of inattention and 9 items that address symptoms of impulsivity and hyperactivity. Each item is rated from 0 to 3. The AISRS total score can range from 0 to 54. A higher score corresponds to a worse severity of ADHD. Data not reported due to failure of primary hypothesis and program termination.
Time frame: after 4 weeks of treatment
Secondary
Mean Change From Baseline in the AISRS Hyperactive/Impulsive Subscale Score
The Adult Attention Deficit Hyperactivity Disorder Investigator Symptom Rating Scale (AISRS) hyperactive/impulsive subscale score consists of 9 items from the original Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS) which address hyperactivity and impulsivity. Each item is rated from 0 to 3. The AISRS hyperactive/impulsive subscale score can range from 0 to 27. A higher score corresponds to a worse severity of ADHD hyperactivity/impulsivity. Data not reported due to failure of primary hypothesis and program termination
Time frame: 4 weeks of treatment
Secondary
Mean Change From Baseline in the AISRS Inattentive Subscale Score After 4 Weeks of Treatment
The AISRS inattentive subscale score consists of 9 items from the original ADHD-RS which address inattention. Each item is rated from 0 to 3. The AISRS inattentive subscale score can range from 0 to 27. A higher score corresponds to a worse severity of ADHD inattentiveness. Data not reported due to failure of primary hypothesis and program termination.
Time frame: after 4 weeks of treatment
Secondary
Mean Change From Baseline in the Clinical Global Impressions-severity of Illness Scale(CGI-S) Score
The Clinical Global Impression - Severity of Illness Scale (CGI-S) is administered by a trained investigator who rates the severity of a patient's illness at the time of assessment, relative to the investigator's past experience with patients who have an ADHD diagnosis. The scores range from 1 to 7. Higher numbers correspond to more severe illness. Data not reported due to failure of primary hypothesis and program termination.
Time frame: 4 weeks of treatment
Secondary
Mean Change From Baseline in the Conners' Adult ADHD Rating Scale - Observer Screening Version (CAARS-O:SV) Total ADHD Symptom Score.
Conners' Adult ADHD Rating Scale - Observer Screening version (CAARS-O: SV) evaluates DSM-IV-oriented inattention, impulsivity and hyperactivity as well as measures of self-concept. It is a 30-item scale administered by a trained investigator or rater with cue questions. Each item is scored from 0 to 3 with higher scores corresponding to worse symptoms. The total score can range from 0 to 90. Data not reported due to failure of primary hypothesis and program termination.
Time frame: 4 weeks of treatment
Other Pre-specified
Baseline AISRS
Baseline values for all treatment groups are equal because the constrained longitudinal data analysis (cLDA) model was used (Liang and Zeger, 2000, Sankhyā: The Indian Journal of Statistics, Series B 62, 134-148).
Time frame: Baseline
Population: Full Analysis Set (FAS): The FAS included all randomized patients who received at least one dose of study medication. Patients with at least one assessment (baseline or post-randomization) were included in the FAS. Missing data were handled using the data as observed (DAO) approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MK-0249 | Baseline AISRS | 34.6 score on scale | Standard Error 2.8 |
| Concerta | Baseline AISRS | 34.6 score on scale | Standard Error 2.8 |
| Placebo | Baseline AISRS | 34.6 score on scale | Standard Error 2.8 |