CONCERTA - Use in Adults with ADHD

Summary

• The results and sub-analyses of a randomized, double-blind, dose-titration study demonstrated that CONCERTA, in a dose range of 36 to 108 mg/day, was effective and well-tolerated for the treatment of attention deficit/hyperactivity disorder (ADHD) in adults.^1,2
• The results of a long-term, open-label study demonstrated that CONCERTA was safe and well-tolerated in treating ADHD in adults between a dose range of 36 and 108 mg once daily for up to 1 year.³
• The safety and efficacy of CONCERTA in adults with ADHD were attested in the LAMDA (Long-Acting Methylphenidate in Adult ADHD) study and open-label extension trials.^4-6

PRODUCT LABELING

Please refer to the following section of the enclosed Full Prescribing Information that is relevant to your inquiry¹: CLINICAL STUDIES, Adults.

CLINICAL DATA

Pivotal Study Conducted in the U.S. and Related Analyses

Adler et al (2009)⁷ conducted a pivotal clinical study investigating the safety and efficacy of CONCERTA in adults with ADHD (N=229).

Study Design/Methods

• Randomized, placebo-controlled, double-blind, dose-escalation study.
• Adults (age range: 18-65 years) with ADHD symptoms consistent with the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria beginning by age 7, an ADHD Investigator Symptom Report Scale (AISRS) score of ≥24, and a Global Assessment of Functioning (GAF) score between 41 and 60 were enrolled in this study.
• After a 7 to 14-day washout period, subjects were randomized in a 1:1 ratio to CONCERTA (n=110) beginning at 36 mg/day or placebo (n=116) for a 5-week titration period.
• Doses were increased in 18 mg increments every 7 days (±2 days) and continued until the primary endpoint was achieved, or maximum dose of 108 mg/day was reached.
• The primary efficacy endpoint was the change from baseline in AISRS total score.
• The percentage of study responders as defined by a 30% decrease in AISRS score, and a Clinical Global Impression-Improvement (CGI-I) rating of 1 (very much improved) or 2 (much improved) from baseline to endpoint was also assessed as a secondary outcome measure.
• Data regarding vital signs, weight, electrocardiogram (ECG), and adverse events (AEs) were recorded throughout the study period.

Results

Efficacy

• Three subjects discontinued the trial prior to randomization.
• The mean final doses for CONCERTA and placebo were 67.7 mg/day and 86.9 mg/day, respectively.
• There was a statistically significantly greater improvement in baseline AISRS total score in subjects treated with CONCERTA (-10.6) compared with placebo (-6.8) at study endpoint (P=0.012).
• Similar results were observed for improvements in CGI-I in subjects taking CONCERTA compared to placebo (3.02 vs 3.43, respectively; P=0.008).
• Additionally, 36.9% of subjects in the CONCERTA group were considered responders based on their AISRS and CGI-I scores compared to 20.9% in the placebo group (P=0.009).

Safety

• In the CONCERTA group, 84.5% of subjects reported an AE compared to 63.8% of subjects in the placebo group.
• AEs reported by at least 10% of CONCERTA subjects compared to the placebo group are displayed in Table: Adverse Events Reported by ≥10% of CONCERTA-Treated Adult Patients.

• AEs leading to discontinuation of therapy were reported in 14.5% of subjects in the CONCERTA group compared to 5.2% of subjects in the placebo group.
• There were no treatment-emergent serious AEs, and no deaths reported in either study group.
• The mean, respective changes in cardiovascular parameters for subjects in the CONCERTA group compared to placebo from baseline to final visit were -1.2 mm Hg and -0.5 mm Hg for systolic blood pressure (SBP), +1.1 mm Hg and +0.4 mm Hg for diastolic blood pressure (DBP), and +3.6 beats per minute (bpm) and -1.6 bpm for heart rate (HR).

Orman et al (2008)⁸ reported additional secondary Efficacy Results from the previously-described study by Adler et al (2009)⁷.

Study Design/Methods

• In addition to the secondary efficacy measures described above, change from baseline to final visit in the Conners’ Adult ADHD Rating Scale-Self Report (CAARS-S:S) total score, change in the Sheehan Disability Scale (SDS), change in the CGI-Severity (CGI-S) rating, and change in the ADHD Impact Model for Adults (AIM-A) Work/Home/School domain score were included in this analysis.

Results

• The CONCERTA treated group experienced greater improvement compared to placebo on the CAARS-S:S (-12.7 and 8.3, respectively; P=0.029).
• The scores for the SDS, CGI-S and AIM-A were not statistically significantly different between the study groups, although the CONCERTA group experienced greater numeric improvement in the CGI-S and AIM-A scores compared to placebo.
• AEs and changes in vital signs from baseline are presented in the previous study.⁷

Pandina et al (2008)² evaluated the Efficacy of CONCERTA in the same study population as Adler et al (2009)⁷.

Study Design/Methods

• Patient-reported (CAARS-S:S) and clinician-rated (AISRS) improvement in ADHD symptoms were evaluated.

Results

• Greater improvement in the CONCERTA-treated subjects was seen on the CAARS-S:S Inattention/Memory (P=0.002) and Hyperactivity/Restlessness (P=0.007) subscales compared to placebo-treated subjects.
• Items from each scale that assessed similar symptoms were compared in order to correlate patient and clinician-rated symptoms.  
• The change from baseline to study endpoint for AISRS and CAARS-S:S scores were highly correlated for both the CONCERTA group (r=0.76; P<0.0001) and the placebo group (r=0.73; P<0.0001).  
• Change in items related to the following domains from the CAARS-S:S corresponded well with items from the AISRS: inattention/memory problems, hyperactivity/restlessness, impulsivity, and half the items from the ADHD index.
• There were no emotional lability or self-concept items in the AISRS which corresponded with items in the CAARS-S:S rating scale.

Adler et al (2011)³ evaluated the long-term Safety of CONCERTA in adult patients with ADHD (N=550).

Study Design/Methods

• Open-label, dose-titration, flexible dose, long-term study
• After a 7 to 14-day washout period, patients (age range: 8-65 years) were initiated on CONCERTA 36 mg once daily and titrated in 18 mg increments every 7 days (±2 days) until they reached a maximum dose of 108 mg daily or until a predefined treatment response of a decrease in AISRS score from baseline by >30% and a CGI-I score of 1 (improved) or 2 (very much improved) was reached.
• Once the subjects reached the maximum dose or met predefined treatment responder criteria, they continued treatment for either 6 or 12 months.
• Dose changes could occur as needed based on the investigator's discretion.
• Efficacy measures included the AISRS scores, the Global Assessment of Effectiveness, and response to treatment (as defined above).
• The CGI-I, CGI-S, and the predefined treatment response were used to evaluate treatment Efficacy during the titration period only.
• Safety assessments included vital signs, AEs, weight, ECG, physical examination, and clinical laboratory tests.

Results

Efficacy

• Subjects who received at least 1 dose of study medication (258 assigned to 6-month duration and 292 to the 12-month duration) were included in the analysis.
• Fifty-six percent (n=146) of subjects in the 6-month duration and 44% (n=129) of subjects in the 12-month duration completed the study.
• The mean final dose of CONCERTA was 67.4 mg daily.
• The mean change in AISRS scores from baseline to final visit was –17.2 points, and 73.5% of subjects were classified as responders at the final titration visit.

Safety

• Of the 91.6% of subjects reporting at least 1 AE, 1.5% reported serious AEs of which none were considered by the investigators to be drug related.
• Overall, 9.6% of the subjects experienced SBP >140 mm Hg, 12% experienced DBP >90 mm Hg, 10.2% experienced HR greater than 100 bpm, and 11.2% experienced greater than 10% weight loss.
• AEs that resulted in study withdrawal occurred in 18.2% of subjects with incidence reported in 2% or more of the subjects were anxiety (3.3%) and insomnia (2.2%).
  • The most commonly reported AEs (in ≥10% of subjects) included: decreased appetite (26.7%), headache (24%), insomnia (20.7%), and dry mouth (14.7%).
• Dose reductions due to an AE were reported in 30.4% of subjects with the most common reasons were increased HR (4%), increased BP (3.8%), and irritability (3.3%).
• Certain cardiovascular and psychiatric events of special interest were reported; however, no subjects experienced myocardial infarction, stroke, or suicidal behavior.
• No clinically significant changes in ECG measurements were observed.

Pivotal Study Conducted in Europe and Related Analyses: The LAMDA Study

Medori et al (2008)⁴ conducted a pivotal study to assess the safety and efficacy of CONCERTA in adults with ADHD (N=401).

Study Design/Methods

• Randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study
• Adults (age range: 18-63 years) with confirmed diagnosis of ADHD based on DSM-IV criteria were randomly assigned to receive CONCERTA 18, 36, or 72 mg/day, or placebo for 5 weeks.
  • For subjects in the 72 mg/day group, 36 mg/day was given on days 1-4, followed by 54 mg/day on days 5-7, and 72 mg/day from day 8 onwards.
• The primary efficacy measure was the change in the sum of the Conners' Adult ADHD Rating Scale-Observer rated (CAARS:O-SV) total score at endpoint compared to baseline.
• Secondary efficacy measures included changes in CAARS:O-SV total and subscale scores at weeks 1, 3, and 5, and changes from baseline to endpoint in the CGI-S, the CAARS:S-S, and the SDS.

Results

Efficacy

• Of the 401 subjects randomized and treated during the double-blind phase, 365 (91%) completed the 5-week double-blind phase and 394 were included in the analysis of efficacy.
• At study endpoint, all 3 doses of CONCERTA demonstrated significantly greater improvements from baseline in CAARS:O-SV total score compared with placebo (-10.6 for 18 mg, -11.5 for 36 mg, -13.7 for 72 mg, and -7.6 for placebo; P<0.015).
• A significantly greater number of subjects in the CONCERTA groups achieved ≥30% (P<0.001) or ≥50% (P<0.01) reduction in CAARS:O-SV total score compared with placebo.
• Additionally, at study endpoint, there were significantly greater improvements from baseline in the CONCERTA groups compared with placebo with respect to CGI-S total score (P≤0.005 for all 3 doses), CAARS:S-S total score (P≤0.003 for 3 doses), and SDS total score (P=0.008 for 18 mg, P=0.061 for 36 mg, and P=0.004 for 72 mg).

Safety

• Treatment-emergent AEs were reported more frequently in the CONCERTA groups compared with the placebo group (75%-82% vs 66%, respectively).
• The highest percentage of AEs was reported in the CONCERTA 72 mg group.
• The most commonly reported AEs (>10% treated with CONCERTA) were decreased appetite, headache, insomnia, nausea, and dry mouth.
• Psychiatric AEs (eg, irritability, anxiety, nervousness) occurred more often in the CONCERTA treated subjects compared with placebo.
• Tachycardia (5.6%) and palpitations (3.9%) were reported in the CONCERTA groups but not in the placebo group.
• Four subjects experienced serious AEs during double-blind treatment: 2 in the 18 mg group (cerebrovascular accident and anxiety disorder), and 2 in the 72 mg group (depression and migraine).
  • However, only 1 event (depression) was considered possibly related to study medication.
• Thirteen (4.3%) subjects in the CONCERTA groups discontinued study medication due to 1 or more AEs.
• There was a significantly greater decrease in weight from baseline at end point with all 3 doses of CONCERTA compared with placebo (P<0.001).
• There were statistically significant increases in HR in all 3 doses of CONCERTA (P<0.05) at weeks 1, 3, and 5, and in the placebo group at week 3.
• Additionally, there were statistically significant (P<0.05) increases in BP from baseline in the 36 mg group (DBP, 2.3 mm Hg at week 3) and in the 72 mg group (DBP, 2.0 mm Hg; SBP, 4.0 mm Hg at week 1).

Buitelaar et al (2009)⁵ continued to evaluate the safety and tolerability of CONCERTA in adults with ADHD who were enrolled in the LAMDA trial conducted by Medori et al (2008)⁴ (N=370).

Study Design/Methods

• Seven-week, open-label extension of the LAMDA trial
• Subjects who completed the LAMDA trial double-blind phase or discontinued study drug due to poor tolerability were eligible to enroll in this trial.
• Subjects were to be started on 36 mg/day initially; however, approximately 25% of subjects started on 18 mg/day due to various local regulatory requirements.
• The dose was then titrated in increments of 18 mg up to 90 mg based on clinical response.
• Safety and efficacy measures were similar to those used in the LAMDA trial.

Results

Efficacy

• Of the 370 subjects who continued on to the open-label phase of the study, 337 completed the 7-week extension phase.
• Subjects were taking an average daily CONCERTA dose of 47.5 mg.
• The results demonstrated that subjects who received placebo previously during the double-blind phase showed a significant improvement in CAARS Total score (P<0.001) from week 1 to the end of the open-label extension study.
• Similarly, those who received CONCERTA during the double-blind phase exhibited a significant improvement in CAARS Total score (P<0.001) from week 3 during the open-label phase.

Safety

• Sixty-eight percent of subjects reported at least 1 AE.
• The most commonly occurring AEs considered by the investigator to be at least possibly related to study medication were decreased appetite (12%), headache (9%), and insomnia (9%).
• There were 17 (5%) subjects who discontinued treatment due to an AE of which 9 were considered very likely or probably related to treatment.
• Two subjects experienced serious AEs during open-label treatment (acute psychological stress and foreign body in the urethra) but neither were considered related to medication treatment.
• Two additional subjects experienced serious AEs poststudy (increased anxiety and temporal arteritis/severe headache) of which the first was not considered to be drug-related while temporal arteritis/severe headache were doubtfully considered to be drug-related.
• With regard to laboratory parameters, no clinically significant changes were observed.
• Between the end of the double-blind phase to the end of the 7-week open label phase, the mean increase in BP was 2.4 mm Hg for both SBP and DBP, and 3.2 bpm for pulse; these changes were not considered clinically significant.
• Discontinuation due to BP changes were as follows:
  • One patient discontinued trial medication due to a moderate raise in BP and the investigator considered this to be probably drug related.
  • A second patient discontinued trial medication due to worsening of high BP and paresthesia.
  • The investigator assessed worsening of high BP and paresthesia as moderate and mild in severity and very likely and possibly related to study medication, respectively.
• Tachycardia was reported in 10 patients and palpitations in 12 patients.
  • Only 1 patient discontinued the trial due to tachycardia and the investigator considered it to be mild and probably drug related.
• The mean decrease in body weight over the 7-week treatment period was -1.5 kg.

Buitelaar et al (2012)⁶ continued to evaluate the Safety and tolerability of CONCERTA in adults with ADHD who were enrolled in the LAMDA trial conducted by Medori et al (2008) ⁴ and the 7-week open-label extension conducted by Buitelaar et al (2009).⁵

Study Design/Methods

• 52-week, open-label extension study of the LAMDA trial
• Subjects who completed the 5-week double-blind LAMDA trial and the 7-week open-label extension were eligible to enroll in the 52-week open-label phase. At the end of the open-label study, subjects who received at least 52 weeks of treatment with CONCERTA were eligible to participate in a 4-week, randomized, double-blind, placebo-controlled withdrawal phase.
• During the open-label phase, subjects received a flexible dose of CONCERTA 18 mg/day up to a maximum of 90 mg/day. The dosage was increased or decreased in 18-mg increments based on response and tolerability.

Results

Safety

• 155 subjects entered the open-label study, and 99 subjects completed the open-label phase.
• The mean daily dose of CONCERTA was 52.8±21.0 mg.
• 126 subjects (81.3%) had at least 1 treatment-emergent AE during the open-label phase.
• The most common treatment-related AEs were restlessness, headache, and drug effect decreased (each n=9, 5.6%).
• AEs that resulted in study discontinuation in >1 patient included insomnia, depressed mood, and hypertension (each n=2, 1.3%).
• Treatment-related AEs of special interest reported by >1 patient included hypertension (n=9, 5.8%), palpitations (n=6, 3.9%), and anxiety (n=4, 2.6%). One patient with palpitations and 1 patient with anxiety were categorized as severe.
• Mean changes from baseline in SBP, DBP, and HR were 0.3±14.0 mm Hg, 1.4±9.7 mm Hg, and 0.9±14.4 bpm, respectively.  Abnormally high BP values were reported in 21.7% of subjects (for SBP >140 mm Hg) and in 17.1% of subjects (for DBP >90 mm Hg) at any postbaseline visit during the open-label phase. HR >100 bpm was reported in 9.2% of subjects.
• There were no significant changes in body weight or BMI throughout the study.
• Of the 99 subjects who completed the open-label phase, 45 (45%) entered the double-blind phase.
• During the double-blind phase, ≥1 AE was reported by 30.4% of CONCERTA subjects and 36.4% of placebo subjects.
• Two subjects receiving CONCERTA reported hypertension as AE.  There were minimal changes in BP and HR for subjects who continued treatment with CONCERTA, while these parameters decreased in subjects who switched to placebo during this phase.  In the CONCERTA group, 2 subjects reported abnormally high DBP (>90 mm Hg) and 2 subjects reported abnormally high HR (>100 bpm).

Efficacy

• In the open-label phase, CAARS:O-SV total score improved from baseline to endpoint (-1.9±7.8; P≤0.01).
• There were also significant improvements from baseline in the Hyperactivity/Impulsivity and Inattention subscale scores of CAARS:O-SV, CAARS:S-S score, CGI-S, and SDS. However, no significant change was observed for the Quality-of-Life Enjoyment and Satisfaction Questionnaire.
• In the double-blind withdrawal phase, mean CAARS:O-SV total score increased from double-blind baseline in both the CONCERTA (4.0±7.6) and placebo (6.5±7.8) groups; difference was not statistically significant.
• There were no statistically significant differences in secondary Efficacy parameters between the treatment groups, with the exception of CGI-C scores which demonstrated significantly less worsening of symptoms at double-blind endpoint with CONCERTA vs placebo.

SELECTED ADDITIONAL REFERENCES

Additional published literature has been found regarding the use of CONCERTA in adults with ADHD, including randomized, placebo-controlled studies^9-15, open-label studies^16,17, post hoc analyses^18-22, a substitution study²³, a quality of life study²⁴, a review article²⁵, and a meta-analysis²⁶. The citations have been included in the REFERENCES section for your reference.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 24 October 2024.