Attention deficit hyperactivity disorder (ADHD), a highly prevalent and clinically heterogeneous behavioral disorder, is estimated to affect up to approximately 3%-5% of children and adolescents world wild,1,2 and often persists into adulthood.3 ADHD is associated with a broad range of negative outcomes for affected subjects4 and puts a serious burden on families and societies.5 As a result, early identification and treatment of symptoms of ADHD is essential to effective management of this disorder.
Stimulant agents are well-established as first-line pharmacotherapy for both school-aged children and adults.6 Immediate-release methylphenidate (IR-MPH) is the most commonly prescribed and best-studied stimulant medication and has been shown to be highly efficacious for treating ADHD.7,8 However, its short duration of action usually results in a requirement to administer multiple times daily in order to achieve optimal clinical benefit. The need for multiple dosing produces problems with medication administration during school and after-school hours and therefore leads to poor compliance. Osmotic release oral system methylphenidate (OROS-MPH) is a once-daily controlled-release formulation developed to overcome some of the limitations associated with IR-MPH9 and has demonstrated efficacy and safety in reducing the core symptoms of ADHD in well-designed, multicenter, placebo-controlled, double-blind trials.10-12
OROS-MPH has been marketed in China since 2005 and it still lacks data from large-sample clinical trials on efficacy and safety profiles. Therefore, the urgent need is to conduct an observational study, collecting the effectiveness and safety data under the naturalistic clinical setting and then provide more supportive evidence for the use of OROS-MPH in the real clinic background.
Twenty-three research centers across China recruited physically healthy, male and female outpatients, aged 6-16 years inclusive, with a documented Diagnostic Statistical Manual-Fourth Edition (DSM-IV) diagnosis of attention-deficit/hyperactivity disorder.1 Subjects were patients willing to take OROS-MPH as the only medicine for ADHD and the written informed content forms must be obtained from their parents/guardians.
Exclusion criteria included: (1) Subjects with anxiety disorder, mood disorder, general development disorder, serious depression, schizophrenia; (2) Known to be allergic to methylphenidate or other ingredients of the study drug; (3) Subjects with glaucoma; (4) Subjects with family history or diagnosed as Tourette syndrome; (5) Taking or having taken monoamine oxidase inhibitor in the past 14 days, taking the following drugs such as clonidine, other α-2 adrenergic receptor agonist, tricyclic antidepressants, theocine, bishydroxycoumarin and so on; (6) Participating in clinical trials of other drugs; (7) Cardiovascular diseases including moderate to severe hypertension, hyperthyroidism; (8) History of drug dependence or alcohol dependence; (9) Subjects with serious gastrointestinal stenosis, dysphagia and other serious somatic diseases.
During the 6-week treatment period, the subjects will be excluded from our observation if the conditions as below occurred: (1) Subjects are unwilling to keep receiving OROS-MPH therapy due to poor therapeutic effect, intolerance of adverse events, etc; (2) Serious adverse events related to OROS-MPH; (3) Violating the study protocol by taking ADHD drugs which are not allowed; (4) Other serious somatic diseases judged by investigators occur (The condition that the child is in danger based on the BP measurement at any time was also included); (5) Tic symptoms increase or new serious tic symptoms appear; (6) Pregnancy.
This study was a prospective, naturalistic, open-label, pilot study of OROS-MPH conducted in an outpatient setting. Potentially eligible school-aged children were screened for categorical diagnosis and willingness of medication to determine eligibility. Subjects were prescribed OROS-MPH (18, 36 or 54 mg once daily) at the discretion of investigators. However, the recommended dosing strategy is: (1) For subjects who have not received methylphenidate treatment before, the initial dosage was 18 mg. (2) For subjects who were receiving methylphenidate treatment, subjects receiving 5 mg IR-MPH 2 or 3 times a day were assigned to OROS-MPH 18 mg q.d.; subjects receiving 10 mg IR-MPH 2 or 3 times a day or receiving a total daily dose of 40 mg IR-MPH were assigned to OROS-MPH 36 mg q.d.; and subjects receiving 15 mg IR-MPH 2 or 3 times a day or a total daily dose of >45-60 mg were assigned to OROS-MPH 54 mg q.d. Doses of OROS-MPH could be adjusted between a total daily dose range of 18 and 54 mg after 14 days of treatment by the investigator on the basis of safety and efficacy.
There were four protocol-specified visits: screening/ baseline, week 2, week 4 and week 6. The visits were scheduled based on the frequency of naturalistic clinical interview which was derived from the consensus of the principle investigators involved in this observational study.
The primary effectiveness measure was the Inattention/ Overactivity with Aggression (IOWA) Conners Rating Scale.13 The IOWA Conners Rating Scale consists of 10 items divided into 2 subsets, I/O and Oppositional/ Defiance (O/D). Items were scored on a 4-point scale (from 0=not at all to 3=very much) and the subsets were analyzed separately. Parents completed both subsets of the IOWA Conners Rating Scale at each visit to evaluate inattention and behavior of children at home. The IOWA Conners Rating Scale has been used in treatment studies and has shown adequate discriminant validity.14
Secondary effectiveness measures included: (1) Physician-rated Clinical Global Impression-Improvement (CGI-I), rated on 7-point scale (1-7, 1=Very much improved, to 7=Very much worse). The rating was based on a review of parents' ratings and a parent interview. The CGI-I has been shown to be sensitive to medication effects in a trial with children and adolescents.15 (2) Global assessment of efficacy rated by parents.10 Parents completed a global assessment of efficacy at baseline, weeks 2, 4 and 6 rating the patient's behavior and attention on a 4-point scale (1=poor; 2=fair; 3=good; 4=excellent) in response to the following question: What is your opinion of the effectiveness of treatment this 2 weeks?
Each subject had a general physical examination and baseline blood work-up (if necessary) before initiating OROS-MPH. Blood pressure, pulse rate measurement, AE review, and concomitant medications and treatment review were conducted by the investigator at baseline and at each subsequent monitoring visit. Additionally, parents rated the subject's sleep quality on days 0, 14, 28 and 42. Sleep quality was rated as good, fair or poor. Parents were also questioned on days 0, 14, 28 and 42 about the presence of motor and/or verbal tics.
Primary analysis was based on the Full Analysis Set (FAS) that was comprised of those children who received at least one dose of OROS-MPH and had Connners scale score evaluated at baseline and had at least one of data above at visit 2 as well. Per-protocol set was defined as a set of all children who reasonably followed the protocol procedures and had good compliance to the treatment drug and had Connners scale score at visits 1-4. Safety analysis was performed in safety set (SS) population that was comprised of those who received at least one dose of the investigational drug and had safety data at visits 2-4.
The demographic descriptive statistics was performed in FAS population. Efficacy analysis was performed in FAS population. Safety analysis was performed in SS population. The t test was performed to compare the difference in mean values between baseline and endpoint of study. Qualitative data were analyzed using the χ2 test and a P value of less than 0.05 was considered as having a significant difference. Number, type, relevance and severity of adverse events were also summarized and the numbers and reasons of withdrawal caused by adverse events were given. The descriptive method was used to summarize vital signs, laboratory tests and other safety data. The statistical software SAS V8.1 was used.
During the period from April 1, 2006 to February 15, 2007, 1447 ADHD patients were enrolled in the observational study and received OROS-MPH treatment. The 1447 subjects were included in the safety analysis. The ITT effectiveness analysis consisted of 1398 subjects based on the criteria of FAS defined in this protocol. Among them, 1154 subjects (79.8%) completed the 6-week trial. The 889 subjects conformed to the PP criteria defined in this protocol and were included in PP set. During the study, 293 subjects (20.2%) dropped out the study, including 34 cases dropped out from baseline to week 2, 182 at week 3-4 and 77 at week 5-6. The reasons of patients discontinued prematurely included: lost to follow-up (n=133, 45.4%); Parent not interested (n=40, 13.7%); AEs (n=34, 11.6%); Economic factors (30, 10.2%); Lack of efficacy (n=27, 9.2%); Concern for side-effects (n=8, 2.7%) and no reason stated (21, 7.2%). The baseline characteristics is shown in Table 1.
At baseline, 99.8% children were treated with an OROS-MPH modal dose of 18 mg and 0.2% with 36 mg at baseline. In contrast, 96.8% children received an OROS-MPH modal dose of 18 mg, 3.1% with 36 mg and 0.1% with 54 mg at the endpoint of study.
Good compliance was defined as more than 80% adherence to the prescribed regimen of OROS-MPH. The 1300 (93.4%) patients meet the criteria at days 1-14, while 1131 (93.5%) at days 14-28, 1045 (93.9%) at days 28-42, and 1301(93.5%) at days 1-42. The results on the compliance suggested that OROS-MPH has a good tolerability in treating ADHD.
Primary effectiveness outcomes
Table 2 shows the baseline, weeks 2, 4 and 6 results for the parent IOWA Conners I/O and O/D subscales. The parent IOWA Conners I/O scores at the end of week 2 showed statistically significant (P <0.001) improvement with OROS-MPH (mean: 6.95±2.71) versus the scores at baseline (10.45±2.72). The trend of improvement was seen in the parent ratings on the IOWA Conners I/O scores over time with OROS-MPH and the I/O score decreased to 4.30±2.52 at the end of this trial. The results of parent IOWA Conners O/D scores also supported the superior efficacy for OROS-MPH treatment.
When analyzed based on the age group (≤12 or >12 years old) and the types of ADHD, the data also suggested that OROS-MPH could improve the core symptoms significantly (P <0.001).
Secondary effectiveness outcomes
Results of the secondary effectiveness analyses are reported in Table 3. The CGI-I scores at the end of weeks 4 and 6 showed statistically significant (P <0.001) improvement with OROS-MPH (mean: 3.34±0.92 and 3.31±0.98, respectively) versus the scores at week 2 (3.44±0.97). On the CGI-I, 1230 (90.1%) subjects were rated as “Very much improved” or “Much improved” at week 6.
The results of the global assessment of efficacy, completed by parent at each visit, also showed significant benefits (P <0.001) for OROS-MPH treatment. At the end of trial, ratings of “Good” or “Excellent” were obtained by 79.4% of patients who were taking OROS-MPH.
Among the subgroup based on the different age (≤ 12 or > 12 years old) and the types of ADHD, the global assessment of efficacy by parent and CGI-I also supported the superior efficacy for OROS-MPH treatment (P <0.001).
In this trial, patients who received at least one dose of OROS-MPH and had Connners scale score evaluated at baseline and had at least one of data above at visit 2 as well were included in the analysis of safety (n=1447). No serious adverse events were reported during the study. Fewer than half of 1447 patients (511(35.3%)) reported AEs, and the majority of the events reported were mild (68.2%). The AE incidence of 18 mg OROS-MPH group was 28.6%, while the incidence of 36 mg OROS-MPH group was 31.8%. A total of 34 patients discontinued the study early due to the following AEs: loss of appetite (n=13), rash (n=1), insomnia (n=1) and other (n=19). The most commonly reported AEs were loss of appetite (47.9%), insomnia (12.6%), headache (12.4%) and stomach ache (12.1%).
In this study, most subjects (89.2%) were not greater than 12 years old. The incidence of AEs was lower in 6-12 years group (34.55%) than that of 13-16 years group (40.79%). When analyzed based on the types of ADHD, the data showed that the incidence of AEs occurred in patients of hyperactive/impulsive type (23.02%) was lower than that of combined type (37.35%) or inattention type (36.38%).
Sleep quality and Tic
Sleep quality was rated as good, fair or poor. At baseline, most patients (59.2%) were assessed as have good sleep quality. As rated on days 14, 28 and 42, the majority of patients (>59%) continued to have good sleep quality (Table 4). During this study, the number of patients who were reported to have Tic at each visit is shown in Table 4. With prolongation of the treatment time, the incidence of tic symptom decreased gradually.
BP and pulse rate
There was no significant difference in blood pressure at weeks 2, 4 after administering versus the value at baseline. Blood pressure at week 6 increased significantly. However, it had no clinical significance since the value still varied within the normal range. After 6-week treatment, the pulse changed (0.28±4.77) beats/min compared with that of the baseline. Pulse was stable and was not affected after OROS-MPH treatment.
To the best of our knowledge, this is the first systematic assessment of the effectiveness and safety of OROS-MPH in a sample of 6- to 16-year old patients with ADHD under naturalistic settings. OROS-MPH improved parent-rated hyperactive, inattentive, oppositional and defiant behaviors of school-aged children diagnosed with ADHD. A significant improvement (mean reduction of score: 6.29±3.12) at the end of study (week 6) was observed over baseline on the parent-rated IOWA Conners I/O subscale, and a similar improvement was also seen on the parent-rated IOWA Conners O/D subscale, physician-rated CGI-I, and global assessment scale of efficacy rated by parents. Improvement in the ADHD symptoms experienced by the school-aged children with OROS-MPH in the current trial is comparable to the previous studies.16,17 In addition to children, OROS-MPH also showed good efficacy and safety in adult ADHD patients.18-20 Since OROS-MPH was approved to use in treating ADHD by FDA in May of 2000 OROS-MPH can extend treatment continuity of patients significantly and improve the compliance of the treatment.10,21-23 It was further demonstrated in our study that a high percentage of patients were in compliance to the dose prescribed by physician throughout the 6-week treatment. Only 34 patients discontinued prematurely due to adverse events and the results suggested that OROS-MPH had good tolerability for the school-aged children.
The incidence of adverse events was 35.3%, which was approximate to 37.8% reported in South Korea24 and 41.2% reported in USA,13 but it was much lower than 72.4% reported in Europe.25 In this study, the AE incidence of 36 mg OROS-MPH group was a little higher than that of 18 mg OROS-MPH group ( 31.8% vs. 28.6%). However, there was only 44 patients taking 36 mg OROS-MPH, needing further evidence in future study. No serious adverse events were reported. Besides, the majority of adverse events reported were mild. This may be attributable, in part, to the fact that the doses prescribed in this trial were lower compared with the other trial.17 However, this is still controversy since several studies indicated that the efficacy of 36 mg and 54 mg dose groups was significantly better than that of 18 mg dose group and the incidence of adverse events was not affected.24-27 A high percentage of patients (96.9%) were treated with an OROS-MPH modal dose of 18 mg at the endpoint of this trial while only 42 patients took 36 mg and one patient took 54 mg. The most common adverse event was loss of appetite (47.9%), but only 13 patients dropped out the study due to significant loss of appetite. Since the patients in this study only received 6-week OROS-MPH treatment, the long-term adverse events such as influence on growth and weight can not be observed. This is a limitation of this study because ADHD patients need long-term treatment.
There was no significantly negative effect on sleep quality in our study. On the contrary, the sleep quality in 6-12 years group was improved after OROS-MPH treatment. It further enforced the available evidence28 that OROS-MPH treatment was not a possible cause of sleep problems in the treated children although this stimulant as well as immediate-release methylphenidate has long been suspected to adversely affect sleep qualities of treated patients, especially children. In a 6-week, prospective, open-label, flexible-dose trial with OROS-MPH monotherapy, the treatment does not seem to impair sleep and may even improve some aspects of sleep demonstrated by both a parental sleep questionnaire and polysomnography.29 Similarly, the data from our study suggested that OROS-MPH therapy did not significantly induce or exacerbate tics in children with ADHD.
The development of OROS-MPH satisfied the need of administering once daily and maintaining an effective dosage. Many multi-center, double-blind, randomized clinical trials showed the efficacy of OROS-MPH was stable and durable home and abroad. Comparing with IR-MPH, it can avoid the fluctuation of plasma concentration, make efficacy more stable, have a good tolerability and safety and increase the compliance significantly.17,25,30,31 Since OROS-MPH came into the market shortly, this multi-center, prospective, open-lable observation filled up information of clinical efficacy and safety in a large sample of treating ADHD with OROS-MPH, had a guiding significance for medication more reasonably in the future and further proved OROS-MPH safe and effective in treating ADHD. In conclusion, OROS-MPH is an effective and safe drug in treating ADHD.
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