Long-Term (1 Year) Safety and Efficacy of Methylphenidate Modified-Release Long-Acting Formulation (MPH-LA) in Adults with Attention-Deficit Hyperactivity Disorder: A 26-Week, Flexible-Dose, Open-Label Extension to a 40-Week, Double-Blind, Randomised, Placebo-Controlled Core Study

The study design of the core study is described elsewhere [22]. Briefly, this was a 6-month, multicentre, open-label extension of a 40-week, double-blind, randomised, placebo-controlled core study (NCT01259492) that comprised three phases: 9-week dose confirmation phase, 5-week open-label dose optimisation phase and 6-month maintenance of effect phase (Fig. 1a). The 6-month maintenance of effect phase was a double-blind, randomised, placebo-controlled, withdrawal period to evaluate the maintenance effect of MPH-LA in adults with ADHD.

Eligible patients entering the extension study (NCT01338818) were initiated on treatment with MPH-LA 20 mg and up-titrated to their optimal doses (dose at which there was an optimal balance between control of symptoms and adverse effects) of 40, 60 or 80 mg/day in increments of 20 mg/week for the first 3 weeks of the extension study (i.e. week 41–43). This re-titration was necessary to accommodate patients who entered the extension study from the placebo arm of the maintenance of effect phase of the core study. The investigator had the flexibility to readjust the doses as necessary (between weeks 44 and 66) as long as the dose remained in the range of MPH-LA 40–80 mg/day (Fig. 1b).

The study population consisted of ADHD patients (18–60 years) with confirmed childhood onset according to DSM-IV diagnostic criteria [24]. Inclusion criteria for the core study have been previously described [22]. Adult ADHD patients entering the extension study had either completed the 6-month maintenance of effect phase of the core study or discontinued from the maintenance of effect phase due to lack of therapeutic effect (defined as ≥30 % worsening from the maintenance of effect phase baseline and <30 % remaining improvement from the beginning of the core study, using DSM-IV ADHD RS).

A total of 298 patients entered the extension study and received treatment with MPH-LA (Ritalin LA^®, Novartis Pharma AG: a racemic mixture of d- and l-threomethylphenidate modified-release hard capsules). Of these, 156 patients were treatment responders (MPH-LA, n = 132; placebo, n = 24) and 91 patients were treatment non-responders (MPH-LA, n = 46; placebo, n = 45) in the maintenance of effect phase. Treatment non-responders were defined as patients who fulfilled both the lack of therapeutic effect criteria in the maintenance of effect phase of the core study. Of the enrolled patients, 51 patients (MPH-LA, n = 38; placebo, n = 13) had discontinued in the maintenance of effect phase of the core study prior to the implementation of an amendment to the inclusion criteria for the extension study protocol (treatment non-responders were required to fulfil both the lack of therapeutic effect criteria). These 51 patients were classified as ‘missing treatment non-responders’.

Details of exclusion criteria for the core study are provided elsewhere [22]. In summary, for the extension study, patients who had developed or showed evidence of psychiatric, cardiovascular, cerebrovascular, respiratory, hepatic, gastrointestinal, renal, haematology or neoplastic disorders during the course of the core study were excluded from the extension study. In addition, other exclusion criteria included pregnancy, seizures, glaucoma, hyperthyroidism, pheochromocytoma and Tourette’s syndrome or a family history of Tourette’s syndrome. Patients with positive urine drug test or abnormal electrocardiogram at the end of the core study or premature discontinuation visit were also excluded from the study. Patients were not allowed to take rescue medication or psychotropic drugs. Patients undergoing psychological or behavioural therapies for treatment of ADHD should have discontinued them at least 1 month prior to the screening visit. Psychological or behavioural treatments for reasons other than ADHD had to be discontinued 3 months prior to entering the study or kept stable with the same therapist during the whole study.

The primary objective of the extension study was to assess the long-term safety of MPH-LA in adults with ADHD. Safety-related events were monitored in terms of adverse events (AEs) and serious adverse events (SAEs), and their severity and relation to the study drug were assessed. In addition, physical examination, changes in vital parameters such as blood pressure, pulse rate and haematological parameters, clinical chemistry and electrocardiogram were also monitored.

Cumulative safety data for 12 months were collected and analysed from the combined period of the maintenance of effect phase of the core study and the extension study. Safety data for 6 months were collected from the extension study. Safety data have been presented from two different baselines: (1) baseline of the maintenance of effect phase until the end of the extension study (12 months’ data); (2) baseline of the extension phase to end of the extension study (6 months’ data).

The secondary objective of the study was to evaluate the long-term efficacy of MPH-LA in adults with ADHD (assessments from the maintenance of effect phase baseline and the extension baseline were recorded). Efficacy was primarily assessed using the DSM-IV ADHD RS and the SDS. DSM-IV ADHD RS is a clinician-rated instrument for assessing the severity of ADHD symptoms; it consists of 18 items directly adapted from the ADHD symptom list according to the DSM-IV [25]. SDS consists of a five-item, self-rated questionnaire that measures the extent to which a patient’s disability due to an illness or health problem (e.g., anxiety disorder, painful conditions, ADHD, depression, etc.) interferes with work/school, social life/leisure activities, and family life/home responsibilities [26].

Secondary efficacy assessments were performed using clinician-rated instruments, namely the Clinical Global Impression-Improvement Scale (CGI-I) and the Clinical Global Impression-Severity Scale (CGI-S). The CGI-I is designed to assess the overall change of illness compared with baseline whereas the CGI-S is designed to assess the patient’s current illness state [27]. The proportion of patients with improvement in the CGI-I and CGI-S scales are reported.

A summary of individual efficacy scales, their sub-scores, assessment time points, scoring criteria, assessment baselines and the improvement criteria are provided in Table 1.

The study sample size was calculated to ensure exposure of ≥300 patients for 6 months and ≥100 patients for 12 months to get the combined exposure data from core and extension studies in accordance with the International Conference on Harmonisation (ICH) guidelines [28] to assess the long-term safety and efficacy of the treatment with MPH-LA.

The All Extension Patients (AEP) analysis set included all patients who had entered the open-label extension study and received at least one dose of MPH-LA. This analysis set was used for all efficacy and safety analyses (Table 2).

Safety analysis of AEP:

Efficacy in AEP (for 12 months and 6 months) was evaluated based on:

For both safety and efficacy parameters, data were summarised using descriptive statistics (n, mean, standard deviation, minimum, median, maximum) for continuous variables and using contingency tables (n, %) for discrete variables.

Patient disposition for the core study was described in the core study manuscript [22]. Overall, 298 patients aged 18–60 years with ADHD who had either completed the core study or discontinued from the maintenance of effect phase of the core study (due to lack of therapeutic effect) entered the extension study. Of these, 262 (87.9 %) completed the extension study and 36 (12.1 %) discontinued from the study. The most common reasons for discontinuation were withdrawal of consent by the subjects (3.7 %, n = 11) followed by discontinuation due to AEs (2.7 %, n = 8) (Fig. 2).

Demographics and baseline characteristics are represented based on treatment (MPH-LA or placebo) received during the maintenance of effect phase and were similar for both MPH-LA and placebo patients (Table 3). Among the patients enrolled in the extension study, 160 (53.7 %) were males, and the mean age in the study was 36.3 ± 11.40 years. Most of the patients (n = 272, 91.3 %) were Caucasians.

Of the 298 patients in the extension study, 85 received a mean daily dose of MPH-LA ≤40 mg; 104 patients received >40–60 mg, and 109 patients received >60 mg during the extension study. The overall mean duration of exposure for MPH-LA was 170.5 days in the AEP group, and the mean duration of exposure to the MPH-LA was 155.2, 172.9, and 180.0 days for the ≤40 mg, >40–60 mg, and >60 mg mean daily dose groups, respectively. A total of 125 patients were treated with MPH-LA continuously for the entire duration of 12 months (maintenance of effect phase and extension phase). A total of 136 patients were continuously exposed to MPH-LA for the duration of >365 days, and 354 patients were continuously exposed to MPH-LA for the duration of >180 days throughout the entire core and extension study. The continuous exposure to MPH-LA was compliant with the ICH guidelines [28] to assess the long-term safety and efficacy of treatment with MPH-LA.

Overall incidence of AEs from the maintenance of effect phase baseline of the core study to end of extension study was 80.5 % (n = 240) in the AEP set. AEs described here are based on treatment (placebo or MPH-LA) received in the maintenance of effect phase. Overall, the incidence of AEs was comparable between patients receiving placebo (79.3 %, n = 65) and those receiving MPH-LA (81.0 %, n = 175) during the maintenance of effect phase of the core study. Incidence of nasopharyngitis, nausea, upper respiratory tract infection and fatigue was higher (≥5 %) in patients receiving MPH-LA, while the incidence of headache, decreased appetite, dry mouth, diarrhoea, back pain, anxiety, gastroenteritis, oropharyngeal pain, influenza and tachycardia was higher (≥5 %) in patients receiving placebo. SAEs were observed only in about 0.7 % (n = 2) of AEPs from the maintenance of effect phase baseline to the end of the extension study. Both SAEs were observed in the MPH-LA group. One patient reported exostosis of moderate severity on extension day 146, and another patient reported pancreatitis and non-Hodgkin’s lymphoma (pre-existing before enrolment into this study) (Table 4). Neither of these SAEs was suspected to be related to the study medication. No clinically significant observations were noted in haematological or clinical chemistry parameters in the extension study. A single patient reported clinically notable low systolic blood pressure, and five patients (1.7 %) reported clinically notable changes in diastolic blood pressure (four patients with high, one patient with low). Six patients (2.0 %) were reported to have a notable change in heart rate (three patients each with a high and a low rate). Clinically notable changes in weight were recorded in 29 (9.9 %) patients in the AEP. None of the patients had a QT, QTcB or QTcF ≥500 ms. There were minor changes from maintenance of effect baseline in the mean QTc intervals (0.7 ms for QTcB and 1.2 ms for QTcF) in the AEP. There were no clinically meaningful dose-related differences observed between the MPH-LA mean daily doses.

The overall incidence of AEs occurring in the extension study was 69.8 % (n = 208). Incidence of AEs was comparable between MPH-LA mean daily dosage groups (69.4 %, n = 59; 75.0 %, n = 78; and 65.1 %, n = 71 in the ≤40, >40–60 and >60 mg dosage groups, respectively). The most common AE was nasopharyngitis, with an overall incidence of 19.1 % (n = 57). Incidence of nasopharyngitis was higher in the >40–60 mg group (27.9 %) compared with that in the ≤40 and >60 mg groups (17.6 % and 11.9 %, respectively). Headache, decreased appetite, dry mouth and nausea were the other AEs reported, with a frequency of more than 5 % among all patients. No deaths were reported in the study. Two patients receiving a dosage of >60 mg/day reported SAEs; one patient reported exostosis, and the other patient reported pancreatitis and non-Hodgkin’s lymphoma. The exostosis reported was of moderate severity, and the patient recovered with non-drug therapy and continued the study. The patient with pancreatitis and non-Hodgkin’s lymphoma received concomitant medication, with temporary discontinuation of the study drug, and then completed the study. Neither of the SAEs was suspected to be related to the study drug (Table 5).

The mean improvement in total score of DSM-IV ADHD RS from the maintenance of effect phase baseline to the end of the extension study was 0.9 (Fig. 3). The mean improvement in SDS total score from the maintenance of effect phase baseline to the end of the extension study was 1.4 (Fig. 3). A total of 91 (31.4 %) patients showed improvement in CGI-S score from the maintenance of effect phase baseline to the end of the extension study (MPH-LA, 68 (32.1 %); Placebo, 23 (29.5 %)).

The mean improvement in total score of DSM-IV ADHD RS and SDS from extension baseline to the end of the study was 7.2 and 4.8, respectively (Fig. 4). Overall, 206 (69.4 %) patients showed improvement in CGI-I rating (MPH-LA, 141 (65.3 %); Placebo, 65 (80.2 %)), and 151 (52.1 %) patients showed improvement in CGI-S scale (MPH-LA, 91 (42.9 %); Placebo, 60 (76.9 %)) from the extension study baseline to the end of the extension study.