An Open Study of Adjunct OROS-Methylphenidate in Children and Adolescents Who Are Atomoxetine Partial Responders: I. Effectiveness

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Of the 50 subjects entered into phase II, 41 completed the protocol; 8 had adverse events and 1 dropped because of a physical illness unrelated to medication.

“Of the 50 subjects entered into phase II, 41 subjects completed the protocol (8 subjects had adverse events and 1 subject dropped because of a physical illness unrelated to medication).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In all, 82 subjects were exposed to ATMX and 50 were exposed to the combination of ATMX and OROS MPH.

“In all, 82 subjects were exposed to ATMX and 50 were exposed to the combination of ATMX and OROS MPH.”

May combine two claims.

Fifty subjects who were partial responders to ATMX were treated with adjunct OROS MPH, and 41 completed the entire protocol.

“Fifty subjects who were partial responders to ATMX were treated with the combination therapy, with 41 subjects completing the entire protocol.”

• Also stated in: § Results · plain

  “In all, 82 subjects were exposed to ATMX and 50 were exposed to the combination of ATMX and OROS MPH.”

• Also stated in: § Results · plain

  “Of the 50 subjects entered into phase II, 41 subjects completed the protocol (8 subjects had adverse events and 1 subject dropped because of a physical illness unrelated to medication).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Of the 50 subjects entered into phase II, 40 started at baseline and 10 were already on ATMX and entered directly into phase II.

“Of the 50 subjects enrolled into phase II, 40 started at baseline, whereas 10 were already on ATMX and entered directly into the beginning of phase II (Fig. 1).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The mean weight-corrected doses of ATMX at the beginning and end of phase II was 1.1 mg/kg per day and for OROS MPH was 1.0 mg/kg per day.

“The mean weight-corrected doses of ATMX at the beginning and end of phase II was 1.1 mg = kg per day and for OROS MPH was 1.0mg = kg per day.”

May combine two claims.

Medical compliance was assessed by pill counts at each follow-up visit and was >80% for all subjects.

“Medical compliance was assessed by pill counts at each follow-up visit and was > 80% for all subjects.”

Probably not a substantial claim: may not pass S3 (load-bearing).

All analyses were intent to treat (at least one dose of OROS MPH) with last observation carried forward.

“All analyses were intent to treat, with last observation carried forward.”

• Also stated in: § Statistical analysis · plain

  “In these 50 subjects, all analyses were intent to treat (at least one dose of OROS MPH) with last observation carried forward.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Using conservative estimates (effect size 0.5 versus baseline; dropout rate 15%; 80% power; 0.05 significance), a total number of 40 children would be necessary for the study.

“Using conservative estimates (effect size of 0.5 versus baseline; dropout rate of 15%; 80% power; 0.05 level of significance), we calculated that a total number of 40 children would be necessary for our study.”

Classified as probably not a substantial claim. May combine two claims.

The study was an open-label 4-week treatment of ATMX with partial ADHD responders completing a subsequent 3-week study of adjunct OROS MPH.

“The study was an open 4-week treatment of ATMX with partial ADHD responders completing a subsequent 3-week study of adjunct OROS MPH.”

Probably not a substantial claim: may not pass S3 (load-bearing).

All diagnostic assessments were made using DSM-IV based structured interviews by raters with bachelor's or master's degrees in psychology who had been extensively trained and supervised by the senior investigators.

“All diagnostic assessments were made using Diagnostic and Statistical Manual of Mental Disorder , 4 th edition (DSM-IV)based (American Psychiatric Association 1994) structured interviews by raters with bachelor's or master's degrees in psychology who had been extensively trained and supervised by the senior investigators (T.W., J.B.).”

Probably not a substantial claim: may not pass S3 (load-bearing).

The reported effect size of ATMX in children and adolescents is between 0.6 and 0.7.

“and the reported effect size in children and adolescents is between 0.6 and 0.7 (Faraone et al. 2004)”

• cites Faraone et al. 2004Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The relatively small sample size may have underestimated the findings.

“The relatively small sample size may have underestimated our findings.”

May combine two claims.

In addition to improved co-morbid conditions, improved cognition and complex problem solving were reported with combined regimens.

“Moreover, in addition to improved co-morbid conditions (e.g., tics), improved cognition and complex problem solving were reported (Pataki et al. 1993; Kurlan 2002).”

• cites Pataki et al. 1993Not checked yet

  Not checked in the free run.

• cites Kurlan 2002Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Approximately one half to two thirds of children and adolescents with ADHD respond favorably to ATMX.

“Similarly, approximately one half to two thirds of children and adolescents with ADHD respond favorably to ATMX (Michelson et al. 2002)”

• cites Michelson et al. 2002Not checked yet

  Not checked in the free run.

May combine two claims.

A lack of normalization of ADHD symptoms was associated with academic failure, interpersonal and family dysfunction, and general social dysfunction.

“Also, a lack of normalization of ADHD symptoms was associated with academic failure, interpersonal and family dysfunction, and general social dysfunction (Biederman et al. 1998).”

• cites Biederman et al. 1998Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

The current study lacked a MPH-only comparator.

“Our current study lacked a MPH-only comparator.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Only 38 subjects completed the BRIEF (mean age 9.4 2.7).

“Only 38 subjects completed the BRIEF (mean age 9.4 2.7).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The BRIEF is a reliable and valid behavior rating scale of EF in children and adolescents.

“The BRIEF is a reliable and valid behavior rating scale of EF in children and adolescents (Gioia et al. 2000; Gioia et al. 2002; Mahone et al. 2002; Vriezen et al. 2002).”

• cites Gioia et al. 2000Not checked yet

  Not checked in the free run.

• cites Gioia et al. 2002Not checked yet

  Not checked in the free run.

• cites Mahone et al. 2002Not checked yet

  Not checked in the free run.

May combine two claims.

The ADHD Rating Scale has established psychometric properties in children and is sensitive to stimulant and atomoxetine drug effects.

“Psychometric properties have been established in children shown to be sensitive to stimulant and atomoxetine drug effects (DuPaul 1990; DuPaul et al. 1998; Faries et al. 2001) and have been used in clinical trials to demonstrate efficacy for ADHD.”

• cites DuPaul 1990Not checked yet

  Not checked in the free run.

• cites DuPaul et al. 1998Not checked yet

  Not checked in the free run.

• cites Faries et al. 2001Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

One small case series in 4 subjects reported a favorable outcome with combined stimulant and ATMX.

“One small case series in 4 subjects reported a favorable outcome (Brown 2004).”

• cites Brown 2004Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The definition of ATMX partial responders has not been validated.

“However, our definition of ATMX partial responders has not been validated.”

Probably not a substantial claim: may not pass S3 (load-bearing).

An unblinded investigator assessed the ADHD RS IV.

“An unblinded investigator assessed the ADHD RS IV.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Psychiatric assessments for subjects under 18 relied on the DSM-IV Kiddie Schedule for Affective Disorders-Epidemiologic Version (KSADS-E) and were based on independent interviews with the primary caregivers.

“Psychiatric assessments for subjects under 18 years old relied on the DSM-IV Kiddie Schedule for Affective Disorders-Epidemiologic Version (KSADS-E) (Ambrosini 2000) and were based on independent interviews with the primary caregivers.”

• cites Ambrosini 2000Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The CGI Ratings are a widely used scale that measures overall severity and improvement.

“As a secondary outcome, we also collected the CGI Ratings (National Institute of Mental Health 1985), a widely used scale that measures the overall severity and improvement.”

• cites National Institute of Mental Health 1985Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Up to one third of prescriptions of ATMX in the United States are in combination with a stimulant.

“For example, chart reviews and use data suggest that up to one third of prescriptions of ATMX in the United States are in combination with a stimulant (IMS Health data) (Adler et al. 2006).”

• cites Adler et al. 2006Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The BRIEF test-retest correlations were at least 0.8 for the indexes, and T scores were stable over 2- to 3-week intervals, supporting that repeating the BRIEF would have no significant variability expected due to the instrument itself.

“The test-retest correlations were at least 0.8 for the indexes. The T scores on test-retest were also carried out and indicated the stability of the T scores over 2- to 3week intervals, supporting the notion that repeating the BRIEF would have no significant variability expected due to the instrument itself (Gioia et al. 2000).”

• cites Gioia et al. 2000Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Because the study was open in nature, there may have been bias in the observations of outcome.

“Because the study was open in nature, there may have been bias in our observations of outcome.”

May combine two claims.

In a prior pilot study (Carlson et al. 2007), 25 children who did not respond to stimulants were titrated on ATMX for 4 weeks, then randomized to ATMX + OROS MPH (n=9) or placebo (n=12) for 6 weeks, with no significant differences between groups.

“In 25 children who did not respond to stimulants, ATMX was titrated to full dose for 4 weeks, at which point subjects not to be considered ''responders'' were randomized to receive ATMX þ OROS MPH ( n ¼ 9) or placebo ( n ¼ 12) for an additional 6 weeks, resulting in no significant differences between groups.”

• cites Carlson et al. 2007Not checked yet

  Not checked in the free run.

May combine two claims.

The small sample size receiving ATMX + OROS MPH and preselection of subjects who were resistant to previous stimulant trials and retested on MPH limits the findings of the Carlson et al. pilot study.

“While helpful, the small sample size receiving ATMX þ OROSMPH and preselection of subjects who were resistant to previous stimulant trials and retested on MPH limits the findings.”

Classified as probably not a substantial claim.

These mechanistic differences may account for the observed improvements in clinical aspects of EF on the BRIEF.

“These mechanistic differences may account for our observed improvements in clinical aspects of EF on the BRIEF.”

May combine two claims.

Despite limitations, this study is clinically relevant because in patients with some improvement in symptoms and functional impairment on ATMX, OROS MPH appears to add to the overall outcome of ADHD.

“Despite these limitations, this study is clinically relevant because in patients with some improvement in symptoms and functional impairment on ATMX, OROS MPH appears to add to the overall outcome of ADHD.”

Classified as probably not a substantial claim. May combine two claims.

All analyses were intent to treat with last observation carried forward.

“All analyses were intent to treat with last observation carried forward.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

For subjects entering phase I, the minimum of 4 weeks on ATMX may have been inadequate.

“For subjects entering into phase I, we relied on a minimum of 4 weeks on ATMX that may have been inadequate.”

Probably not a substantial claim: may not pass S3 (load-bearing).

For measurement of executive functioning, the study relied on self-report of children and adolescents with assistance of parents and caregivers on the BRIEF, instead of repeated neuropsychological testing.

“For measurement of executive functioning, we relied on the self-report of children and adolescents with the assistance of their parents and caregivers on a clinical scale of executive functioning, the BRIEF, instead of repeated neuropsychological testing.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Information on the duration of treatment prior to entrance into the study was not collected.

“We also did not collect information on the duration of treatment prior to entrance into the study.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Including subjects who entered directly into phase II who were already on ATMX for clinical reasons and manifested a partial response may have confounded the results.

“We also included subjects who entered directly into phase II who were already on ATMX for clinical reasons and manifested a partial response, which may have confounded our results.”