Online Resources

A cost-utility analysis of lisdexamfetamineversus atomoxetinein the treatment of children and adolescents with inadequate response to methylphenidate

CNS Drugs

Evelina A. Zimovetz,1* Stephen M. Beard,2†‡ Paul Hodgkins,3†$ Matthias Bischof,4† Josephine A. Mauskopf,5† Juliana Setyawan3†$

Corresponding author’s contact details:

EvelinaZimovetz

Associate Director, Market Access and Outcomes Strategy

RTI Health Solutions

2nd Floor, The Pavilion, Towers Business Park

Wilmslow Road, Didsbury

Manchester, M20 2LS, United Kingdom

E-mail:

Online Resource 1. Systematic literature reviewmethods

Objective

Systematically review and synthesise the clinical evidence of treatments for attention deficit hyperactivity disorder (ADHD) by indirectly comparing established treatments with a drug recently approved in Europe (lisdexamfetamine [LDX]).

Research design and methods

Population: children and adolescents. Setting: Europe. Comparators: methylphenidate (MPH), atomoxetine (ATX), and dexamphetamine (DEX). Electronic databases and relevant conference proceedings were searched for randomised, controlled clinical trials evaluating efficacy and safety of at least one of the comparators or treatment of interest. Quality assessments for each included trial were performed using criteria recommended by the Centre for Reviews and Dissemination. The available evidence consisted of placebo- and active-controlled trials including three-arm trials; therefore, a network meta-analysis (NMA) or mixed-treatment comparison (MTC) methods were used to robustly and simultaneously combine direct and indirect treatment comparison estimates across studies.NMA play an important role by enabling indirect treatment comparisons for treatments that have not been compared directly within a trial. MTC methods for dichotomous outcomes were employed to evaluate treatment efficacy (see Online Resource 2).The MTC focusedon how the treatment of interest, LDX, compares with other active treatment options, in terms of both efficacy and safety.

Main outcome measures

Response, as defined by either a reduction from baseline of at least 25% in the ADHD Rating Scale (ADHD-RS) total score or, separately, as assessed on the Clinical Global Impression–Improvement (CGI-I) scale (response defined as proportion of patients with CGI-I value of 1 [very much improved] or 2 [much improved] out of all patients included), and safety (all-cause withdrawals and withdrawal due to adverse events).

Results

The systematic review found 32 trials for the meta-analysis, including data on LDX, ATX, and different formulations of MPH. No trials for DEX meeting the inclusion criteria were found. Sufficient data were identified for each outcome: ADHD-RS, 16 trials; CGI-I, 20 trials; all-cause withdrawals, 28 trials; and withdrawals due to adverse events, 27 trials. The relative probability of treatment response for CGI-I (95% confidence intervals [CI]) for ATX versus LDX was 0.65 (0.53-0.78); for long acting MPH versus LDX, 0.82 (0.69-0.97); for intermediate release MPH versus LDX, 0.51 (0.40-0.65); and for short-acting MPH versus LDX, 0.62 (0.51-0.76). The relative probabilities of ADHD-RS treatment response also favoured LDX.

Conclusions

This research systematically collated and synthesised the currently available evidence, yielding our conclusion that LDX is an efficacious treatment option available for physicians in prescribing treatments for children and adolescents with ADHD.

Online Resource2. Mixed-treatment comparison method

Mixed-treatment comparison methods for dichotomous outcomes

The data from dichotomous endpoints (i.e., response and nonresponse) that followed a binomial distribution were analyzed according to the methods described herein. A mixed log-binomial model was fit for each dichotomous endpoint. A generic version of this type of model, where i indicates the study and j indicates the treatment, can be written as follows:

whereyij and nij are the number of patients with the response and the total number of patients, respectively, in study i and on treatment j. We assumed the following:

  • tj represents the logarithm of overall event probability for treatment j when xij=0.
  • si represents fixed effects following a normal distribution (mean zero and unknown variance) that estimate the study effect. This study effect can be considered to be the within-study baseline treatment effect, thus retaining the information on the treatment comparisons from within each trial where the treatments were randomized.
  • vij represents random effects following a normal distribution (mean zero and unknown variance) that allow the treatment effects to vary from study to study.
  • xij represents a covariate (or covariate matrix if more than one) common to all patients in study i and on treatment j (e.g., mean age within the treatment group).

Therefore, it follows that the relative risk of treatment a versus treatment b is

wherepa is the estimated probability (“risk”) of response for treatment a and pb is the estimated probability (“risk”) of response for treatment b.

The indicative PROC GLIMMIX code suitable for dichotomous mixed-treatment comparisons is given in Online Resource Figure 1. (Note: r=number of patients with the endpoint and n=total number of patients in that study or treatment arm.) The code can easily be extended to include more covariates if the data merit such inclusion.

The initial data step in the SAS code (SAS Institute; Cary, North Carolina) in Online Resource Figure 1 is used to constrain to zero the sum of the random effects within a study. In this code, narm is the number of treatment arms within the study and index is the order of the treatment arm within the study (e.g., 1, 2, …narm). This code can be easily extended if the maximum number of treatments within any study is greater than three.

[Online Resource FIGURE 1 HERE]

Online Resource Figure 1. SAS code for the mixed-treatment comparisonmodel for dichotomous outcomes: fixed study effect and random treatment-by-study interaction

data outcome_data2;
set outcome_data;
array x[3] x1-x3;
do i=1 to 3;
if i<=narm then x[i]=sqrt(0.5)*((i=index)-1/narm);
else x[i]=0;
end;
run;
procglimmix data=outcome_data2 method=QUAD;
class trt study;
model r/n=trt study xcovar / dist=bin link=log;
solution cl ddfm=none;
random X1 X2 X3 / subject=study solution type=TOEP(1);
lsmeanstrt / cl diff;
run;

Online Resource 3. Search Terms and Results

MEDLINE Search Strategy and Results

Term Group / Search Number / Search Terms / Returns
Population / #1 / “Attention Deficit Disorder with Hyperactivity”[MeSH] OR “attention deficit hyperactivity disorder”[Text Word] OR attention deficit disorder*[Text Word] OR “attention-deficit hyperactivity disorder”[Text Word] OR “adhd”[Text word] OR “ad hd”[Text Word] OR “addh”[Text word] OR “ADD”[Text word] OR “hyperkinetic disorder”[Text word] OR (“Attention deficit”[Text Word] AND disruptive behavior*[Text Word]) OR (“Attention deficit”[Text Word] AND disruptive behavior*[Text Word]) OR hyperactiv*[Title] OR disruptiv*[Title] OR impulsiv*[Title] OR inattentiv*[Title] OR inattention*[Title] OR hyperkin*[Title] OR hyper kin*[Title] OR “hkd”[Title] OR “minimal brain dysfunction”[Title] OR “hyperkinetic syndrome”[Text Word] OR attention deficit*[Text Word] OR “attention disturbance”[Text Word] OR “disruptive behavior”[Text Word] OR (overactive[Text word] NOT “overactive bladder”[Text Word]) / 59204
#2 / adolescen*[Title] OR child*[Title] OR “class”[Text Word] OR classroom*[Text Word] OR youngster*[Text Word] OR girl*[Text Word] OR boy*[Text Word] OR school*[Text Word] OR paediatric*[Text Word] OR pediatric*[Text Word] OR student*[Text Word] / 1300617
#3 / #1 AND #2 / 15543
Interventions / #4 / “Drug Therapy”[MeSH] OR “drug therapy”[Subheading] / 1933668
Clinical trials / #5 / “Controlled Clinical Trial”[Publication Type] OR “Randomized Controlled Trials as Topic”[MeSH] OR “Randomized Controlled Trial”[Publication Type] OR “Clinical Trials as Topic”[MeSH:NoExp] OR “randomized”[Title/Abstract] OR randomly[Title/Abstract] OR “Cross-Over Studies”[MeSH] OR “Double-Blind Method”[MeSH] OR “Single-Blind Method”[MeSH] OR “Random Allocation”[MeSH] OR randomized controlled trial*[Text Word] OR randomised controlled trial*[Text Word] OR randomized clinical trial*[Text Word] OR randomised clinical trial*[Text Word] OR randomized trial*[Text Word] OR randomised trial*[Text Word] OR “Clinical Trial, Phase II”[Publication Type] OR “Clinical Trial, Phase III”[Publication Type] OR “Clinical Trial, Phase IV”[Publication Type] / 788122
Other clinical studies (prospective studies) / #6 / “Cohort Studies”[MeSH] OR cohort*[Title] OR “longitudinal”[Title] OR “Follow-Up Studies”[MeSH] OR evaluation stud*[Title] OR “Prospective Studies”[MeSH] / 1089595
All clinical studies / #7 / #3 AND #4 AND #5 / 1127
All other prospective studies / #8 / #3 AND #4 AND #6 / 540
Exclusion terms: exclude animals / #9 / “Animals”[MeSH] NOT “Humans”[MeSH] / 3556354
Exclusion terms: study type / #10 / (“Comment”[Publication Type] OR “Letter”[Publication Type] OR “Editorial”[Publication Type] OR “Case Reports”[Publication Type] OR “Clinical Trial, Phase I”[Publication Type] OR “case study”[Title] OR “case studies”[Title] OR “case report”[Title] OR “case reports”[Title] OR “case series”[Title] OR “Review Literature as Topic”[MeSH] OR “Review”[Publication Type]) NOT (“Meta-Analysis”[Publication Type] OR “Meta-Analysis as Topic”[MeSH] OR “systematic review”[Title] OR “systematic literature review”[Title] OR “meta-analysis”[Text Word] OR “meta analysis”[Text Word]) / 3953799
All clinical studies / #11 / #7 NOT (#9 OR #10) / 981
All other prospective studies / #12 / #8 NOT (#9 OR #10) / 493
All Studies / #13 / #11 OR #12 / 1347
#14 / #13 Limited to English language publications / 1288

MeSH=Medical Subject Heading (MEDLINE medical index term).

Note: the asterisk (*) stands for any character(s).

The Cochrane Library Search Strategy and Results

Search Number / Search Terms / Returns
#1 / “attention deficit*” OR adhd OR “ad hd” OR addh OR “hyperkinetic disorder” OR “hyperkinetic syndrome” OR “attention disturbance” OR “disruptive behavior” or (hyperactiv* OR disruptiv* OR impulsiv* OR inattentiv* OR inattention*OR hyperkin* OR hyper kin* OR hkd OR “minimal brain dysfunction” OR ADD):ti / 4510
#2 / (overactive) not “overactive bladder” / 75
#3 / (#1 OR #2) / 4576
#4 / (adolescen* OR child*):ti / 2589
#5 / class OR classroom* OR youngster* OR girl* OR boy* OR school* OR paediatric* OR pediatric* OR student* / 102043
#6 / (#3 AND (#4 OR #5)) / 2116
#7 / MeSH descriptor Drug Therapy explode all trees / 103094
#8 / Any MeSH descriptor with qualifier: DT / 149787
#9 / #9 (#6 AND (#7 OR #8)) / 1026
#10 / “Controlled Clinical Trial” OR “Randomized Controlled Trial” OR “Clinical Trial, Phase II” OR “Clinical Trial, Phase III” OR “ OR randomly):ti or (randomized OR randomly):ab or “randomized controlled trial” Clinical Trial, Phase IV” OR “phase 2 clinical trial” OR “phase 3 clinical trial” OR “phase 4 clinical trial”:pt or (randomized OR “randomised controlled trial” OR “randomized clinical trial” OR “randomised clinical trial” OR “randomized trial” OR “randomised trial” OR “randomized controlled trials” OR “randomised controlled trials” OR “randomized clinical trials” OR “randomised clinical trials” OR “randomized trials” OR “randomised trials” / 468677
#11 / MeSH descriptor Randomized Controlled Trials as Topic explode all trees / 15324
#12 / MeSH descriptor Clinical Trials as Topic, this term only / 34387
#13 / MeSH descriptor Cross-Over Studies explode all trees / 21664
#14 / MeSH descriptor Double-Blind Method explode all trees / 93163
#15 / MeSH descriptor Single-Blind Method explode all trees / 9797
#16 / MeSH descriptor Random Allocation explode all trees / 20404
#17 / (#10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16) / 469801
#18 / MeSH descriptor Cohort Studies explode all trees / 96821
#19 / MeSH descriptor Follow-Up Studies explode all trees / 35619
#20 / MeSH descriptor Prospective Studies explode all trees / 58509
#21 / (cohort* OR longitudinal OR “evaluation study” OR “evaluation studies”):ti / 2226
#22 / (#18 OR #19 OR #20 OR #21) / 97868
#23 / (#9 AND (#17 OR #22)) / 1007
#24 / (Comment OR Letter OR Editorial OR “Case Reports” OR “Clinical Trial, Phase I” OR “clinical trial phase 1” OR review):pt or “case study” OR “case studies” OR “case report” OR “case reports” OR “case series”:ti or (review):kw / 21301
#25 / “systematic review” OR “systematic literature review”:ti / 7927
#26 / “Meta-Analysis”:ti,ab,kw / 10121
#27 / (#24 AND NOT (#25 OR #26)) / 19063
#28 / (#23 AND NOT #27) / 993
Cochrane Reviews – 35 (33 imported)
Other Reviews – 20 (19 imported)
Clinical Trials – 929 (245 imported)
Technology Assessments – 1 (0 imported)
Economic Evaluations - 8 (4 imported)

MeSH=Medical Subject Heading (MEDLINE medical index term); pt=publication type; ti=title; DT=drug therapy. Note: the asterisk (*) stands for any character(s).

EMBASE Search Strategy and Results

Search Number / Search Terms / Returns
S1 / ATTENTION()DEFICIT()DISORDER/MAJ OR ATTENTION()DEFICIT()HYPERACTIVITY()DISORDER OR ATTENTION()DEFICIT()DISORDER? OR ADHDOR AD()HD OR ADDH OR HYPERKINETIC()DISORDER OR (ATTENTION()DEFICIT AND DISRUPTIVE()BEHAVIOR?) OR (ATTENTION()DEFICIT AND DISRUPTIVE()BEHAV?) OR HYPERACTIV?/TI OR DISRUPTIV?/TI OR IMPULSIV?/TI OR INATTENTIV?/TI OR INATTENTION?/TI OR HYPERKIN?/TI OR HYPER()KIN?/TI OR HKD/TI OR MINIMAL()BRAIN()DYSFUNCTION/TI OR HYPERKINETIC()SYNDROME OR ATTENTION()DEFICIT? OR ATTENTION()DISTURBANCE OR DISRUPTIVE()BEHAVIOUR OR (OVERACTIVE NOT OVERACTIVE()BLADDER) / 39184
S2 / ADOLESCEN?/TI OR CHILD?/TI OR CLASS OR CLASSROOM? OR YOUNGSTER? OR GIRL? OR BOY? OR SCHOOL? OR PAEDIATRIC? OR PEDIATRIC? OR STUDENT? / 2053753
S3 / S1 AND S2 / 18959
S4 / DRUG THERAPY! OR ATTENTION()DEFICIT()DISORDER/MAJ(L)DRUG()THERAPY / 3451455
S5 / CONTROLLED CLINICAL TRIAL! OR RANDOMIZED()CONTROLLED()TRIAL/DE OR CLINICAL()TRIAL/DE OR RANDOMIZED/TI,AB OR RANDOMLY/TI,AB OR CROSSOVER()PROCEDURE/DE OR DOUBLE()BLIND()PROCEDURE/DE OR SINGLE()BLIND()PROCEDURE/DE OR RANDOMIZATION/DE OR RANDOMIZED()CONTROLLED()TRIAL? OR RANDOMISED()CONTROLLED()TRIAL? OR RANDOMIZED()CLINICAL()TRIAL? OR RANDOMISED()CLINICAL()TRIAL? OR RANDOMIZED()TRIAL? OR RANDOMISED()TRIAL? OR PHASE()2()CLINICAL()TRIAL/DE OR PHASE()3()CLINICAL()TRIAL/DE OR PHASE()4()CLINICAL()TRIAL/DE / 1113908
S6 / COHORT()ANALYSIS/DE OR COHORT?/TI OR LONGITUDINAL/TI OR FOLLOW()UP/DE OR EVALUATION()STUD?/TI OR PROSPECTIVE()STUDY/DE / 716635
S7 / S3 AND S4 AND (S5 OR S6) / 2259
S8 / S7/HUMAN / 2233
S9 / (COMMENT?/TI OR DT=LETTER OR DT=EDITORIAL OR CASE()REPORT/DE OR CASE()STUDY/DE OR PHASE()1()CLINICAL()TRIAL/DE OR CASE()STUDY/TI OR CASE()STUDIES/TI OR CASE()REPORT/TI OR CASE()REPORTS/TI OR CASE()SERIES/TI OR DT=REVIEW) NOT (META()ANALYSIS/DE OR SYSTEMATIC()REVIEW/TI,DE OR SYSTEMATIC()LITERATURE()REVIEW/TI OR META()ANALYSIS) / 4478402
S10 / S8 NOT S9 / 1575
S11 / S10 AND LA=ENGLISH / 1482
S12 / RD S12 (unique items) / 1436

DE=descriptor; DT=document type; TI=title.

Symbols: “!” means to “explode” a descriptor; “?” is a wildcard symbol for plural forms.