The randomized clinical trial by McElroy et al. «McElroy SL, Hudson JI, Mitchell JE, ym. Efficacy a...»1 examined the efficacy and safety of lisdexamfetamine dimesylate to treat moderate to severe BED. Participants included adults (8-55 years) with DSM-IV-TR BED, and with BMI of 25-45. The diagnosis was confirmed using the the Structural Clinical Interview for DSM-IV-TR and the Eating Disorder Examination Questionnaire.
Exclusion criteria included current bulimia nervosa, anorexia nervosa, ADHD, or another psychiatric disorder; a lifetime history of bipolar disorder or psychosis or other conditions that may confound efficacy and safety assessments; a total Montgomery-Åsberg Depression Rating Scale (MADRS) score of at least 18; psychological or weight-loss interventions initiated within 3 months of screening; use of a psychostimulant within the prior 6 months; and a personal or family history of cardiovascular disease that could increase vulnerability to the sympathomimetic effects of psychostimulants. Anyone with a recent history of suspected substance abuse or a lifetime history of psychostimulant abuse and/or dependence were excluded. Prior (within the past 30 days) or current therapy with investigational compounds, sedatives, anxiolytics, antipsychotics, antidepressants, norepinephrine reuptake inhibitors, sedative hypnotics, benzodiazepines, antihistamines (centrally and peripherally acting), herbal preparations, over-the-counter medications, and weight-reducing agents and prior (within the past 60 days) or current therapy with psychostimulants was prohibited.
Initially, 495 individuals were screened, and 260 randomized; 196 were randomized to lisdexamfetamine dimesylate treatment groups: 66 to 30-mg/d group, 65 to 50-mg/d group, and 65 to 70-mg/d group. Of 495 screened individuals, 235 were excluded: 89 did not meet inclusion criteria, 146 had other reasons. Of 260 enrolled participants, 255 were included in the efficacy analyses (intention-to-treat) and 259 in the safety analyses (intention-to-treat).
58 participants did not complete the study (17 in the placebo group: 15 in the 30-mg/d treatment group and 13 each in the 50-mg/d and 70-mg/d treatment groups). Seven participants withdrew because of Treatment Emergent Adverse Events (TEAEs, all in the treatment groups) and none for lack of efficacy.
Participants were randomized (1:1:1:1) to receive placebo or 30, 50, or 70 mg/d of lisdexamfetamine dimesylate (treatment groups) using an interactive voice-response system/ interactive web-response system. Of the 260 enrolled participants, 64 were randomized to placebo group.
The study blind was maintained by overencapsulation, and making placebo and active treatments appear identical. The 3-week titration period was followed by an 8-week dose-maintenance period. Once-daily oral doses for participants assigned to 30-, 50-, or 70-mg/d treatment groups were initiated at the 30-mg/d dosage and titrated weekly in increments of 20 mg/d to the assigned dosage. Dosage changes and reductions were not permitted during the maintenance period; participants could discontinue treatment if they experienced intolerance.
The primary efficacy measure was the number of binge eating days per week based on clinician interview and binge eating episodes in self-reported binge eating diaries. The primary efficacy end point was the change from baseline to week 11 on the log-transformed scale (binge eating days per week) + 1.
Safety assessments included treatment-emergent adverse events (TEAEs), the Columbia–Suicide Severity Rating Scale, vital signs, electrocardiography, weight, and laboratory test results (biochemistry, hematologic analysis, and urinalysis).
At baseline, the mean (SD) binge eating days per week for the placebo and the 30-, 50-, and 70-mg/d treatment groups were 4.3 (1.4), 4.5 (1.4), 4.5 (1.3), and 4.6 (1.3), respectively. The mean (SD) changes from baseline to week 11 or early termination in nontransformed binge eating days per week for the placebo and the 30-, 50-, and 70-mg/d treatment groups were −3.3 (2.04), −3.5 (1.95), −4.1 (1.52), and −4.1 (1.57), respectively. The primary efficacy end point from baseline to week 11 (binge eating days per week) was significantly decreased in the 50- and 70-mg/d treatment groups but not in the 30-mg/d treatment group compared with the placebo group.
At baseline, the mean (SD) binge eating episodes per week were for the placebo and the 30-, 50-, and 70-mg/d treatment groups were 5.2 (2.1), 5.8 (3.0), 5.6 (2.8), and 5.6 (2.4), respectively. The mean change from baseline to week 11 binge eating episodes per week was significantly decreased for the 50- and 70-mg/d treatment groups. At week 11 or early termination, the 1-week response status was improved in the 50- and 70-mg/d treatment groups compared with the placebo group, and the 4-week binge eating cessation response status was improved in the 50- and 70-mg/d treatment groups compared with the placebo group.
Greater proportions of participants receiving lisdexamfetaminewere rated improved (CGI-I rating, 1 or 2) compared with those receiving placebo at week 11 or early termination. The mean total scores for YBOCS-BE improved in all treatment groups compared with the placebo group at week 11. At baseline, mean Binge Eating Scale scores were in the severe range (≥27) and demonstrated greater improvement at week 11 in all the treatment groups compared with the placebo group. Baseline mean MADRS and Hamilton Anxiety Rating Scale symptom scores indicated that depression and anxiety symptoms were low across all groups; none of the changes in the mean scores for the MADRS and Hamilton Anxiety Rating Scale across the treatment groups were significantly different from those of the placebo group at week 11. In the placebo group, no discontinuations owing to TEAE, no serious TEAEs, and no deaths occurred. The percentages for experiencing any TEAEs were 58%, 86%, 86%, 82% for the placebo group, and the 30-, 50-, and 70-mg/d treatment groups. The most common TEAEs in the intervention groups were dry mouth, decreased appetite, insomnia, and headache. Among the 196 participants receiving lisdexamfetamine, 6 (3.1%) discontinued treatment owing to TEAEs and 3 (1.5%) had serious TEAEs. One participant (in the 70-mg/d treatment group) died because of toxicology findings consistent with a methamphetamine overdose. The study investigator did not consider this death to be related to the study drug. Two other serious TEAEs (acute pancreatitis and appendicitis) occurred in participants in the 30-mg/d treatment group and were considered unrelated to the study drug. No participant had suicidal ideation, thoughts, or attempts during treatment. Mean heart rate tended to increase from baseline to week 11 or early termination with lisdexamfetamine treatment. No comparable trends were observed with blood pressure. Also, no clinically meaningful trends were observed for clinical laboratory results or electrocardiography interval data.
Participants' mean weight in the treatment groups decreased with treatment; the placebo group experienced no mean weight change. The mean (SD) change in body weight was −0.1 (3.09), −3.1 (3.64), −4.9 (4.43), −4.9 (3.93), and −4.3 (4.09) kg for the placebo group; the 30-, 50-, and 70-mg/d treatment groups; and the combined treatment groups, respectively. In a post hoc analysis, the percentage of reduction in body weight was greater for all treatment groups compared with the placebo group at week 11 (P<0.001).
The another study by McElroy et al. «McElroy SL, Hudson J, Ferreira-Cornwell MC, ym. Li...»2 reported the efficacy, safety, and tolerability findings of lisdexamfetamine (LDX) in two pivotal phase 3 randomized controlled trials. Eligible participants were men or nonpregnant women (18–55 years). Participants were recruited from investigators' databases and via advertisements.
The studies implemented dual criteria for moderate to severe BED that were based on DSM-IV-TR criteria. These dual criteria designated moderate to severe BED as the presence of a binge eating frequency of ≥3 binge eating days/week for 2 consecutive weeks before baseline and a Clinical Global Impressions-Severity score at screening and baseline of ≥4. At screening and baseline, eligible participants had BMI of 18-45.
Most participants were white, female, and obese (BMI ⩾30.0 kg/m2). The overall proportion of individuals with comorbid psychiatric disorders was low, with the most common psychiatric disorder in each study being past major depressive disorder.
Key exclusion criteria included: current anorexia nervosa or bulimia nervosa; comorbid current psychiatric disorders either controlled with prohibited medications or uncontrolled and associated with significant symptoms or any condition/symptom that may confound clinical assessment; psychotherapy or weight loss support for BED≤ 3 months before screening (psychotherapy for conditions other than BED was not recorded); use of psychostimulants for fasting or dieting for BED ≤6 months before screening; Montgomery–Åsberg Depression Rating Scale total score ≥18 at screening; being considered at a suicide risk, previous suicide attempt, or current active suicidal ideation; lifetime histories of psychosis, mania, hypomania, dementia, or attention-deficit/hyperactivity disorder; histories of symptomatic cardiovascular disease, structural cardiac or heart rhythm abnormalities, cardiomyopathy, or coronary artery disease; moderate or severe hypertension, resting average sitting systolic blood pressure ≥139 mm Hg, or average diastolic blood pressure ≥89 mm Hg at screening or baseline; a clinically significant electrocardiogram (ECG) at screening or baseline; lifetime amphetamine or stimulant abuse/dependence histories; recent history of substance abuse/dependence (except nicotine); and having known/ suspected intolerance or hypersensitivity to LDX or related compounds.
In studies 1 and 2, respectively, 642 and 700 individuals were assessed for eligibility. In study 1, 259 individuals and in study 2, 310 individuals were excluded (for reasons ‘other' than not meeting inclusion/ exclusion criteria, n=25 and n=59, respectively). In studies 1 and 2, respectively, 383 and 390 participants were randomized (for placebo, n=191 and n=195; for LDX, n=192 and n=195 respectively). In studies 1 and 2, 162 and 153 participants completed the follow-up visit in the placebo group; while 172 and 160 participants completed the follow-up visit in the LDX group.
After a 2- to 4-week screening period, eligible participants were randomized 1:1 to 12 weeks of dose-optimized LDX or matching placebo. The randomization schedule was assigned by an interactive web response system. For blinding, both treatments were identical in appearance; the blind was not to be broken during the study. During week 1, LDX was given at a daily dosage of 30 mg for initial titration only. During week 2, the daily LDX dosage was titrated to 50 mg. During weeks 3–4, increases to 70 mg LDX were made based on tolerability and clinical need. A single downward titration to 50 mg was allowed at week 3 if the 70-mg dose was not tolerated. During weeks 4–12, the optimized LDX dosage (50 or 70 mg) was maintained. Throughout the study, participants were instructed to consume one capsule daily.
After screening, eligible participants were randomized 1:1 to 12 weeks of dose-optimized LDX or matching placebo. For blinding, both treatments were identical in appearance; the blind was not to be broken during the study.
The primary efficacy endpoint was change from baseline in binge eating days/week at weeks 11–12 (visit 8) based on participants' daily binge eating diaries. Prespecified key secondary endpoints assessed global BED improvement (CGI–Improvement) at week 12/ early termination, proportion of participants with 4-week binge eating cessation at week 12/early termination (no binge eating episodes for 28 consecutive days before the last visit), Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating (Y-BOCS-BE) total score changes from baseline at week 12), and medical aspects (percentage weight change from baseline at week 12 and fasting triglyceride changes from baseline to week 12) of BED.
Safety and tolerability assessments included adverse events (AEs), vital signs, weight, ECGs, clinical laboratories, and scores on the Columbia-Suicide Severity Rating Scale (C-SSRS) and Amphetamine Cessation Symptom Assessment (ACSA).
Clinical adherence (participants taking 80–100% of study medication) was determined by the investigator at every visit for study management purposes; calculated adherence (participants taking 80 − 120% of study medication: total capsules taken × 100/total days of dosing) was determined as a statistical compliance assessment.
Study 1 included 50 unique sites (United States, n= 44; Sweden, n= 3; Spain, n= 1; Germany, n = 2). Study 2 included 43 unique sites (United States, n= 41; Germany, n= 2).
Most LDX participants received 70 mg as the optimized dosage; 50 mg was the optimized dosage in 29.7% (57/192) and 28.7% (52/181) of LDX in participants in study 1 and study 2, respectively. Mean (SD) days of exposure (placebo vs LDX) were 76.6 ± 20.72 and 75.7 ± 20.81 in study 1 and 73.1 ±22.99 and 75.8 ±20.14 in study 2. Most participants were regarded as clinically adherent; calculated adherence was high (study 1: placebo = 187/187 [100%], LDX =188/192 [97.9%]; study 2: placebo = 183/185 [98.9%], LDX =180/181 [99.4%]).
Efficacy:
The baseline mean ± SD number of binge eating days/week was 4.69± 1.237 in study 1 and 4.75 ± 1.359 in study 2.
Primary endpoint: The least squares mean (SEM) changes from baseline in binge eating days/week at weeks 11 − 12 were –2.51 (0.125) with placebo and –3.87 (0.124) with LDX in study 1 and –2.26 (0.137) with placebo and –3.92 (0.135) with LDX in study 2; least squares mean (95% CI) treatment differences for change from baseline at weeks 11 − 12 favored LDX for both studies (study 1: –1.35 [–1.70, –1.01], P<0.001; effect size [95% CI], 0.83 [0.60, 1.05]; study 2: –1.66 [–2.04, –1.28], P<0.001; effect size [95% CI], 0.97 [0.72, 1.21]).
Secondary endpoints: Statistically highly significant (p<0.001) treatment effects favoring LDX were seen for CGI-I, 4-week cessation, body weight (percentage change, LDX-placebo, 12%; effect sizes, study 1: 1,6, 95% CI 1.4-1.9; study 2: 1,2, 95% CI 0.97-1,48), and Y-BOCS-BE in both studies. Differences in the reduction in triglyceride levels for LDX vs placebo were also statistically significant in both studies, with mean values being within the normal range at baseline and week 12/ early termination.
Safety and Tolerability:
In each study, >50% of the participants in the treatment group reported TEAEs (Treatment Emergent Adverse Events); more TEAEs were related to study drug with LDX than with placebo. Most TEAEs in each study were mild or moderate in severity. In each study, TEAEs reported by >10% of LDX-treated participants were dry mouth, headache, and insomnia; no TEAE was reported in >10% of placebo-treated participants. Discontinuations due to TEAEs with LDX in these studies were 6.3% and 3.9%. Serious TEAEs were infrequent and reported in equal proportions with LDX and placebo in each study and generally reflected intercurrent illness and accidental or potential BED-associated comorbidities. LDX-associated SAEs were considered unrelated to treatment by investigators, except for two syncope cases which resulted in participant discontinuation.
Post Hoc Sensitivity Analyses:
The overall efficacy, safety, and tolerability findings of study 2 did not change based on the inclusion of data from the 2 excluded study sites.
LDX produced statistically significant and clinically meaningful reductions in binge eating days/week (primary efficacy endpoint) relative to placebo in adults with moderate to severe BED. This same effect was observed in each identically designed studies. In studies 1 and 2, LDX was also associated with statistically significant and clinically meaningful greater response on outcomes of global improvement in BED pathology, 4-week cessation of binge eating at endpoint, and BED-related obsessive and compulsive psychopathology. In addition, the percent weight reduction from baseline with LDX was statistically and clinically significantly greater than with placebo.
Overall comment:
In addition to ADHD, lisdexamphetamine has an indication for the treatment of binge eating disorder (BED) in at least the United States, Canada, Israel and some South American countries (Brazil, Mexico). In Australia and Europe, including Finland, the indication for the drug is ADHD. When prescribing lisdexamfetamine, the physician must take into account the possibility of medicine abuse (e.g. substance abuse, resale).
In addition to the two RTCs on efficacy and side effects of lisdexamfetamine described in this review «McElroy SL, Hudson JI, Mitchell JE, ym. Efficacy a...»1, «McElroy SL, Hudson J, Ferreira-Cornwell MC, ym. Li...»2, other RCTs have been conducted, including on the persistence of efficacy «Hudson JI, McElroy SL, Ferreira-Cornwell MC, ym. E...»3, longer-term safety «Gasior M, Hudson J, Quintero J, ym. A Phase 3, Mul...»4, and possible differences in efficacy by age and gender «Kornstein SG, Bliss C, Kando J, ym. Clinical Chara...»5.
One study «Hudson JI, McElroy SL, Ferreira-Cornwell MC, ym. E...»3 showed a significantly lower risk of relapse at 6-month follow-up in the lisdexamfetamine group (3.7%, 5/136) than in the placebo group (32.1%, 42/131). In another study «Gasior M, Hudson J, Quintero J, ym. A Phase 3, Mul...»4, at 12-month follow-up, adverse events were reported by 84.5% (506/587) of participants in the intervention group. The most common adverse events were dry mouth (27%), headache (13%), insomnia (12%) and respiratory tract infections (11%). Serious adverse events were reported for 2.8% (17/599), two of which (acute coronary syndrome, supraventricular tachycardia) were thought to be drug-related.
Study by Kornstein et al. «Kornstein SG, Bliss C, Kando J, ym. Clinical Chara...»5 was a secondary analysis of data from study by McElroy et al «McElroy SL, Hudson J, Ferreira-Cornwell MC, ym. Li...»2. No significant or clinically relevant differences in the efficacy, safety, or adverse event profile of lisdexamfetamine were observed in women vs. men, or in those over 40 vs. those under 40 years of age.