Supplementary appendix

Transcription

1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Herpertz-Dahlmann B, Schwarte R, Krei M, et al. Day-patient treatment after short inpatient care versus continued inpatient treatment in adolescents with anorexia nervosa (ANDI): a multicentre, randomised, open-label, non-inferiority trial. Lancet 2014; published online Jan 17.

2 Supplementary Appendix Supplement to B Herpertz-Dahlmann, R Schwarte, M Krei et al. Day Patient Treatment after Short Inpatient Care vs. Inpatient Treatment in Adolescent Anorexia Nervosa (ANDI): A Multicentre, Randomised, Open-Label, Non-Inferiority Trial Methods Assessments Diagnosis of AN, eating disorder specific and comorbid psychopathology The diagnosis of AN and eating disorder-associated psychopathology was assessed using the Structured Interview for Anorexia and Bulimia Nervosa (SIAB-EX 1 ). The SIAB-EX is a semi-standardised expert interview that assesses the occurrence and severity of specific eating disorder-related symptoms according to the DSM-IV diagnostic criteria. This interview also differentiates between the two subtypes of AN according to the DSM-IV (restrictive and binge-purging subtypes). All of the research assessors were trained in performing the interview and were regularly video-supervised. The onset of AN was defined as the approximate time point at which the weight loss first occurred, the time point at which no further weight gain occurred despite an age-appropriate growth spurt, or the first occurrence of secondary amenorrhea, whichever came first. The duration of illness was calculated as the time between the onset of AN and the time of admission. We calculated age-adjusted BMI percentiles, standard deviation scores (BMI-SDS), and the percentage of expected body weight (%EBW). Expected body weight (EBW) is the median age-adjusted BMI (50 th BMIpercentile), and %EBW is observed BMI/50 th BMI percentile x 100, based on a large German reference set ( 2. The latter procedure has been recommended recently by Le Grange and colleagues 3 and was applied by Faust and colleagues. 4 Comorbid psychiatric disorders Comorbid psychiatric disorders were assessed using the K-SADS-PL 5 (German version by Delmo et al. 6 ), which is a semistructured interview designed to assess current and previous episodes of mental disorders in children and adolescents according to DSM-IV criteria. The assessment is based on interviews with the patient and the patient s parents. Eating Disorder Inventory (EDI-2) The EDI-2 7 (German version by Paul and Thiel 8 ) is one of the most widely used eating disorder self-report questionnaires. This survey has good psychometric properties and is recommended for children and adolescents 11 years of age. Brief Symptom Inventory 9 (BSI) The German language version of the BSI, 10 which is a shortened version of the SCL-90-R, 11 is an easily applicable, reliable, and valid self-report measure that has been widely used internationally. This inventory consists of 53 items that are evaluated along nine scales and three global parameters. The General Morgan and Russell Score 12,13 This instrument is divided into three outcome categories: good (BMI 10 th percentile and regular menstruation, oral contraceptive use after the resumption of menses, or a premenarchal state, i.e., no menarche in adolescents under the age of 16), intermediate (BMI 10 th percentile, irregular menses), and poor (BMI <10th percentile and/or the absence of menses, including oral contraceptive use without prior resumption of menses, or primary amenorrhea). The inclusion of the menstruation status implies a poorer outcome than shown in comparable studies, 14 and the criterion of amenorrhea will be no longer listed in DSM-5. However, we consider it to be an important criterion given its long-term prognostic relevance in adolescent AN, 15 especially for brain maturation and function. 16,17 1

3 Inpatient and day patient treatment In addition to a BMI <10 th percentile, the following medical indicators were considered for admission to the hospital: 18 a) rapid weight loss, low energy intake, and refusal to drink; b) medical complications; and c) severe psychiatric comorbidity. In addition, the following psychosocial criteria were used: a) severe social isolation, b) high parental criticism and/or dysfunctional family interactions, and/or c) lack of outpatient facilities and/or insufficient response to outpatient treatment trials. In all cases, the decision to admit a patient to the hospital was independent of and prior to inclusion into the study. Treatment modalities During the three week medical observation/stabilisation period, an intensive medical assessment (including physical, laboratory, and ECG assessments) and monitoring of binging and purging behaviour occurred. A nutritional rehabilitation programme with progressive weight goals was started, beginning with low calorie levels on a regular meal basis, limitation of exercise, and normalisation of fluid intake. In addition, patients received regular sessions of supportive psychotherapy (for further details, see Herpertz-Dahlmann and Salbach- Andrae 18 ). A multimodal multidisciplinary treatment programme based on the following main components was used in both treatment arms for each patient 18,19 (for additional details, see Herpertz-Dahlmann and Salbach- Andrae 18 ): (1) Weight restoration by means of a behavioural programme. The expected weight gain was g/week as recommended by several national guidelines (2) Individual and group nutritional counselling to restore healthy eating behaviours. Patients received individualised meal plans consisting of three main meals and three snacks. In individual and group sessions, the patients were advised about the effects of starvation and informed about standard nutritional recommendations. The patients also participated in cooking sessions and were supported by staff during meals. (3) Individual therapy based on cognitive-behavioural principles that targeted dysfunctional thoughts regarding shape, weight, and self-esteem. (4) Group therapy for AN patients to enhance motivation and self-confidence. (5) Group psychoeducation programme for parents of AN patients and individual family sessions. Individual and group sessions for patients each occurred twice a week. The group psychoeducation programme for parents consisted of 5 sessions in which the participants were comprehensively informed about the nature and consequences of AN and the content and goals of the treatment programme. 23 Individual family sessions were provided every two weeks. The patients participated in the following therapies: occupational, art, body-oriented (e.g., gymnastics), and relaxation. 18 The treatment intensity was identical in both arms, as verified by monitoring through the independent Clinical Trials Centre. Outpatient treatment After discharge from both IP and DP, all of the patients were provided with the same outpatient treatment programme until the 12-month follow-up: Individual therapy occurred twice a week during the first six months after the time of discharge, and subsequently usually every fortnight. Special eating disorder group sessions were conducted between five and seven times, while joint family sessions occurred every four weeks. Patients received advice from a nutritional therapist upon request. This treatment programme largely corresponded to standard after-discharge outpatient treatment in Germany. Statistical analyses The non-inferiority margin for BMI difference from the time of admission to the 12-month follow-up was based on clinical experience. We decided that a difference in BMI of 0 75 kg/m² would not be clinically relevant; for example, it would imply a difference of 2 kg in weight for a 15-year-old girl with a height of 1 65 m. 2

4 The General Morgan and Russell Score (with the three categories of good, intermediate, and poor) was compared between the IP and DP arms using the Cochran-Armitage test for trend; as an association measure, Somers D (General Morgan and Russell Score treatment group) was calculated together with a 95% confidence interval using SAS. The number of readmissions was compared using Fisher s exact test. Sensitivity analyses A dual approach of intention-to-treat (ITT) and per-protocol analyses for the primary outcome is recommended for non-inferiority trials because non-adherence to the randomised treatment might cause effect estimates to be more similar in the two groups, thus biasing the results. The correspondence of ITT and per-protocol analyses would thus strengthen the results. 24,25 To further explore this effect, we performed a second, modified per-protocol analysis which included only patients who completed the randomised treatment as intended (excluding those who changed from DP to IP due to reasons specified in the protocol). With respect to sensitivity analyses, we included AN subtype (binge-purging or restrictive) as an additional covariate in our original model because AN subtype could be another important prognostic factor. 26 Furthermore, we computed a linear mixed model with the same covariates as in the original model and a random effect for centre, which was used in the randomisation as a balancing factor. Additionally, we applied a last observation carried forward (LOCF) approach for the missing data (including all patients for whom at least one observation after discharge was available) or imputed missing data using a worst-case strategy of assigning IP patients the highest observed change in BMI and assigning DP patients the lowest observed change in BMI. Results Participants A total of 275 eligible patients were approached to participate in the study; 95 patients did not consent to being randomised, and 4 were unable to participate because of organisational reasons. Two weeks after admission, 176 eligible patients who agreed to participate in the study were randomised to either DP or IP (figure 1). Three patients were randomised even though they did not fulfil the DSM-IV weight criterion but did fulfil all the other DSM-IV- criteria for AN: two patients had lost more than 10 kg, and one patient lost 6 kg in less than three months. Additionally, the latter patient had stopped eating almost completely during the last days before admission to the hospital. The mean age of the sample was 15 2 years (SD: 1 5), the mean duration of illness was 48 0 weeks (SD: 36 8), and the mean BMI was 15 0 kg/m 2 (SD: 1 3). A total of 140 patients (82%) were classified as the restricting subtype of AN, and 31 patients (18%) were classified as the binge/purging subtype (table 1). A total of 118 participants (68 8%) lived with an intact family. Overall, 61 patients (41%) (n=148, 24 missing) had a comorbid psychiatric disorder, as assessed by the K-SADS- PL. With the exception of anxiety disorders (more frequent in the IP arm), comorbid disorders had a similar prevalence in both treatment arms. The mean duration of illness was slightly longer in the IP arm than in the DP arm (table 1). Of the 176 patients randomised to treatment, one patient was excluded after randomisation but before starting the treatment due to a misdiagnosis; this patient was later reclassified as having a simple phobia of choking. Additionally, three patients were excluded due to complete withdrawal of data. Delivery of treatment and adherence to allocation A total of 35 patients did not complete the allocated treatment (for the Consort diagram (trial profile), see figure 1). Six patients who were randomised to DP remained in IP: two patients stayed for medical reasons defined a priori (one patient had suicidal ideation and one patient had extreme difficulties with eating), while four patients refused to change into DP. A total of 16 patients changed from DP to IP; of the 16 patients, eight patients refused to continue DP due to conflicts at home or for fear of not getting better in DP and eight patients changed due to reasons defined a priori (five due to insufficient weight gain, two patients with suicidal risk, and one patient with bradycardia). Seven patients in DP, of whom four had been readmitted to IP for 3

5 medical reasons defined a priori, and patients in IP were discharged against medical advice (figure 1). There was no compulsory treatment; however, one DP patient had been transferred to an intensive treatment unit (see SAE below). Medication The use of psychotropic medication was similar in both groups. At some point (e.g., at admission or during treatment), 24 patients in the DP group (28%) and 32 patients in the IP group (38%) received typical antipsychotics, olanzapine, or selective serotonin reuptake inhibitors (SSRI). This medication use was allowed as part of the pragmatic clinical trial. Sensitivity analyses for the primary outcome All sensitivity analyses consistently demonstrated the non-inferiority of DP compared to IP with respect to change in BMI between the time of admission and follow-up (supplementary table 1). Including AN subtype (binge-purging or restrictive) as a covariate in the model did not change the results for the therapy effect, and the difference in outcome between subtypes was minimal (0 06 kg/m²) and non-significant (p=0 86). The different methods for handling missing data also consistently showed non-inferiority; thus, we are convinced that missing data due to loss-to-follow-up did not compromise our results. Supplementary Table 1: Sensitivity analyses for the primary outcome Analysis Mean (SD) n Mean (SD) n IP DP Difference (95% CI) DP- IP p Inclusion of additional covariates Random centre effect 17 8 (1 7) (2.0) (-0 12 to 1 01) < a Fixed effect for AN subtype 17 8 (1 7) (1 9) ( to 1 06) < b Missing data handling LOCF 17 8 (1 7) (2 0) (-0 11 to 0 97) < c All missing values were set to the smallest observed difference not useful 85 not useful (0 29 to 1 52) < d Missing values in the IP arm were set to the largest observed difference and in the DP arm to the smallest observed difference not useful 85 not useful (-0 56 to 0 68) d Further patient subsets Only patients who completed the therapy as intended (second, modified per-protocol analysis) 18 0 (1 7) (1 9) (-0 2 to 1 08) c a Linear mixed model with therapy group; BMI, age, and duration of illness as fixed effects and centre as the random effect. b ANCOVA with BMI, age, duration of illness, and subtype as covariates. c ANCOVA with BMI, age, and duration of illness as covariates. d One-sided Wilcoxon-rank-sum test for the shifted null hypothesis. 4

6 Supplementary Table 2: Serious adverse events SAEs during differential treatment IP or DP patient 1. Suicidal ideation IP 2. Appendectomy IP 3. Intensive compulsory treatment because of nearly DP complete refusal of eating (change to IP) 4. Suicidal ideation (change to IP) DP 5. Suicidal ideation (change to IP) DP SAEs after discharge from IP/DP 1. Suicidal ideation IP 2. Suicidal ideation IP 3. Inpatient treatment for depression and obsessive IP compulsive symptoms 4. Inpatient treatment for depression IP 5. Admission to hospital because of circulatory collapse IP 6. Appendectomy IP 7. Suicide attempt DP 8. Inpatient treatment for depression DP 9. Inpatient treatment for depression DP 10. Surgical intervention DP 5

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