Despite the encouraging results presented earlier, most of those programs (a notable exception being TEACCH) do not target school-aged children and are not proposed to occur in a school setting. This is unfortunate because schools are a favorable location for autism interventions (13). Additionally, many children with ASD do not receive a sufficient amount of treatment (14), even in countries with free access to health care (15). Because children with ASD benefit from being with other peers at school, the gap between education research and education practice (16) may be a missed opportunity to offer more support to these children. Additionally, larger doses of treatment could be offered in school contexts, especially when interventions are administered 1:1 (17). Several agencies have recommended conducting interventions in school-based settings (18, 19). Two objectives should be combined: school-based core deficit interventions and school-based social communication practice (20). There are already several studies that have shown that school-based interventions are able to reach larger numbers of children with ASD. This may improve challenges with generalization by using learned skills regarding communication in a natural environment, such as in the classroom (21, 22). Additionally, the preschool context seems to offer opportunities to develop communication skills (23, 24), and by offering opportunities to enter into play groups, teachers can supply reinforcements of the non-verbal ASD child requests (25).

However, there are very few school-based social communication interventions, and in many cases, teachers at school do their best without guided specific interventions for ASD children in the classroom. Consequently, there is a lack of response from teachers to the communicative acts produced by children with ASD (26). General educational teachers provide infrequent verbal prompting with ASD children (27), and they more frequently engage in functional play than symbolic play (28). They also lack supervision (20). Thus, there is a paradox between the need for appropriate intensive interventions for ASD and what is proposed in most school settings. For example, Mudford and colleagues (29) showed that the implementation of an evidence-based ABA program in preschoolers was not complete: 93% of the participants were not provided the dose of treatment (40 h/week). Additionally, from an efficiency perspective, although several programs support the concept of tailoring interventions to the child’s needs and skills, to our knowledge, no one has questioned whether programs could be adapted according to teaching local skills.

As expressed in the dimensional approach of the new classifications in the DSM-5 (30), intellectual disability (ID) is a frequent challenge and comorbidity in ASD. According to studies, ID co-occurs in 50 to 75% of ASD cases (31). Risk factors of comorbid ID in ASD are gender (despite the high number of males with ASD, the male/female ratio decreases in ASD comorbid with ID) and the existence of seizures or of a neurodevelopmental or genetic syndrome (32, 33). The co-occurrence of ID also appears to be a prognostic factor for long-term outcomes of ASD (12, 34) and a risk factor of the incidence of challenging behaviors that provoke severe morbidity in some cases (35). To date, very few models have specifically addressed ASD comorbid with ID, in particular when ID is in the severe-to-moderate range. Therefore, the need to focus on this understudied population is warranted. Here, we wonder whether or not children with comorbid ASD and severe ID may be receptive to a pedagogical content? For such children over 5 years, could an adapted and one-to-one cognitive program in school be a road to improve non-verbal and verbal communication and to promote social skills?

In this paper, our aims are to describe a school-based intervention program (a developmental and sequenced one-to-one educational intervention, DS1-EI) that was adapted to the French health and education system; to justify the principles that were followed to implement the method and adapt it to a low-functioning population (i.e., ASD comorbid with ID); to describe the randomized controlled trial we began; and to present the sociodemographic and clinical characteristics of the participants at baseline.

All participants were recruited in outpatient French health care institutions that are specialized in treating children with autism and intellectual handicaps. At the request of the French national health regulatory authority [Agence nationale de sécurité du médicament et des produits de santé (ANSM)] and the main sponsor [Caisse Nationale de Solidarité pour l’Autonomie (CNSA)], we balanced day care hospitals and special education clinics to have a representative sample of French institutions. In each institution, we obtained a specific commitment to accept the implementation of a DS1-EI school-based program as described below and to recruit the same number of participants to be randomized into a DS1-EI exposed group (called the DS1-EI group) or a treatment as usual (TAU) group who would serve as controls. The commitment also entailed having the required resources from local school authorities to implement the DS1-EI and to have the leading teacher from the classroom be supervised. To avoid bias in the TAU group as a result of the diversity of institutions, we decided to randomize participants by site. Figure 1 summarizes the list of institutions involved in the protocol and the number of patients by site. In total, we enrolled 75 participants.

Each parent provided informed written consent before inclusion. The inclusion criteria were a current diagnosis of ASD confirmed by a clinical assessment based on the International Classification of Diseases, 10th edition criteria and the Autism Diagnostic Interview-Revised (ADI-R) (36); an intellectual handicap with financial compensation from local agencies [Maison Départementale du Handicap (MDPH)]; being aged between 5 and 9 years; and having a communication developmental age of 24 months and under based on a Vineland assessment or a 3-year speech delay based on a Psycho-Educational Profile, third edition. We did not exclude children with known organic syndromes and/or non-stabilized neuropaediatric (e.g., seizures) or medical (e.g., diabetes mellitus) comorbidities. However, during the medical assessment, we specifically listed comorbidities. The exclusion criteria were limited to parents’ refusal to participate; family’s plans to change institutions in the short term for any reason; and patient’s severe behavioral impairments that would challenge treatment adherence. Of note, this last exclusion criterion was based on local institution staff decision. Before randomization, each site was requested to assess the IQ of the participants based on the Kaufman Assessment Battery for Children second edition (KABC-II) or, failing that, Vineland scores. Based on these results, dyads of participants matched for sex, age, and developmental quotient (DQ) were formed to limit the risk of bias between groups. Randomization before group allocation to TAU or DS1-EI group was performed by drawing lots in each dyad per site so that each site could have a TAU group and a DS1-EI group of three to four participants each. Randomization was performed by the methodological coordinating team at the Salpêtrière Hospital and was independent from local inclusion sites. TAU was defined as all therapeutic interventions given to a specific child. Given the study duration, we did not recommend not to change children’s therapeutic protocol in the TAU group during the study period. The trial duration was defined as 36 months but included 12-, 18-, and 24-month intermediate assessments.

Participants randomized to the DS1-EI group received the specific experimental protocol four mornings per week (2 h 30 min); the rest of the week they continued to receive the usual protocol of each site. The treatment principles are summarized in Table 1. The setting was a small classroom with four pupils, but an adapted environment was proposed. Following the principles of TEACCH (5), each child was offered a desk, two chairs (one for the child, one for the adult working with the child), a screen where pictures of the child’s schedule and activities were provided, and a locker with his or her picture. In contrast to TEACCH, the child sat with his back close to the wall where the screen was placed (see pictures in the supplementary material S1). The setting also included a large table for mid-session group collaboration and a place offering benches and carpets where group participants (both children and adults) met at the beginning and ending of a session. Although the program did not reach the 40 h per week recommended by some programs (37), it remained intensive, with 10 h of DS1-EI plus other therapeutic practices according to each institution (e.g., occupational therapy; speech therapy; social skill group activities). The program followed developmental rules, meaning the training was focused on the nearest expected activity/skill of a given child’s development in a specific domain as recommended by the ESDM (9). In terms of timing, the program was sequenced in two ways. First, as in TEACCH, the 2 h 30 min sessions followed an anticipated and structured agenda that was presented for each child on a screen. When a novel activity started, the corresponding pictogram was shown on the child’s desk. Second, teachers were asked to change desk and activities every 10–15 min to maintain the child’s attention and to help him improve by challenging patient’s need of sameness. Thus, each 10–15 min, the child has a new activity and a new teacher. The program was also curriculum based and had specific educational objectives (see details below).

Because DS1-EI was a program implemented in classrooms, both the curriculum and the objectives followed academic recommendations from the French Ministry of National Education. The curriculum was adapted from the French program for nursery and primary schools and handiscol principles (http://eduscol.education.fr). This was decided based on the idea that these recommendations were part of a teacher’s area of expertise and that it would promote participation in the program. Additionally, each classroom of N children was under the responsibility of one teacher helped by (N − 1) assistants, according to the 1-to-1 design of the program. In the same vein, one of the principles of the program was capitalizing on teachers’ individual skills. We believed that implementation of the program would benefit from using teachers’ specific knowledge (e.g., the use of the Picture Exchange Program). A detailed assessment/curriculum was a prerequisite of each child’s academic program because the DS1-EI was designed to follow a developmental approach, which required the selection of appropriate cognitive/motor activities for training within each domain. The curriculum is described in detail in the supplementary material S2. Regarding the academic/educational objectives, they were grouped into four domains: mathematics, language and communication, intermodality, and autonomy. Table 2 provides some examples of the activities by domain and level of child’s performance.

Each teacher and each assistant were trained by Annik Hubert-Barthelemy during a 1-week session. They were provided with a method presentation and were trained to use positive affect, shared engagement, responsiveness, and sensitivity to child cues, to focus on both verbal and non-verbal communication, and to support positive behaviors rather than tackle challenging behaviors. The DS1-EI detailed assessment/curriculum was explained, including how to keep learning proposals close to a given child’s developmental needs. The last 2 days of the training session was dedicated to define new objectives and adaptations. During the morning, the teacher with the help of his/her assistants had to fulfill children curriculums and to have related written observation. During the afternoon, curriculum was discussed and first learning activities for all domains were decided for each child.

Supervision was organized in three different steps: (i) daily sessions of verbal exchanges and written observations after the class about each child in each domain with all professionals (the teacher and the assistants); (ii) weekly supervisions by a psychologist; (iii) monthly supervisions by the main investigator to ensure the conformity of the program application and to help the teacher adapting the directives according to each child outcome.

Table 3 summarizes the variables that we planned to measure at enrollment and at several time points throughout the trial. The primary outcome variables were (i) the Childhood Autism Rating scale (CARS), which measures autism severity (38); (ii) the psychoeducational profile, third edition (PEP-3), which measures the total DQ and 5-dimensional DQs related to cognition, receptive language, expressive language, fine motor skills, gross motor skills, and imitation, and (iii) the school’s assessment (39). Secondary variables included the following measures: (i) the Vineland Adaptive Behavior Scale II (VABS-II) as a behavioral scale of independence; this scale is assessed through a parent/educator interview and is used to assess the ability of children to perform the daily activities required for personal and social sufficiency. The VABS-II examines four specific domains: Communication, Daily Living Skills, Socialization, and Motor Skills. The subscale scores are totaled to yield an Adaptive Behavior Composite score (40). (ii) The KABC-II standardized neuropsychological assessment to measure intelligence skills. This battery measures Verbal, Performance, Working Memory, Processing Speed and Total quotients (41). (iii) The Clinical Global Impression (CGI), which was used to assess global severity (42). (iv) Finally, the Children Global Assessment Scale (CGAS) (43). To assess clinical change during the 36-month study, we used a single-blind procedure (independent raters were blind to study group allocation) for all clinical assessments (PEP-3, KABC-II, CARS). Blind assessment was not possible for the measures that required 2-week observations of the participants (CGI, CGAS, school tests) or a parental interview (ADI-R, VABS-II).

From previous studies that showed significant results in terms of efficacy it appears that the minimal number of patients in parallel design was 50 (2). This was the case for behavioral ABA approach [e.g., Ref. (6)] or for developmental ESDM approach [e.g., Ref. (3)]. The number of patients to enroll was based on the following theoretical statistics estimation: for a moderate effect size (α = 0.6), a power fixed at 80%, and a level of significance for a p-value fixed at <0.05, 80 patients randomized into two groups are required for a student t-test. Given our choice to use linear mixed models (see below) to take into account participant’s effect, we planned to recruit from 70 to 80 participants.

Statistical analyses will be performed using R Software, Version 2.12.2. To assess whether improvement occurs in both primary and secondary variables, we will use linear mixed models with change in a given variable explained by group exposure (DS1-EI vs. TAU), time (baseline vs. 18 vs. 36 months) and their interaction (group exposure × time). We will also include a random effect and a site effect. This should account for individual heterogeneity, site heterogeneity, variable scores at inclusion, and change specific to DS1-EI within the same statistical regression. For missing data when available, we will use the last observation carried forward. In case of a non-Gaussian distribution, we will study the log transformation (or other transformation when appropriate) to achieve a normal distribution. Lost or drop-out patients will also be compared between groups using a separate non-parametric comparison.

Table 4 summarizes the participants’ sociodemographic and clinical characteristics at enrollment. As expected, we found no significant differences at enrollment between the DS1-EI and TAU groups, indicating that the randomization by site did not introduce bias. As expected, exposure to school was the only significant difference found between the two groups: 9.4 (±4.1) hours per week in the DS1-EI group vs. 3.4 (±4.5) hours per week in the TAU group, Student’s t-test, t = 5.83, p < 0.001.

The current trial protocol was authorized by the competent national health regulatory authority [Agence nationale de sécurité du médicament et des produits de santé (ANSM)]. The trial registration number (ANSM 130282B-31) was obtained on April 16, 2013. The protocol was approved by the local Ethics Committee (Comité de Protection des Personnes) of the University Hospital Saint-Antoine on May 7, 2013. Also, it was registered on the Australian New Zealand Clinical Trial Registry for public information availability (ACTRN12616000592448). Potential participants received oral and accessible information about the study given participants’ cognitive profiles, and all parents/guardians were provided a written information leaflet about the trial. The information leaflet adhered to the current French guidelines for researchers on writing information sheets and consent forms. Only after written consent was obtained from the parents of potential participants did randomization occur.

Persons’ data and images contained in this article are published with the consent of their parents/guardians.

A pilot study committee has been formed and includes the principal investigator of the trial and all local investigators and study collaborators. They will meet three times a year. A scientific study committee has also been established and includes two administrative members of the promotor (La Croix Rouge Française), four members of the pilot study committee and four other independent members (two professionals, two family representatives). They will meet once a year.