The project involves a 10-year prospective longitudinal cohort multicentre study where orthodontic treatment and treatment effect is followed in children with Cl III due to maxillary retrognathia who undergo standardized orthodontic interceptive treatment. Standard clinical procedures are followed as usual at each clinic where standard diagnostic and follow up materials are taken before treatment, after treatment and follow ups after 5 and 10 years. The project will not introduce or test new treatment modalities, additional procedures or behavioural regulation in relation to normal clinical practice or new medical devices. The standard diagnostic and follow up materials in each clinic include examination of the dentition, occlusion, craniofacial morphology, and orofacial function. The analyses are based on the following standardized registration methods which are carried out on all the patients. Information from the patient record is included.

The patient related outcome measurements will be assessed by five different questionnaires. No biological material is collected for the project.

The aims of this project on treatment of young patients with Cl III due to maxillary retrognathia are to: 1) compare timing and treatment approaches for orthodontic treatment between national clinics and between two Scandinavian countries, Sweden and Denmark; 2) compare the treatment effect immediately after treatment between various orthodontic treatment approaches; 3) compare the treatment effect and side effects as well as patient perspectives in the short and long term after treatment between different orthodontic treatment approaches; 4) analyse the significance of timing, treatment approaches, and craniofacial morphology for short- and long-term predictions, treatment effects and side effects in the orthodontic treatment.

The project is based upon a comparison of well-established treatment approaches for Cl III due to maxillary retrognathia. It will not introduce or test new treatment modalities, additional procedures or behavioural regulation in relation to normal clinical practice or the use of medical devices.

Relevance of the project The project may contribute to identifying which treatment approaches and timing are most effective for orthodontic treatment of Cl III due to maxillary retrognathia. The results are therefore important for the choice of treatment approach and prognosis for the individual patient, and socio-economically important as treatment of Cl III in a better way may be tailored the individual patient whereby treatment effect may be optimised.

Method The project involves a 10-year prospective longitudinal cohort multicentre study where orthodontic treatment and treatment effect is followed in children with Cl III due to maxillary retrognathia who undergo standardized orthodontic interceptive treatment. Standard clinical procedures are followed as usual at each clinic where standard diagnostic and follow up materials are taken before treatment, after treatment and follow ups after 5 and 10 years. The project will not introduce or test new treatment modalities, additional procedures or behavioural regulation in relation to normal clinical practice or new medical devices. The standard diagnostic and follow up materials in each clinic include examination of the dentition, occlusion, craniofacial morphology, and orofacial function. The analyses are based on the following standardized registration methods which are carried out on all the patients. Information from the patient record is included.

General registrations:

• Height
• Weight
• General health information, including information regarding asthma, chronic bronchitis, hypertrophic tonsils and adenoid vegetations, mouth breathing, constantly runny nose, removal of tonsils and adenoid vegetations (17).
• Subjective sleep/sleepiness questionnaires: Epworth Sleepiness Scale for Children and Adolescents (18) (ESS-CHAD, Appendix 2), Berlin Questionnaire (19) (BQ) and Pediatric Sleep Questionnaire (20) (PSQ)
• Children's general well-being questionnaire: Strength and Difficulties Questionnaire (21, 22) (SDQ)
• Children's general quality of life questionnaire: KIDSCREEN (23, 24)
• Subjective experience with Cl III treatment (25) (OHIP-14)

Standard diagnostic and follow up examinations:

Dental occlusion, dentition, and craniofacial morphology:

• Dental occlusion is examined through analyses on intraoral scans which use video technology to reproduce teeth and dental arches in three dimensions (26)
• Tooth contact in the intercuspal position (ICP) is registered with a plastic strip (27)
• Dentition is examined on orthopantomogram (OP) (28)
• Craniofacial morphology is measured by lateral profile x-rays (29)

Oro-facial function:

- Standard screening (short form) based on Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) (30) Practical execution of the project The project will be carried out in close collaboration between the University of Copenhagen and Malmö University and publicly funded orthodontic clinics in Denmark and Sweden. In Denmark, the orthodontic, interceptive treatment will take place at the School of Dentistry, University of Copenhagen, and in the municipal dental care in the Copenhagen and Funen area. In Sweden, the orthodontic, interceptive treatment will take place at Malmö School of Dentistry, Faculty of Odontology, Malmö University and the Orthodontic Specialist Clinic in County of Blekinge and Scania. The specialists in orthodontics at orthodontic clinics which have accepted to participate in the study are responsible for the treatment, collection of data and the forwarding of data to the University of Copenhagen, Institute of Odontology, where Professor Liselotte Sonnesen is responsible for the data, and to Malmö University, Department of Orthodontics, where Associate Professor Mikael Sonesson is responsible for the data. The data from Sweden will be forwarded to the University of Copenhagen. Even though the prevalence of Cl III is relatively low in Scandinavian countries, the baseline sample size is considered possible to obtain within a reasonable period of 6 months by including three to four governmentally funded public clinics in Denmark and two governmentally funded public clinics in Sweden with a large flow of patients. Moreover, all software and the necessary skills to analyse the date are available at the University of Copenhagen, Institute of Odontology, Denmark, and at Malmö University, Sweden.

The standard registration and examinations are all taken as usual procedures in connection with the treatment at the clinics. The patients will only be coming to their regular appointments and their regular follow ups. All information is treated confidentially. The names and CPR numbers of the patients are deleted before the data is published, and all employees on the project are subject to a duty of confidentiality.

Statistical considerations Power analysis and estimated number of participants The required sample size will be determined through a priori power analysis, assuming a significance level (α) of 0.05 and a statistical power (1-β) of 0.80, assuming a two-sided test. The calculation is based on detecting a mean difference of 2.0° (S.D. 2.5°) in ANB angle between the treatment modalities (31) (tooth-borne (with and without facemask), and bone-borne (with and without mentoplates) and extraction only). Accordingly, the estimated sample size is 36 patients in each group approximately 180 patients in total, accounting for an anticipated dropout rate of 20%.

Statistical methods Differences in timing and treatment approaches for orthodontic treatment of Cl III between national clinics and between Sweden and Denmark are tested with logistical and linear regression analyses. Differences in treatment effect, short- and long-term effects (in occlusion, craniofacial morphology, and orofacial function including sleep) between various treatment approaches are tested with logistical and linear regression analyses. The association between timing, treatment approaches, craniofacial morphology, and the treatment effect of the treatment approaches as well as any short- and long-term side effects during Cl III treatment are tested with multiple linear and logistical regression analyses.

Trial subjects Inclusion criteria

• Children enrolled in a standardized orthodontic interceptive treatment for Cl III due to maxillary retrognathia
• Mandibular overjet due to maxillary retrognathia with indication for treatment
• Children 9-12 years of age

Exclusion criteria Mandibular overjet Known general and/or craniofacial syndromes/diseases Adenoid vegetations, hypertrophic tonsils Functional disorders in muscles and jaw joints

The project also has the direct prospect of being able to offer benefits to the patient group that is included in the same age group and condition as the trial participants, by contributing to better choice of treatment and prognosis for the individual patients. Treatment may thereby be better tailored the individual patients, and the treatment effect can be optimised. Thereby the children may gain a better well-being and self-esteem and avoid a much more comprehensive orthodontic treatment in their adult life. The project involves minimal risks and inconveniences for the trial participants.

Risks, side effects, and disadvantages in the short and long term The study only includes standard, validated and recognized registrations and treatment which are usual procedures and routines at the publicly funded orthodontic clinics in Denmark and Sweden. Furthermore, all examinations and treatment are carried out under the responsibility of authorized professionals with many years of experience and expertise in their respective fields. There are no known side effects, risks or disadvantages of participating in the project, apart from the lateral profile x-ray at 10 years follow up which may not be routine at all clinics. Under this circumstance the x-ray dose from the lateral profile x-ray is <6 μSv, which corresponds to approx. 0.5% of the average natural background radiation per year. This x-ray dose is not expected to entail any significant risk of later development of stochastic damage. No risks for the patients' health or well-being are expected to arise.

Data management and information from patient records All registrations of the patients are protected by law on management on personal data and by the Danish Health Act (Sundhedsloven) as well as the Swedish National Board of Social Services (Socialstyrelsen). The patients are assigned a trial number and all data are pseudonymised. A list of full names, CPR-numbers and trial numbers is kept separate from additional data. Data are archived for a minimum of 5 years after the last patient's visit. Data are kept on secure drives at the University. The project will be approved by the Danish Scientific Ethical Committee, by the Danish Data Protection Agency (journal number), by the Swedish Ethical Review Authority and will be registered with ClinicalTrials.gov prior to start-up.

The following information will be passed on from the patient dental records to the dental specialist responsible for the trial: Type of interceptive treatment, duration of the interceptive treatment, compliance during treatment, number of appointments and number of emergency appointments. Any necessary approval for this will be obtained from the data authorities. The record information will be used to verify the type, timing, and patient compliance during treatment and thereby contribute to verifying the hypothesis of the project. The information will be used for the project after consent to participate has been given. The consent gives the trial investigators direct access to obtain information in the patient's dental record which is necessary as part of the implementation of the research project.

Economics The person behind the initiative for the project is professor, specialist in orthodontics, PhD, Dr. Odont. Liselotte Sonnesen in collaboration with Associate Professor, PhD, senior Consultant in Orthodontics Mikael Sonesson. The initiative for the scientific trial comes from the professor behind the initiative alone, who has no economic interest in the conduction of or the results from the trial. No commercial institution will influence the completion, results or decision-making regarding publication of the trial. There are no expenses for this project as all the children under the age of 22 years (Denmark) and 19 years (Sweden) already receive free orthodontic treatment when indication for treatment at the governmentally funded public orthodontic clinics. As the children will receive orthodontic treatment regardless of participation in this project, and no extra appointments are required if the children and their parents accept to participate in the project, no compensation is given for participation in the project.

Benefits for the patients No extra appointments are required if the children and their parents accept to participate in the project. The children's participation in the project will contribute to identifying which treatment approach and timing is most effective for orthodontic treatment of Cl III due to maxillary retrognathia. Therefore, the results are extremely important for choice of treatment and prognosis for the individual patient so that the treatment may be better tailored the individual patient and the treatment effect can be optimised. Thereby the children may get a better well-being and self-esteem and avoid a much more comprehensive orthodontic treatment in their adult life.

Recruitment of trial subjects and informed consent Children together with their parents treated at the School of Dentistry, University of Copenhagen, and the governmentally funded public orthodontic clinics at the Copenhagen and Funen area and at the counties in south of Sweden will be given a brief introduction to the study and asked if they would like to participate in it. The child and their parents/guardians will then be invited to an oral participant information session at a time of their choice and informed of the right to bring an observer to the information session, which will be ensured by providing a printed version of the 'Rights of Subjects in a Health Science Research Project' prepared by the National Research Ethics Committee.

The oral information will be given by the specialist in orthodontics responsible for the treatment, and this will take place in an undisturbed, closed clinic at the clinic where the child is affiliated, prior to the provision of the written information. The information is thus provided by a person with good knowledge of the treatment and pedagogical knowledge for communication. There will be a reflection period of one week between the oral/written information before informed consent is obtained with signature on the consent form. Consent is thus sought after this reflection period and prior to participation in the study. The children will receive the same treatment regardless of whether they are included in the study or not.

Substitute consent is obtained from both holders of parental authority.

Publication of results The research conducted in this project will lead to the preparation of at least 4 research articles for publication in leading national and international medical and dental journals. Moreover, the results will be presented at relevant scientific conferences, at governmental funded public orthodontic clinics, the Danish and Swedish Dental and Medical Associations and for the Danish and Swedish Health Authorities. Both positive, negative, and inconclusive results will be published.

Section for scientific ethical committee Only well-established and acknowledged diagnostic methods and treatment approaches are used. The project is a comparison of well-established approaches for Cl III due to maxillary retrognathia. The project will not introduce or test new treatment approaches, additional procedures or behavioural regulation in relation to normal clinical practice or new medical devices. All examinations and treatment are carried out under the responsibility of authorized professionals with extensive experience and expertise in their respective fields. It is estimated that there is no risk to the health and well-being of the patients.

Participation in the study is voluntary, and project participants participate after written, informed consent is signed by the parent/guardian. Project participants can withdraw from the study at any time without consequences for orthodontic treatment or future dental check-ups. For parents/guardians who do not want their child to participate in the study, or children who are withdrawn from the study, there will be no consequences for the child's orthodontic treatment, dental check-ups and treatment.

Inclusion Criteria:

• Mandibular overjet due to maxillary retrognathia (Overjet \

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