Study EffTwicare

INTERVENTIONAL PROTOCOL (ROUTINE MEDICAL CARE) : EffTwicare

TRIAL ADMINISTRATOR MEDVENTIV Laboratory

ZAC de Saint-Sulpice

4, rue du Pâtis Tatelin

35700 Rennes

FRANCE

Study CODE EffTwicare

Identification Number RCB 2014-A01629-38

INDICATION Early Orthodontic Treatment in Class II skeletal malocclusion in

children.

INVESTIGATORS - Dr Stéphane Renaudin (coordinator), CHU Nantes (44).

- Prof. Olivier Sorel, CHU Rennes (35).

- Dr Carl Baudiffier, Private orthodontic office in Rennes (35) and

Cherbourg (50).

- Dr Yann Le Fur, Private orthodontic office in Vienne (38).

PROTOCOL VERSION NUMBER Version 1.2

PROTOCOL DATE 01/15/2015

Ethics Committee CPP (Ethics Committee) Ouest IV– Session of the 06th of January
2015.

CCTIRS and CNIL (Boards which In the frame of the routine medical care trial, a study describing
enforce law on data protection) file will be sent to the CCTIRS, and then an authorization
application will have to be filled at the CNIL once Ethics Committee
and CCTIRS approvals are received.

THIS CONFIDENTIAL DOCUMENT is FCI System/MEDVENTIV property. No unpublished information

mentioned in this document should be revealed without FCI System/MEDVENTIV previous written
authorization.

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Study Title Prospective multicentric, open-label, randomized Study assessing the

efficacy of the removable and adjustable preformed Twicare® appliance
versus removable Herbst Appliance treatment in class II malocclusion.

Key words Activator, class II, orthodontic treatment, Twicare®, Herbst appliance,
mandibular advancement.

Study Schedule Total Study Duration : 24 months

Recruitment Period : 12 months

Patient follow-up Period : 6 to 12 months

Study Design Noninferiority, prospective, multicentric, randomized, open-label and

controlled versus Herbst appliance study, including a group of non-treated
with interceptive appliance patients. The assessment of the main criteria
and secondary cephalometric criteria will be performed through double-
blind reading of the profile tele-radiographies (PROBE method).

Study Medical Device The Twicare® appliance is a removable mandibular propulsive adjustable
preformed medical device. It is made out of soft and stiff thermoplastics.
Its two gutters are linked to each other according to different antero-
posterior positions depending on the therapeutic objective. It is EC marked
since 2011.

Reference Medical Herbst appliance is a medical device measured made composed of telescopic
Device metallic hinges (with EC marking) and resin gutters made-to-measure based
on dental impression. Herbst has presented this mandibular propulsive
system in 1904.

Internal validity of the Non-treated with interceptive removable appliance but natural growth
study which will not modify, in any case, the continuation of the orthodontics
treatment.

Study Objectives Primary Objective:

Efficacy assessment of the orthopedic Twicare® appliance in mandibular

growth showing its noninferiority compared to removable Herbst appliance
in Children in the course of their growth presenting a Class II division 1
malocclusion.

Secondary Objective:

Complete cephalometric exploration on lateral cephalograms at T0 and T1

based on Tweed analysis.

Assessment of the overjet modification using dental silicone impression,

Assessment of the nasal ventilation at T0 and T1 (PNIF),

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Clinical Assessment of the appliance wearing compliance,

Study Objectives
Subjective assessment of the appliance wearing compliance,

Subjective assessment of the treatment,

Appropriate follow-up (second phase of orthodontic treatment).

Endpoints Primary endpoint:

ANB change between beginning (T0) and end (T1) of the treatment.

Secondary endpoints:

Evolution of the several cephalometric measurements analyzed on profile

tele-radiographies at T0 and T1 based on Tweed analysis: the incisors
position values improvement compared to the set of teeth and growth of
mandibular corpus length increase will be investigated in particular.

Evolution of the nasal ventilation calculated on Peak Nasal Inspiratory

Flow (result in L/min) between T0 and T1 with the use of a spirometer.

Clinical Assessment of appliance wearing based on dental movements

analysis, appliance condition and patient interview.

Subjective assessment of the appliance wearing compliance and treatment

tolerance/acceptability with auto-questionnaire and filling up of a diary
(wearing timesheet).

Inclusion Criteria:
Volunteers’ eligibility
- Boy or girl aged from 7 to 12 years old, healthy,
criteria
- In Class II division 1 malocclusion,
- Overjet ≥ 4 mm,
- ANB > 4°,
- Good cooperation (motivation and good dental hygiene),
- Incisors width compatible with the available Twicare ® appliance sizes,
according to the manufacturer recommendations.
- Written Informed Consent of the Child,
- Affiliated to health insurance,
- Parents able to receive informed consent and to express their approval for
their child to take part in this investigation.
Exclusion Criteria:
- Non well-balanced periodontal disease,
- Temporal-mandibular dysfunction,
- Severe bruxism noctural episodes,
- Known allergy or intolerance to one of the activators’ components.
- Foreseeable follow-up difficulties,
- Minor under guardianship,
- Simultaneous participation to an interventional study.

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Study Calendar with Pre-inclusion: The participants will be recruited in the course of
different visits and consultations performed by investigators. Each of them will pre-select their
exams patients answering all protocol inclusion criteria and none of the exclusion
ones. Information related to the study and its course will firstly be given
orally, then, information note and informed consent form will be handed for
reflection time.

The study will consist of evaluations every two months (which are usual
visits planned for patients with functional appliance), and as well at home,
with an auto-questionnaire.

Inclusion and beginning of treatment Visit (M0) = inclusion clinical evaluation

and checking of eligibility criteria, randomization, dental silicone impression
and initial lateral cephalograms, exo and endo-buccal photography,
measurement of the nasal ventilation (PNIF), placing of the Twicare ®
appliance or dental alginate impression for making an Herbst removable
appliance if applicable, wearing and hygiene recommendations. Patients
allocated with interceptive appliance will also be called (together with at
least one of their parents within 15 days following the beginning of their
treatment by a person of SLB Pharma in charge of the management of the
study, in order to make sure of their good compliance and good tolerability
to the dental appliance).

Follow-up visits every 2 months (M2 to ≤ M10): clinical assessment (Overjet

measurement, canine and molar ANGLE Class, PNIF) and patient’s auto-
questionnaire, acceptability.

End of study visit (≤ M12): final clinical assessment similar to the one
performed during inclusion visit, patient’s auto-questionnaire, profile lateral
cephalograms and end of study dental silicone impression.

Sample size In this investigation, one wishes to show the noninferiority of the Twicare®
appliance orthopedic treatment compared to the Herbst appliance assessing
the reduction of the ANB from the beginning and the end of the treatment
with a type I error set at 5%.

The noninferiority margin (ΔNI) is fixed at 0.5 degrees and the standard
deviation at 1. If we suppose a similar efficacy in the two treatments in
reality, 49 subjects have to be included per groups in order to show
noninferiority of the Twicare® compared to the Herbst appliance with
statistical power of 80%. Besides, 25 subjects will be included in the non-
treated group (randomization 2:2:1). We recommend adding a 20%
projection of discontinued patients before end of the treatment, 148
patients will thus need to be included (59:59:30).

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Statistical Methods The person responsible for the statistical analysis will be Anne-Laure
Sérandour, in charge of Biostatistics Department in SLB PHARMA.

The per protocol analysis is recommended to demonstrate the noninferiority

and will be complemented with the Intention to treat (ITT) analysis in order
to make sure of the results stability and confirm the efficacy of the
2 treatments. Noninferiority conclusion will be considered if the 2 analysis
are significant statistically.

The clinical data collected at T0 and T1, as well as their variations between
these two periods, (if applicable), will be described in each group. The
descriptive statistics will be presented depending on the nature of the
analyzed variables and graphics could be ended. The groups’ characteristics
at inclusion will be presented in order to make sure of their initial
comparability. The T0 data will, as well, be compared on sex basis using
appropriate statistical tests.

The primary endpoint, reduction of the ANB between T0 and T1 is

quantitative. The principal statistical analysis will be based on the observed
mean difference between the two groups (Dobs). This difference will be
associated with a standard deviation and the confidence interval 1-α will be
given. In case of initial non-comparability of the ANBTO values of the groups,
an adjusted analysis will be supportive, as recommended in ICH-E9
Guidelines.

We will use the one-sided confidence interval approach to conclude on

noninferiority of the Twicare® compared to Herbst. The 95% confidence
interval will be used in order to have a 5% global type I error and its lower
limit will be studied to conclude on noninferiority or not. The Twicare®
appliance will be considered as non-inferior to the removable Herbst’s if the
lower confidence interval is higher than the ΔNI noninferiority margin. On
the contrary, if the ΔNI is included in the confidence interval of the
difference between the two appliances, the noninferiority will not be
demonstrated.

In order to validate the study, the superiority of the Herbst appliance

compared to the non-treated group will be verified, as well as the
superiority of the study device. In this group, the natural growth will be
solely evaluated with possible correction of their malocclusion.

The secondary endpoints will be described in each group and compared with
appropriate two-sided statistical tests according to variables nature. The
type I error (α risk) is set at 5%.

The statistical plan has no interim analysis scheduled.

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Ethics Considerations Written informed consent: the investigator agrees to give the child and
his/her parents accurate and clear information regarding the course of the
study and to ask, each of them, a written informed consent. He will give
the parents, one copy of the information note and the informed consent
form. The child will receive a specific information note adapted to his/her
age.

The child will only be included in the study after he/she and his/her
parents have read the information note and signed and dated the informed
consent form. They will be have to have sufficient time to ponder on in
order to take their decision and to ask all needed questions before signing
the consent form. The investigator will also have to sign and date the
informed consent form. These documents will be handed on papers in
3 copies meant to be given to the signatories, the investigator (original
copy) and the study administrator. The investigator original copies will be
filed in the trial master file.

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Scientific Justification and Rational of the study:

The ANGLE Class II (1907) is a dysmorphia of the anteropostal dimension, characterized by a distal
occlusion of inferior lateral sectors compared to upper lateral sectors. The first mandibular molars are in
distal occlusion with the upper ones with at least a half-cuspide distance. Division 1 is defined by a
vestibulo-version of the upper incisors.

The functional therapeutics in orthodontia consists in getting back a normal function, wearing an
appliance or not, and to obtain orthopedics and-or orthodontics side-effects to this therapeutics or taking
themselves part in the functional correction.

A large number of functional appliances, mandibular growth activators, are used in Class II malocclusion
correction; they have various designs, fixed or removable. Appliance can be individualized, made to
measure by the prosthetist or standardized (on market). One of the largest means being used is the
Herbst appliance, existing since 1904. In 2011, a new medical device EC marked has been marketed, the
Twicare®, used as positioner, growth activator, but also for lingual reeducation. Up to now, no studies on
the removable Twicare® appliance have been published.

In literature review, there are numerous studies assessing the dental-alveolar and skeletal effects of
functional appliances. The orthopedic efficacy of these devices is mainly based on comparison of lateral
cephalograms measured values. The therapeutic results on growth and mandibular repositioning are at
the heart of the debate and stay controversial. Experimental investigations, long term performed,
highlight minor and insignificant modification. Retrospective studies, based on treated case with
satisfactory results, suggest that functional appliance can favorably change the mandibular length
(increase of mandibular growth of 1 to 2 mm). In 1996, in a literature review, Aelbers and Dermaut
pointed out that 86% of the conducted studies show ANB significant changes, consecutive to a functional
appliance treatment and that 33% of these lead to a maxilla growth reduction of 1 to 1.5 degrees.

Cozza and coll. have suggested in 2006 a systematic review of literature highlighting mandibular
modification due to functional appliance in Class II patients. This review gathered articles from January
1966 to January 2005. On 704 listed articles, only 22 have been selected. Two thirds of the studies
reported a mandibular growth of more than 2 millimeters in the treated group compared to the non-
treated. None of the randomized clinical trials have shown a significant induced mandibular growth
linked to functional appliances. The Herbst has obtained the best efficacy coefficient on mandibular
growth (0.288 mm/month), followed by Twin-Block (0.23 mm/month).

On long term, no significant difference has been demonstrated between the various positives. Besides, a
metaanalysis conducted by the Cochrane Collaboration in 2013 has shown by comparing an orthodontic
two phases treatment (treatment with functional appliance on phase 1 from 7 to 11 years old followed by
a fixed appliance during adolescence) versus a one phase treatment during adolescence, no significant
difference on the overjet evolution, on the ANB or on the PAR score at the end of orthodontic treatment.

Despite scientific proves on functional appliance action modes which are often contradictory, maybe
because of problems due to lack of rigor in experimental investigation. The shown clinical effects allow
functional appliances to be placed in our therapeutic arsenal; they represent an effective mean, among
others, in Class II malocclusion treatment.

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The goal of this study is to assess the efficacy of the removable Twicare® as mandibular propulsive
appliance in children aged from 7 to 12 years old in the course of their orthodontic treatment, showing
its noninferiority with the removable Herbst; one untreated group will be included to control the internal
validity of the study as recommend in noninferiority trials. Patients will have a follow-up every two
months during 6 to 12 months as planned in usual care.

A lateral cephalogram and a dental silicon impression will be performed at the beginning (T0) and at the
end of the treatment (T1) in order to evaluate cephalometric measurement variations, overjet and
canine and molar class evolutions. The data collected at the beginning and at the end of the treatment
will be analyzed and compared in blind from patient, treatment and period, in order to assess the
Twicare® noninferiority compared to the Herbst and to confirm the superiority of these two appliances
compared to lack of treatment. We will study, in parallel, the nasal ventilator function as well as
comfort, compliance, tolerance and acceptability of the device via an auto-questionnaire.

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STUDY SCHEDULE
M12
M-1 M0
Action M2 M4 M6 M8 M10 End of
screening Inclusion
study

Verification of inclusion and non-inclusion criteria X

Handing of information notes to parents and child X

Returning of signed informed consent forms X

Inclusion and Randomization (phone + fax) X

Data collection (demographic, anthropometric and orthodontic history) X

Clinical examinations :
- Measure of overjet and ANGLE class, X X X X X X X
- Measure of advanced maximum mandibular, X X X X X X
- Exo and endo buccal photographies, X X
- Measure of PNIF by spirometry, X X X X X X X
- Buccal ventilation screening questionnaire. X X

Para-clinics examinations :
X X
- Dental silicone impression,
X X
- Lateral cephalograms.

For «Study device» and «Reference device» Treatment Arm:

dental impression and bite wax (only for « reference device ») X

Handling of Treatment + Recommendations X

Treatment by Twicare® or Herbst 14h/24h during 6 to 12 months

Control of the appliance condition and compliance to treatment X X X X X X

Safety evaluation continuous

*The end-of-study visit will take place between M6 and M12, depending on treatment requirement.

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