Effect of Interceptive Strategies on the Clinical Outcome of Maxillary Impacted Canines
Phase: NA
Conditions: Tooth, Impacted
Sponsor: Universitaire Ziekenhuizen KU Leuven

 
 
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Protocol Full Title Prospective Trial: 
Effect of interceptive strategies on the clinical outcome of impacted maxillary permanent canines. 
Protocol Acronym/short title: 
RCT Impacted canines. 
Version and date of final protocol: 
Version 4.0 d.d. 01 July, 2016. 
UZ Leuven Clinical Trial Center number S59030 
Sponsor: 
Name: UZ Leuven 
Address: Herestraat 49, 3000 Leuven 
Principal Investigator: 
Name: Prof Dr. Guy Willems 
Address: Department of Oral Health Sciences – Orthodontics, KU Leuven & Dentistry, UZ Leuven, 
Kapucijnenvoer 7, 3000 Leuven, Belgium 
Telephone: +32 16 33.27.50 
Fax: +32 16 337578 
Email: guy.willems@med.kuleuven.be 
Sub-investigator: 
Name: Dr. Maria Cadenas De Llano Perula 
Address: Department of Oral Health Sciences – Orthodontics, KU Leuven & Dentistry, UZ Leuven, 
Kapucijnenvoer 7, 3000 Leuven, Belgium 
Telephone: +32 16 33.27.50 
Fax: +32 16 337578 
Email: maria.cadenasdellanoperula@uzleuven.be 
 
Participating Investigator: 
Name: Prof. Ali Alqerban 
Address: Orthodontic Division, Department of Preventive Dental Sciences 
College of Dentistry, Prince Sattam Bin Abdelaziz University, P.O. Box 153 AlKharj 11942, Saudi Arabia 
Telephone: +966554214557 
Email: ali.alqerban@gmail.com 
 
 

 
 
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Signatures 
 
 
 
 
_________________________  
 
 
____________________ 
Principal Investigator 
 
 
 
 
 
Date 
Prof. Dr. Guy Willems 
 
 
 
 
_________________________  
 
 
____________________ 
 
 
 
 
 
 
 
 
Date 
Sub-investigator 
Dr. Maria Cadenas De Llano Perula 
 
 
In accordance with local laws of Participating Site: 
 
 Participating Site/Investigator shall foresee in adequate insurance coverage for possible 
damages linked directly or indirectly to the patients’ participation to the Study at Participating 
Site and shall provide proof of such certificate to Principal Investigator 
 no insurance coverage for possible damages linked directly or indirectly to the patients’ 
participation to the Study at Participating Site is needed 
Participating Investigator hereby represents and warrants that it shall comply with the local laws of 
Participating Site applicable to clinical studies and will present this protocol to the local ethical 
committee if required by local laws.   
 
 
 
 
 
_________________________  
 
 
____________________ 
Participating Investigator 
Prof. Dr. Ali Alqerban 
 
 
 
 
Date 
 
 

 
 
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Table of Contents 
1. 
Study Synopsis ................................................................................................................................. 5 
2. 
Background and rationale ............................................................................................................... 6 
3. 
Trial objectives and Design .............................................................................................................. 6 
3.1. 
Trial objectives..................................................................................................................... 6 
3.2. 
Primary endpoints ............................................................................................................... 6 
3.3. 
Secondary endpoints ........................................................................................................... 6 
3.4. 
Trial Design .......................................................................................................................... 7 
3.5. 
Study diagram .................................................................................................................... 10 
3.6. 
Trial Flowchart ................................................................................................................... 11 
4. 
Selection and withdrawal of subjects ........................................................................................... 11 
4.1. 
Inclusion criteria ................................................................................................................ 11 
4.2. 
Exclusion criteria ............................................................................................................... 12 
4.3. 
Expected duration of trial .................................................................................................. 13 
5. 
Trial Procedures ............................................................................................................................. 13 
5.1. 
By visit................................................................................................................................ 13 
5.2. 
Laboratory tests................................................................................................................. 15 
5.3. 
Other investigations .......................................................................................................... 15 
6. 
Assessment of efficacy .................................................................................................................. 15 
7. 
Assessment of safety ..................................................................................................................... 16 
7.1. 
Specification, timing and recording of safety parameters ................................................ 16 
7.2. 
Procedures for recording and reporting adverse events (AE) ........................................... 16 
7.3. 
Treatment stopping rules .................................................................................................. 16 
8. 
Statistics ........................................................................................................................................ 16 
8.1. 
Sample size ........................................................................................................................ 17 
8.2. 
Analysis .............................................................................................................................. 17 
9. 
Quality assurance .......................................................................................................................... 18 
10. Direct access to source data and documents ................................................................................ 18 
11. Ethics and regulatory approvals .................................................................................................... 18 
12. Data Handling ................................................................................................................................ 19 

 
 
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13. Data Management ......................................................................................................................... 19 
14. Translational research ................................................................................................................... 19 
15. Publication Policy .......................................................................................................................... 19 
16. Insurance/Indemnity ..................................................................................................................... 20 
17. Financial Aspects ........................................................................................................................... 20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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1. Study Synopsis  
Title of clinical trial 
 
Effect of interceptive strategies on the clinical outcome of 
impacted maxillary permanent canines. 
Protocol Short Title/Acronym 
 
Impacted Canines 
Sponsor name 
 
UZ Leuven 
Principal Investigator 
 
Prof. Dr. Guy Willems 
Medical condition or disease under 
investigation 
 
Maxillary permanent canine impaction 
Purpose of the clinical trial 
 
Prospective interventional study of maxillary permanent 
canines using classic interceptive measures for preventing 
impaction 
Primary objective 
 
To define the most optimal interceptive action for prevention 
of maxillary permanent canine impaction 
Secondary objective (s) 
 
To predict the risk of maxillary permanent canine impaction in 
young children 
Trial Design 
 
International Prospective Interventional Study 
Endpoints 
 
Eruption of maxillary permanent canines into the occlusal 
plane of the dentition. 
Sample Size Estimation 
 
For 80% power, 78 subjects needed in each group (for a 50% 
(nCLA) and 75% success rate (nCLB)). To increase the amount 
of information for the development of a prediction model for 
success at 18 months (2nd aim of the study) we need to 
increase the sample to 100/group (300 patients in total). 
Summary of eligibility criteria 
 
Untreated impacted maxillary canines with incomplete root 
formation, no resorption, no syndromes, no radiotherapy 
Maximum duration of interceptive treatment 
of a subject 
 
6 months 
Minimum duration of interceptive treatment 
follow-up of a subject 
 
6-18 months 
Version and date of final protocol 
 
Version 4.0 April 18, 2016 
Version and date of protocol amendments 
 
 

 
 
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2. Background and rationale 
Maxillary canines contribute significantly to the function and esthetics of the permanent dentition. 
Completion of their development occurs relatively late. The germs are situated high in the maxilla of 
three year old children and canine crowns are mesially and palatally inclined. During eruption, the 
canine migrates down and forward towards the occlusal plane, while the tooth becomes gradually 
more upright until it reaches the distal aspect of the lateral incisor root and the mesial aspect of the 
deciduous canine’s root apex. Deviation from the standard path of eruption leads to maxillary canine 
impaction possibly affecting neighboring tooth structures, i.e. causing mild to severe root resorption. 
Unfortunately, the incidence of maxillary permanent canine impaction is 1 to 3% and its treatment 
often requires surgical intervention. The purpose of surgically exposing the canine is to enable 
correction of the pathological path of eruption by applying orthodontic traction guiding the canine to 
its natural position in the dental arch. Simple interceptive measures taken at early age such as maxillary 
arch expansion or deciduous canine extraction have been advocated as successfully interfering with 
the pathological eruption of maxillary canines, avoiding the need for surgery and reducing the 
orthodontic treatment time and complexity. 
3. Trial objectives and Design 
3.1. Trial objectives and definitions 
The purpose of this study is to detect the differences, if any, between three well known, validated 
interceptive measures in case of maxillary permanent canine impaction, and to prospectively follow 
up on these treated patients until further permanent canine alignment in the dental arch is achieved. 
This long term follow up is necessary in order to evaluate the effects of the interceptive treatment on 
permanent maxillary canine eruption.  
In the present study, a maxillary permanent canine impaction would be defined as the inability of this 
tooth to erupt, failure of eruption, deviation of the canine from its normal eruption pathway or 
retention of the canine in the maxilla. 
Success of a particular interceptive measure would be defined as eruption of the canine without the 
need for surgical intervention and integrity of the adjacent teeth.  
3.2. Primary endpoints 
The primary objective is to search for the most optimal interceptive action to prevent maxillary 
permanent canine impaction. 
3.3. Secondary endpoints 
The secondary objective is to evaluate whether based on the observations of the present study 
prediction of maxillary permanent canine impaction in young children is feasible. 

 
 
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3.4. Trial Design 
The present trial is a non-commercial prospective randomized controlled trial of patients presenting 
with permanent maxillary canine impaction. These patients are selected at the intake consultation of 
the department of Orthodontics, UZ Leuven. A panoramic radiograph is the standard radiographic 
examination procedure at this particular moment in time for visualization of dental development and 
associated pathology. Maxillary permanent canine impaction may be diagnosed based on this 
radiograph by analysing predefined parameters correlated with maxillary permanent canine 
impaction. In case of signs of mild to severe canine impaction, an additional standard long cone apical 
radiograph (LCAR) is taken radial to the dental arch at the estimated normal permanent canine position 
to detect possible root resorption of the adjacent lateral incisor and to document the vertical 
permanent canine position. A CBCT will only be taken in the following two cases: evidence of damage 
to the adjacent teeth and for the purposes of canine exposure surgery. Specific inclusion and exclusion 
criteria are described in paragraph 4.  
 
Patients are stratified based on the presence of a cross bite (Group C) versus no cross bite (Group nC), 
either a frontal or a uni-/bilateral cross bite. Further categorization is performed for both groups C and 
nC into 3 subgroups, A, B and C, depending on the obtained parameters related to canine position and 
angulation. Subgroup CA contains the rather normally positioned canines, indicative for rather normal 
maxillary permanent canine eruption. This group will function as the control group within Group C. 
Badly positioned canines will be categorized into subgroup CB constituting the study group. Finally 
subgroup CC includes those canines that are extremely badly positioned (see paragraph 4) requiring 
specific additional action. 
 
Cross bite group. 
In line with normal standard treatment procedures, the cross bite group (Subgroups CA, CB and CC) 
will receive interceptive maxillary expansion (IME) using the standard techniques that are available 
and commonly applied in the university hospital. Patients in Subgroup CC, after receiving interceptive 
expansion treatment, will be further subjected to extraction of the deciduous canine (EX-III), whenever 
still present in the dental arch, and, depending on the severity of canine angulation and position, of 
the first deciduous molar (EX-IV). Decision for extraction of one or both of these deciduous teeth will 
be the responsibility of the treating dentist who will have to evaluate the clinical circumstances 
presenting in this patient with very badly positioned permanent maxillary canines (Subgroup CC).  
After this IME intervention, including III-EX or not, all patients will be enrolled in a standard follow up 
protocol, requiring a maximum of 3 recall visits at 6, 12 and 18 months. 
 
Non cross bite group. 
The non-cross bite group (Group nC) will be further allocated in two groups based on the available 
space in the dental arch, commonly determined in the discipline of orthodontics with the Arch Length 

 
 
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Discrepancy (ALD) methodology: lack of space (subgroup L) versus normal adequate space (subgroup 
N) for tooth alignment in the dental arch. The lack of space subgroup L may show symptoms of 
inadequate space in the dental arch such as ‘no spacing in the deciduous dentition’, ‘rotated maxillary 
permanent incisors’, ‘space lack for eruption of maxillary permanent lateral incisors’, etc. 
Both categories in this non cross bite group (Group nC), -either lacking space or displaying normal 
adequate space for tooth alignment- will consist of four subgroups, including A, B and C, as detailed 
above, plus subgroup D, in the case of absence of deciduous maxillary canines (due to premature loss 
or extraction).  
 
1. Non cross bite group with lack of space. 
Patients without cross bite but lacking space in the dental arch are subcategorized into the following 
4 subgroups: 
Patients in Subgroup nCLA, constituting patients with no cross bite present but lacking space for 
adequate tooth alignment in the dental arch, will be randomly attributed to one of our three usual 
treatment options, being interceptive maxillary expansion (IME), extraction of the deciduous 
canines (EXIII), or no treatment (CO). The latter will constitute the control group within Group nCLA, 
indicative for maxillary permanent canine eruption in case of lack of space in the dental arch. After 
this interceptive treatment, all the patients will be enrolled in a standard follow up protocol. In case 
of absence of deciduous maxillary canines, randomization will not be possible. These patients will 
still be treated with expansion because of the lack of space and will also be enrolled in subsequent 
follow-up. 
Patients in Subgroup nCLB will also be randomly attributed to one of these three usual treatment 
protocols, being interceptive maxillary expansion (IME), extraction of the deciduous canines (EXIII), 
or no treatment (CO). The latter will constitute the control group within Subgroup nCLB. After this 
interceptive treatment, all the patients will be enrolled in a standard follow up protocol. In case of 
absence of deciduous maxillary canines, randomization will not be possible. These patients will still 
be treated with expansion because of the lack of space and will also be enrolled in subsequent 
follow-up. 
Subgroup nCLC, constituting the patients with no cross bite present but lacking space for adequate 
tooth alignment in the dental arch and with very badly positioned and angulated permanent 
maxillary canine(s), will receive interceptive maxillary expansion (IME) using the standard 
expansion techniques described above and commonly applied in the university hospital. Patients in 
Subgroup nCLC, after receiving interceptive expansion treatment, will be further subjected to 
extraction of the deciduous canine at 6month follow-up, whenever still present in the dental arch, 
as well as, depending on the severity of canine angulation and position, of the first deciduous molar. 
Decision for extraction of one or both of these deciduous teeth will be the responsibility of the 
treating dentist who will have to evaluate the clinical circumstances presenting in this patient with 

 
 
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very badly positioned permanent maxillary canines. Sequence of eruption other than 3-4-5 will also 
constitute a criterion for extraction of these deciduous teeth. 
After this interceptive treatment, which will last for a maximum of 6 months, all patients will be 
enrolled in a standard follow up protocol, requiring a minimum of 3 recall visits at 6, 12 and 18 months. 
2. Non cross bite group with normal adequate space. 
Accordingly, Group nCN will constitute all other eligible patients, consecutively seen at the first 
consultation of the Department of Orthodontics, with one/two impacted permanent maxillary canines 
without cross bite and showing normal adequate space in the dental arch for tooth alignment. Also 
these subjects will be categorized into the three subgroups A, B and C. They will receive no interceptive 
treatment (CO) at all except for subgroup nCNC, constituting of patients with normal alignment and 
adequate amount of space present but presenting with very badly positioned and angulated 
permanent maxillary canines. They will be further subjected to extraction of the deciduous canine (EX-
III), whenever still present in the dental arch, as well as, depending on the severity of canine angulation 
and position, of the first deciduous molar (EX-IV). Decision for extraction of one or both of these 
deciduous teeth will be the responsibility of the treating dentist who will have to evaluate the clinical 
circumstances presenting in this patient with very badly positioned permanent maxillary canines. 
Sequence of eruption in the maxilla other than 3-4-5 (canine, first and second premolar)  will also 
constitute a criterion for extraction of these deciduous teeth 
After this intervention, all patients in this Subgroup nCN will be enrolled in a standard follow up 
protocol, requiring minimum one recall visit at 12 months for follow up of normal eruption, eventually 
a second one after 24 months, provided the maxillary permanent canine is not erupted yet, its root is 
still not completely formed and no other orthodontic treatment needs are present. 
 
All subjects included in this trial will eventually be subjected to the described follow up procedures, 
which are described in more detail in Chapter 5. The follow up procedure is designed in order to detect 
positional changes of the permanent canine position, either spontaneous changes in the control group 
or changes associated with the interceptive measures taken. Follow up is a necessary and standard 
procedure for pointing out impacted canines and their true indication for surgical exposure of this 
tooth.  
 

 
 
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3.5. Study diagram 
 
 * = randomisation 
 = not randomised 

 
 
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3.6. Trial Flowchart 
 
Screen 
visit 
Record 
collection 
Third 
visit 
Follow up 
6 months 
Follow up 
12 months 
Follow up 
18 months 
Follow up 
End result 
Informed consent 
 
X 
 
 
 
 
 
Physical/Oral examination 
X 
 
 
X 
X 
X 
X 
Clinical photograph (if needed) 
 
X 
 
X 
X 
X 
X 
Panoramic radiograph (if needed) 
X 
 
 
 
 
 
X 
Long cone apical radiograph  
(if needed) 
X 
 
 
X 
X 
X 
 
CBCT scan (if needed) 
 
 
 
 
X 
 
 
Identification as potential inclusion 
in the study 
X 
 
 
 
 
 
 
Inclusion in one of the groups and 
randomized treatment assignment 
 
X 
 
 
 
 
 
Start of the assigned treatment 
(expansion, extraction deciduous 
canine/molar or no treatment) 
 
 
X 
X 
X 
X 
 
Surgical exposure of the maxillary 
permanent canine 
 
 
 
 
X 
X 
 
4. Selection and withdrawal of subjects 
4.1. Inclusion criteria 
 General inclusion criteria: 
o Female or male patients coming to the department of Orthodontics of the UZ Leuven 
seeking for orthodontic advice. 
o Presenting with one or two non-fully erupted or impacted maxillary permanent 
canines (If bilateral impaction occurs, categorization into the different protocol 
groups will be based on the canine showing the worst position.) 
o Presenting with one or two maxillary permanent canines showing no more than ¾ 
root formation.  
o Any race 
 In case of cyst around the area of the impacted canine, extraction of the persisting deciduous 
canine will be the treatment of choice. Also these cases will remain in follow up according to 

 
 
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our protocol but will not be randomized or attributed in one or other group.Specific canine 
related inclusion criteria for the allocation of patients in 3 different groups based on the 
presence of a cross bite (Group C), the absence of a cross bite with lack of space in the dental 
arch (Group nCL) and the absence of a cross bite with normal adequate space dimensions 
present in the dental arch (Group nCN): 
o Group C (cross bite present) 
▪ Presence of a cross bite for all three subgroups: uni/bilateral/anterior cross 
bite. If end-to-end cross bite is present or tendency to cross bite, this will be 
considered as cross bite 
▪ Group CA: canine position sector ≤1. 
▪ Group CB: canine position sector >1. 
▪ Group CC: canine position sector >1, canine angulation towards the midline 
≥45°. 
o Group nCL (no cross bite present) 
▪ Absence of cross bite and lack of space in the dental arch. 
▪ Group nCLA: canine position sector ≤1. 
▪ Group nCLB: canine position sector >1. 
▪ Group nCLC: canine position sector >1, canine angulation towards the 
midline ≥45°. 
o Group nCN (no cross bite present and normal space conditions in the dental arch) 
▪ Absence of cross bite and normal space conditions in the dental arch. 
▪ Group nCNA: canine position sector ≤1. 
▪ Group nCNB: canine position sector >1. 
▪ Group nCNC: canine position sector >1, canine angulation towards the 
midline ≥45°. 
4.2. Exclusion criteria 
 Fully erupted permanent canines 
 Previous orthodontic treatment. 
 Canines with completed root formation 

 
 
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 Evidence of root resorption of adjacent teeth or root malformation of the canines that would 
obligate to extract any adjacent teeth or the canine(s). 
 Craniofacial syndromes  
 Systemic disease that would impede orthodontic treatment/surgery 
 Recent exposure to radiotherapy. 
4.3. Expected duration of trial 
The trial will start at the first screening visit, where physical/oral examination will take place. If needed, 
standard radiographic screening images will be taken as well. If the patient is identified as complying 
with the inclusion criteria, a second visit will be programmed for the collection of standard orthodontic 
records and randomization for inclusion in any of the groups. The assigned interceptive treatment will 
start on a third visit. After a maximum of 6 months of interceptive treatment, follow up visits will be 
scheduled after 6, 12 and 18 months. At any of those recalls, if the canine has erupted, the patients 
may opt to start regular orthodontic treatment with fixed appliances if needed or desired (average 
duration of 24 months) and a last follow up visit will be programmed after the end of this treatment 
for evaluation of the final canine position.  
5. Trial Procedures 
5.1. By visit 
Screening visit 
Patients come to our service seeking orthodontic advice. After physical/oral examination, a panoramic 
radiograph will be taken if considered necessary. Patients needing interceptive treatment and 
complying with the selection criteria will be identified.  
Second Visit (Record taking) 
Clinical photographs and orthodontic study casts, constituting normal orthodontic records for 
adequate diagnostics and treatment planning will be taken, as well as a standard long cone apical 
radiograph (LCAR) to determine the position of the canine. Depending on the obtained parameters 
related to canine position and angulation, the patient will be included in one of the groups detailed in 
chapters 3 and 4. The patient and parents will be informed about the need for treatment and they will 
be asked for consent when using the data for the purposes of the study. They will be given the 
informed consent, included in our regular contract for orthodontic treatment, with all the necessary 
details and information.  
Third visit 
If the patient decides to start treatment, the assigned treatment option will start (expansion, 
extraction of deciduous canine/molar or no treatment). Patients in the expansion group will be in 
treatment during a maximum of 6 months taking on average 4 and maximum 6 consultations. After 

 
 
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interceptive treatment with a removable expansion appliance, it might be necessary to wear the 
modified removable appliance at night for an extended period of 2 months. 
Follow up 6 months 
 If the canine has erupted, a revaluation of the specific presenting malocclusion will be 
performed and the need for further orthopedic or fixed appliance treatment will be discussed 
with the patient or his/her parents/guardians. Normal orthodontic treatment can be 
performed if desired. Only at the end of orthodontic treatment or, in case of no treatment 
need, at the end of late mixed dentition transition into permanent dentition, a last follow up 
visit will be planned in order to evaluate the end result. 
 If the canine has not erupted yet, a long cone apical radiograph will be taken for evaluation of 
the canine position and reevaluation will take place after 6 months (= follow up visit 12 
months). 
Follow up 12 months 
 If the canine has erupted, a revaluation of the specific presenting malocclusion will be 
performed and the need for further orthopedic or fixed appliance treatment will be discussed 
with the patient or his/her parents/guardians. Normal orthodontic treatment can be 
performed if desired. Only at the end of orthodontic treatment or, in case of no treatment 
need, at the end of late mixed dentition transition into permanent dentition, a last follow up 
visit will be planned in order to evaluate the end result. 
 If the canine has not erupted yet, a long cone apical radiograph will be taken for evaluation of 
the canine position.  
o If a difference in vertical position is found when comparing with the LCAR taken during 
the last follow up visit, showing positive progression in canine eruption, revaluation 
will take place after 6 months (= follow up visit 18 months). 
o If canine position between 6 and 12 months follow up remains unchanged, a CBCT 
might be indicated to evaluate canine position and its relation to the neighboring 
teeth. Depending on the CBCT evaluation, it might be decided to surgically expose the 
canine, either via a closed or open technique depending on its position. When the 
canine is exposed, further active orthodontic treatment will be needed to guide the 
canine into its position in the dental arch. Only at the end of orthodontic treatment, a 
last follow up visit will be planned in order to evaluate the end result, being the final 
position of the maxillary permanent canine in the dental arch. 
Follow up 18 months 
 If the canine has erupted, a revaluation of the specific presenting malocclusion will be 
performed and, in case this should not have been made already, the need for further 
orthopedic or fixed appliance treatment will be discussed with the patient or his/her 

 
 
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parents/guardians. Normal orthodontic treatment can be performed if desired. Only at the 
end of orthodontic treatment or, in case of no treatment need, at the moment the canine 
reaches its final position in the dental arch, a last follow up visit will be planned in order to 
evaluate the end result. 
 If the canine has not erupted yet, and positive progress was monitored at the 12 months follow 
up visit, a new LCAR will be taken to revaluate canine eruption process, unless clear clinical 
indicators are present witnessing successful path of eruption, i.e. clear bulging of the canine 
crown in the vestibulum or clear canine cusp morphology visible in the buccal mucosa. Patient 
will then be instructed to report for follow up appointment at the time of canine eruption into 
the dental arch or at the latest after 6 months, being an extra 24 months recall. Anyhow, at 
the 18 months follow up visit, a revaluation of the specific presenting malocclusion will be 
performed and the need for further orthopedic or fixed appliance treatment will be discussed 
with the patient or his/her parents/guardians. Normal orthodontic treatment can be 
performed if desired or needed at the time. In this case, further spontaneous canine eruption 
will be monitored during orthodontic treatment. Only at the end of this orthodontic treatment 
or, in case of no further treatment need, at the end of late mixed dentition transition into 
permanent dentition, a last follow up visit will be planned in order to evaluate the end result. 
Follow up End result 
As indicated above, two aspects of interceptive orthodontic treatment will be monitored. First of all 
the process of canine eruption being the maxillary permanent canine perforating the oral mucosa and 
erupting into the dental arch, and second the final position of the canine in the dental arch and its 
occlusion. Evaluation of the final result, eventually after orthodontic treatment, will include esthetics 
as well as functional occlusion and periodontal parameters giving an indication of gingival health. 
Assessment of the following parameters will be made: final position of the canine, final occlusion, root 
integrity of the canine and adjacent teeth, level of gingiva, general esthetic and functional result, 
gingival health. In order to do this, routine final records (clinical pictures, casts, LCAR or panoramic 
radiographs) will be taken as is performed for evaluation of standard orthodontic treatment.  
5.2. Laboratory tests 
Not applicable. 
5.3. Other investigations 
Not applicable. 
6. Assessment of efficacy 
 Primary efficacy parameters  
o Eruption of the canine 
o Integrity of the roots of adjacent teeth 

 
 
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 Secondary efficacy parameters  
o Improvement of canine angulation (root and crown tip) 
o In case of expansion or extraction of the deciduous canines:  
▪ Improvement of transversal and sagittal occlusion 
7. Assessment of Safety 
7.1. Specification, timing and recording of safety parameters 
The following measures will be used to determine subject safety during the study: 
 Physical/oral examination 
 Radiographic examination 
 Frequent follow up 
 Adverse event reporting 
7.2. Procedures for recording and reporting adverse events (AE) 
Every visit is officially reported in the patient’s file in order to identify possible problems and keep a 
track of them. In case of impacted canines, the major adverse event that could possibly occur is root 
resorption of the adjacent teeth, which is most of the time unpredictable and even inevitable. In case 
of such inevitable events, everything will be done to limit the possible damage, including prioritizing 
surgical exposure of the canine in an effort to reduce the damage, or even extraction of the lateral 
incisor/s in case of advanced root resorption. However, there is no evidence on existing predictors of 
this situation. In other words, resorption of the lateral incisors remains unpredictable. 
7.3. Treatment stopping rules 
Treatment or follow up will immediately stop when compliance of the patient becomes a problem or 
when for one or other reason, the patient or his/her parents/guardians want to discontinue follow 
up/treatment: 
 The patient does not comply with treatment (does not follow the given instructions, misses 
the appointments). 
 The patient’s poor levels of oral hygiene compromise the health of the teeth and/or 
surrounding soft tissues. 
 The patient wishes to stop treatment.  
8. Statistics 
Measures taken to minimize bias: 

 
 
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 Allocation concealment: randomization of the treatment options by a randomization list. 
 Blinding measures: measurements of canine inclination on OPG will be taken by two 
operators, blinded to each other’s measurements as well as to the name of the patient, 
treatment followed or occlusion details. 
 Previous power calculation 
8.1. Sample size 
Randomisation into expansion, extraction and control will be applied for patients without cross-bite 
having lack of space and – based on canine position and angulation - belonging to strata nCLB and 
nCLA. Within each of both strata, a randomisation will be performed using permuted blocks of varying 
size, yielding an equal number of patients in each of the three groups.  
Success of the approach is defined as eruption without necessity of surgical intervention and integrity 
of the roots of the adjacent teeth. The primary endpoint is defined as the percentage success after 18 
months. The trial is powered to show a difference between any of the pairs of groups. To have at least 
80% power to show a higher success rate in one group compared to the other group, there are 78 
subjects needed in each group assuming a success rate of 50% in the first group and 75% in the second 
group. The calculation is based on a two-sided χ²-test with alpha set at 0.05/3=0.0167 to control the 
family-wise error rate at 5% (3 pairwise comparisons). However, to increase the amount of information 
for the development of a prediction model for success at 18 months (cfr. second aim of the study) it 
has been decided to increase the number of patients to  100 per group (300 patients in total).  
8.2. Analysis 
The analysis of the primary endpoint will be based on a stratified χ²-test using a Bonferroni-Holm 
correction to correct for multiple testing (the strata are nCLB and nCLA). The same approach will be 
used for the comparison at the earlier timepoints (6 and 12 months). No interim analyses are planned, 
neither for efficacy, nor for futility. The analysis will be performed on an intent-to-treat basis. 
A multivariable logistic regression model will be used to predict maxillary permanent canine impaction 
(=lack of success) on all included subjects. A backward selection procedure will be applied with 0.157 
as critical level for the p-value. This critical value corresponds to the use of the Aikake Information 
Criterion (AIC) for model selection. With AIC we require that the increase in model χ² has to be larger 
than two times the degrees of freedom. This strategy provides a trade-off between erroneous 
inclusion and exclusion of covariates in a prediction model (Sauerbrei W. The use of resampling 
methods to simplify regression models in medical statistics. Applied Statistics1999;48 (3):313–329.). 
The considered predictors are: strata formed by presence of cross-bite and parameters related to 
canine position and angulation, non-eruption, interceptive strategy, patient’s age, stage of canine root 
formation, premature loss of deciduous teeth, familial history, space deficiency (arch length 
discrepancy). 

 
 
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As a sensitivity analysis, the prediction model will also be applied separately on the patients from the 
randomized and non-randomized part of the study. 
 
9. Quality assurance 
During this randomized clinical trial only standard operating procedures will be employed, such as i.e. 
removable expansion device, fixed expansion device, headgear, etc.. They are all validated, thoroughly 
described and widely used techniques. It will be up to the treating professional to decide for a given 
case which procedure to follow, in line with existing traditions in the specific collaborating centres. 
However, the main purpose should be attained which is expansion or in other words gaining extra 
space for tooth alignment. Depending on the interceptive treatment to be accomplished, decision will 
be taken to employ one specific treatment protocol to reach the goal set forward. 
 
Randomisation will only be used when the different treatment options could be equally beneficial to 
the patient, with the objective of identifying possible differences in treatment outcomes. There is no 
new intervention to test, which minimizes the risk for negative impact.  
10. Direct access to source data and documents 
The investigators and the involved institutions will permit trial-related monitoring, audits, EC review, 
and regulatory inspections (where appropriate) by providing direct access to source data and other 
documents (i.e. patients’ case sheets, X-ray reports, etc.).  
11. Ethics and regulatory approvals 
The trial will be conducted in compliance with the principles of the Declaration of Helsinki (2013), the 
principles of GCP and in accordance with all applicable regulatory requirements. This protocol and 
related documents will be submitted for review to the Ethics Committee of the UZ/KU Leuven for 
Clinical Trial Authorization. 
 
The Study can and will be conducted only on the basis of prior informed consent by the Subjects, or 
their legal representatives, to participate in the Study. The Participating Site shall obtain a signed 
informed consent form (ICF) for all patients prior to their enrolment and participation in the Study in 
compliance with all applicable laws, regulations and the approval of the UZ/KU Leuven Ethics 
Committee. The Participating Site shall retain such ICFs in accordance with the requirements of all 
applicable regulatory agencies and laws. 
 
The Investigator and the Participating Site shall treat all information and data relating to the Study 
disclosed to Participating Site and/or Investigator in this Study as confidential and shall not disclose 

 
 
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such information to any third parties or use such information for any purpose other than the 
performance of the Study. The collection, processing and disclosure of personal data, such as patient 
health and medical information is subject to compliance with applicable personal data protection and 
the processing of personal data (Directive 95/46/EC and Belgian law of December 8, 1992 on the 
Protection of the Privacy in relation to the Processing of Personal Data). 
 
In this study, data will be coded. 
 
(Data are anonymous if no one, not even the researcher, can connect the data to the individual who 
provided it. No identifying information is collected from the individual. 
When data are coded, there continues to be a link between the data and the individual who provided 
it. The research team is obligated to protect the data from disclosure outside the research according to 
the terms of the research protocol and the informed consent document. The subject’s name or other 
identifiers will be stored separately from their research data and replaced with a unique code to create 
a new identity for the subject, as coded data are not anonymous.) 
12. Data Handling 
The patient’s data (radiographs, follow up reports, …) will be stored in the patient’s electronic folder, 
without linking it to the study. A randomization list will be electronically made in order to manage the 
allocation of the patients. Everything related to the University Hospitals Leuven patient treatment will 
be stored on the University Hospitals Leuven database. In case of further use of the data (for statistical 
purpose, etc.), the identity of the patients will remain anonymous.  
13. Data Management 
All data will be managed electronically, except for the informed consent (included in our regular 
contract for orthodontic treatment), a copy of which will be printed in paper for the patient and 
parents. A signed copy will be electronically saved with the rest of the data in the University Hospitals 
Leuven database.  
14. Translational research 
No biological material will be collected/shipped/stored/used for the study. 
15. Publication Policy 
As it is an international multicentre trial: 
 
It is anticipated that the results of the overall Study will be published in a multi-centre publication, 
involving the data of all clinical sites participating in the Study. 

 
 
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The Participating Site is not allowed to publish any data or results from the Study prior to the 
multicentre publication, provided however that Participating Site is allowed to publish the results 
generated at the Participating Site if the multicentre publication has not occurred after 12 months 
from Study database lock. 
Any publication by Participating Site will be submitted to the Sponsor for review at least thirty (30) 
days prior to submission or disclosure. Sponsor shall have the right to delay the projected publication 
for a period of up to three (3) months from the date of first submission to the Sponsor in order to 
enable the Sponsor to take steps to protect its intellectual property rights and know-how.  
Publications will be coordinated by the Investigator of Sponsor. Authorship to publications will be 
determined in accordance with the requirements published by the International Committee of Medical 
Journal Editors and in accordance with the requirements of the respective medical journal. 
16. Insurance/Indemnity 
In accordance with the Belgian Law relating to experiments on human persons dated May 7, 2004, 
University Hospitals Leuven shall assume, even without fault, the responsibility of any damages 
incurred by a Study Patient in the Leuven Centre and linked directly or indirectly to the participation 
to the Study, and shall provide compensation therefore through its insurance. 
 
If an insurance coverage is required by local laws of Participating Site, the Participating Site shall have 
and maintain in full force and effect during the term of this Agreement (and following termination of 
the Study to cover any claims arising from the Study) adequate insurance coverage for possible 
damages linked directly or indirectly to the patients’ participation to the Study at Participating Site. 
 
17. Financial Aspects 
There are no financial issues, meaning that this randomized clinical trial is not financially supported by 
any third party. Every Participating Site will manage its randomized clinical trial autonomously.