Class II Correction Study Using the Invisalign System
Phase: NA
Conditions: Malocclusion
Sponsor: Align Technology, Inc.

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning 
Feature (MRF)  
 
        Protocol Number: MRF-002   
  
  
Rev H  
 
 
 
 
 
     1   
 
 
 
NCT02376829 
ALIGN CONFIDENTIAL  
 
 
07-02-2018 
 
  
                                                               CSP-300291-00  
Sponsor:  
Align Technology, Inc.  
2820 Orchard Parkway  
San Jose, CA 95134  
(408)-470-1000  
Amendment No.:  
H (Continued Access)   
   
 

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning 
Feature (MRF)  
 
        Protocol Number: MRF-002   
  
  
Rev H  
 
 
 
 
 
     2   
 
 
 
NCT02376829 
ALIGN CONFIDENTIAL  
 
 
07-02-2018 
 
  
INVESTIGATOR SIGNATURE PAGE  
 Invisalign System with Buccal and Occlusal Mandibular Repositioning Feature  
  
  
  
Approved by:  Victor Chen  
  
  
Victor Chen   
  
_________________________  
         ________  
Director of Clinical Affairs  
Signature  
  
  
           Date  
  
Investigator signature:  
I confirm that I have read and will follow this protocol.  I understand it, and I will work according to the 
principles of Good Clinical Practices (GCP) as described in the ICH E6, Good Clinical Practice: 
Consolidated Guidelines and in the United States Code of Federal Regulations (CFR) – 21 CFR parts 50  
(Protection of Human Subjects), 56 (Institutional Review Boards), and 812 (Investigational Device 
Exemptions). Further, I will conduct the study in keeping with any other federal, state, local, and 
institutional legal and regulatory requirements.  
  
Investigator   
  
 
________________________  
_________________________  
________  
 
Print name  
Signature  
  
  
  
Date  
 
 

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning 
Feature (MRF)  
 
        Protocol Number: MRF-002   
  
  
Rev H  
 
 
 
 
 
     3   
 
 
 
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07-02-2018 
 
  
  
 
Table of Contents  
  
INVESTIGATOR SIGNATURE PAGE ................................................................................................. 2 
1. INTRODUCTION AND BACKGROUND ......................................................................................... 5 
1.1 Background ........................................................................................................................................ 5 
2. DESCRIPTION AND INDICATIONS FOR USE ............................................................................. 5 
2.1 Device Description ............................................................................................................................ 5 
2.2 Invisalign Intended Use ..................................................................................................................... 6 
3. STUDY PURPOSE AND OBJECTIVES ............................................................................................ 6 
3.1 Study Objectives ................................................................................................................................ 6 
3.2 Definitions ......................................................................................................................................... 7 
4. STUDY DESIGN ................................................................................................................................... 9 
4.1 Overview of Study Design ................................................................................................................ 9 
4.1.1 Materials ..................................................................................................................................... 9 
4.1.2 Methods ..................................................................................................................................... 10 
4.1.3 End Study .................................................................................................................................. 14 
4.2 Number of Subjects/ Assignment to Treatment Groups .................................................................. 14 
4.3 Sites ................................................................................................................................................. 14 
4.4   
Subject Withdrawal .................................................................................................................... 15 
5. DATA COLLECTION PLAN ............................................................................................................ 15 
6. DATA ANALYSIS ............................................................................................................................... 15 
6.1 Primary endpoint analysis: .............................................................................................................. 15 
6.2 Sample Size Calculation .................................................................................................................. 16 
7. SAFETY INSTRUCTIONS AND GUIDANCE ............................................................................... 16 
7.1 Clinical Adverse Events .................................................................................................................. 16 
7.1.1 Assessment of Adverse Events................................................................................................... 17 
7.1.2 Treatment and Follow-up of AEs .............................................................................................. 17 
7.2 Handling of Safety Parameters ........................................................................................................ 17 
7.2.1 Reporting of Adverse Events ..................................................................................................... 17 
7.3 Study Risks and Benefits ................................................................................................................. 18 
8. POTENTIAL SUBJECT RISKS AND BENEFITS ......................................................................... 18 
8.1.1 Potential Subject Risks.............................................................................................................. 18 

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning 
Feature (MRF)  
 
        Protocol Number: MRF-002   
  
  
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8.1.2 Potential Subject Benefits ......................................................................................................... 18 
9. STUDY COMPENSATION ............................................................................................................... 18 
9.1 For the Investigator .......................................................................................................................... 18 
9.2 Study Related Costs ......................................................................................................................... 19 
10. SUBJECT CARE ............................................................................................................................... 19 
11. ETHICAL ASPECTS ........................................................................................................................ 19 
11.1 Local Regulations/Declaration of Helsinki ................................................................................... 19 
11.2 Informed Consent .......................................................................................................................... 19 
11.3 Institutional Review Board ............................................................................................................ 19 
12. CONDITIONS FOR MODIFYING THE PROTOCOL ............................................................... 19 
13. CONDITIONS FOR TERMINATING THE STUDY ................................................................... 20 
14. STUDY DOCUMENTATION, CRFS AND RECORD KEEPING .............................................. 20 
14.1 Investigator's Files / Retention of Documents ............................................................................... 20 
14.2 Source Documents and Background Data ..................................................................................... 20 
14.3 Audits and Inspections................................................................................................................... 21 
14.4 Case Report Forms ........................................................................................................................ 21 
15. MONITORING THE STUDY .......................................................................................................... 21 
16. CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS ...................... 21 
17. PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS ................................ 22 
18. REFERENCECS: .............................................................................................................................. 22 
19. TABLE 1: SCHEDULE OF  ASSESSMENTS ............................................................................... 24 
 
  
 
 

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning 
Feature (MRF)  
 
        Protocol Number: MRF-002   
  
  
Rev H  
 
 
 
 
 
     5   
 
 
 
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07-02-2018 
 
  
1. INTRODUCTION AND BACKGROUND  
1.1 Background  
In 1945, Dr. H.D. Kesling envisioned that one day modern technology would enable the use of a series of 
tooth positioners to produce the kinds of movements required for comprehensive orthodontic treatment. 
Technology has made this vision a reality. Using advanced computer technology, Align Technology Inc. 
generates Invisalign®, a series of customized clear appliances, called "aligners." Each aligner is worn 
sequentially by the patient to produce extensive tooth movements in both upper and lower arches.  
Class II malocclusions are often characterized by mandibular retrognathia and increased overjet. In 
patients with Class II malocclusions that are undergoing growth, appliances that reposition the mandible 
in a forward position can be used to correct class relationship. Such appliances include the Clark twin 
block, Bionator, Mandibular Anterior Repositioning Appliance (MARA), and Herbst (Figure 1). 
Numerous clinical studies have demonstrated the effectiveness of such appliances in treating Class II 
malocclusions, as indicated by improved overjet, molar relationship, canine relationship, and/or 
orthopedic changes (Siara-Olds 2010, O’Brien 2004, Pangrazio-Kulbersh 2003). The aim of these 
appliances is to maintain the lower jaw in a forward position for as long as the appliances are worn, such 
that orthopedic and/or postural changes can take place to correct the patient’s occlusion to a Class I by 
the end of the appliance treatment.  
Most existing Class II appliances reposition the mandible in one step, such that the patient’s jaw is 
positioned at the desired final position (or an overcorrected position) throughout the course of treatment. 
An alternative to this method is incremental repositioning, in which the total amount of A-P correction is 
divided into multiple steps. This method has been shown to be effective with the Clark Twin Block 
therapy (Banks 2004), and one advantage to this method is increased patient comfort especially at the 
start of therapy.  
  
2. DESCRIPTION AND INDICATIONS FOR USE  
2.1 Device Description  
The Invisalign® System consists of a series of clear plastic aligners that are intended to replace 
conventional wire and bracket technology for many orthodontic cases.  Each custom manufactured aligner 
exerts gentle, continuous forces to move teeth incrementally from their original state to a final, treated 
state.  Each aligner is worn for about two weeks, then replaced by the next in the series until the final 
position is achieved.  For years, orthodontists and dentists have used removable appliances for orthodontic 
treatment. Today, with the application of computer technology and custom manufacturing, Invisalign 
treats a broader range of cases with greater precision.   

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning 
Feature (MRF)  
 
        Protocol Number: MRF-002   
  
  
Rev H  
 
 
 
 
 
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The Invisalign System with buccal and occlusal Mandibular Repositioning Feature (MRF) are 
removable devices that consist of an aligner with two ramps (blocks), upper and lower, which interlock 
on the occlusal or buccal planes (Figure 2).  The upper and lower ramps are designed to interlock in such 
a manner that the mandible is held in a more protrusive position.  The repositioning of the mandible can 
be done sequentially in multiple increments (steps), in order to meet the doctor’s treatment goal.  The 
Invisalign System with MRF is made from the SmartTrack material, a clear thermoplastic and utilizes 
current Invisalign System manufacturing processes.  
  
  
The following reference and guidance documents are utilized in the development of the Align’s Quality 
Manual and Standard Operating Procedures, and this protocol:  
• 
ISO 9001-2009– Quality Management Systems- Guidelines for performance improvements  
• 
ISO 13485:2003 – Medical Devices-Quality Management Systems- Requirements for 
regulatory purposes  
• 
U.S. Code of Federal Regulations, Title 21, Part 812: Investigational Device Exemptions  
• 
U.S. Code of Federal Regulations, Title 21, Part 820 – Quality System Regulation  
• 
SOR/98-282 - Canadian, Medical Device Regulation- P.C. 1998 - 783, 7 May 1998  
• 
EN ISO 14971:2012 Medical Devices-Application of Risk Management to Medical Devices 
(ISO 14971:2007 corrected version 2007-10-01)  
2.2 Invisalign Intended Use  
The Invisalign® System is indicated for the alignment of teeth during orthodontic treatment of 
malocclusion.  
3. STUDY PURPOSE AND OBJECTIVES   
3.1 Study Objectives  
To demonstrate that growing teenagers which present up to full cusp Class II malocclusions can be 
treated using Invisalign with MRF. The primary objective of the study will be to demonstrate that 
Invisalign with MRF is not inferior to existing functional appliances to treat up to full cusp Class II 
malocclusions in growing teenagers. The objective will be met if Invisalign aligners with MRF correct 
Class II malocclusions at a rate that is not inferior to previously reported repositioning rates.  This will 
be achieved if the median rate of correction using Invisalign with MRF at the end of mandible 
repositioning is non-inferior to published rates of movement (e.g. 0.42 mm/mo. for Dynamax) 
(Thiruvenkatachari, Sandler et al.)  to a confidence level of 80%.  The rate of movement will be 

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning 
Feature (MRF)  
 
        Protocol Number: MRF-002   
  
  
Rev H  
 
 
 
 
 
     7   
 
 
 
NCT02376829 
ALIGN CONFIDENTIAL  
 
 
07-02-2018 
 
  
measured by measuring overjet over time. (Initial overjet vs. overjet at the end of mandible 
repositioning).  
Secondary objectives will include demonstration that Invisalign treatment with MRF can be completed 
predictably with both buccal and occlusal configurations. The secondary endpoints will be measured by 
comparing length of treatment to the predicted ClinCheck treatment plan. Additionally, validation of 
subjects dental and jaw positioning will be assessed via comparisons of subject’s photos and 
radiographs. Both subject and doctor perception will be assessed.   
All statistical comparisons will be conducted to an 80% confidence level.   
3.2 Definitions  
Term or Abbreviation  
Definition  
AE  
Adverse event  
A-P   
Type of anterior-posterior orthodontic 
malocclusion treatment correction  
Buccal  
Surfaces of crowns of teeth that face away 
from the tongue (toward the lips or toward the 
cheek)  
Class II Malocclusion  
A type of orthodontic malocclusion  
CRF  
Case Report Form  
FDA  
Food and Drug Administration  
IRB  
Institutional Review Board  
Investigator  
The person responsible for the conduction of 
this study at each individual site.  This will be 
the treating orthodontist. The term  
“Investigator” is used synonymously in this 
Protocol with “Principle Investigator”, 
“Orthodontist” and “Doctor”.  

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning 
Feature (MRF)  
 
        Protocol Number: MRF-002   
  
  
Rev H  
 
 
 
 
 
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IO   
Intraoral scans  
IPR  
Interproximal Reduction   
Midcourse Correction or Refinement  
Invisalign system secondary orders are 
MidCourse 
Correction 
(MCC) 
or 
Refinement to complete treatment goals  
Occlusal  
Surfaces of crowns of teeth an arch that contact 
the opposing arch   
OPG  
Panoramic radiograph  
PVS  
An orthodontic impression material (polyvinyl 
siloxane material)  
SAE  
Serious adverse event  
SLA  
Stereolithography  
Sponsor  
Align Technology, Inc.  
Study Monitor or Clinical Research 
Associate (CRA)  
Person from the Sponsor who monitors the 
study data for completeness, accuracy through 
on site visits, remote monitoring, etc.  
TMD  
Temporomandibular joint dysfunction  
MRF  
Mandibular Repositioning Feature  
SOP  
Standard Operating Procedure  
  
 
 

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning 
Feature (MRF)  
 
        Protocol Number: MRF-002   
  
  
Rev H  
 
 
 
 
 
     9   
 
 
 
NCT02376829 
ALIGN CONFIDENTIAL  
 
 
07-02-2018 
 
  
4. STUDY DESIGN  
4.1 Overview of Study Design  
This study is a prospective, non-randomized Investigational Device Exemption study.  It is designed to 
measure how safely and effectively Class II malocclusions are corrected in teenagers by repositioning 
the mandible.  It will also examine how efficiently the repositioning will occur.  There are  different 
mandibular repositioning features with the Invisalign System.  The designs will be observed in the 
following two groups.    
• 
Subjects wearing buccal MRF (designated as B1)  o Subjects wearing buccal with 
rib feature MRF (designated as B2)  
• 
Subjects wearing occlusal MRF (designated as O1)  
During the course of treatment, Investigators will monitor the use of the MRF in subjects and complete 
case report forms.  Monitoring of the cases and completion of the case report forms will continue 
throughout the treatment of the Class II to Class I correction as well as through to the subject’s end of 
Invisalign treatment or withdrawal from the study.  Data from this correction will be analyzed and may 
be used for publication or regulatory purposes.  After the use of the Invisalign aligners with  MRF 
portion of treatment is completed, the subject will continue with their Invisalign treatment through to the 
end of treatment for the final study visit.  
Additional Prospective and Retrospective Follow-Up will be collected to provide additional data on the 
impact of breakage and deformation on the treatment outcome.  This data collection will coincide with 
the 3 and 6 month follow-up periods of the IDE clinical study.  The data collected will be similar to that 
obtained at follow up visits.   
All study subjects will be treated with Invisalign aligners that have been modified to meet the study 
requirements.  All sites will be monitored by the Sponsor in accordance to the monitoring plan.  All data 
collected will be analyzed by the Sponsor or a designated statistician.  
This modified protocol provides continued access to the Study devices until FDA clearance is granted.  
All participating Investigators and designated office coordinators will be trained on the clinical study 
protocol and good clinical practices (GCP) by representatives of the Sponsor.   
4.1.1 Materials  
The cases will be submitted and fabricated at Align Technology, Inc. with the same material as that is 
currently used on normal Invisalign patient cases (SmartTrack material).    

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning 
Feature (MRF)  
 
        Protocol Number: MRF-002   
  
  
Rev H  
 
 
 
 
 
     10   
 
 
 
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ALIGN CONFIDENTIAL  
 
 
07-02-2018 
 
  
4.1.2 Methods  
Clinical and diagnostic methods to be used during this study are those which are routinely used in the 
diagnosis and treatment of malocclusions including, intraoral and extraoral photos, panoramic, 
cephalometric radiographs, and bite registrations. Investigators will also complete case report forms at 
each follow-up period as part of this study.   
Inclusion Criteria:    
A subject will be considered eligible if all of following inclusion criteria are fulfilled:  
• 
Subject must have fully erupted dentition* excluding second premolars (5s), 2nd and 3rd 
molars  
• 
Age range 11-19 years old   
• 
Subject that requires bilateral Class II correction and must require at least 3mm of correction 
as measured by first molar relationship   
Exclusion Criteria:  
A subject will be considered ineligible if any one of following exclusion criteria are fulfilled:  
• 
Subject who has unerupted, erupting, partially erupted dentition (except unerupted second 
premolars with less than half root development, for 2nd and 3rd molars)   
• 
Subject who has spaces between adjacent teeth larger than 3mm   
• 
Subject with active caries  
• 
Subject with periodontal disease   
• 
Subject does not have at least 1st molar fully captured in PVS impression or intraoral scan.   
• 
Subject with TMD symptoms    
• 
Subject has undergone pre-treatment with any sagittal orthodontic appliance  
• 
Subject has undergone pre-treatment with any orthodontic appliance 1 year prior to enrollment in 
the study   
• 
Subject has known allergy to latex and plastic   
• 
Subjects who are pregnant or will become pregnant during treatment   
  
*Subject may have Es present with primary root structure with congenitally missing 5s or with unerupted 
5s which have approximately less than half of the permanent root development. The Es should be 
approximately 1 year from exfoliation and that the MRF appliance can be worn for at least 1 year without 
exfoliation or loss of the Es (and thus eruption of the 5s).  Es = primary second molars.  5s  
= permanent second premolars  
All subjects are free to withdraw from the study at any time without stating a reason or suffering from 
any disadvantage. In addition, the Sponsor or Investigator may exclude subjects subsequently due to the 
following reasons:  

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning 
Feature (MRF)  
 
        Protocol Number: MRF-002   
  
  
Rev H  
 
 
 
 
 
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• 
Non-compliance to the study protocol  
• 
Intolerable health state of the subject  
• 
Administrative reasons  
• 
Inability to use the product  
Group Assignment   
Treating doctor will choose which feature (either  Buccal, or Occlusal feature) that he/she wishes to have 
placed on each of the subjects enrolled into the study. The subject should be with the chosen feature 
throughout treatment unless there are clinical reasons to switch instead of being excluded from the 
study.   
Schedule of Study Visits  
Screening  
Subjects must be screened before enrollment in the study. Screening procedures by the investigator will 
include the following:  
1. Perform a dental history exam  
2. Review inclusion and exclusion criteria (Eligibility criteria)  
3. Inform subject and obtain written informed consent  
  
Initial Visit   
Initial visit procedures and tasks will include the following:  
1. Prescription form: Standard Invisalign Full or Teen prescription form for orthodontic treatment.  
2. Impression or Intraoral Scan: This is an impression taken either with an Intraoral iTero™ Optical 
scanner or using PVS material. An intraoral scan is a 3-dimensional optical digital scan of 
subjects dentition which is captured using the iTero™ scanner and a PVS impression is a model 
of subject’s dentition using polyvinyl siloxane material.  
3. Protrusive bite registration: Incisal edge to edge bite, a record of the jaw relationship when 
incisal surfaces of the maxillary anterior teeth meet the incisial edges of the mandible’s anterior 
teeth. The bite registration can be taken with the IO Scanner or PVS material.   
4. Panoramic radiograph: Full mouth x-ray view of the upper and lower dentition which displays a 
2-dimensional image of subjects teeth and roots. Must be taken within 1 year of enrollment.   
5. Lateral cephalogram: Sagittal x-ray of the subject’s profile. Must be taken within 1 year of 
enrollment.   
6. Intraoral photos:   

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning 
Feature (MRF)  
 
        Protocol Number: MRF-002   
  
  
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a. Six (6) views of the subject’s intraoral dentition with centric occlusion-upper occlusal, 
lower occlusal, right buccal, left buccal, anterior and anterior overjet  
b. Three (3) views with incisal edge to edge bite- right buccal, left buccal, and anterior  
7. Extraoral Photos: Includes 3 views of the subject’s face (smile, profile, and repos)  
8. Case Report Form: Enrollment Form  
  
Aligner Delivery Visit  
1. Deliver Aligners: Give the prescribed aligners to the subject and instruct them on how to wear 
the aligners with MRF features  
2. Subject (QoL) Form: To be filled out by the subject.   
 
 3 Months After Start of Mandibular Advancement 
For prospective patients, all records must be collected at time of visit. For retrospective patients, please 
provide any available photos or scans obtained from the follow up visit, and complete the Mandibular 
Advancement Treatment Progress Form. 
1. PVS Impression or Intraoral Scan: This is an impression taken either with an Intraoral iTero™ 
Optical scanner or using PVS material. An intraoral scan is a 3-dimensional optical digital scan of 
subjects dentition which is captured using the iTero™ scanner and a PVS impression is a model of 
subject’s dentition using polyvinyl siloxane material.  
2. Intraoral photos:  
a. Six (6) views of the subject’s intraoral dentition with centric occlusion, lower occlusal, right 
buccal, left buccal, anterior and anterior overjet) 
b. Three (3) views with aligners (anterior smile, right buccal and left buccal) 
3. Extraoral Photos: Includes three (3) views of the subject’s face (smile, profile, and repose) 
4. Case Report Form: Mandibular Advancement Progress Form (3 month)  
 
6 Months After Start of Mandibular Advancement 
For prospective patients, all records must be collected at time of visit. For retrospective patients, please 
provide any available photos or scans obtained from the follow up visit, and complete the Mandibular 
Advancement Treatment Progress Form. 

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning 
Feature (MRF)  
 
        Protocol Number: MRF-002   
  
  
Rev H  
 
 
 
 
 
     13   
 
 
 
NCT02376829 
ALIGN CONFIDENTIAL  
 
 
07-02-2018 
 
  
1. PVS Impression or Intraoral Scan: This is an impression taken either with an Intraoral iTero™ 
Optical scanner or using PVS material. An intraoral scan is a 3-dimensional optical digital scan of 
subjects dentition which is captured using the iTero™ scanner and a PVS impression is a model of 
subject’s dentition using polyvinyl siloxane material.  
2. Intraoral photos:  
a. Six (6) views of the subject’s intraoral dentition with centric occlusion (upper occlusal, lower 
occlusal, right buccal, left buccal, anterior and anterior overjet) 
b. Three (3) views with aligners (anterior smile, right buccal and left buccal). 
3. Extraoral Photos: Includes 3 views of the subject’s face (smile, profile, and repose) 
4. Case Report Form: Mandibular Advancement Progress Form (6 month) 
 
End of Mandible Repositioning (Class II to Class I Correction)-MCC/Refinement  
End of mandible repositioning is defined as the point at which the Class II malocclusion is corrected to 
Class I. MCC/Refinement orders should be submitted for patients at this time to request additional 
Invisalign aligners for subjects.  
1. Prescription form: Standard Invisalign prescription form for MCC/Refinement   
2. PVS Impression or Intraoral Scan: This is an impression taken either with an Intraoral iTero™ 
Optical scanner or using PVS material. An intraoral scan is a 3-dimensional optical digital scan 
of subjects dentition which is captured using the iTero™ scanner and a PVS impression is a 
model of subject’s dentition using polyvinyl siloxane material.  
3. Bite registration: Centric occlusion bite, a record of the jaw relationship when the subject’s upper 
and lower jaws are positioned to the subject’s habitual bite.  
4. Panoramic radiograph:  Full mouth x-ray view of the upper and lower dentition which displays a 
2-dimensional image of subjects teeth and roots.  
5. Lateral cephalogram: Sagittal x-ray of the subjects profile.  
6. Intraoral photos:   
a. Six (6) views of the subject’s intraoral dentition with centric occlusion- upper 
occlusal,lower occlusal, right buccal, left buccal, anterior and anterior overjet.  
b. Three (3) views with aligners (anterior smile, right buccal and left buccal)  
      7. Extraoral Photos: Includes 3 views of the subject’s face (smile, profile, and repose).  
8. Case Report Form: End of Mandible Repositioning Phase Form.  

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning 
Feature (MRF)  
 
        Protocol Number: MRF-002   
  
  
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9. Subject (QoL) Form: To be filled out by the subject.  
  
Final Visit/ Withdrawal From Study  
Final visit procedures and tasks will include the following:  
1. PVS Impression or Intraoral Scan: This is an impression taken either with an Intraoral iTero™ 
Optical scanner or using PVS material. An intraoral scan is a 3-dimensional optical digital scan 
of subjects dentition which is captured using the iTero™ scanner and a PVS impression is a 
model of subject’s dentition using polyvinyl siloxane material.  
2. Bite registration: Centric occlusion bite, a record of the jaw relationship when the subject’s upper 
and lower jaws are positioned to the subject’s habitual bite.  
3. Panoramic radiograph: Full mouth x-ray view of the upper and lower dentition which displays a 
2-dimensional image of subjects teeth and roots.  
4. Lateral cephalogram: Sagittal x-ray of the subject’s profile.   
5. Intraoral photos:  
a. Six (6) views of the subject’s intraoral dentition with centric occlusion- upper occlusal, 
lower occlusal, right buccal, left buccal, anterior and anterior overjet.  
6. Extraoral Photos: Includes 3 views of the subject’s face (smile, profile, and repose) 
7. Case Report Form: End of Treatment Form.   
8. Subject QoL Form: To be filled out by subject. For additional details see Table 1 at the end of 
this document.   
4.1.3 End Study  
The End of Study occurs when a subject has completed all study related visits.  When all subjects have 
completed the study, a report will be written concluding the findings from the study.  
4.2 Number of Subjects/ Assignment to Treatment Groups  
This study will enroll up to 165 patients. It is recommended that each site enroll a minimum of 10 
subjects, to facilitate pooling of the data.  It is recommended that each site recruits a minimum of 1 
subject to have the occlusal feature set and a minimum of 1 subject to have the buccal feature set.   
4.3 Sites  
This study will be conducted at multiple sites in North America.  

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning 
Feature (MRF)  
 
        Protocol Number: MRF-002   
  
  
Rev H  
 
 
 
 
 
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4.4   
Subject Withdrawal   
Subjects have the right to withdraw from the study at any time for any reason. The Investigator or 
Sponsor may withdraw the subject at any time for any reason.  If any subject withdraws or is withdrawn 
from the study, any non-study records that were taken while the subject was enrolled in the study will 
not be shared with the study Sponsor and there will be no requirement to continue treatment according to 
this protocol.  Withdrawal from the study will not result in any penalties and will not preclude or 
interfere with the investigator’s treatment of the subject outside of the study. Additional subjects may be 
enrolled to substitute for any withdrawn subject until the study target enrollment is reached.  
If MRF cannot be placed, the subject will be removed from the study, and be revaluated; and the 
Invisalign setup will be normal Invisalign treatment as prescribed by the treating doctor.   
5. DATA COLLECTION PLAN   
The schedule of all study activities and procedures is provided in Table 1. Bold text indicates standard  
Invisalign System records and standard treatment for Class II correction, independent of appliance used. 
No additional invasive or other burdensome interventions in comparison to the standard care will be 
performed.  
6. DATA ANALYSIS  
Data will be analysed by the Sponsor’s statisticians or an identified consultant. The data will be analysed 
using standard univariate and bivariate techniques.  All continuous variables will be expressed as means, 
standard deviations and ranges, while discrete variables will be expressed as proportions and 
percentages. Medians will be expressed where appropriate. Significance will be demonstrated to a 80% 
confidence level.   
6.1 Primary endpoint analysis:  
The primary objective of the study will be to demonstrate that Invisalign with MRF is not inferior to 
existing functional appliances to treat up to full cusp Class II malocclusions in growing teenagers. The 
objective will be met if Invisalign aligners with MRF correct Class II malocclusions at a rate that is not 
inferior to previously reported repositioning rates.  This will be achieved if the median rate of correction 
using Invisalign with MRF at the end of the mandible repositioning is non-inferior to published rates of 
movement (0.42 mm/mo. Dynamax) (Thiruvenkatachari, Sandler et al.)  to a confidence level of 80%.  
The rate of movement will be measured by measuring overjet over time. (Initial overjet vs. overjet at the 
end of mandible repositioning).  
Secondary objectives will include demonstration that Invisalign treatment with MRF can be completed 
predictably with both buccal and occlusal configurations. The secondary endpoints measured by 
comparing the length of treatment to the predicted ClinCheck treatment plan. Additionally, validation of 

  
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subjects dental and jaw positioning will be assessed via comparisons of subject’s photos and 
radiographs. Both subject and doctor perception will be assessed.   
6.2 Sample Size Calculation  
The sample needed to demonstrate non-inferiority of the Invisalign with MRF to literature is found using 
a single sided proportion value, with the hypothesis that Ho P=Po and a 80% power is 63 patients.  
Additional patients will be recruited to the study, to compensate for patients who do not respond to 
treatment from insufficient wear of the appliance, and to compensate for lost to follow-up and 
uncompliant data.     
7. SAFETY INSTRUCTIONS AND GUIDANCE   
7.1 Clinical Adverse Events   
An adverse event (AE) is any unwanted dental occurence which a subject experiences during a clinical 
investigation, whether or not the AE is suspected of having a causal relationship with study treatment.  
Pre-existing dental events, which increase in frequency or severity or change in nature during or as a 
consequence of use of an appliance clinical trials, will also be considered as adverse events.    
An adverse event will not include non-compliance, lost or abuse of aligners which includes soaking of 
aligners in any substance or cutting of aligners without the permission of the treating orthodontist.  This 
also includes a subject eating or drinking while wearing their aligners.   
Examples of known adverse events are:  
Blisters/Lesions/Ulcerations  
Coughing/Sneezing/ Wheezing  
Diarrhea/Upset Stomach/Nausea  
Enamel Decalcification/White Spot Lesions  
Headaches/Migraines  
Localized Hives/Itching/Rash  
Necrosis/Nerve Damage Root 
Resorption  
Runny Nose/Nasal Congestion  
Soft Tissue Recession  
Sore lips, gums or tongue  
Sore throat  
Swollen throat/Sensation of throat closing  
Swelling of lymph nodes  
TMJ/Jaw pain  

  
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Vomiting  
7.1.1 Assessment of Adverse Events  
All AEs assessed by the investigator shall contact Align Clinical Research group and provide to Align 
information about the AE. This includes the date of onset and resolution, severity, causality (relationship 
to aligners), outcome and action taken with respect to study appliance.  In addition, the events will be 
assessed by Align Clincial Research to see if it meets the definition of a serious adverse event (SAE). A 
serious adverse event will be defined as:  
• 
Led to a death  
• 
Led to a serious deterioration in the health of the subject that:  
o Resulted in a life-threatening illness or injury  
o Resulted in a permanent impairment of a body structure or a body function o Required 
in-subject hospitalization or prolongation of existing hospitalization o Resulted in 
medical or surgical intervention to prevent permanent impartment to body structure or a 
body function  
7.1.2 Treatment and Follow-up of AEs   
Any AE will be followed until a satisfactory result is reached or until it becomes stable or until it is 
proven that it resulted from another cause (concurrent condition) and clinical judgment concludes that 
further evaluation is not indicated.  
7.2 Handling of Safety Parameters  
7.2.1 Reporting of Adverse Events   
Each investigator will report any AE (whether or not a relationship to aligners is suspected) with an 
onset date, after signing the informed consent form and follow this subject until the last aligners are 
worn, to the Align Clinical Research group at the following e-mail: clinicalresearch@aligntech.com.  
Investigators should report an incident using the AE CRF within 24 to 48 hours, 7 days a week.  
The Investigator will need to report observations and findings potentially relevant to the final outcome of 
an AE in the subject’s medical record.  
The Sponsor may request return of the involved device or any potential device-related event, for 
investigation. A procedure for cleaning and returning of the device will be provided by the Sponsor.   
The Sponsor will discuss all AEs and initiate and coordinate the appropriate actions. This includes in 
particular the notification of the competent authority in case of a device-related AE and - in accordance 
with the Declaration of Helsinki – the notification of the responsible ethics committee for all SAEs.    

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning 
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7.3 Study Risks and Benefits  
The Invisalign System is indicated for the alignment of teeth during orthodontic treatment of 
malocclusion. The product labeling that describes the use and any warnings and precautions in the use of 
this device will be provided to Investigators.  There is no additional risk involved with participating in 
this study beyond that associated with current orthodontic treatment practices. Procedures and treatments 
described in this protocol are in accordance with current orthodontic practices.  
8. POTENTIAL SUBJECT RISKS AND BENEFITS   
8.1.1 Potential Subject Risks  
The Invisalign System is a dental device for the alignment of teeth during orthodontic treatment of 
malocclusions. A risk analysis of the Invisalign System has been performed for the 510(k) clearance. All 
identified risks have been minimized or eliminated through appropriate risk control measures, which are 
largely based on the compliance with harmonized standards. Hazards associated with use errors are 
reduced to an acceptable risk level by descriptions in the instructions for use. The product labeling that 
describes the use and any warnings and precautions in the use of the device will be provided to 
Investigators. There is no risk or foreseeable discomfort involved with being in this study beyond that 
associated with current orthodontic treatment practices. Procedures and treatments described in this 
protocol are in accordance with current orthodontic practices and identical to the ones a subject would 
undergo during clinical care of alignment of malocclusion. As such, subjects will not be subject to 
additional clinical burden while participating in the study.  
8.1.2 Potential Subject Benefits  
There are no known additional benefits to the subject as a result of participating in this study other than 
the benefits of the orthodontic treatment. As no orthodontic treatment is guaranteed to be effective, the 
use of the Invisalign System may or may not improve the positioning of the subjects teeth or the 
positioning of the mandible. However, in contrast to conventional braces - requiring brackets and wires 
with the risk of irritating the mouth - the Invisalign System features clear aligners with a smooth surface.  
The aligners may be removed for easy cleaning and eating, resulting in lower interference in life-style.   
   
9. STUDY COMPENSATION  
9.1 For the Investigator  
Compensation details will be described in a separate Investigator agreement.   

  
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9.2 Study Related Costs   
The subject will incur minimal costs associated with traveling to and from the doctors’ office for study 
visits.   
10. SUBJECT CARE  
The Investigator shall be completely responsible for the care of their respective subjects before, during, 
and after treatment.  The Investigator’s office may assist the Investigator (as directed by the 
Investigator) throughout the study.  
11. ETHICAL ASPECTS  
11.1 Local Regulations/Declaration of Helsinki  
The investigator will ensure that this study is conducted in full conformance with the principles of the 
“Declaration of Helsinki” or with the laws and regulations of the country in which the research is 
conducted, whichever affords the greater protection to the individual.  The study must fully adhere to the 
principles outlined in ICH E6, Good Clinical Practice: Consolidated Guideline or with local law if it 
affords greater protection to the subject. All investigators will additionally ensure that the basic principles 
of “Good Clinical Practice” as outlined in the current version of United States 21 CFR, Part 812 
"Investigational Device Exemptions", Part 50, “Protection of Human Subjects”, and Part 56, “Institutional 
Review Boards”, are adhered to.  
11.2 Informed Consent   
It is the responsibility of the Investigator, or a person designated by the Investigator (if acceptable by local 
regulations), to obtain written informed consent from each individual participating in this study after 
adequate explanation of the aims, methods, objectives and potential risks of the study. It must also be 
explained to the subjects that they are completely free to refuse to enter the study or to withdraw from it 
at any time for any reason without any penalty. The Informed Consent will be reviewed and approved by 
the reviewing IRB.  
11.3 Institutional Review Board  
It is the understanding of the Sponsor that this protocol and any modifications as well as appropriate 
consent forms/procedures, will be reviewed and approved by an Institutional Review Board. This board 
must operate in accordance with the current Federal, State, Local and institutional regulations and 
requirements. A letter or certificate of approval will be sent by the Investigator to the Sponsor prior to 
initiation of the study and also whenever any subsequent modifications to the protocol are made.  
12. CONDITIONS FOR MODIFYING THE PROTOCOL   
Protocol modifications to ongoing studies must be made only after consultation between an appropriate 
representative of the Sponsor and the Investigators in this multi-center trial.  Protocol modifications must 
be prepared by a representative of the sponsor and initially reviewed and approved by the Sponsor.  

  
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All protocol modifications must be submitted to the appropriate Institutional Review Board for 
information and approval in accordance with local requirements, and to Regulatory Agencies, if required. 
Approval must be awaited before any changes can be implemented, except for changes necessary to 
eliminate an immediate hazard to trial subjects, or when the change[s] involve[s] only logistical or 
administrative aspects of the trial (e.g. change in monitor[s], change of telephone number[s]).  
13. CONDITIONS FOR TERMINATING THE STUDY  
The Sponsor reserves the right to terminate the study at any time.  Should this be necessary, both parties 
will arrange the procedures on an individual study basis after review and consultation.  In terminating the 
study, Align Technology, Inc., or its designee, and the Investigator will assure that adequate consideration 
is given to the protection of the subject’s interests.  
14. STUDY DOCUMENTATION, CRFS AND RECORD KEEPING  
14.1 Investigator's Files / Retention of Documents  
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. These documents should be classified 
into two separate categories [1] Investigator's Study File, and [2] subject clinical source documents.  
The Investigator's Study File will contain the protocol/amendments, Case Report and Query Forms, 
Institutional Review Board and governmental approval with correspondence, sample informed consent, 
staff curriculum vitae and authorization forms and other appropriate documents correspondence etc.   
Subject clinical source documents include subject records, Doctor's notes, appointment book, original 
laboratory reports, and special assessment reports, signed informed consent forms, consultant letters, and 
subject screening.  In general, study-related records must be kept for at least 3 years after completion of 
the clinical trial and at least 2 years after the last approval of a marketing application or formal 
discontinuation of clinical development. After that period of time the documents may be destroyed, subject 
to local regulations.   
Should the Investigator wish to assign the study records to another party or move them to another 
location, the Sponsor or its designee must be notified in advance.  
If the Investigator cannot guarantee this archiving requirement at the investigational site for any or all of 
the documents, special arrangements must be made between the Investigator and the Sponsor, or its 
designee, to store these in a sealed container[s] outside of the site so that they can be returned sealed to 
the Investigator in case of a regulatory audit. Where source documents are required for the continued care 
of the subject, appropriate copies should be made for storing outside of the site.  
14.2 Source Documents and Background Data  
The Investigator shall supply the Sponsor, on request, with any required background data from the study 
documentation or clinic records. This is particularly important when CRFs are illegible or when errors in 

  
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data transcription are suspected. In case of special problems and/or governmental queries or requests for 
audit inspections, it is also necessary to have access to the complete study records, provided that subject 
confidentiality is protected.  
14.3 Audits and Inspections  
The Investigator should understand that source documents for this trial must be made available to 
appropriately qualified personnel from the Sponsor or its designees, or to health authority inspectors after 
appropriate notification. The verification of the CRF data must be by direct inspection of source 
documents.  
14.4 Case Report Forms  
• Enrollment Form  
• Mandibular Repositioning Feature Continue Access Treatment Progress Form (3 month) 
• Mandibular Repositioning Feature Continue Access Treatment Progress Form (6 month) 
• End of Mandible Repositioning  Form  
• Post Mandible Repositioning Progress Form  
• End of Treatment Form  
• Adverse Event Form  
• Subject Quality of Life (QoL) Form  
  
15. MONITORING THE STUDY  
It is understood that the responsible monitor or designee will contact and visit the Investigator and will be 
allowed, on request, to inspect the various records of the trial including CRFs and other pertinent data, 
provided that subject confidentiality is maintained, and in accord with local requirements.  
It will be the study monitor's responsibility to inspect the CRFs at regular intervals throughout the study 
to verify the adherence to the protocol and the completeness, consistency and accuracy of the data being 
entered on them. The study monitor should have access to laboratory test reports and other subject records 
needed to verify the entries on the CRF. The Investigator or his/her deputy agrees to cooperate with the 
study monitor to ensure that any problems detected in the course of these monitoring visits are resolved.  
Remote monitoring will be performed on a regular basis, and on site monitoring will be performed for 
cause, if compliance is compromised, or discrepancies in data are found.  
16. CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS  
The Investigator must assure that subjects’ anonymity will be maintained and that their identities are 
protected from unauthorized parties. On CRFs or other documents submitted to the Sponsor, subjects 
should not be identified by their names, but by Patient Identification numbers (PID) code. The 

  
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Investigator should maintain documents not for submission to the Sponsor, e.g., subjects’ written 
consent forms, in strict confidence.  
17. PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS  
The Sponsor must receive copies of any intended communication in advance of publication (at least 30 
days for an abstract or oral presentation, and 60 working days for a journal submission). The Sponsor will 
review the communications for accuracy (thus avoiding potential discrepancies with submissions to health 
authorities), verify that confidential information is not being inadvertently divulged, as well as supply any 
supplementary information.  Authorship of communications arising from pooled data will include 
members of each of the contributing centers as well as the Sponsor’s personnel.  
  
18. REFERENCECS:  
1) Phil Banks, Jean Wright, Kevin O'Brien, Incremental versus maximum bite advancement during 
twin-block therapy: A randomized controlled clinical trial, American Journal of Orthodontics 
and Dentofacial Orthopedics, Volume 126, Issue 5, November 2004, Pages 583-588, ISSN 
08895406, http://dx.doi.org/10.1016/j.ajodo.2004.03.024.  
2) Nicole J. Siara-Olds, Valmy Pangrazio-Kulbersh, Jeff Berger, and Burcu Bayirli (2010) 
LongTerm Dentoskeletal Changes with the Bionator, Herbst, Twin Block, and MARA 
Functional Appliances. The Angle Orthodontist: January 2010, Vol. 80, No. 1, pp. 18-29, doi: 
http://dx.doi.org/10.2319/020109-11.1  
3) Kevin O'Brien, Jean Wright, Frances Conboy, Priscilla Appelbe, Linda Davies, Ivan Connolly, 
Laura Mitchell, Simon Littlewood, Nicola Mandall, David Lewis, Jonathan Sandler, Mark  
Hammond, Stephen Chadwick, Julian O'Neill, Catherine McDade, Mojtaba Oskouei, Badri  
Thiruvenkatachari, Michael Read, Stephen Robinson, David Birnie, Alison Murray, Iain Shaw, 
Nigel Harradine, Helen Worthington, Early treatment for Class II Division 1 malocclusion with 
the Twin-block appliance: A multi-center, randomized, controlled trial, American Journal of 
Orthodontics and Dentofacial Orthopedics, Volume 135, Issue 5, May 2009, Pages 573-579, 
ISSN 0889-5406, http://dx.doi.org/10.1016/j.ajodo.2007.10.042.  
4) Valmy Pangrazio-Kulbersh, Jeffrey L. Berger, David S. Chermak, Richard Kaczynski, Eugene S. 
Simon, Andre Haerian, Treatment effects of the mandibular anterior repositioning appliance on 
subjects with Class II malocclusion, American Journal of Orthodontics and Dentofacial 
Orthopedics, Volume 123, Issue 3, March 2003, Pages 286-295, ISSN 0889-5406, 
http://dx.doi.org/10.1067/mod.2003.8.  
5) Luis Tomas Huanca Ghislanzoni, Douglas Edward Toll, Efisio Defraia, Tiziano Baccetti, and 
Lorenzo Franchi (2011) Treatment and posttreatment outcomes induced by the Mandibular  

  
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Advancement Repositioning Appliance; A controlled clinical study. The Angle Orthodontist:  
July 2011, Vol. 81, No. 4, pp. 684-691, doi: http://dx.doi.org/10.2319/111010-656.1  
6) Thiruvenkatachari, B., et al., Comparison of Twin-block and Dynamax appliances for the 
treatment of Class II malocclusion in adolescents: A randomized controlled trial. American 
Journal of Orthodontics and Dentofacial Orthopedics. Aug 2010.138(2): p. 144.e1-144.e9.  
  

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning Feature 
(MRF)  
 
        Protocol Number: MRF-002  
 
  
T00009 Rev F                                                              24  
ALIGN 
CONFIDENTIAL  
  
  
19. TABLE 1: SCHEDULE OF  
ASSESSMENTS  
  

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning Feature 
(MRF)  
 
        Protocol Number: MRF-002  
 
  
T00009 Rev F                                                              25  
ALIGN 
CONFIDENTIAL  
  
Procedures/forms  
  
Screening 
/ Initial    
Aligner 
Delivery  
Mandibular 
Advancement 
Treatment Progress  
(3 month) 
Mandibular 
Advancement 
Treatment Progress   
(6 month) 
End of Mandible  
Repositioning (class II 
to class I correction) –  
MCC/ Refinement   
Final Visit/ 
Withdrawal 
from Study  
Perform dental history 
exam  
Yes  
  
  
  
  
  
Evaluation of  
eligibility criteria 
(Inclusion/Exclusio n) 
Yes  
  
  
  
  
  
Subject Informed 
Consent  
Yes  
  
  
  
  
  
Prescription form  
Yes  
  
  
  
Yes  
  
PVS impressions +  
Bite Registration 
(centric occlusion 
bite) – OR – IO Scan 
(centric occlusion 
bite)  
  
  
Yes  
 Yes 
Yes  
Yes  
 

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning Feature 
(MRF)  
 
        Protocol Number: MRF-002  
 
  
T00009 Rev F                                                              26  
ALIGN 
CONFIDENTIAL  
  
Procedures/forms  
  
Screening 
/ Initial    
Aligner 
Delivery  
Mandibular 
Advancement 
Treatment Progress 
(3 month) 
Mandibular 
Advancement 
Treatment Progress   
(6 month) 
End of Mandible  
Repositioning (class II 
to class I correction) – 
MCC/Refinement   
Final Visit/ 
Withdrawal 
from Study  
PVS impression + 
Protrusive bite 
registration (inscial  
edge to edge bite) – 
OR – IO Scan 
(inscial edge to edge 
bite)   
Yes  
  
  
  
  
  
Panoramic  
Radiograph (OPG x-
ray)  
Yes  
  
  
  
Yes  
Yes  
Lateral  
Cephalogram (xray)  
Yes  
  
  
  
Yes  
Yes  
Intraoral Photos (6)-
centric occlusion   
Yes  
  
Yes  
Yes  
Yes  
Yes  
  

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning Feature 
(MRF)  
 
        Protocol Number: MRF-002  
 
  
T00009 Rev F                                                              27  
ALIGN 
CONFIDENTIAL  
  
Procedures/forms  
  
Screening 
/ Initial    
Aligner 
Delivery  
Mandibular 
Advancement 
Treatment Progress 
(3 month) 
Mandibular 
Advancement 
Treatment Progress   
(6 month) 
End of Mandible  
Repositioning  
(class II to class I 
correction) – 
MCC/Refinement   
Final Visit/ 
Withdrawal 
from Study  
Intraoral Photos (3) 
- with Aligners  
  
     Yes  
Yes  
 Yes 
Yes  
  
Intraoral Photos (3)-
incisal edge to edge  
Yes  
  
  
  
  
  
Extraoral Photos (3)  
Yes  
  
Yes  
Yes  
Yes  
Yes  
Case Report Form  
(CRF)- Enrollment  
Form  
Yes  
  
  
  
  
  
  
  
 
Procedures/forms  
  
Screening 
/ Initial    
Aligner 
Delivery  
Mandibular 
Advancement 
Treatment Progress 
(3 month) 
Mandibular 
Advancement 
Treatment Progress (6 
month) 
End of Mandible  
Repositioning  
(class II to class I 
correction) – 
MCC/Refinement   
Final Visit/ 
Withdrawal 
from Study  

  
Invisalign System with Buccal and Occlusal Mandibular Repositioning Feature 
(MRF)  
 
        Protocol Number: MRF-002  
 
  
T00009 Rev F                                                              28  
ALIGN 
CONFIDENTIAL  
  
Mandibular 
Advancement 
Treatment Progress 
Form 
 
 
 
 
Yes 
 
 
Yes 
 
 
CRF-End of  
Mandible  
Repositioning Form  
  
  
  
  
Yes  
  
CRF-End of  
Treatment Form  
  
  
  
  
  
Yes  
Subject Quality of 
Life (QoL)  
  
Yes  
  
  
Yes  
  
Aligner Delivery  
  
  
Yes