A Prospective, Two-armed, Multicenter Clinical Study to Evaluate Efficacy, Performance, and Safety of Nighttime Aligners (Worn 10-12 Hours Day or Night) Compared to Daytime Aligners (Worn 20-22 Hours Day/Night)
Phase: NA
Conditions: Teeth Straightening, Aligner Therapy, Orthodontic Aligner
Sponsor: Dentsply Sirona Implants and Consumables

 
 
Clinical Investigation Plan 
 
CIP number: 2000-CIP-0001 
Version: 1.0 
Date: 15-May-2024 
Title: A prospective, two-armed, multicenter clinical study to evaluate 
e@icacy, performance, and safety of Nighttime Aligners (worn 10-12 hours 
day or night) compared to Daytime Aligners (worn 20-22 hours day/night) 
NCT number: NCT06539676 
 

 
 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
PROTOCOL NUMBER: 
2000-CIP-0001 
CLINICAL STUDY CODE: C-OR-24-017 
 
 
Title: A prospective, two-armed, multicenter clinical study to evaluate efficacy, 
performance, and safety of Nighttime Aligners (worn 10-12 hours day or night) compared 
to Daytime Aligners (worn 20-22 hours day/night) 
 
Sponsor: 
 
 
Straight Smile, LLC 
 
 
 
 
(a Dentsply Sirona company, doing business as Byte) 
 
 
 
 
1556 20th Street, Suite A 
Santa Monica, CA 90404, U.S.A.  
1-866-765-2327 
 
Investigational Product: 
Nighttime Aligners 
 
Investigational Sites: 
Multi-center clinical study with up to 15 sites in the US. 
See separate study specific investigational site list. 
 
Revision: 
 
 
1 
REVISION HISTORY 
Rev. 
Change By 
Description of Change 
Rationale for Change 
0 
Louis Erazo 
Initial draft 
Draft for FDA pre-sub 
1 
Freja Freedman 
Initial release 
New 
 
 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 2 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
DD 
Device deficiencies 
SAE 
Serious adverse event 
CFR 
Code of Federal Regulations 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ERP 
Enterprise resource planning 
DSM 
Digital Study Model 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IC 
Informed Consent 
ICH 
International Conference on Harmonization 
IP 
Investigational Product (equivalent with Investigational device) 
IRB 
Institutional Review Board 
NSR 
Non-significant risk 
PAR 
Peer Assessment Rating 
CoCR 
Center of Clinical Research 
US 
United States 
 
 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 3 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
STUDY STAFF CONTACT INFO 
 
 
 
Study Director: 
Jay Khorsandi, DDS 
Clinical Director 
Straight Smile, LLC 
Jay.Khorsandi@byteme.com 
310-709-9002 [mobile] 
 
Sponsor Study Compliance: 
Gretchen Heasley 
 
Senior Regulatory Affairs Manager 
 
Dentsply Sirona  
 
Gretchen.Heasley@dentsplysirona.com 
 
303-809-7489 [mobile] 
  
Study Team Leader: 
 
Freja Freedman 
 
Clinical Research Manager 
 
Dentsply Sirona 
 
Freja.Freedman@dentsplysirona.com 
 
+46 70 210 74157415 
 
 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 4 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
TABLE OF CONTENTS 
1. 
STUDY OBJECTIVES ............................................................................................................................. 10 
1.1 
PRIMARY OBJECTIVE: .......................................................................................................................................... 10 
1.2 
SECONDARY OBJECTIVES: ..................................................................................................................................... 10 
2. 
BACKGROUND AND RATIONALE ....................................................................................................... 10 
2.1 
BACKGROUND: .................................................................................................................................................. 10 
2.2 
RATIONALE: ...................................................................................................................................................... 11 
3. 
REFERENCES ......................................................................................................................................... 11 
4. 
STUDY DESIGN ............................................................................................................................................ 12 
4.1 
POPULATION ..................................................................................................................................................... 13 
4.2 
NUMBER OF SUBJECTS......................................................................................................................................... 13 
4.3 
STUDY DURATION............................................................................................................................................... 13 
5. 
SELECTION AND ENROLLMENT OF STUDY SUBJECTS ............................................................... 13 
5.1 
INCLUSION CRITERIA ........................................................................................................................................... 13 
5.2 
EXCLUSION CRITERIA ........................................................................................................................................... 14 
5.3 
SCREENING AND ENROLLMENT PROCEDURES ........................................................................................................... 15 
5.4 
SUBJECT CONSENT/ASSENT PROCEDURE ................................................................................................................. 15 
6. 
INVESTIGATIONAL DEVICE ................................................................................................................. 16 
6.1 
DEVICE DESCRIPTION .......................................................................................................................................... 16 
6.2 
ACCOUNTABILITY OF INVESTIGATIONAL PRODUCT (IP) ............................................................................................... 18 
6.3 
STUDY RELATED MATERIALS ................................................................................................................................. 19 
7. 
RISKS AND BENEFITS OF PARTICIPATION .................................................................................................... 19 
7.1 
RISKS ............................................................................................................................................................... 19 
7.2 
BENEFITS .......................................................................................................................................................... 20 
8. 
STUDY PROCEDURES ................................................................................................................................... 21 
8.1 
SCREENING ....................................................................................................................................................... 21 
8.2 
ENROLLMENT .................................................................................................................................................... 22 
8.3 
STUDY SCHEDULE ............................................................................................................................................... 23 
8.4 
SUBJECT ELIGIBILITY ............................................................................................................................................ 24 
8.5 
SUBJECT INFORMATION ....................................................................................................................................... 24 
8.6 
PRE-TREATMENT PERIOD ..................................................................................................................................... 24 
8.7 
TREATMENT START ............................................................................................................................................. 25 
8.8 
IN-TREATMENT PERIOD ....................................................................................................................................... 25 
8.9 
TREATMENT FINAL .............................................................................................................................................. 25 
8.10 SUBJECT DISCONTINUATION ................................................................................................................................. 26 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 5 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
9. 
ENDPOINTS ................................................................................................................................................. 26 
9.1 
PRIMARY SAFETY ENDPOINT ................................................................................................................................. 26 
9.2 
SECONDARY SAFETY ENDPOINT ............................................................................................................................. 26 
9.3 
PRIMARY EFFICACY ENDPOINT .............................................................................................................................. 27 
9.4 
SECONDARY EFFICACY ENDPOINT .......................................................................................................................... 27 
10. 
DEVIATIONS ................................................................................................................................................ 28 
10.1 DEVIATIONS ...................................................................................................................................................... 28 
11. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..................................................................................... 28 
11.1 ADVERSE EVENT (AES) ........................................................................................................................................ 28 
11.2 SERIOUS ADVERSE EVENTS (SAES) ........................................................................................................................ 30 
11.3 DEVICE DEFICIENCIES (DDS) ................................................................................................................................. 31 
12. 
DATA AND STATISTICAL ANALYSIS .............................................................................................................. 31 
12.1 STATISTICAL SAMPLE SIZE AND POWER (PROVIDED AS AN EXAMPLE) ............................................................................. 31 
12.2 DATA ANALYSIS.................................................................................................................................................. 32 
12.3 SAFETY ANALYSIS ............................................................................................................................................... 34 
13. 
DATA COLLECTION AND MONITORING ....................................................................................................... 34 
13.1 SOURCE DOCUMENTS & ECRFS ............................................................................................................................ 34 
13.2 CASE REPORT FORMS (CRFS) ............................................................................................................................... 35 
13.3 DATA ENTRY AND MANAGEMENT .......................................................................................................................... 36 
13.4 DATA MONITORING ............................................................................................................................................ 36 
14. 
QUALITY ASSURANCE ................................................................................................................................. 37 
14.1 RESPONSIBILITIES ............................................................................................................................................... 37 
14.2 TRAINING ......................................................................................................................................................... 37 
15. 
DOCUMENTATION REQUIREMENTS ............................................................................................................ 38 
15.1 ENROLLED SUBJECTS: .......................................................................................................................................... 38 
15.2 SPONSOR: ......................................................................................................................................................... 38 
15.3 INVESTIGATOR: .................................................................................................................................................. 38 
15.4 RECORD RETENTION: .......................................................................................................................................... 38 
16. 
SUBJECT RIGHTS AND CONFIDENTIALITY .................................................................................................... 39 
16.1 IRB REVIEW ...................................................................................................................................................... 39 
16.2 INSURANCE ....................................................................................................................................................... 39 
16.3 PROTECTED HEALTH INFORMATION & SUBJECT CONFIDENTIALITY ................................................................................ 39 
16.4 SUBJECT WITHDRAWAL ....................................................................................................................................... 40 
17. 
ASSOCIATED DOCUMENTS .......................................................................................................................... 40 
18. 
SIGNATURES ............................................................................................................................................... 41 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 6 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
PROTOCOL SYNOPSIS 
TITLE 
A Prospective, multi-center Clinical Study to Support Substantial Equivalence of 
Safety and Effectiveness of Nighttime Aligners (worn 10-12 hours day or night) 
DESIGN 
Multi-site, two-armed, prospective, controlled clinical study 
STUDY 
LOCATION 
United States 
SUBJECT 
POPULATION 
Permanent dentition (i.e., all second molars), ages 12 and up 
SAMPLE SIZE 
The study will enroll up to 100 subjects [50 per treatment arm] to have a minimum 
of 23 fully evaluable subjects per treatment arm at end of treatment 
NUMBER OF 
SITES 
Up to 15 investigational sites 
STUDY 
DURATION 
18 months, inclusive of enrollment period, where typical treatment duration is 6-8 
months 
TEST 
Treatment arm 1 – Test group 
Nighttime Aligners (worn 10-12 hours per day or night) 
CONTROL 
Treatment arm 2 – Control group 
Daytime Aligners (worn 20-22 hours day/night) 
OBJECTIVE 
This clinical study is designed to provide Straight Smile, LLC and Dentsply Sirona 
data to support substantial equivalence, including safety and efficacy, of wearing 
Nighttime Aligners for 10-12 continuous hours per day (or night). The expressed 
movements demonstrated by the Nighttime Aligners (investigational/test group) 
will be compared to the expressed movements demonstrated by the Daytime 
Aligners (control group), which are worn for 20-22-hours per day/night. 
CLINICAL STUDY 
PROCEDURE  
The flowchart below provides an overview of the clinical study. For visit-specific 
procedures, see section 8: Visit and procedure plan. 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 7 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
 
 
 
EFFECTIVENESS 
ASSESSMENTS 
Efficacy of Nighttime Aligners (worn 10-12 hours per day or night) will be assessed 
by demonstrating no statistically significant difference between expressed tooth 
movement versus programmed tooth movement at the end of treatment when 
compared to the Daytime aligners (worn 20-22 hours day/night). Quantification 
and comparison of expressed and programmed tooth movements will be 
conducted using Peer Assessment Rating (PAR) index to measure orthodontic 
treatment need and outcome, using the built-in weighted PAR analysis tool of 
3Shape Ortho System software.  
SAFETY 
ASSESSMENTS 
The primary safety endpoint of the study will be the incidence of (device or dental) 
related AEs associated with the planned investigational treatment, as well as the  
occurrence of SAEs. Additionally, safety will be assessed through a post-
treatment questionnaire administered to the subject asking about subject 
perceived comfort during treatment. Results will be quantified using a visual 
analogue scale. Both numerical values and a Wong Baker face scale will be used. 
INCLUSION 
CRITERIA 
For inclusion in this clinical study subjects must meet all of the following criteria: 
1. Subject willing to participate in the clinical study and able to 
understand the content of the clinical study. 
2. Subject must have permanent dentition (i.e. all second molars). 
3. Subject must be 12 years of age or older. 
4. Subject must be able to provide and sign consent for themselves, 
without requiring consent to be given by a legally authorized 
representative. Parental consent is also required for all participants 
who are not of the legal age to provide consent themselves (based 
on participant state of residence).  
5. The subject requires correction of teeth without planned extrusive 
movements on either or both arches. 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 8 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
6. The subject has no greater than 5 mm of crowding and/or spacing 
(based on estimation by Investigator).  
7. The subject does not require planned correction of molar tooth 
positions, posterior bite or molar classic relationship corrections. 
Subjects with Class II or Class III malocclusions requiring posterior 
bite / class correction are not eligible. 
8. Subjects without prior orthodontic treatment within the past 18 
months. 
9. Subjects who are periodontally stable. 
10. Subjects without a known history of plastic allergies. 
11. Subjects who have not had or do not require tooth extractions in 
preparation for orthodontic treatment with aligners. 
12. Subjects with a treatment plan that does not include the use of 
elastics. 
EXCLUSION 
CRITERIA 
 
Any of the following is regarded as a criterion for exclusion from the clinical 
study: 
1. Unlikely to be able to comply with clinical study procedures 
according to Investigator’s judgement.  
2. Unable or unwilling to return for follow-up visits.  
3. Previous enrolment in the present clinical study.  
4. Involvement in the planning and conduct of the clinical study 
(applies to both Sponsor personnel and the clinical study site) 
5. Participation in another clinical study that may interfere with the 
present clinical study.  
6. Subjects who have active carries, where there is no plan to correct 
them prior to the start of aligner therapy. 
7. Other dental or clinical pathologies, which in the judgment of the 
Investigator, deem the candidates inappropriate for participation in 
the study (e.g. clinically significant periodontal disease or gingivitis, 
interproximal decay, etc.). 
8. The subject require interproximal reduction or attachments to 
obtain a corrected malocclusion. 
9. In addition to the criteria listed above, this product is 
contraindicated for use in adult and adolescent subjects presenting 
with the following dental conditions: 
• 
Active periodontal disease 
• 
Severe open bite or severe overjet 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 9 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
• 
Tooth malocclusion requiring surgical correction 
• 
Subject with mixed dentition 
• 
Subject with a skeletally narrow jaw 
• 
Dental prosthetics/implants or significant number of 
missing teeth 
10.  Known pregnancy, pregnancy tests will be performed as per local 
requirements. 
 
 
 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 10 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
1.  
STUDY OBJECTIVES 
1.1 Primary Objective: 
The primary efficacy objective of this study is the comparison between groups of 
the quantification of actual vs planned tooth movements. Changes in tooth position 
from pre-treatment baseline to end of treatment results will be measured for both 
Daytime Aligners (control) and Nighttime Aligners (test).  
The safety objective of the study will be the incidence of (device or dental) related 
AEs associated with the planned investigational treatment, in comparison to the 
incidence of AEs associated with control treatment.   
 
1.2 Secondary Objectives: 
The secondary efficacy objective of this study will be to assess overall dentist and 
subject satisfaction with the treatment.  
Safety will also be assessed through subject questionnaire during and after 
treatment. 
2.  
BACKGROUND AND RATIONALE 
2.1 Background:   
2.1.1 
Orthodontic clear aligners have become increasingly popular since the 
advent by Align Technologies in 1998. The esthetics and comfort of using 
clear aligners instead of traditional wire and bracket braces have greatly  
contributed to their adoption for orthodontic treatment around the world. 
Applying slow, continuous force to a subject’s teeth is the premise behind 
clear aligners being safe and effective at treating malocclusions. 
2.1.2 
The aligner system positions teeth by way of continuous gentle force and 
this system has been applied to the Daytime Aligners which are indicated 
for the treatment of tooth malocclusion in subjects with permanent 
dentition (i.e. second molars).  The Daytime Aligners (worn 20-22 hours 
per day) have been available in the US market since 2019 and were 
initially cleared by the US FDA under pre-market notification K180346. 
Recently, design changes to the aligners were subsequently cleared by 
the US FDA under pre-market notifications K230199.  
2.1.3 
Nighttime Aligners have not been cleared by the US FDA, and the 
purpose of this clinical study is, in part, to gain valid scientific evidence 
for device safety and efficacy to support  US FDA pre-market clearance 
for the device system. These aligners are to be worn by the subject 
continuously for 10-12 hours per day (or night). When worn while 
sleeping, the therapy complements the circadian rhythm of bone 
remodeling and metabolism for tooth movement (Qin 2019, Luo 2021).  
 
 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 11 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
2.2 Rationale: 
2.2.1 
Nighttime Aligners program smaller incremental tooth movements into 
each aligner tray/stage allowing for activation of biological cascade 
governing orthodontic tooth movement (Krishnan 2006, Kumasako-Haga 
2019), with an added advantage of intermittent force resulting in reduced 
root resorption (Ozkalavci 2018). Movements of molar teeth and extrusive 
tooth movements are not eligible in the treatment plans for these aligners. 
2.2.2 
This clinical study is designed to provide Straight Smile (doing business 
as Byte) and Dentsply Sirona data to support performance,  efficacy and 
safety of wearing Nighttime Aligners for 10-12 continuous hours per day 
(or night). The expressed movements demonstrated by the Nighttime 
Aligners (investigational/test group) will be compared to the expressed 
movements demonstrated by the Daytime Aligners (control group), which 
are worn for 20-22-hours per day. Both control and investigational groups 
are for subjects with mild malocclusion. 
2.2.3 
This clinical study involves no more than minimal risk (as defined in 21 
CFR 50.3(k) or 56.102(i)) to the subjects. Based on this assessment, the 
IRB will be asked to make a determination that the clinical study does not 
pose more than minimal risk to the study subjects (non-significant risk) 
and thus the clinical study is considered to have abbreviated IDE 
requirements and does not require FDA approval of the study (21 CFR 
8.12.2(b)). 
• This request is made in part by reviewing the recommendations 
provided by the Office of Good Clinical Practice, Office of Special 
Medical Programs, Office of the Commissioner Food and Drug US 
FDA in the document “Information Sheet Guidance for IRBs, Clinical 
Investigators, and Sponsors: Significant Risk and Non-significant Risk 
Medical Device Studies”. 
(https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/significant-risk-and-nonsignificant-risk-medical-device-
studies) 
3.  
REFERENCES 
1. Green, J.I., 2016. An overview of the peer assessment rating (PAR) index 
for primary dental care practitioners. Primary dental journal, 5(4), pp.28-37. 
2. Griffith, M., Fields, H.W., Ni, A., Guo, X., Lee, D.J. and Deguchi, T., 2021. 
Comparison of 2 Invisalign tray generations using the Peer Assessment 
Rating index. American Journal of Orthodontics and Dentofacial 
Orthopedics, 160(5), pp.718-724.  
3. Grünheid, T., Tasca, A.W., Kanyusik, J.S., Walters, S.A. and Larson, B.E., 
2022. Assessment of orthodontic treatment efficacy of clarity aligners using 
the peer assessment rating index and the American Board of Orthodontics 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 12 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
Cast-Radiograph Evaluation. American Journal of Orthodontics and 
Dentofacial Orthopedics, 162(6), pp.861-869. 
4. Krishnan, V. and Davidovitch, Z.E., 2006. Cellular, molecular, and tissue-
level reactions to orthodontic force. American Journal of Orthodontics and 
Dentofacial Orthopedics, 129(4), pp.469-e1.  
5. Kumasako-Haga, T., Konoo, T., Yamaguchi, K. and Hayashi, H., 2009. 
Effect of 8-hour intermittent orthodontic force on osteoclasts and root 
resorption. American Journal of Orthodontics and Dentofacial Orthopedics, 
135(3), pp.278-e1.  
6. Luo, B., Zhou, X., Tang, Q., Yin, Y., Feng, G., Li, S. and Chen, L., 2021. 
Circadian rhythms affect bone reconstruction by regulating bone energy 
metabolism. Journal of Translational Medicine, 19(1), pp.1-15.  
7. Ozkalayci, N., Karadeniz, E.I., Elekdag-Turk, S., Turk, T., Cheng, L.L. and 
Darendeliler, M.A., 2018. Effect of continuous versus intermittent 
orthodontic forces on root resorption: A microcomputed tomography study. 
The Angle Orthodontist, 88(6), pp.733-739.  
8. Qin, X., Li, Q., Chen, W., Bai, Y., Baban, B. and Mao, J., 2019. The circadian 
expression of osteogenic factors .in periodontal tissue loading mechanical 
force: new concepts of the personalized orthodontic care. EPMA J. 2019; 
10 (1): 13–20.  
9. Richmond, S., Shaw, W.C., Roberts, C.T. and Andrews, M., 1992. The PAR 
Index (Peer Assessment Rating): methods to determine outcome of 
orthodontic treatment in terms of improvement and standards. The 
European Journal of Orthodontics, 14(3), pp.180-187. 
4.  
STUDY DESIGN 
The clinical study is a multi-center, controlled, prospective study enrolling on a 
convenience basis.  
The study period for each study subject shall end when the subject discontinues 
use of the investigational or control devices (i.e., withdraws from the study or 
completes aligner treatment under the study time frame). 
All study subjects will be provided with removable retainers after completion of 
aligner therapy. 
This study shall be carried out in compliance with FDA regulations and Good 
Clinical Practices (GCP), including but not limited to the Protection of Human 
Subjects, Informed Consent, Institutional Review Boards, and the Obligations of 
Clinical Investigators and Sponsors. 
 
 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 13 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
4.1 Population 
This study will seek to enroll subjects who are clinically eligible candidates for 
aligner therapy as outlined in the inclusion/exclusion criteria and are interested in 
voluntarily participating in this study. Only subjects with permanent dentition (i.e., 
all second molars) will be screened for enrollment in the study (this is consistent 
with the intended use statement for the Daytime Aligners [control]). 
The clinical study shall be conducted only in the United States.   
4.2 Number of Subjects 
The study shall prospectively enroll up to 100 subjects (50 per treatment arm) on a 
convenience basis, with a minimum of 50 eligible subjects per treatment arm. A 
minimum of 23 fully evaluable, compliant, and viable subjects completing treatment 
in each study treatment arm is required.  
4.3 Study Duration 
4.3.1 
The study, as a whole is expected to run for up to 18 months, inclusive of 
the enrollment period. 
4.3.2 
The minimum planned orthodontic treatment period per subject will be 2 
months. 
4.3.3 
The maximum planned orthodontic treatment period per subject will be 8 
months, unless a refinement is required. 
4.3.4 
Study subjects will remain on-study until treatment with the final 
investigational or control device is complete or if the subject wishes to no 
longer participate in the study (withdraws consent) or Severe non-
compliance to protocol as judged by the Investigator and/or Sponsor 
causing the subject to be withdrawn from the study. 
5.  
SELECTION AND ENROLLMENT OF STUDY SUBJECTS 
5.1 Inclusion Criteria 
For inclusion in this clinical study subjects must meet all of the following criteria: 
1. Subject willing to participate in the clinical study and able to understand 
the content of the clinical study. 
2. Subject must have permanent dentition (i.e. all second molars). 
3. Subject must be 12 years of age or older. 
4. Subject must be able to provide and sign consent for themselves, without 
requiring consent to be given by a legally authorized representative. 
Parental consent is also required for all participants who are not of the 
legal age to provide consent themselves (based on participant state of 
residence).  

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 14 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
5. The subject requires correction of teeth without planned extrusive 
movements on either or both arches. 
6. The subject has no greater than 5 mm of crowding and/or spacing (based 
on estimation by Investigator).  
7. The subject does not require planned correction of molar tooth positions, 
posterior bite or molar classic relationship corrections. Subjects with Class 
II or Class III malocclusions requiring posterior bite / class correction are 
not eligible. 
8. Subjects without prior orthodontic treatment within the past 18 months. 
9. Subjects who are periodontally stable. 
10. Subjects without a known history of plastic allergies. 
11. Subjects who have not had or do not require tooth extractions in 
preparation for orthodontic treatment with aligners. 
12. Subjects with a treatment plan that does not include the use of elastics. 
5.2 Exclusion Criteria 
Any of the following is regarded as a criterion for exclusion from the clinical study: 
1. Unlikely to be able to comply with clinical study procedures according to 
Investigator’s judgement.  
2. Unable or unwilling to return for follow-up visits.  
3. Previous enrolment in the present clinical study.  
4. Involvement in the planning and conduct of the clinical study (applies to 
both Sponsor personnel and the clinical study site) 
5. Participation in another clinical study that may interfere with the present 
clinical study.  
6. Subjects who have active carries, where there is no plan to correct them 
prior to the start of aligner therapy. 
7. Other dental or clinical pathologies, which in the judgment of the 
Investigator, deem the candidates inappropriate for participation in the 
study (e.g. clinically significant periodontal disease or gingivitis, 
interproximal decay, etc.). 
8. The subject require interproximal reduction or attachments to obtain a 
corrected malocclusion. 
9. In addition to the criteria listed above, this product is contraindicated for 
use in adult and adolescent subjects presenting with the following dental 
conditions: 
• 
Active periodontal disease 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 15 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
• 
Severe open bite or severe overjet 
• 
Tooth malocclusion requiring surgical correction 
• 
Subject with mixed dentition 
• 
Subject with a skeletally narrow jaw 
• 
Dental prosthetics/implants or significant number of missing teeth 
10. Known pregnancy, pregnancy tests will be performed as per local 
requirements. 
5.3 Screening and Enrollment Procedures 
5.3.1 
Subjects seeking orthodontic treatment through the Byte+ network of 
dentists will be pre-screened for enrollment. 
5.3.2 
Subjects shall meet all inclusion and none of the exclusion criteria. 
Subject scanned will be invited to participate in the study. If they agree 
and consent to participate, they will be included and subsequently 
enrolled in this study. 
5.3.3 
Subjects will be enrolled on a convenience basis by their voluntary 
selection to participate in a clinical study after first expressing interest in 
aligner therapy. 
• 
Consented subjects will be assigned a unique subject 
identification number randomly generated by the ERP system. 
This number will be used as the primary identifier on all study 
related documents. In addition subject will receive a subject Id 
when enrolled in the study. Subject IDs are unique to each 
individual subject and cannot be changed. 
All screening activities shall be documented in the screening Log, 
including but not limited to the determination of eligibility for each 
screened subject Any protected health information shall be de-
identified. The Sponsor shall be able to review protected health 
information upon request for the purpose of study data monitoring. 
5.4 Subject Consent/Assent Procedure 
5.4.1 
Subjects will be fully informed of the nature of the study, the risks involved 
in participating in the study, and the procedures that will need to be 
followed during the study period. 
5.4.2 
The Investigator shall explain the terms of the clinical study, objectives of 
the research being conducted, benefits and risks of participation, benefits 
and risks of not participating, duration of the study, possible continuation 
of treatment after the study ends, subject responsibilities, subject 
compliance, and subject expectations. 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 16 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
5.4.3 
It is important that the Investigator discusses alternative and traditional 
(non-research) treatments available, as well as the risks and benefits of 
those options. 
5.4.4 
All subjects are required to go through the formal consent process and 
sign and date the consent form prior to participating as a study subject in 
this study. 
5.4.5 
Informed Consent is required prior to participation in this study. Eligible 
subjects, 18 years of age or older, who are willing to participate in the 
study will read and sign the written, study specific Informed Consent Form 
prior to undergoing any study-specific procedures. 
5.4.6 
Assent: Eligible subjects under the age of 18 require parental consent to 
participate in this study, in addition to the subject’s consent for 
participation. Eligible subjects under the age of 18 will require a parent or 
legal guardian’s approval via the study specific Informed Consent Form 
prior to undergoing any study-specific procedures.  
5.4.7 
Each subject will receive a copy of their signed Informed Consent Form. 
5.4.8 
The study Informed Consent Form does not replace any consent-for-
treatment agreement the Investigator currently requires to accept and 
begin treatment.   
• 
The enrolled subject (or parent/legal guardian’s if applicable) will 
be offered a rebate for their participation in this study. The 
subject will receive a rebate on their aligner order following 
enrollment in the study, and an additional rebate upon compliant 
and successful completion of aligner therapy under this study 
protocol.  Providing discounts or payments to clinical study 
subjects in exchange for their participation is a common and, in 
general, acceptable practice. These actions are not considered a 
benefit that would be part of the weighing of benefits or risks; it is 
a recruitment incentive.  
• 
If the subject is removed from the study by the Sponsor or 
Investigator due to non-compliance to the study protocol, they 
will not be eligible for the second rebate, attained at the end of 
the study. 
6.  
INVESTIGATIONAL DEVICE 
6.1 Device Description 
6.1.1 
All investigational and control aligner devices will be made using FDA 
cleared plastic materials [Essix ACE (PETG), K062828]. 
6.1.2 
Nighttime Aligners are indicated for the treatment of tooth malocclusion in 
subjects with permanent dentition (i.e., second molars). The aligner 
system positions teeth by way of continuous gentle force. These aligners 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 17 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
are to be worn by the subjects continuously for 10-12 hours per day (or 
night); aligners may be removed for small periods of time while eating, 
drinking or brushing. Subjects will wear each aligner tray for 1-2 weeks, 
or as instructed by their dentist. When worn while sleeping, the therapy 
complements the circadian rhythm of bone remodeling and metabolism 
for tooth movement.  Smaller incremental tooth movements are 
programmed into each aligner tray/stage allowing for activation of 
biological cascade governing orthodontic tooth movement, with an added 
advantage of intermittent force resulting in reduced root resorption. 
Nighttime aligners (investigational) are made with material that is 0.35-
0.40 inch thick and the planned tooth movement rate is 20% less than that 
of the Daytime Aligners (control).  
Tooth movement treatment planning constraints of Nighttime Aligners 
(investigational): 
Movement 
Type 
Translate 
[B/L] (mm) 
Torque / 
Incline (°) 
Tip (°) 
Rotate 
(°) 
Intrude 
(mm) 
Extrude 
(mm) 
Per aligner 
0.25 mm 
1 ° 
1 ° 
1.6 ° 
0.1 mm 
N/A 
Tooth 
Totals per treatment plan 
Incisors 
5 
25 
25 
45 
2.5 
N/A 
Laterals 
5 
25 
25 
45 
2.5 
N/A 
Canines 
3 
25 
25 
35 
2.5 
N/A 
Premolars 
2 
10 
10 
10 
1 
N/A 
Molars* 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
*Movements of molar teeth are not in the treatment plans for these aligners. 
 
 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 18 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
6.1.3 
Daytime Aligners are indicated for the treatment of tooth 
malocclusion in subjects with permanent dentition (i.e., second molars). 
The aligner system positions teeth by way of continuous gentle force. 
These aligners are to be worn by the subject 20-22 hours per day and 
night; aligners may be removed for small periods of time while eating, 
drinking or brushing.  
Subjects will wear each aligner tray for 1-2 weeks, or as instructed by 
their dentist. When worn while sleeping, the therapy complements the 
circadian rhythm of bone remodeling and metabolism for tooth 
movement. Smaller incremental tooth movements are programmed into 
each aligner tray/stage allowing for activation of biological cascade 
governing orthodontic tooth movement, with an added advantage of 
intermittent force resulting in reduced root resorption. Daytime aligners 
(control) are made with material that is 0.30-0.35 inch thick and the 
planned tooth movement rate is 20% more than that of the Nighttime 
Aligners (investigational). 
Tooth movement treatment planning constraints of Daytime Aligners 
(control): 
Movement 
Type 
Translate 
[B/L] (mm) 
Torque / 
Incline (°) 
Tip (°) 
Rotate 
(°) 
Intrude 
(mm) 
Extrude* 
(mm) 
Per aligner 
0.3 mm 
1 ° 
1 ° 
2 ° 
0.1 mm 
N/A 
Tooth 
Totals per treatment plan 
Incisors 
5 
25 
25 
45 
2.5 
N/A 
Laterals 
5 
25 
25 
45 
2.5 
N/A 
Canines 
3 
25 
25 
35 
2.5 
N/A 
Premolars 
2 
10 
10 
10 
1 
N/A 
Molars* 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
*Extrusive and molar movements are allowable with standard, Daytime Aligners, however, for the 
purposes of this study, they will not be allowed. 
6.2 Accountability of Investigational Product (IP) 
All investigational and control devices must be accounted for. 
6.2.1 
Accountability of all investigational and control devices provided to the 
Investigator shall be documented by the Sponsor and the Investigator. 
6.2.2 
Accountability of all investigational and control devices provided to the 
subject shall be documented by the Investigator. 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 19 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
6.2.3 
The documentation shall provide lot/batch/serial numbers and any 
pertinent tracking or traceability information provided on product labels or 
packaging. 
6.2.4 
This information shall be maintained in the clinical trial master file for the 
life of investigational device. 
6.2.5 
Used investigational and control devices will not be returned to the 
Sponsor. 
6.2.6 
Any unused investigational and control devices provided to subjects shall 
be returned to the Sponsor at the end of the study, at the expense of the 
Sponsor. 
6.3 Study Related Materials 
6.3.1 
All investigational materials provided to the Investigator shall be 
documented by the Sponsor. 
6.3.2 
All investigational materials provided to subject shall be documented by 
the Investigator. 
6.3.3 
All documents and study related materials required to conduct this study 
will be provided to each Investigator by the Sponsor. Additional materials 
may be sent upon request. 
7.  
RISKS AND BENEFITS OF PARTICIPATION 
7.1 Risks 
7.1.1 
The Sponsor has not identified any additional risks by participation in this 
clinical study. However, there are some risks that have an increased 
probability of occurrence with a reduced wear time aligner regimen 
including: 
• 
Reduced wear time causes teeth to shift while aligner is not 
worn; treatment takes longer than expected → Treatment Delay 
• 
Only wearing aligners for 10-12 hours per day can lead to 
greater subject discomfort when aligners are worn → Subject 
Discomfort 
 
7.1.2 
Additionally, there are risks associated with orthodontic treatment in 
general, including: 
• 
Discomfort:  There may be some discomfort due to wearing an 
aligner for the first time, as the mouth is very sensitive. As the 
teeth move, often some discomfort is to be expected, however 
this usually wears off in a couple of days after each aligner tray 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 20 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
change. Aligners may cause irritation to the surrounding cheeks 
and lips.   
• 
Allergy:  Although rare, some people may be allergic to the 
plastic in aligners. If the subject knows that they have a plastic 
allergy or sensitivity, they should notify the Investigator prior to 
starting aligner therapy. Subject with known allergies to plastic 
materials are not eligible to participate in this clinical study.  If an 
allergy to the aligner occurs, the Sponsor and/or the Investigator 
may recommend that treatment be paused and continued using 
alternative methods. 
• 
Cavities: The surface of teeth may become weaker, and may 
have more cavities. Excellent oral hygiene will help to prevent 
this from happening during treatment. 
• 
Resorption: The roots of teeth may become shorter or weaker 
during treatment. The Sponsor and/or the Investigator may 
recommend that treatment be paused if this process called root 
resorption occurs. 
• 
Tooth movement not tracking according to the prescribed 
treatment plan: This can be caused by several factors; the top 
factor being subject compliance in wearing aligners the required 
number of hours per day/night. Treatment time may take longer 
than expected, or final outcomes may be different than what was 
planned when aligners are not worn as prescribed. 
• 
X-ray: Standard procedures will be used i.e., all attempts to limit 
X-ray exposure will be made during the clinical study, including 
proper shielding. 
7.1.3 
Accidental Disclosure of Personal Health Information:  Although rare, 
there is a risk that personal health information may be disclosed to others 
who do not have the right to see it. The US HIPAA and EU GDPR privacy 
rules help your dentist and the Sponsor ensure they have the appropriate 
processes in place to prevent this from occurring. 
7.2 Benefits 
7.2.1 
The investigational device being used in this study may help straighten 
the subject’s teeth or improve their smile. While there are no guarantees 
the study of this product will provide a conclusive outcome.  
7.2.2 
One benefit of the reduced wear time aligner therapy is aesthetics. 
Subjects are able to wear the aligners during periods when they are 
sleeping or otherwise at home; offering a more discrete option of therapy. 
7.2.3 
Another benefit of the reduced wear time aligner therapy is increased 
subject ease of using the device. Aligners must be removed prior to eating 
and drinking anything except cool water. The subject must also brush their 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 21 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
teeth prior to reinserting the aligners. If the aligners are only worn during 
sleep or times when the subject is not eating or drinking for a continuous 
10-12 hours, subjects do not need to worry about this additional 
device/oral hygiene process. 
7.2.4 
Information from this study might help researchers develop a better 
orthodontic device that will help others in the future. 
8.  
STUDY PROCEDURES 
 
8.1 Screening 
8.1.1 
Subjects seeking orthodontic treatment will be screened through the 
Byte+ network of dental providers. Subjects who opt to receive 
orthodontic aligner treatment using the Byte® system will be screened for 
eligibility by the Investigator in the dental office. Screening will be based 
on potential study subject case complexity and eligibility. 
8.1.2 
Subjects will visit one of the Byte+ network dentists for an initial intraoral 
scan, x-ray (PAN, CBCT, CEPH and/or FMX), intraoral and extraoral 
photographs. An X-ray taken within a year from study visit  may be used 
for treatment planning if deemed adequate by the Investigator. 
8.1.3 
Subjects will be screened based on the inclusion and exclusion criteria 
defined above. 
8.1.4 
Subjects will be informed that the investigational device is being studied 
for its safety and efficacy in achieving prescribed tooth movement per 
each individual subject’s subject treatment plan and is not currently 
cleared by the FDA. 
8.1.5 
Informed consent (and parental consent for minors under the age of 18) 
will be obtained from the subject. 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 22 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
8.1.6 
All subjects screened will be documented in the Screening Log 
maintained at each investigational site. 
8.1.7 
Once the treatment plan is created, the Byte+ account manager will 
ensure that the subject’s prescribed tooth movements are within the 
constraints and criteria outlined within this study’s inclusion/exclusion 
criteria.  
• 
If the subject requires movements outside of the study’s eligibility 
criteria, they can continue with their orthodontic treatment with 
Daytime aligners outside of the confines of this clinical study. In 
these cases, the Investigator will be informed by the digital lab as 
to why the subject is not eligible for the study; the Investigator in 
turn shall notify the subject and withdraw them from the study.  
8.2 Enrollment 
8.2.1 
Subjects who meet the inclusion and exclusion criteria defined above are 
eligible to participate in this clinical study. 
8.2.2 
Eligible subjects who agree to participate in this study and meet the 
eligibility criteria will be informed that their case has been accepted into 
the study and they are eligible to participate.  
8.2.3 
Once a subject has been enrolled, the order will be placed in the Byte 
system and a treatment plan is created by the Byte digital lab, using the 
digital impression received and FDA cleared treatment planning software 
(refer to K230199), to stage the subject’s orthodontic treatment. 
8.2.4 
Subjects will be assigned a unique subject identification number randomly 
generated by the ERP system. This number will be used as the primary 
identifier on all study related documents. In addition subject will receive a 
subject Id when enrolled in the study. Subject IDs are unique to each 
individual subject and cannot be changed. 
8.2.5 
All enrolled subjects will be documented in the Screening Log. 
 
 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 23 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
8.3 Study Schedule 
 
 
8.3.1 
Once aligners are manufacturered, the first fifteen (15) aligner stages will 
be provided to the Investigator. Additional aligner stages in sets up to 
fifteen (15) are provided to the Investigator to continue treatment after 
completion of the first fifteen (15) sets. 
8.3.2 
The Investigator will provide the subject with aligners at treatment start 
and at monthly check-ins with the Investigator at clinic visits.  
8.3.3 
Once the aligner trays are received by the subject, they can start their 
treatment. The date the aligners are received will be recorded as the start 
date of each subject’s participation (TS). The initial visit worksheet must 
be completed at this time. 
8.3.4 
The subject visits will be performed monthly (every 4-6 weeks). The 
Investigator will review the subject’s treatment progress, confirm 
treatment plan and follow-up on any safety events. A visit worksheet must 
be completed at each visit (T1, T2, T3, etc.). 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 24 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
8.3.5 
The study aims to collect the following data at the following time points: 
• 
Intraoral scans of the subject prior to the start of treatment (TS) 
and end of treatment (TF). 
• 
X-ray (PAN, CBCT, CEPH, and/or FMX) prior to the start of 
treatment (TS) and at the end of treatment final visit (TF). 
• 
Intraoral and extraoral photographs prior to the start of treatment 
(TS), at every check-in visit, and end of treatment final visit (TF).  
• 
Completed visit worksheet at initial aligner visit (TS), scheduled 
monthly check in visits (4-6 week intervals: T1, T2, T3, T4, etc.), 
and final aligner visit (TF). 
• 
Completed subject questionnaire at check in visits (4-6 week 
intervals: T1, T2, T3, T4, etc.), 
• 
Subject post-treatment questionnaire at the end of the treatment 
(TF). 
• 
Relevant medical conditions and concomitant medication incl. 
trade name, dosage, route and start. 
• 
AE/DD documentation 
8.3.6 
At the final aligner treatment visit (TF), the dentist will complete a final visit 
worksheet and subject will complete the post-treatment questionnaire. 
8.3.7 
Each subject will receive removable retainers following completion of 
aligner therapy. 
8.4 Subject Eligibility 
8.4.1 
Subject Eligibility, informed consent, and if applicable parental consent 
shall be documented and later transferred to the eCRF. 
8.5 Subject Information 
8.5.1 
Subject demographic information including subject ID, age, gender, 
ethnicity and race will be collected and transferred to the corresponding 
eCRF. 
8.6 Pre-Treatment Period 
8.6.1 
The following will be collected prior to aligner treatment, and are required 
for the treatment planning phase of aligner therapy: 
• 
Intraoral scan  
• 
X-ray (CBCT, CEPH, PAN and/or FMX) 
• 
Intraoral and extraoral photographs 
 
 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 25 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
8.7 Treatment Start  
8.7.1 
The initial delivery of the investigational or control devices will be received 
by the subject (TS). A visit worksheet is required for the initial aligner visit. 
Visit worksheet data will be transferred to the eCRF. 
• 
The subject will be directed on use and care of the 
investigational or control device during the treatment period. 
8.8 In-Treatment Period 
8.8.1 
The subject will check in with the Investigator at their dental practice/office 
monthly (every 4-6 weeks).  
• 
The Investigator will review the subject’s treatment progress and 
provide feedback to the subject and the Sponsor related to 
compliance and tracking via completion of a visit worksheet at 
each visit (T1, T2, T3, etc.). 
• 
The Investigator will also take subject progress intraoral and 
extraoral photographs at each check in visit and submit them to 
the Sponsor. 
• 
In-treatment subject questionnaire 
8.8.2 
The Investigators and the Sponsor will assess the progression of 
investigational treatment through information subject submitted to the 
eCRF. 
8.9 Treatment Final  
8.9.1 
The following will be collected at final treatment visit (TF). 
• 
Intraoral scan  
• 
X-ray (CBCT, CEPH, PAN, and/or FMX) 
• 
Intraoral and extraoral photographs 
• 
Final visit worksheet (TF) 
• 
Post-treatment subject questionnaire 
8.9.2 
Each subject will receive removable retainers following completion of 
aligner therapy. 
8.9.3 
Participation in this study ends for each subject when: 
• 
Subjects complete treatment with the investigational or control 
device and the Investigator determine that a retainer can be 
ordered.  

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 26 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
• 
When a subject withdraws their consent to continue participating 
in the study.  
• 
If an Investigator removes a subject from the study due to 
ineligibility or non-compliance with study protocols.  
8.10 Subject Discontinuation 
8.10.1 
The Investigator and/or the Sponsor may discontinuing a subject if severe 
non-compliance to the protocol. Subject may also be discontinued due to 
safety reasons as judged by the Investigator and/or Sponsor.  
8.10.2 
If a subject for any reason desires to no longer participate in the study or 
continue treatment, they are free to discontinue participation in the study, 
at any time and without providing a reason for the withdrawal. 
Discontinuation from the clinical study will not affect future treatment /care 
of the subject.  
8.10.3 
Subjects who discontinue should always be inquired about the reason(s) 
for their discontinuation and any potential safety issues. If possible, they 
should be seen and assessed by an Investigator. The termination section 
in the eCRF should be completed. Safety events should be followed up. 
Any study specific material provided to the subject should be collected. 
9.  
 ENDPOINTS 
9.1 Primary Safety Endpoint 
The primary safety endpoint of the study will be the incidence of (device or dental) 
related AEs and SAEs associated with the planned investigational treatment, 
compared to the incidence from treatment with the control device. 
9.2 Secondary Safety Endpoint 
The secondary safety endpoint of the study will be the subject self-reported values 
pertaining to pain/discomfort during treatment and comfort in wearing the aligners 
captured in the questionnaire. For this endpoint, a Visual Analogue Scale (VAS) 
with a Wong Baker face scale is used. 
9.2.1 
Subject comfort wearing aligners during treatment via visual analogue 
scales (VAS): This question is directed to the subject. “How comfortable 
were the aligners to wear during your treatment?” (VAS: 0 very 
comfortable - 10 very uncomfortable). 
9.2.2 
Subject pain associated with new tooth movements during treatment via 
visual analogue scales (VAS): This question is directed to the subject. 
“Did you experience any pain associated with new tooth movement?” 
(VAS: 0 no pain – 10 worst possible pain). 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 27 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
9.3 Primary Efficacy Endpoint 
The primary effectiveness endpoint is the comparison between the treatment 
groups of the quantification of actual vs planned tooth movements using weighted 
Peer Assessment Rating (PAR) index. 
• 
Planned percentage reduction in PAR Score (Planned 
Improvement of Malocclusion [PIM]) 
In addition comparison between treatment groups will also be performed for: 
• 
 Actual percentage reduction in PAR Score (Actual Improvement 
of Malocclusion [AIM]) 
• 
Percentage of Accuracy of Outcome 
Quantification and comparison of expressed and programmed tooth movements 
will be conducted using to measure orthodontic treatment need and outcome, the 
built-in weighted PAR analysis tool of 3Shape Ortho System software (K152086). 
 
9.3.1 
The weighted PAR scores for each Digital Study Model (DSM) would be 
compared as follows: 
• 
Planned percentage reduction in PAR Score (Planned 
Improvement of Malocclusion [PIM]) = PAR Score TS- PAR 
Score TP / PAR Score TS * 100 
• 
 Actual percentage reduction in PAR Score (Actual Improvement 
of Malocclusion [AIM]) = PAR Score TS- PAR Score TF / PAR 
Score TS * 100 
• 
Percentage of Accuracy of Outcome = 100% - [(|PIM - 
AIM|/|AIM|) *100%] 
9.4 Secondary Efficacy Endpoint 
The secondary endpoint of this study will be to assess overall subject and dentist 
(Investigator) satisfaction with their treatment. This will be assessed through a 
questionnaire provided to both the dentist and the subject when treatment is 
completed. For this endpoint, a rating scale (1 very satisfied - 10 very unsatisfied) 
is used. 
9.4.1 
Doctor satisfaction with treatment results: “How satisfied are you with the 
results obtained?” (1 very satisfied - 10 very unsatisfied). 
9.4.2 
Subject satisfaction with treatment results: This question is directed to the 
subject “How satisfied are you with the results obtained?” (1 very satisfied 
- 10 very unsatisfied). 
 
 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 28 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
10.  DEVIATIONS 
10.1 Deviations 
10.1.1 
All deviations from this protocol will be reported in the study report. If it is 
necessary for the protocol to be amended, the amendment and/or a new 
version of the protocol (Substantial Amendment) must be notified to or 
approved by IRB before implementation. Local requirements must be 
followed. If a protocol amendment requires a change to a particular 
investigational site’s ICF, then Sponsor and IRB must be notified. 
Approval of the revised ICF by Sponsor and by the IRB is required before 
the revised form is used. Sponsor will distribute amendments and new 
versions of the protocol to each Investigator and IRB. In general, a non-
substantial amendment does not require a notification to or approval by 
IRB. 
10.1.2 
The Investigator is not allowed to deviate from the protocol except in case 
of emergency to protect a subject’s rights, safety, and wellbeing. In such 
a case, the Investigator may proceed without prior approval from Sponsor 
or the IRB. However, the deviation should be documented and reported 
to Sponsor and the IRB as soon as possible.  
10.1.3 
Any protocol deviation that occurs, which is not approved by the Sponsor, 
will render the study subject ineligible for continued participation in this 
clinical study. 
10.1.4 
The Investigator should promptly report any  protocol deviations to the 
Sponsor. It is the responsibility of the Sponsor to report all protocol 
deviations affecting study subject safety to the IRB in a timely manner. 
11.  ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
11.1 Adverse Event (AEs) 
11.1.1 
All adverse events must be reported to the divisional complaint officer and 
regulatory compliance. 
11.1.2 
All Adverse Events (AEs) will be documented and recorded by the 
Investigator in the eCRF throughout the study period. 
• 
AE is defined as: Any untoward medical occurrence, unintended 
disease, effect or injury, or untoward clinical sign in a subject, 
whether related to the investigational product or not.  
• 
For example, a rash, bleeding, or blistering appearing on the soft 
tissue in contact with the investigational device. 
• 
Another example is clinically significant root resorption. 
11.1.3 
All adverse events shall be reported for that particular study subject’s 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 29 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
appointment. 
• 
This documentation should list the event, the cause of the event 
if known, consequences and resulting actions by the Investigator, 
or designee, and any other medically pertinent information. 
• 
Where possible, a diagnosis rather than a list of symptoms 
should be given. 
• 
The intensity to be recorded is the worst intensity experienced 
during the course of the event.  The Investigator should complete 
all related information, including date(s) of onset, severity, 
corrective therapies given, outcome, and professional opinion as 
to whether the AE had a relationship to the investigational 
device. 
11.1.4 
The Center of Clinical Research (CoCR) team must make the 
determination of relationship to the investigational device for each 
recorded AE in the corresponding eCRF. The CoCR should decide 
whether there is a reasonable possibility that the event may have been 
caused by the investigational device. 
11.1.5 
If there is any valid reason, even if undetermined or untested, for 
suspecting a possible cause-and-effect relationship between the 
investigational device and the occurrence of the AE, then the AE should 
be considered “possibly” or “probably related”. 
11.1.6 
Otherwise, if no valid reason exists for suggesting a relationship, then the 
AE should be classified as “unrelated”.  The following guidance may also 
be helpful: 
• 
Unrelated:  There is no medical evidence to suggest that the AE 
is related to the investigational device.  The AE can be readily 
explained by the subject’s underlying medical condition or 
concomitant therapy or lacks a plausible temporal relationship to 
investigational device. 
• 
Possibly Related:  A direct cause and effect relationship between 
the investigational device and the AE has not been 
demonstrated, but there is a reasonable possibility that the AE 
was caused by the investigational device. 
• 
Probably Related:  The AE is likely related to the investigational 
device.  This category applies when the experience most likely 
seems to be related to the investigational device but there is a 
modest suspicion that it could be related to other causes. 
• 
 Related:  There is a direct cause and effect relationship between 
the AE and the investigational device. 
11.1.7 
The medical assessment of related AE severity will be determined by 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 30 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
using the following definitions: 
• 
Mild:  The AE is easily tolerated and does not interfere with usual 
activity. 
• 
Moderate:  The AE interferes with daily activity, but the subject is 
still able to function. 
• 
Severe:  The AE is incapacitating, and the subject is unable to 
work or complete usual activity, i.e. a serious injury has occurred. 
• 
Life Threatening:  The SAE places the subject, in the view of the 
Investigator, at immediate risk of death from the reaction as it 
occurred, i.e., it does not include a reaction that had it occurred 
in a more severe form, might have caused death. 
11.1.8 
Outcome may be classified as resolved, ongoing, resolved with sequelae, 
or death. 
• 
Unexpected severe or life threatening related events will be 
followed until resolved (the subject’s health has returned to 
his/her baseline status or all variables have returned to normal), 
an outcome is reached, stabilization (the Investigator does not 
expect any further improvement or worsening of the AE), or the 
event is otherwise explained regardless of whether the subject is 
still participating in the study. 
• 
Where appropriate, medical testing and examinations will be 
performed to document AE resolution. 
11.1.9 
The types of adverse events that are known to occur with orthodontic 
treatment include mild to moderate gum pain, inflammation, and redness; 
allergic reaction to plastic(s) or metal(s); and root resorption. 
11.2 Serious Adverse Events (SAEs) 
11.2.1 
A SAE is any AE that results in any of the following outcomes: 
• 
Death 
• 
Immediate threat to life 
• 
Hospitalization or prolongation of an existing hospitalization 
• 
Persistent or significant disability/incapacity 
• 
Congenital anomaly/birth defect 
11.2.2 
Important medical events that do not result in one of these outcomes, but 
based on appropriate medical judgment, are deemed to jeopardize the 
subject or require medical or surgical intervention to avert one of the listed 
outcomes, may also be considered SAEs at the Investigator’s discretion. 
• 
Allergic reactions are a known risk with clear aligners.  Subjects 
with known plastic allergies have been excluded from this study.  

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 31 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
As there may be some subjects enrolled who are unaware of a 
plastic allergy, allergic reactions will not be documented as 
SAEs.  They should however be documented as Adverse Events 
(AE). 
11.2.3 
Any AE considered serious (SAE) according to the criteria above that 
occurs during the study must also be documented by the Investigator and 
recorded in the eCRF.All deaths and immediately life-threatening events, 
whether related or unrelated, will be recorded on the SAE Form and 
documented via the eCRF system within 24 hours of Investigators 
awareness. 
11.2.4 
All SAEs will be followed until satisfactory resolution has been reached, 
or until the Investigator deems the SAE to be chronic or the subject to be 
stable. 
11.2.5 
All SAEs must also be reported by the Sponsor as soon as possible to the 
IRB. 
11.2.6 
It is the responsibility of the device Sponsor to report the event as 
specified in 21 CFR Part 812.46.  All SAEs designated as “unrelated” to 
the product will be reported to the FDA at least annually in a summary 
format by the Sponsor. 
11.2.7 
Subjects will be notified of any unexpected SAEs within the timelines 
specified by the U.S. CFR. 
11.3 Device Deficiencies (DDs) 
11.3.1 
Device Deficiency (DD) is defined as: Inadequacy of a medical device with 
respect to its identity, quality, durability, reliability, usability, safety, or 
performance. 
• 
Device deficiencies include malfunctions, use errors, and 
inadequacy in the information supplied by the manufacturer 
including labelling. 
• 
This definition includes device deficiencies related to the 
investigational medical device or the comparator. 
11.3.2 
All DDs must be reported to the divisional complaint officer and regulatory 
compliance. 
12.  DATA AND STATISTICAL ANALYSIS 
12.1 Statistical Sample Size and Power (provided as an example) 
12.1.1 
The current study is a controlled prospective study to determine the 
expressed movements demonstrated by investigational device, Nighttime 
Aligners for 10-12 continous hours per day/night compared to the control 
group, Daytime Aligners, which are worn for 20-22 hours per day. 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 32 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
12.1.2 Sample size calculations for this study were determined using statistical 
software Minitab to ensure proper powering. The desired sample size per 
arm is 23 based on power calculations previously developed by Dentsply 
Sirona. The desired level of power is 90%. The desired confidence is 95% 
(p <0.05). Calculations are based on a standard deviation of 1, a power 
value of 0.9 and a detected difference of 1.  The calculation also assumes 
a 2-sided, alpha = 0.05 level of significance. 
1.0
0.5
0.0
-0.5
-1.0
1.0
0.8
0.6
0.4
0.2
0.0
Difference
Power
Alpha
0.05
StDev
1
Alternative
Not =
Assumptions
23
Size
Sample
Power Curve for 2-Sample t Test
 
 
12.2 Data Analysis 
12.2.1 
The Sponsor and Investigators are not blinded to the study data during 
the conduct of the trial, and may at periodic intervals analyze the data to 
assess study progress. 
12.2.2 
If nothing else is stated, descriptive statistics will be given for each 
variable in the clinical study and p-values may be complemented by 
confidence intervals as appropriate. When using the terminology 
descriptive statistics, it is meant that the number of subjects (N), mean, 
median, standard deviation (Sd), minimum (Min) and maximum (Max) 
values will be presented for continuous data and frequencies and 
percentages for categorical data. 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 33 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
12.2.3 
All tooth movement data analyses will be performedusing 3Shape Ortho 
System (K152086).  
12.2.4 
Three .stl files from each subject would be used for the analysis: 
• 
A pre-treatment STL file (TS) would be generated by scanning 
subject’s pre-treatment intraoral scan taken before the start of 
treatment. 
• 
A planned or programmed STL (TP) file would be obtained from 
Archform Orthodontic Software System (K213916) after planned 
or programmed tooth movements have been made based on the 
treatment plan finalized by the digital lab and study Investigators. 
• 
The actual post-treatment STL file (TF) would be generated by 
scanning subject’s post-treatment intraoral scan at the end of 
treatment. 
12.2.5 
Each STL file would convert into a Digital Study Model within the 3Shape 
Ortho System software to standardize the analysis. 
12.2.6 
Each DSM would be segmented using the “auto segmentation tool” of the 
software to demarcate each tooth separately.  
12.2.7 
This would be followed by Peer Assessment Rating (PAR) index to 
measure orthodontic treatment need and outcome (Richmond, 1992). 
This would be done using the built-in weighted PAR analysis tool of 
3Shape Ortho System software. The PAR index will be performed by an 
external evaluator. 
12.2.8 
The weightage for each component of the PAR index would be set as: 
maxillary and mandibular anterior segment alignment x 1; buccal 
occlusion x 1; overjet x 6; overbite x 2; centerline x 4; following the ABO 
guidelines. The weighted PAR scores for each DSM would be compared 
as follows: 
The PAR Score values for TS, TP, and TF will be transferred to the eCRF 
and the following will be calculated: 
• 
Planned percentage reduction in PAR Score (Planned 
Improvement of Malocclusion [PIM]) = PAR Score TS- PAR 
Score TP / PAR Score TS * 100 
• 
 Actual percentage reduction in PAR Score (Actual Improvement 
of Malocclusion [AIM]) = PAR Score TS- PAR Score TF / PAR 
Score TS * 100 
• 
Percentage of Accuracy of Outcome = 100% - [(|PIM - 
AIM|/|AIM|) *100%] 
Statistical analysis comparing the two treatment groups using the 
Wilcoxon rank sum test will pe performed. A two-sided p-value below 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 34 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
5% will be regarded as statistically significant. The null hypothesis of 
the study is that there is no difference between the two groups. 
12.2.9 
Additional comparisons between treatment groups may be performed and 
p-values presented using the Wilcoxon rank sum test. Wilcoxon signed 
rank test may be used for analysis within treatment groups over time. 
12.2.10 Calculation of Spearman’s rank correlation coefficients will be performed 
to elucidate the relationships between the accuracy of outcome with 
treatment duration, number of aligners, subject pain levels, and overall 
subject and doctor satisfaction for each group.   
12.2.11 All methods used in this clinical study have been previously published and 
reviewed (Griffith 2021, Grünheid 2022). All data in this clinical study will 
be analyzed by an independent contractor to remove bias. Any 
adjustments or modifications to these methods will be duly documented 
and reported. 
12.3 Safety Analysis 
12.3.1 
As this is a non-significant risk study, the Sponsor does not intend to use 
a Data Safety Monitoring Board for this clinical study. 
12.3.2 
Safety aspects of the investigational device will be evaluated in terms of 
related adverse events (AEs) and serious adverse events (SAEs) 
documented during the course of treatment beginning at the time of 
application of the device through the time of completion of the treatment 
period; i.e., the time of removal of the final treatment aligner.  
12.3.3 
Evaluation of adverse events will be based on the risk management file 
and known risks/harms documented by Sponsor for aligner systems (e.g. 
design / process FMEAs, harms libraries, historical complaint files and 
post-market surveillance data). 
13.  DATA COLLECTION AND MONITORING 
13.1 Source Documents & eCRFs 
13.1.1 
Within the scope of this study, the Sponsor will record information related 
to the subject’s treatment as outlined above. These data points shall be 
recorded and entered into the study specific eCRF by each investigational 
site participating in this clinical study. 
13.1.2 
During and at the end of the study, all data will be reviewed for 
completeness and accuracy against the data contained in the eCRFs. 
13.1.3 
A Monitoring Plan (MP) will be finalized prior to the first monitoring visit. 
The MP will describe the level of source data verification and tasks to be 
performed at monitoring visits, including frequency and intervals. A risk-
based approach will be used when determining the extent and nature of 
monitoring activities.  During the course of the clinical study, a monitor 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 35 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
from the Sponsor or representative will have regular contacts with the 
investigational site. The monitor or another Sponsor representative will 
also be available between visits if the Investigator or other personnel at 
the investigational site needs information and advice. 
13.1.4 
The Investigator is responsible to ensure that study information is 
recorded in the medical record, in accordance with national regulations 
and requirements. In general, the following information should be 
recorded in the medical record: 
• 
Study code, and/or clinical study title. 
• 
That informed consent for participating in the clinical study was 
obtained, and signature date. 
• 
Diagnosis. 
• 
All visits during the clinical study period including visit date. 
• 
All AEs/ADEs/SADEs. 
• 
Treatments and medications. 
• 
Subject health service identification number, if applicable.  
The Investigator is responsible for ensuring that source data, and data 
reported to the Sponsor, is attributable, legible, contemporaneous, 
original, accurate, and complete. The Investigator is responsible for 
providing the monitor, auditor, IRB, or RA if required, with access to all 
clinical investigational-related records, including source documents. 
For data recorded directly in the eCRF, the eCRF is considered source 
data this should be documented on the source data specification form.  
13.1.5 
The Investigator should comply with the terms, conditions, and obligations 
of the Clinical Study Agreement (CSA). In the event of any discrepancy 
between the protocol and the CSA, the protocol shall prevail with respect 
to the conduct of the study and the treatment of subjects. For 
inconsistencies not related to the conduct of the clinical study or treatment 
of subjects, the terms of the CSA shall prevail over the protocol. The CSA 
should be finalized and signed before any study-related procedures, 
including subject enrollment, are performed at site. Should the 
Investigator break any obligations under the CSA and fail to remedy such 
a breach where it is capable of cure, Sponsor retains the right to disqualify 
the site from the clinical 
13.2 Case Report Forms (CRFs) 
13.2.1 
All study data will be entered into the eCRF by personnel at the clinical 
study sites and signed by the site Investigator. Worksheets must be 
entered into eCRF within 48 hours of each visit. 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 36 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
13.2.2 
When data  has been reviewed and found to be clean, by CoCR, the data 
shall be locked in the eCRF. 
13.2.3 
Once data has been entered into the eCRF and locked, it cannot be 
modified by the personnel at the Investigational Sites unless unlocked by 
the CoCR. 
13.3 Data Entry and Management 
13.3.1 
The handling of data, including data quality assurance, will comply with 
applicable regulatory guidelines (e.g.,ICH and GCP) and the Sponsor’s 
operating procedures and work instructions. All steps and actions taken 
regarding data management and quality assurance will follow the 
Sponsor’s policies and the data handling guidelines. 
13.3.2 
Completed CRFs will be verified and checked against source data, by 
CoCR, for completeness (i.e., source data verification), consistency, and 
legibility according to the study monitoring plan. In addition 
• 
Edit checks will be implemented to ensure data quality and 
accuracy. 
• 
Responses to requests for further clarification of data recorded in 
the eCRF will be documented, dated, and signed by the 
Investigator in the software. 
• 
All adverse event terms recorded on the CRF will be collected 
and entered into the Sponsor’s AE tracking system. 
13.3.3 
Data contained within the eCRFs will be exported from the Electronic Data 
Capture (EDC) system software Viedoc. 
• 
When all study data has been entered, signed and locked and all 
queries are resolved Clean File will be declared and, the study 
database will be locked, and data will be exported for the 
purpose of statistical analysis and reporting. 
13.4 Data Monitoring 
13.4.1 
The CoCR shall review the data entered into the eCRFs to ensure that it 
is accurate and corresponds with the information contained in the Source 
Documents. 
13.4.2 
Only personnel at the Study sites shall have access to modify data 
entered into the eCRFs and corresponding study database(s). 
13.4.3 
CoCR  will query the personnel at the Investigational Site for any 
unclarities that are identified during data review and source data 
verification.  
13.4.4 
The queries are solved by personnel at the Investigational Site and 
approved by CoCR. 
13.4.5 
All eCRF data changes, updates and query handling is tracked in the EDC 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 37 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
software audit trail. 
14.  QUALITY ASSURANCE 
14.1 Responsibilities 
14.1.1 
The Sponsor and Investigators must agree to conduct the study in 
accordance with the applicable regulations and Good Clinical Practice 
(GCP) guidelines. 
14.1.2 
Sponsor Study Director is responsible for signing this clinical protocol and 
all protocol amendments.  The Sponsor Study Director is also responsible 
for ensuring that all study personnel are adequately trained and that the 
required material(s) are sent to each subject in a timely fashion.  Sponsor 
Study Director is also responsible for ensuring the completion of the 
clinical study report at the conclusion of the study.  CoCR shall assist in 
statistical analyses associated with the protocol. 
• 
Sponsor responsibilities include the creation and oversight of 
protocol development, data monitoring, maintaining GCP 
conduct of the study, and the submission of final study report(s) 
to the FDA.  Additionally, 
• 
Sponsor shall conduct a timely evaluation of any unanticipated 
adverse device event. 
• 
Sponsor who determines that an unanticipated adverse device 
event presents an unreasonable risk to subjects shall terminate 
all investigations or parts of investigations presenting that risk as 
soon as possible. Termination shall occur not later than 5 
working days after the Sponsor makes this determination and not 
later than 15 working days after the Sponsor first received notice 
of the event. 
• 
If the study is halted due to a safety concern, the Sponsor will 
submit the safety information to the FDA and will receive IRB 
approval prior to restarting the study. 
14.2 Training 
14.2.1 
All Sponsor and site personnel involved in the execution of this clinical 
study shall be appropriately trained prior to participating in any study 
related tasks.   
 
 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 38 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
15.  DOCUMENTATION REQUIREMENTS 
15.1 Enrolled Subjects: 
15.1.1 
The original consent form, along with detailed information on the subject, 
will be kept at site. A copy of the signed informed consent  will be provided 
to the subject. 
15.1.2 
In order to protect confidentiality of the study subjects, any information 
that could identify the individual, such as name, initials or address, will not 
be included in the eCRF nor the data set provided for analysis. This also 
include any files uploaded to the EDC system such as photos, scan files 
or x-rays. All eCRF data in the EDC system is pseudonymized. 
15.1.3 
Each subject must agree to allow CoCR team to view any and all relevant 
source documentation to aid in study related monitoring and data 
analysis. 
15.2 Sponsor: 
15.2.1 
Study results shall be documented and approved in a final report.  The 
report shall summarize the study data, present the results of the 
conducted statistical analysis, and document the conclusion of the study. 
15.2.2 
All data collected during the execution of this clinical study shall be 
maintained by the Sponsor in the clinical trial master file. 
15.2.3 
These records are accessible to Sponsor staff and regulatory agencies 
for review upon request. 
15.3 Investigator: 
15.3.1 
All data collected at the clinical study site shall be maintained by the 
Investigator in the Investigator site file (ISF). 
15.4 Record Retention: 
15.4.1 
Sponsor will be responsible for long-term storage of the clinical trial 
master file in accordance with applicable local laws. Clinical study data 
will be securely stored at Sponsor, with restricted access. Data will be 
retained at Sponsor for 15 years after the last device was placed on the 
market. 
15.4.2 
The medical records of clinical study subjects must be retained in 
accordance with local legislation and in accordance with the maximum 
period of time permitted by the clinic. The Investigator shall retain all 
clinical study records during the study and for the period required by 
applicable regulatory requirements or for at least 10 years after the 
premature termination or completion of the clinical study, whichever ever 
is the longest. The Investigator must take measures to prevent accidental 
or premature destruction of the records. The Investigator should contact 
Sponsor prior to destruction of any records or reports pertaining to the 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 39 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
clinical study to ensure they no longer need to be retained. In addition, if 
the Investigator leaves the hospital, he/she should provide Sponsor with 
the name and address of the person who will take over the responsibility 
for the clinical study-related records. If the records are transferred to 
another person/party, the transfer should be documented at the clinical 
study site or at Sponsor.  
16.  SUBJECT RIGHTS AND CONFIDENTIALITY 
16.1 IRB Review 
16.1.1 
This protocol and each subsequent revision shall be reviewed and 
approved by an Institutional Review Board prior to initiation. 
16.1.2 
All associated consent, assent, and advertising materials associated with 
the protocol shall be reviewed and approved by the same IRB prior to use.  
16.1.3 
The Investigator is responsible for submitting amendments, and updated 
ICFs, to IRB and approval(s) must be obtained prior to implementation at 
site. Any additional requirements by the IRB should be met. 
16.2 Insurance  
16.2.1 
The Sponsor is responsible for ensuring adequate insurance coverage of 
any injuries to subject(s) caused by the Aligner.  
16.3 Protected Health Information & Subject Confidentiality 
16.3.1 
Subjects will be assigned a unique subject identification number during 
enrollment generated by the ERP system at the time of placing the 
subject’s orthodontic treatment order. 
• 
This number will be used as the primary identifier on all study 
related documents. In addition subject will receive a subject Id 
when enrolled in the study. 
16.3.2 
Each investigational site shall maintain a Screening Log. All enrolled  
subjects are included in the Subject Id log that links each subject to their 
assigned subject identification number. 
• 
The Sponsor shall have access to this information solely for the 
purposes of data monitoring. 
16.3.3 
No personal identification information such as subject’s first or last name, 
initials, social security number shall be included in study related 
documents. 
• 
In cases where records containing protected health information 
must be sent to the Sponsor, FDA, or other agency, it will be 
appropriately de-identified to ensure that subject’s privacy is 
maintained in accordance with the Health Insurance Portability 
and Accountability Act (HIPAA) and EU GDPR. 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 40 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
16.4 Subject Withdrawal 
16.4.1 
During the informed consent process, eligible study subjects will be 
advised that they are free to withdraw their consent to participate in the 
study at any time, without prejudice by the Sponsor. 
16.4.2 
Every reasonable effort should be made to ensure that each subject 
complies with the protocol and completes all study visits.  However, a 
subject may withdraw or be withdrawn from participation if: 
• 
The subject withdraws consent, 
• 
CoCR or study Investigators recommend discontinuation in the 
interest of the subject’s safety (i.e., AE-related) or because of 
significant and irremediable protocol non-compliance, 
• 
There is a report of a SAE that warrants discontinuation, 
• 
The subject is lost to follow-up, or 
• 
The Sponsor or the Institutional Review Board (IRB) terminates 
the clinical trial. 
16.4.3 
Data for subjects that are withdrawn from the study, but have already 
completed a portion of the trial, will be retained and used in the statistical 
analyses described in this protocol. 
16.4.4 
Withdrawals from the study shall be documented, with the primary reason 
for withdrawal recorded by the Investigator. 
17.  ASSOCIATED DOCUMENTS 
1. Nighttime Aligners Instructions for Use (Investigator) 
2. Nighttime Aligners Instruction for Use (Subject) 
3. Daytime Aligners Instructions for Use (Investigator) 
4. Daytime Aligners Instructions for Use (Subject ) 
 
 

 
Protocol:  2000-CIP-0001, Revision: 1                           Page 41 of 41 
 
CONFIDENTIAL: The information in this study protocol is strictly confidential and is available for review to Investigators, study 
center personnel, the ethics committee, and the health authorities.  It will not be disclosed to third parties without written 
authorization from the Sponsor, except to obtain informed consent from persons receiving the study treatment.  Once the protocol is 
signed, its terms are binding for all parties. 
 
 
              2000-TP-7.3-08-1[02] 
 
18.  SIGNATURES 
I agree to the terms of the Clinical Study Protocol. 
 
 
Approval of Study Protocol  
 
 
 
Nick Sarnoff 
VP, Byte 
Date (DD/MMM/YYYY) 
 
 
 
Jay Khorsandi 
Study Director 
Date (DD/MMM/YYYY) 
 
 
 
 
Scott Lurgio 
Quality Assurance & Regulatory 
Date (DD/MMM/YYYY) 
 
 
 
 
Gretchen Heasley 
Regulatory Affairs 
Date (DD/MMM/YYYY) 
 
 
 
 
Bharat Patel 
Research & Development 
Date (DD/MMM/YYYY) 
 
 
 
 
AnnaKarin Lundgren 
Director Center of Clinical Research  
Date (DD/MMM/YYYY)