Effect of Non-Surgical Periodontal Therapy With and Without Minocycline HCl Microspheres, 1 mg on Bacterial Load and Systemic Markers of Inflammation
Phase: PHASE4
Conditions: SRP, Minocycline HCl Microspheres, Biomarkers
Sponsor: University of Minnesota

PROTOCOL TITLE: Effect of Non-Surgical Periodontal Therapy With and Without 
Minocycline HCl Microspheres, 1 mg on Bacterial Load and Systemic Markers of 
Inflammation 
VERSION DATE: September 26, 2022 
 
Page 1 of 13 
Template Revised On: 7/26/2018 
 
 
 
 

PROTOCOL TITLE: Effect of Non-Surgical Periodontal Therapy With and Without 
Minocycline HCl Microspheres, 1 mg on Bacterial Load and Systemic Markers of 
Inflammation 
VERSION DATE: September 26, 2022 
 
Page 2 of 13 
Template Revised On: 7/26/2018 
PROTOCOL COVER PAGE 
 
 
 
 
Protocol Title 
Effect of Non-Surgical Periodontal Therapy With and Without 
Minocycline HCl Microspheres, 1 mgon Bacterial Load and 
Systemic Markers of Inflammation 
Principal 
Investigator/Faculty 
Advisor 
Name: Michelle Arnett (PI) and Christine Blue (Co-PI) 
Department: School of Dentistry, Primary Care 
Telephone Number: 612-624-3457 
Email Address: marnett@umn.edu 
Student 
Investigator 
Name: N/A 
Current Academic Status (Student, Fellow, Resident): N/A 
  
Department: N/A 
Telephone Number: N/A 
Institutional Email Address: N/A 
Scientific 
Assessment 
HRPP facilitated scientific assessment 
IND/IDE # (if 
applicable) 
N/A 
IND/IDE Holder 
N/A 
Investigational Drug 
Services # (if 
applicable) 
N/A 
Version 
Number/Date: 
Version 1.4 
April 8, 2020  
 

PROTOCOL TITLE: Effect of Non-Surgical Periodontal Therapy With and Without 
Minocycline HCl Microspheres, 1 mg on Bacterial Load and Systemic Markers of 
Inflammation 
VERSION DATE: September 26, 2022 
 
Page 3 of 13 
Template Revised On: 7/26/2018 
REVISION HISTORY 
 
Revision # 
Version Date 
Summary of Changes 
Consent Change? 
1.2 
September 8, 
2019 
Page 9 was revised to state patient 
charts that are pre-screen and 
have a email address will be 
emailed to subjects instead of sent 
by mail. Page 9 was also revised to 
state the study information will be 
posted on the U of M OHCRC 
website. 
No 
1.3 
February 21, 
2020 
Page 7 was revised to include the 
use of de-identified data for future 
research.  
Yes 
1.4 
April 8, 2020 
COVID-19 plan to mitigate risks on 
page  
No 
1.5 
September 8, 
2022 
Add MMP-8 to GCF and serum 
biomarkers 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PROTOCOL TITLE: Effect of Non-Surgical Periodontal Therapy With and Without 
Minocycline HCl Microspheres, 1 mg on Bacterial Load and Systemic Markers of 
Inflammation 
VERSION DATE: September 26, 2022 
 
Page 4 of 13 
Template Revised On: 7/26/2018 
Table of Contents 
 
1.0 
Study Intervention(s)/Investigational Agent(s) ....................................................... 6 
2.0 
Local Procedures Involved and Local Requirements ............................................... 7 
3.0 
Provisions to Monitor the Data to Ensure the Safety of Participants ..................... 7 
4.0 
Data and Specimen Banking .................................................................................... 7 
5.0 
Sharing of Results with Participants ........................................................................ 8 
6.0 
Local Study Population............................................................................................. 8 
7.0 
Vulnerable Populations ............................................................................................ 8 
8.0 
Local Number of Participants................................................................................... 9 
9.0 
Local Recruitment Methods ..................................................................................... 9 
10.0 Withdrawal of Participants .................................................................................... 10 
11.0 Risks to Participants ............................................................................................... 10 
12.0 Potential Benefits to Participants .......................................................................... 11 
13.0 Confidentiality ........................................................................................................ 11 
14.0 Provisions to Protect the Privacy Interests of Participants ................................... 11 
15.0 Compensation for Research-Related Injury ........................................................... 11 
16.0 Consent Process ..................................................................................................... 11 
17.0 Setting .................................................................................................................... 12 
18.0 Multi-Site Research ................................................................................................ 12 
19.0 Resources Available ............................................................................................... 12 
 

PROTOCOL TITLE: Effect of Non-Surgical Periodontal Therapy With and Without 
Minocycline HCl Microspheres, 1 mg on Bacterial Load and Systemic Markers of 
Inflammation 
VERSION DATE: September 26, 2022 
 
Page 5 of 13 
Template Revised On: 7/26/2018 
ABBREVIATIONS/DEFINITIONS 
AE 
Adverse Event/Adverse Experience 
FDA 
Food and Drug Administration 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SCR 
Scheduled Continuing Review 
US 
United States 
SRP 
Scaling and Root Planing 
GCF 
Gingival Crevicular Fluid 
hsCRP 
High Sensitivity C-Reactive Protein 
Hp 
Haptoglobin 
Hgb Alc 
Hemoglobin A1c 
MMP-8 
Matrix metalloproteinase-8 
TNF-α 
Tumor Necrosis Factor alpha  
IL-1 
Interleukin 1 
IL-6 
CVD 
Interleukin 6 
Cardiovascular disease 
U of M 
University of Minnesota 
School of Dentistry 
SoD 
 
 

PROTOCOL TITLE: Effect of Non-Surgical Periodontal Therapy With and Without 
Minocycline HCl Microspheres, 1 mg on Bacterial Load and Systemic Markers of 
Inflammation 
VERSION DATE: September 26, 2022 
 
Page 6 of 13 
Template Revised On: 7/26/2018 
1.0 
Study Intervention(s)/Investigational Agent(s) 
1.1 Description:  
The primary goal of this study is to investigate the qualitative and 
quantitative effects of SRP with and without minocycline HCL 
microspheres, 1 mg on periodontal pathogens and overall bacterial load. 
A randomized controlled clinical trial of a control (scaling and root planing) 
(SRP)) group and an experimental (SRP with minocycline HCl microspheres, 
1 mg) group is planned. 
 
The intervention of minocycline HCl microspheres, 1 mg will be 
administered in the experimental group at baseline and the three month 
periodontal maintenance visit. Saliva samples, gingival crevicular fluid 
(GCF), and blood serum will be collected at four time points (baseline, 1, 3, 
and 6 month follow up). Saliva will be analyzed for overall pathogen 
burden. GCF will be analyzed for IL-1, IL-6, TNF-α, MMP-8. Serum will be 
analyzed for C-reactive protein (hsCRP), haptoglobin (Hp), hemoglobin 
(Hgb) Alc,  IL-1, IL-6, TNF-α, and MMP-8.  
 
Primary: Investigate the pathogenic burden and overall bacterial load 
utilizing the MyPerioPath® salivary test as a measure of the effect of SRP 
with and without minocycline HCl microspheres, 1 mg. 
 
Secondary: Evaluate the effects of SRP with and without minocycline HCl 
microspheres, 1 mg on serum biomarkers of systemic inflammation, 
including IL-1, IL-6, TNF-α, MMP-8, hsCRP, Hp, and Hgb A1c  and GCF levels 
of IL-, IL-6, TNF-α, MMP-8. 
1.2 Drug/Device Handling:  
Minocycline HCl microspheres, 1 mg are approved by the Food and Drug 
Administration (FDA) as an adjunct to SRP procedures for reduction of 
pocket depth in patients with adult periodontitis. Minocycline HCL, 1 mg is 
a subgingival unit dose of 4 mg of drug containing 1 mg of minocycline and 
3 mg of poly (glycolide-co-dl-lactide) (PGLA). The drug is in a powder form 
and prepackaged in a disposal plastic cartridge tip. The tip is loaded into a 
stainless steel spring- loaded cartridge handle to deliver subgingivally. The 
packaging is clearly labeled for the administration of the drug.  
 
Minocycline HCL, 1 mg will be stored in a locked cabinet in the U of M SoD 
Oral Health Clinical Research Clinic (OHCRC) at room temperature (68o to 
77o F). The product will not be exposed to heat or pressure. 

PROTOCOL TITLE: Effect of Non-Surgical Periodontal Therapy With and Without 
Minocycline HCl Microspheres, 1 mg on Bacterial Load and Systemic Markers of 
Inflammation 
VERSION DATE: September 26, 2022 
 
Page 7 of 13 
Template Revised On: 7/26/2018 
 
 
The drug is prepackaged and no preparation is required. The prepackaged 
drug is located inside a disposal plastic cartridge tip to ensure exact dosage 
delivered. The tip is loaded into a stainless steel spring-loaded cartridge 
handle to deliver subgingivally.  
 
1.3 Biosafety: N/A 
1.4 Stem Cells: N/A 
 
2.0 
Local Procedures Involved and Local Requirements 
2.1 Local Procedures:  
All study procedures are located on page 14-16 of the protocol.  
2.2 Individually Identifiable Health Information:  
 
Identifiable information from the PHI will be used for recruitment. PHI 
information used for research purposes will be age and gender. See the 
HIPCO Survey and permission to use PHI for research and HIPAA 
authorization form uploaded in ETHOS. Subjects who agree to participate in 
the study will also sign the HIPAA authorization. 
 
2.3 Use of radiation: N/A 
2.4 Use of Center for Magnetic Resonance Research: N/A 
3.0 
Provisions to Monitor the Data to Ensure the Safety of Participants 
3.1 Data Integrity Monitoring.  
The specimen collect, data, and monitoring plan is located on page 21-24. 
Additionally the use of de-identified data for future research. The adverse 
events definitions are located on page 20. Additional information is on 
page 20 under the header ASSESSMENT OF SAFETY.  
3.2 Data Safety Monitoring.  
This study does not include a DSMA or DSMC. However, the data safety 
plan is on page 20-24 of the protocol and can be found on the HIPCO 
Survey. 
3.3     See page 5-6 of the protocol for the plan to mitigate COVID-19 risks. 
 
4.0 
Data and Specimen Banking 

PROTOCOL TITLE: Effect of Non-Surgical Periodontal Therapy With and Without 
Minocycline HCl Microspheres, 1 mg on Bacterial Load and Systemic Markers of 
Inflammation 
VERSION DATE: September 26, 2022 
 
Page 8 of 13 
Template Revised On: 7/26/2018 
4.1 Storage and Access: N/A 
4.2 Data: N/A 
4.3 Release/Sharing: N/A 
5.0 
Sharing of Results with Participants 
5.1 The results of this study could be published in an article, but results will  
not be disclosed to participants. If the participants elects a portfolio of their 
oral pathogenic bacteria burden and inflammatory markers a written 
request will be obtained. See page 16 of the protocol.  
6.0 
Local Study Population 
The inclusion and exclusion criteria is on page 9 of the protocol. The premature 
exclusion criteria, handling of participant withdrawals, and premature 
termination or suspension is located on page 11. The screening procedures are 
found on page 14. 
 
Vulnerable Populations:  
☐ Children 
☐ Pregnant women/Fetuses/Neonates 
☐ Prisoners 
☐ Adults lacking capacity to consent and/or adults with diminished 
capacity to consent, including, but not limited to, those with acute 
medical conditions, psychiatric disorders, neurologic disorders, 
developmental disorders, and behavioral disorders 
☐ Approached for participation in research during a stressful situation such 
as emergency room setting, childbirth (labor), etc. 
☐ Disadvantaged in the distribution of social goods and services such as 
income, housing, or healthcare 
☐ Serious health condition for which there are no satisfactory standard 
treatments 
☐ Fear of negative consequences for not participating in the research (e.g. 
institutionalization, deportation, disclosure of stigmatizing behavior) 
☐ Any other circumstance/dynamic that could increase vulnerability to 
coercion or exploitation that might influence consent to research or 
decision to continue in research 
☐ Undervalued or disenfranchised social group 
☐ Members of the military 
☐ Non-English speakers 
☐ Those unable to read (illiterate) 
☐ Employees of the researcher 

PROTOCOL TITLE: Effect of Non-Surgical Periodontal Therapy With and Without 
Minocycline HCl Microspheres, 1 mg on Bacterial Load and Systemic Markers of 
Inflammation 
VERSION DATE: September 26, 2022 
 
Page 9 of 13 
Template Revised On: 7/26/2018 
☒ Students of the researcher 
☐ None of the above 
6.1 Additional Safeguards:  
Students and patients of study team members will have equal opportunity 
to participate if they elect to enroll and meet the inclusion criteria. 
7.0 
Local Number of Participants 
7.1 Local Number of Participants to be Consented:  
A sample size of 30 in each group will have 80% power to detect a 
difference in means of 0.736 standard deviations using a two group t-test 
with a 0.05 level of significance. In addition, with an estimated 20% 
attrition rate, we may enroll up to 75 participants. 
8.0 
Local Recruitment Methods 
8.1 Recruitment Methods: 
A U of M Institutional Review Board (IRB) for full or partial waiver of HIPAA 
and protected health information (PHI) will be requested for pre-screening.  
 
As part of the pre-screening process, charts of patients of record at the U 
of M SoD will be reviewed for inclusion criteria. Participants who may be 
eligible to participate will have an invitation letter mailed to them or 
emailed requesting participation.  
 
In addition, a follow-up phone call will me made 1-2 weeks after the 
invitation letter is mailed or emailed. All potential participants will have the 
option to opt out of participation.  
 
Flyers will be posted on each floor of the U of M SoD with study 
participation and contact information. Also, patients currently receiving 
oral healthcare in the dental clinics may be approached by a study team 
member, their assigned student provider, or the attending faculty with a 
flyer inviting them to participate in this study.  
 
Email may be used only after initial contact or with enrolled participant 
permission to use their email for questions or scheduling. Also, email 
communication may be used if an interested person contacts the PI first via 
email from the letter or the flyer.  
The study will also be posted on the U of M Oral Health Clinical Research 
Clinicwebsite. This will allow recruitment of subjects from the surrounding 

PROTOCOL TITLE: Effect of Non-Surgical Periodontal Therapy With and Without 
Minocycline HCl Microspheres, 1 mg on Bacterial Load and Systemic Markers of 
Inflammation 
VERSION DATE: September 26, 2022 
 
Page 10 of 13 
Template Revised On: 7/26/2018 
cities near Minneapolis or subjects that may be interested and are not 
patients of record at the U of M SoD. 
See page 9-10 of the protocol.  
 
8.2 Identification of Potential Participants:  
A U of M Institutional Review Board (IRB) for full or partial waiver of HIPAA 
and protected health information (PHI) will be requested for pre-screening. 
A HIPCO survey will be submitted.  As part of the pre-screening process, 
charts of patients of record at the U of M SoD will be reviewed for inclusion 
criteria. Participants who may be eligible to participate will have an 
invitation letter mailed to them requesting participation. In addition, a 
follow-up phone call will me made 1-2 weeks after the invitation letter is 
sent. All potential participants will have the option to opt out of 
participation.  
Interested participants may also self-identify in response to the flyer or 
invitation letter (Page 11 of the protocol).  
• 
Information contained in private/protected records (mailing address) 
will be obtained from AxiUm only after IRB confirm PHI and HIPAA 
waiver to use for recruitment purposes.  
• 
The PI will make initial contact with potential participants. 
 
8.3 Recruitment Materials:  
Recruitment materials are described on page 10 of the protocol and 
uploaded in ETHOS.  
 
8.4 Payment:  
A $50 prepaid ClinCard will be given to each participant at the conclusion 
of the one month and three month follow up visits. At the last visit, a $100 
will be loaded in the ClinCard for completing all study visits. This is noted 
on page 15-16 of the protocol and in the schedule of events on page 29.  
 
9.0 
Withdrawal of Participants 
Participant withdrawal and termination is outline in the premature 
exclusion criteria/participant withdrawal on page 11 of the protocol. 
10.0 Risks to Participants 

PROTOCOL TITLE: Effect of Non-Surgical Periodontal Therapy With and Without 
Minocycline HCl Microspheres, 1 mg on Bacterial Load and Systemic Markers of 
Inflammation 
VERSION DATE: September 26, 2022 
 
Page 11 of 13 
Template Revised On: 7/26/2018 
There are no risks greater than the risk of a regular dental visits. Risks are 
described on page of the protocol and in the informed consent form on page 6. 
In addition, research activities are in the protocol on page 14-16. All activities are 
the standard of care and minocycline HCl microspheres, 1 mg will be used in the 
context of the standard of care and FDA approved administration.  
 
11.0 Potential Benefits to Participants 
The potential benefits are on page 5 of the protocol.  
 
12.0 Confidentiality 
 
12.1 Protecting Privacy:  
Protections for confidentiality are on page 22 of the protocol. Protection of 
data are described in the protocol on page 22-24.   
12.2 Access to Participants:  
Having access to dental records of enrolled/consented participants is 
needed to conduct the study and maintain the standard of care.  
13.0 Compensation for Research-Related Injury 
13.1 Compensation for Research-Related Injury:  
This study is not greater than minimal risk, however, details regarding a 
research injury is described on page 8 of the informed consent.  
13.2 Contract Language:  
Below is the language from page 8 of the protocol: 
What happens if I am injured while participating in this research? 
In the event that this research activity results in an injury, treatment will be 
available, including first aid, emergency treatment and follow-up care as 
needed.  Care for such injuries will be billed in the ordinary manner, to you 
or your insurance company.  If you think that you have suffered a research 
related injury let the study physicians know right away. 
14.0 Consent Process 
The consent process is on page 14 of the protocol. The consent process and all 
study visits will take place at the U of M SoD Oral Health Clinical Research Clinic 
(OHCRC).  
 
14.1 Consent Process (when consent will be obtained): N/A 

PROTOCOL TITLE: Effect of Non-Surgical Periodontal Therapy With and Without 
Minocycline HCl Microspheres, 1 mg on Bacterial Load and Systemic Markers of 
Inflammation 
VERSION DATE: September 26, 2022 
 
Page 12 of 13 
Template Revised On: 7/26/2018 
14.2 Waiver or Alteration of Consent Process (when consent will not be 
obtained): N/A 
14.3 Waiver of Written/Signed Documentation of Consent (when written/signed 
consent will not be obtained): N/A  
14.4 Non-English Speaking Participants: N/A 
14.5 Participants Who Are Not Yet Adults (infants, children, teenagers under 18 
years of age): N/A 
14.6 Cognitively Impaired Adults, or adults with fluctuating or diminished 
capacity to consent: N/A 
14.7 Adults Unable to Consent: N/A 
15.0 Setting 
15.1 Research Sites:  
A convenience sample of up to 75 participants from the University of 
Minnesota (U of M) School of Dentistry (SoD) or outside of the university  
(U of M StudyFinder website) will be invited to participate in this study. The 
goal is two groups of 30 participants. Participants in both groups will have 
four clinical visits over a 6 month period in the U of M SoD Oral Health 
Clinical Research Clinic (OHCRC). Page 13, 14 and 29 of the protocol.  
 
15.2 International Research: N/A 
16.0 Multi-Site Research 
 
N/A 
17.0 Resources Available 
17.1 Resources Available: 
It is feasible to recruit up to 75 periodontal patients from the U of M SoD. 
There is an abundance of patients of record that meet the inclusion 
criteria. In addition, patients from the U of M StudyFinder may participate.  
The PI will have one full clinic day (8 am- 5pm) for research activities. The 
research assistant will have one and half days to recruit, manage study 
documents, and assist in research activities.   
The OHCRC is located at the U of M SoD. It is a dental clinic and has a 
private room to conduct the informed consent process if potential 
participants elect a private room instead of a cubicle.  
https://www.dentistry.umn.edu/research/centers-institutes-labs/oral-
health-clinical-research-clinic 

PROTOCOL TITLE: Effect of Non-Surgical Periodontal Therapy With and Without 
Minocycline HCl Microspheres, 1 mg on Bacterial Load and Systemic Markers of 
Inflammation 
VERSION DATE: September 26, 2022 
 
Page 13 of 13 
Template Revised On: 7/26/2018 
 
The U of M SoD is equip if a medical emergency occurred. 
The M Health Clinical Research Unit (CRU) is located on the second floor 
and participants will be escorted to the blood draw visit.  
There will be regular study team meetings on a monthly basis. See the 
monitoring plan on page 17-18 of the protocol.