Obstetrics and Periodontal Therapy (opt) Study Manual of Operations Version 1 March 3, 2003 Brief Table of Contents


HIPAA1 AUTHORIZATION TO USE AND DISCLOSE



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HIPAA1 AUTHORIZATION TO USE AND DISCLOSE


INDIVIDUAL HEALTH INFORMATION FOR RESEARCH PURPOSES
1. Purpose. As a research participant, I authorize [name of PI] and the researcher’s staff to use and disclose my individual health information for the purpose of conducting the research project entitled [title of study], [Human Subjects’ Code].
2. Individual Health Information to be Used or Disclosed. My individual health information that may be used or disclosed to conduct this research includes: [List all of the individual health information to be collected for this protocol/study such as demographic information, results of physical exams, blood tests, x-rays, and other diagnostic and medical procedures as well as medical history].
3. Parties Who May Disclose My Individual Health Information. The researcher and the researcher’s staff may obtain my individual health information from [list hospitals, clinics, other providers, or health plans from which you will request individual health information about the research participant to conduct the study, OR, leave the space open for the patient to fill in as needed].
4. Parties Who May Receive or Use My Individual Health Information. The individual health information disclosed by parties listed in item 3 and information disclosed by me during the course of the research may be received and used by [name of researcher] and the researcher’s staff and [list any collaborators, other clinical sites involved in the research, sponsors if applicable, outside laboratories]. [OPTIONAL: Also, if I receive compensation for participating in this study, identifying information about me may be used or disclosed as necessary to provide compensation.]
5. Right to Refuse to Sign this Authorization. I do not have to sign this Authorization. If I decide not to sign the Authorization, I will not be allowed to participate in this study or receive any research related treatment that is provided through the study. However, my decision not to sign this authorization will not affect any other treatment, payment, or enrollment in health plans or eligibility for benefits.
6. Right to Revoke. I can change my mind and withdraw this authorization at any time by sending a written notice to [researcher’s name and address] to inform the researcher of my decision. If I withdraw this authorization, the researcher may only use and disclose the protected health information already collected for this research study. No further health information about me will be collected by or disclosed to the researcher for this study.
7. Potential for Re-disclosure. My individual health information disclosed under this authorization may be subject to re-disclosure outside the research study and no longer protected. Examples include potential disclosures for law enforcement purposes, mandated reporting of abuse or neglect, judicial proceedings, health oversight activities and public health measures.
8. [Optional Item] Suspension of Access. I may not be allowed to review the information collected for this study, including information recorded in my medical record, until after the study is completed. When the study is over, I will have the right to access the information again.
III.7.2 Obtaining A Medical Release
A medical release is required from each subject in order to legally access pre- and postnatal records as well as delivery records from the hospital. Each site should have a pre-printed medical release form specifying the exact information requested, the purpose of the request and the time period related to the request.
The Study Coordinator should review the medical release form with the subject in advance of the subject signing the form. Each medical release should include the following information:

1. The exact name of the clinic and/or hospital that will have the medical

records.

2. The exact information that you are requesting, e.g., pre-natal records,

ultrasound results, delivery records.

3. The reason for the request. Most medical release forms have a box that you can

check to state that the purpose of collecting the information is for, “research

purposes only.”

4. The signature of the mother and the signature of the mother (as the legal

guardian) on the signature line for the infant.

5. The length of time the release is valid. This is usually one year from the date of

signature.


A copy of the medical release should be given to the nurse abstractor as proof that she has legal access to the medical information of the subject and the infant.
The medical release should be signed during the informed consent process.
III.8. Blinding and Unblinding
The OPT study is a single-blind study. The subjects know whether they are receiving immediate periodontal therapy (Test Group) or deferred periodontal therapy (Control Group). However, until the study is completed, each subject's intervention group (Test or Control) must be concealed from anyone providing study care or making measurements, i.e., from personnel at the Enrollment Sites, and from personnel at both Labs. This includes the following personnel:
• Enrollment Site PIs, Site Periodontal and Obstetrical Investigators, the Host Response and Microbiology Investigators,
• Recruitment and Retention Coordinator, Calibrated Periodontal Examiner, Obstetrical Nurse Data Recorder, Consulting Periodontist, General Dentist, and Dental Assistants.
Personnel at the Data Coordinating Center (DCC) can link patient IDs (PID) to their treatment assignments. However, under the normal operation of the OPT study's confidentiality procedures, DCC personnel should never receive any information permitting them to link PIDs to subject names (see Section III.7, "Maintaining Confidentiality" for details). Thus, if introduced to a subject of this study, a member of the DCC staff should not know whether the subject is receiving immediate or deferred periodontal therapy.
Maintaining the blind is crucial to the study's scientific validity. Study personnel use clinical judgment constantly to make treatment decisions or to take measurements. If a clinician, examiner, or lab technician knows a subject's study-assigned therapy, that knowledge could potentially influence their judgment, even if they try to ignore that piece of information. This potential alone is enough to undermine the study's credibility.
Therefore, under normal circumstances, only two people should know a given subject's name, PID, and treatment assignment: the subject and the Study Coordinator at her Site.
The subject should never reveal her treatment assignment to anyone. The Study Coordinator should remind the subject of this at each visit.
The Study Coordinator should not reveal a subject's treatment assignment to anyone, except in one situation: if the subject is found to have breakthrough periodontal disease and must depart from normal study procedures for rescue treatment.
For details on procedures in case of breakthrough periodontal disease, see Section II.5.5. "Monitoring the periodontal status of subjects". If a subject is found to have 6 or more cumulative tooth sites with more than 2 mm of clinical attachment loss (CAL), the Examiner tells the Study Coordinator, who determines the subject's treatment assignment (Test or Control) and uses it to arrange for the appropriate rescue treatment, as described in Section II.5.5. The examiner, however, remains blinded to the subject's assignment.

III.9. Reporting Adverse Events
III.9.1. General considerations
The OPT study does not involve investigational drugs, so adverse event reporting is not as integral to the study as it would be in a drug study. Also, periodontal therapy has been studied in pregnant women at high risk for pre-term delivery, more than once, with no indication that it creates any hazard. Thus, adverse experiences are unlikely to be an important part of this study's results, and serious adverse experiences should be rare.
However, concern for subjects' well-being, not to mention federal law, forbid us from simply assuming there is no adverse-event problem to be documented. This section describes how adverse events are determined and documented. Serious adverse events are of special urgency; they are reported on their own form using specially urgent procedures, as described in Section III.9.4, below.
III.9.2. Periodontal Adverse Events (Form 40)
III.9.2.1. When are periodontal adverse events detected? Periodontal adverse events can be detected at any visit after the Baseline/Randomization Visit (Visit 1). Periodontal measurements are scheduled for Visits 3 and 5, and most periodontal adverse events will be detected at these visits. However, subjects receive a brief oral exam at Visits 2, 4, and 6, during which adverse events may be detected.
III.9.2.2. Who detects periodontal adverse events? Generally periodontal adverse events are tentatively diagnosed by the Blinded Measurement Hygienist, who takes the periodontal measurements at Visits 3 and 5 for all subjects, provides supragingival polishing and oral health instruction at Visits 2, 4, and 6 for subjects in the Test Group, and provides the brief oral exam and "attention placebo" at Visits 2, 4, and 6 for subjects in the Control Group.
Periodontal adverse events are definitively diagnosed by a dentist, usually after a tentative diagnosis by the Measurement Hygienist. The sequence of steps from tentative to definitive diagnosis and then to reporting is described below in Section III.9.2.3. "Procedures for detecting and reporting periodontal adverse events".
The Measurement Hygienist has the most opportunity to detect periodontal adverse events. However, from time to time other clinicians will look in the subject's mouth and these clinicians should be alert for evidence of periodontal adverse events. If a clinician suspects a periodontal adverse event, s/he should contact the Study Coordinator to arrange a definitive events.
III.9.2.3. Procedures for detecting and reporting periodontal adverse events (Form 40, Periodontal Adverse Events).
In detecting and reporting periodontal adverse events, the following sequence should occur:
• The Measurement Hygienist discovers evidence suggesting that a subject is having a periodontal adverse event. At Visits 3 and 5, this would occur during the study-mandated periodontal measurements. At Visits 2, 4, and 6, this would during the supragingival polishing (Test Group) or the brief oral exam (Control Group).
– If the Measurement Hygienist suspects progressive attachment loss at Visit 2, 4, or 6 at five (5) or fewer sites, s/he probes those sites before making a tentative diagnosis.
– If the Measurement Hygienist suspects progressive attachment loss at Visit 2, 4, or 6 at six (6) or more sites, s/he performs full-mouth probing and records the measurements on Form 11 (Periodontal Measurements) before making a tentative diagnosis.
• The Measurement Hygienist fills out Part A of Form 40 (Periodontal Adverse Events) for the subject, as described below.
If the Measurement Hygienist has tentatively diagnosed a serious adverse event, s/he contacts a dentist immediately. However, periodontal adverse events should rarely, if ever, be serious adverse events. None of the adverse events listed on Form 40 is a serious adverse event; any serious adverse event would be reported as "other" using Item A.5. If a serious adverse event is detected, the Measurement Hygienist informs the Study Coordinator and one of these two people attempts to contact the following personnel in this order: the Site's Periodontal Treatment Consultant; the Site's Periodontal Investigator; the attending dentist at the Site's institution.
– If the Measurement Hygienist has tentatively diagnosed a non-serious adverse event, there is no need to urgently contact a dentist for a definitive diagnosis. Instead, the Site's Periodontal Treatment Consultant examines and treatment-plans the subject with due diligence.
• After completing Part A, the Measurement Hygienist faxes the partly-completed Form 40 to the Data Coordinating Center (DCC) at (612) 625-0080 and to the Site's Consulting Periodontist. The Measurement Hygienist then gives the partly-completed original form to the Study Coordinator.
• When the dentist (usually the Site's Periodontal Treatment Consultant) examines the subject, s/he obtains from the Study Coordinator the original of the subject's Form 40 and completes Part B.
– If the dentist confirms a diagnosis of a serious adverse event, s/he completes Form 41 (Serious Adverse Events), described in Section III.9.4. "Reporting Serious Adverse Events (Form 41)" below.
Form 40 (Periodontal Adverse Experiences) is completed as follows.
B
egin a subject's Form 40 by attaching a PID label to the upper right-hand corner of the form, filling in the Enrollment Site's identifier (NY for New York, MN for Minneapolis, KY for Lexington, MS for Jackson), the date on which the form is completed, and the Study Visit.
• Part A of the form records the tentative diagnoses, usually made by the Measurement Hygienist.
• The person completing Part A enters his/her study code in the space provided.
• Item A. 1 is checked "yes" if the Measurement Hygienist finds that the subject has tooth sites that have lost attachment. Specifically, "progressive attachment loss" means a loss of 3 mm or more at a site since the baseline periodontal exam.
• Inside the box for Item A.1, check the box for "Progressive Attachment Loss" if the Measurement Hygienist finds that the subject has 5 or fewer tooth sites cumulatively having progressive attachment loss. "Cumulatively" means total since the baseline periodontal exam. For example, suppose the subject is having her Visit 5 and the Measurement Hygienist detects three sites with progressive attachment loss. The Measurement Hygienist consults the subject's chart to see if any sites were found to have progressive attachment loss at previous visits. If 0, 1, or 2 sites with progressive attachment loss were detected at previous visits, then the cumulative total of sites with progressive attachment loss is 3, 4, or 5 sites respectively and "Progressive Attachment Loss" should be checked. However, if 3 or more sites with progressive attachment loss were detected at previous visits, then the cumulative total of sites with progressive attachment loss is 6 or greater. By the OPT Study's definition, the subject has generalized progressive attachment loss, described at the next bullet.
• Inside the box for Item A.1, check the box for "Generalized Progressive Attachment Loss" if the Measurement Hygienist finds that the subject has 6 or more tooth sites cumulatively having progressive attachment loss. For example, suppose the subject is having her Visit 3 and the Measurement Hygienist detects 10 sites with progressive attachment loss. Then by the OPT Study's definition, this subject has generalized progressive attachment loss and "Generalized Progressive Attachment Loss" should be checked. Suppose instead that the subject has only 5 sites with progressive attachment loss. On consulting the subject's chart, the Measurement Hygienist finds that no other sites have been diagnosed as having progressive attachment loss. Then by the OPT Study's definition, the subject has only localized progressive attachment loss and "Progressive Attachment Loss" should be checked.
• Generalized Progressive Attachment Loss: Once the Measurement Hygienist makes a tentative diagnosis of generalized progressive attachment loss, s/he completes (if s/he hasn't already) a Form 11 (Periodontal Measurements) based on a full-mouth probing.
• Progressive Attachment Loss: Once the Measurement Hygienist makes a tentative diagnosis of progressive attachment loss at 5 or fewer sites cumulatively, s/he records the following information about each progressing site:
– The tooth number, using the Universal system (numbering teeth 1 to 32)

– Whether the site is buccal or lingual (B or L, respectively)

– Whether the site is mesial, mid- (or direct), or distal, (ME, DR, or DS, respectively)

– The just-measured values of pocket depth (PD) and clinical attachment loss (CAL).


The definitions that follow are adapted from those in Carranza'a Clinical Periodontology, Ninth Edition. Editors MG Newman, HH Takei, FA Carranza, WB Saunders Co. Philadelphia , 2002.
• Item A.2, "Periodontal or gingival abscess" is checked under the following conditions. A periodontal or gingival abscess is a fluctuant (not firm) mass within the gingiva. Pus can usually be expressed from the lesion, either through the crevice, pocket, or a sinus tract. The surface of the lesion is usually red and shiny. Symptoms may include throbbing, radiating pain, tenderness to touch, and tender and enlarged lymph nodes. Periodontal and gingival abscesses are distinguished from each other based on whether the lesion is localized to the gingival tissues (gingival abscess) or if it extends apically along the root surface (periodontal abscess). Gingival abscesses are more common in the maxillary tuberosity area distal to second or third molars. Care must be taken to distinguish a periodontal from a periapical abscess. Pulp vitality testing is the most reliable means of making this distinction. Swellings adjacent to non-vital teeth are likely periapical abscesses. Finally, it is possible that an abscess may be both periodontal and periapical in origin.



• Item A.3, "Pyogenic granuloma ("pregnancy tumor")" is checked under the following conditions. A pregnancy tumor is a discrete, mushroom-like flattened mass that protrudes from the gingival margin or interproximal space. The surface is deep red and smooth. The lesion is usually painless but may become ulcerated and tender if it interferes with the patient's bite. The tissue bleeds easily and is usually associated with some local irritants.


• Item A.4, "Pregnancy gingivitis" is checked under the following conditions. In pregnancy gingivitis, the marginal tissue are moderately to severely enlarged. The gingiva are bright red or magenta, soft and friable, and have a smooth shiny surface. Moderate to profuse bleeding can occur spontaneously or with slight manipulation (e.g., mastication, during tooth brushing or flossing, or following gentle probing). While pregnancy does not cause gingivitis, it can exacerbate existing inflammation due to local irritants.
• Item A.5, "Other" is checked if the Measurement Hygienist suspects any other adverse event. Any serious adverse event will fall under this category. If the Measurement Hygienist tentatively diagnoses a serious adverse event, s/he must have the diagnosis confirmed by a dentist immediately for the subject's safety and the safety of other study subjects. Therefore, the Measurement Hygienist contacts a dentist immediately, by attempting to contact the following personnel in this order: the Site's Periodontal Treatment Consultant; the Site's Periodontal Investigator; the attending dentist at the Site's institution.
• Upon completing Part A of a subject's Form 40, the Measurement Hygienist faxes the partly-completed Form 40 to the Data Coordinating Center (DCC) at (612) 625-0080 and to the Site's Consulting periodontist. The Measurement Hygienist gives the original Form 40 to the Study Coordinator.
• Part B of the original Form 40 is completed while the dentist (usually the Site's Periodontal Treatment Consultant) examines the subject, either by the dentist or by the Measurement Hygienist or Study Coordinator.
• Item B.1 records which dentist examined the subject and filled out the form, with the dentist's initials recorded in the boxes provided.
• Item B.2 records the dentist's definitive diagnosis or lack of diagnosis. A check mark must be placed in the appropriate box in each of the six rows. For example, suppose the Measurement Hygienist tentatively diagnosed Generalized Progressive Attachment Loss. Then row b is completed with a check in either the "Confirmed" or "Not Confirmed" box, while the other 5 rows (a, c, d, e, f) are completed with a check in the "Not Applicable" box.
• Item B.3 records whether treatment was accepted, and if so, which treatments were rendered.
– If treatment is indicated but the subject refuses it, box a, "Treatment was indicated but refused" is checked and the date of refusal is recorded in the spaces provided.
– If treatment is indicated and rendered, the appropriate boxes are checked from among boxes b through g, and dates of treatment are placed in the spaces provided.
• If the dentist confirms a diagnosis of a serious adverse event, s/he completes Form 41 (Serious Adverse Events), described in Section III.9.4. "Reporting Serious Adverse Events (Form 41)" below.
III.9.3. Pregnancy Adverse Events (Form 60, Delivery Data/Pregnancy Adverse Events)
III.9.3.1. General considerations about pregnancy adverse events. Most adverse events relating specifically to the pregnancy will be detected when the Obstetrical Nurse Recorder abstracts birth information for Form 60, Delivery Data/Pregnancy Adverse Events. Definitions and instructions for completing Form 60 are given in Section II.6 "After the Birth", particularly II.6.3 "Data Collection for Deliveries at the Enrollment Site" and II.6.4 "Obtaining Data for Deliveries Outside the Enrollment Site".
III.9.3.2. Serious adverse events recorded on Form 60. Only two serious adverse events are recorded on Form 60, and both involve the child but not the mother:
• The pregnancy ends in a spontaneous abortion, or the child is stillborn; or

• The child is diagnosed with fetal congenital abnormalities by ultrasound or at delivery.


As detailed below, serious adverse events must be reported within 24 hours of their detection. Responsibility for such reporting lies with each Site's Principal Investigator (PI), although for pregnancy adverse events this responsibility will usually be delegated to the Obstetrical PI. It is impractical for an Obstetrical PI to be present at each subject's delivery, so each Obstetrical PI must devise and implement a procedure for reporting these two kinds of serious adverse events within 24 hours of their occurrence, using the procedure described in Section III.9.4, below.
III.9.3.3. Other serious pregnancy adverse events. Any other serious pregnancy adverse event occurs before delivery and should be reported as described in Section III.9.4, below.
III.9.4. Reporting Serious Adverse Events (Form 41)
III.9.4.1. What is a serious adverse event? A serious adverse event is "any untoward medical occurrence that results in death, is life-threatening, requires or prolongs hospitalization, causes persistent or significant disability or incapacity, results in congenital anomalies or birth defects or, in the opinion of the investigators, represents other significant hazards or potentially serious harm to research participants or others." (From Section 3.l of "Guidelines for Developing a Manual of Operations (MOP)", National Institute of Dental and Craniofacial Research, draft dated 15 November 2002.)
Although serious adverse events are expected to be rare in the OPT study, they are no less serious for their rarity and must be reported within 24 hours, following procedures described in the section following.
III.9.4.2. Procedure for reporting serious adverse events (Form 41).
A serious adverse event can be detected at any time. However, most serious adverse events will probably be detected:
• at the delivery;

during routine pre-natal exams, by physicians at the Site; or

• during oral exams, by the Measurement Hygienist.
Regardless of where a serious adverse event is detected, responsibility for reporting it lies with the Site's Principal Investigator (PI).
– Generally, the responsibility for pregnancy adverse events will be delegated to the Obstetrical PI. It is impractical for an Obstetrical PI to be present at each subject's delivery, so each Obstetrical PI must devise and implement a procedure for reporting these two kinds of adverse events.
– Because periodontal adverse events are almost always detected by the Measurement Hygienist, their reporting procedure can be standardized and is described above in Section III.9.2 "Periodontal Adverse Events".
Completing Form 41. Form 41 is sent to the Data Coordinating Center (DCC), so the subject's name must not appear on it anywhere. Instead, the subject is identified to the DCC by her patient ID (PID) and enrollment code. Each Site must make provisions to ensure that the PID is available to the person responsible for completing Form 41.
When a serious adverse event is detected, the responsible person completes and transmits a Form 41 (Serious Adverse Event) according to the following procedure.

Begin a subject's Form 41 by either writing the subject's PID in the upper right-hand corner of the form or by attaching a PID label to the upper right-hand corner of the form
• Fill in the Enrollment Site's identifier (NY for New York, MN for Minneapolis, KY for Lexington, MS for Jackson), the date on which the form is completed, and the initials of the person completing it.
• Items 2 and 3 may be difficult to determine but are required by law. The person completing the form should use his or her clinical judgment to answer the question as accurately as possible.

• Item 4 records the sense or senses in which the adverse event is serious. If the adverse event is a fetal congenital abnormality (Item B. 2 of Form 60, Delivery Data and Pregnancy Adverse Events), it is categorized as "Congenital anomaly / birth defect". If the adverse event is a stillbirth or spontaneous abortion, it is categorized as "Other", and described in the space provided as "spontaneous abortion" or "stillbirth", as appropriate.


Any other adverse events should be categorized by the clinician using his/her clinical judgment.
• Item 5 provides space to describe the serious adverse event. If the serious adverse event is any of the following, no description is necessary: fetal congenital abnormality, stillbirth or spontaneous abortion, periodontal or gingival abscess, pyogenic granuloma. Any other serious adverse event requires a text description under Item 5. Additional pages may be attached as needed.
• Item 6 is not filled out at the Site, but is used by the Data Coordinating Center (DCC) to code serious adverse events.
Transmit Form 41 to the Data Coordinating Center (DCC) and the Site's Principal Investigator. Upon completing the Form 41, fax the form to the DCC at (612) 625-0080. If the form is not completed by the Site's Principal Investigator (PI), it should be transmitted as soon as possible, by any appropriate means, to the PI or, in the PI's absence, to a person designated by the PI.
Procedure at the Data Coordinating Center (DCC). Once the DCC has received the Form 41, it adds other necessary information to the report and transmits the Form 41 and the other information to the Data and Safety Monitoring Board (DSMB), to the sponsor (the National Institute of Dental and Craniofacial Research [NIDCR]), and to the Site's Institutional Review Board (IRB), as required by the NIDCR.
Responsibility for this transmission lies with the DCC's Director, though it is generally delegated to the Statistical Study Manager.
Per NIDCR guidelines (Section 3.l of "Guidelines for Developing a Manual of Operations (MOP)", National Institute of Dental and Craniofacial Research, draft dated 15 November 2002), the DCC will remove the subject's patient ID (PID) from copies of the Form 41 intended the DSMB and the Site's IRB, while adding the protocol number and title and the Site's PI to all copies. The DCC will also draw the following information from the database to send along with the Form 41:
• The subject's gender, age, and information from the Baseline Obstetrical Data (Form 10) and Periodontal Measurements (Form 11)

• Location of the Site



• Whether any similar serious adverse events have occurred during the study, and if so, how many.
III.10. Data and Safety Monitoring Activities
III.10.1. Safety Monitoring
III.10.1.1. Monitoring consent. Each Site's Principal Investigators (PIs) will monitor the adequacy of consent at that site. Once every six months, the PI will sample 5% of enrollments since the previous monitoring, using a random sample of patient IDs (PIDs) supplied by the Data Coordinating Center for this purpose. The main burden of this monitoring will be to ensure that consents have been performed appropriately, including checking that they were signed by the subject and checking against the enrollment form that they were signed on or before the date they were enrolled.
III.10.1.2. Monitoring for progressive periodontal disease. All subjects will be evaluated clinically every two months for evidence of progressive clinical attachment loss (CAL), defined as an increase from baseline in clinical attachment loss (CAL) greater than 2 mm. The examiner will compare CAL recordings to baseline values and record the location of sites that display progressive CAL, along with the magnitude of change.
If a subject has fewer than 5 cumulative sites with CAL greater than 2 mm, the subject will be referred to the treatment hygienist for localized scaling and root planning, regardless of the subject’s initial treatment assignment. (See Section III.9.2. "Periodontal Adverse Events (Form 40)" for more details.) In this manner, the examiner will remain blinded to treatment assignment. Tooth sites requiring such care will be considered to be exited from the study and their periodontal data will be carried forward on an intent-to-treat basis, though the subject will be followed through delivery.
If a subject experiences progressive attachment loss from baseline at 5 or more sites, the subject will be considered to have generalized progressive attachment loss and will be exited from her study-assigned therapy. (See Section III.9.2. "Periodontal Adverse Events (Form 40)" for more details.) The subject’s records will be forwarded to the consulting periodontist who will be informed of the subject’s group assignment by the study coordinator. The consultant will review clinical records to confirm the diagnosis of generalized progressive periodontitis if s/he deems it appropriate, and either refer the subject to the treatment hygienist for full-mouth scaling and root planning (if originally assigned to the control group) or for additional assessment and care (if in the test group). For test subjects who experience generalized CAL, the consulting periodontist will determine tooth sites to be sampled for microbial analysis. The subgingival plaque samples will be submitted to a commercial laboratory for microbial analysis and antibiotic sensitivity testing. The consulting periodontist will review the results from the laboratory, select and prescribe an appropriate antibiotic regimen, and arrange to personally re-instrument the subject or refer her to the treatment hygienist for this treatment. This treatment will not be delayed until postpartum.
Based on published reports of disease progression in untreated populations, a conservative estimate is that 2-3% of subjects will experience progressive disease.
Subjects will also be monitored at monthly intervals for additional adverse periodontal events including abscess, necrotizing ulcerative gingivitis, pregnancy tumor, and severe or diffuse inflammation.
III.10.1.3. Obstetrical safety monitoring. Obstetrical adverse events will be detected during the subject's regular pre-natal visits and during post-partum chart abstraction. Most if not all of the study's serious adverse events will be obstetrical in nature and will be detected at a regular pre-natal visit or at delivery. Each enrollment site's obstetrical principal investigator (PI) will implement procedures to ensure that all serious adverse events are reported to the Data Coordinating Center (DCC) within 24 hours. (See Section III.9.4. "Reporting Serious Adverse Events (Form 41)" for a detailed description of procedures.) Adverse events of lesser severity will generally be detected during the post-natal chart abstraction and will be reported with birth-related data. (See Section III.9.3. "Pregnancy Adverse Events (Form 60, Delivery Data/Pregnancy Adverse Events" for further details.)
III.10.1.4. Data and Safety Monitoring Board (DSMB). All subjects will be monitored for preterm delivery and other prenatal adverse events that occur during the course of this trial. Periodontal probing and scaling and root planing cause transient bacteremias. Therefore, while unlikely and not supported by data from other trials, periodontal therapy could increase the incidence of pre-term delivery or other adverse events. To minimize this risk, all periodontal therapy and dental care will be done after the first trimester, when fetal formation is complete and after the time when most spontaneous miscarriages occur. Conversely, periodontal therapy may reduce the incidence of preterm birth and this may become evident before all subjects are enrolled or complete the trial.
Given these concerns, a Data and Safety Monitoring Board has been established consistent with NIDCR Policies and Procedures. The DSMB is scheduled to meet in Minneapolis, MN prior to start of enrollment and in the fall of years 1, 2 and 3. Interim conference calls may be scheduled at the discretion of the board, the NIDCR, or the study leadership.
At each meeting after enrollment begins, the DSMB will receive a formal report prepared by the Data Coordinating Center (DCC). In general, the report will include data about enrollment and quality of data collection, baseline comparisons of treatment groups, and treatment group comparisons according to each study outcome. Each report will have an open section containing materials suitable for blinded study staff, and a closed section giving outcomes and treatment-group comparisons. The closed section will be seen only by the DSMB, the NIH program officer, and DCC staff. Treatment groups will be coded as A and B, with the identities of groups A and B sent under separate cover.
Production of DSMB reports is one of the DCC's highest priorities. Data will be shown in tables and graphs to ease detection of patterns, trends, and group differences. In general, the report will include quality-control data (described below), baseline comparisons of treatment groups, and treatment group comparisons according to each study outcome.
III.10.2. General Study Monitoring
The Principal Investigator (PI) and Study Coordinator at each Enrollment Site have local responsibility for monitoring the trial. The Study Chairman (Dr. Bryan Michalowicz) and the Statistical Study Manager at the Data Coordinating Center will be responsible for external monitoring (see Section III.10.3 "Monitoring Data Quality", below). Dr. Michalowicz will monitor overall study management, enrollment, and compliance with protocol as specified in the Manual of Procedures. He will provide oversight to assure that quality data are collected, and that adverse events are reported in a timely manner. He will work closely with NIH/NIDCR staff to oversee the trial as specified in NIH/NIDCR Policies and Procedures for Investigator Initiated Clinical Trials.
III.10.3. Monitoring Data Quality
III.10.3.1. Local monitoring of data quality. Each Enrollment Site's Study Coordinator will be responsible for ensuring that forms are completed fully and accurately, that forms are completed and transmitted in a timely manner, and that error correction requests are answered in a timely manner. (See Sections III.14 "Data Collection Procedures" and III.15 "Data Management and Error Correction" for details.)
III.10.3.2. Central monitoring of data quality (DCC). The Statistical Study Manager at the DCC will monitor completeness and timeliness of data collection, data transmission, and error correction. Specifically, each site’s performance will be described in a monthly quality assessment report, where performance is assessed according to recruitment, visit attendance, protocol adherence, error rates on forms, and timeliness of response to error corrections, weekly forms packages, and birth-data collection. These reports will be sent monthly to the Sites' Study Coordinators and will be the subject of monthly conference calls among the Study Coordinators and the Statistical Study Manager. See Section IV.2 "Reports" for more details.
III.10.3.3. Monitoring source documentation. The DCC's Statistical Study Manager travels once each year to each site to compare case report forms to source documentation. Before going to the Site, the Study Manager draws a random sample of 5% of forms completed in the last year. At the Site, the Study Manager pulls the Site's copy of each form in the random sample and compares it to source documents provided by the Site's Study Coordinator.
III.11. Study Compliance
III.11.1. Objectives and General Considerations
The objectives the OPT Study's compliance policy are:
• to protect subjects;

• to preserve the study's scientific integrity; and

• to identify problems and correct them quickly.
This policy is founded on the presumption that all OPT Study personnel want to conduct the study in accordance with accepted ethical and scientific standards. Therefore, these compliance procedures are not punitive toward study staff unless there is a clear pattern of violations that persists despite repeated attempts to correct the underlying problems.
Accordingly, the general approach to protocol violations is first, to prevent them by thorough training and careful procedures, and second, to detect and correct problems so as to prevent future violations.
III.11.2. Types of Protocol Violations
The following list gives the most serious and most likely protocol violations, although other violations are possible:
(a) Failing to obtain signed informed consent from a subject.

(b) Failing to obtain signed HIPAA Authorization of Disclosure.

(c) Breaching subject confidentiality.

(d) Failing to keep Institutional Review Board (IRB) approval up to date.

(e) Administering the wrong therapy to a subject.

(f) Randomizing ineligible subjects. The most likely instances are:

– The subject's periodontal disease is not extensive or severe enough, because of a computational error on Form 11.

– The subject's gestational age is not between 13 and 16 weeks at randomization.

– There were errors in assessing or recording medical conditions that make the subject ineligible.

(g) Not completing Essential Dental Care and/or study periodontal therapy (Test Group only) before 20 weeks gestational age


Items (a) , (b) and (c) are grave ethical violations. Item (d) does not necessarily indicate that any subject's rights have been violated but it does point to a serious administrative failure. Items (a), (b), (c) or (d) are sufficiently serious that if they persist or are extensive in nature, the Enrollment Site could be forced to stop enrolling subjects or the entire Study could be terminated. If these problems are extensive and severe enough, they could result in criminal or civil liability.
Items (e), (f), and (g) are concerns mainly because they endanger the scientific integrity of the study. Item (e) corrupts the randomization, which is the basis for attributing the study's result to the treatment. Items (f) and (g) tend to dilute any treatment effect that may be present. Also, if either of these violations is detected, it may be necessary to exclude the affected subjects from any analyses of study data, which reduces the study's power to detect treatment effects.
III.11.3. Procedures
III.11.3.1. How violations are detected. Protocol violations are mainly detected by the following procedures.
Routine data processing at the Data Coordinating Center (DCC) will probably uncover most violations. For example, when a subject's Baseline Form 11 (Periodontal Measurements) is processed, the periodontal eligibility criteria can be checked by the computer. Similarly, if Essential Dental Care or study periodontal therapy is not completed on time, this will be detected from form dates. If the wrong treatment is administered to a subject, this will be revealed by an inappropriate pattern of forms arriving at the DCC.
The Site Principal Investigator's (PI's) monthly monitoring will detect consent irregularities, unsafe confidentiality practices and subjects who are ineligible because of errors in assessing or recording relevant medical conditions.
Site monitoring by the Statistical Study Manager will also detect consent irregularities, unsafe confidentiality practices and, to a lesser extent, subjects who are ineligible because of errors in assessing or recording relevant medical conditions.
If IRB approval has been allowed to lapse at a Site, the affected IRB will contact the Site's PI. If protocol changes have been made requiring new IRB approval, the Site's PI is responsible for obtaining this approval and site monitoring by the Statistical Study Manager will include checking that the Site has current approval from the IRB.
III.11.3.2. Procedure upon detecting a violation. If a protocol violation is detected, the person detecting the violation should report it the same day to the Statistical Study Manager at DCC. The Statistical Study Manager maintains a log of violations for each Site. Immediately upon entering the violation in the log, the Statistical Study Manager will inform the project officer at NIDCR.
As soon after detection as possible, the Enrollment Site's PI and Study Coordinator will have a conference call with the DCC's Statistical Study Manager and any other appropriate personnel. The conference call's purpose is to identify procedural weaknesses that may have caused the violation and to propose corrective measures. The Site's PI then records, in a memo to the NIDCR program officer, the likely cause of the violation and any proposed corrective measures. This memo is copied to the Site's Study Coordinator and the Statistical Study Manager. It is then the Site PI's responsibility to ensure that the corrective measures are implemented and, if unsuccessful, that further corrective measures are identified and implemented.
If a procedural problem is present at more than one Site, it may reflect a procedural defect affecting all four Sites. In such a case, the Study Coordinators from the four Sites and the Statistical Study Manager should discuss the problem at their next regular conference call, identifying likely causes and corrective actions. The Statistical Study Manager then writes a memo to the NIDCR program officer recording the likely cause of the problem and any proposed corrective measures, with copies to each Site's PI and Study Coordinators.
III.11.3.3. Procedure in case of a persistent problem. If a problem persists despite repeated attempts to solve it locally, the entire OPT Study may be endangered. Such a situation demands the immediate attention of the Steering Committee (SC).
Any member of the SC may call for the whole SC to meet to consider a persistent problem. The Study Chair, upon receiving such a call from a SC member, will convene a meeting of the SC by conference call. The first agenda item in this conference call will be to determine whether there is, in fact, a persistent problem requiring the SC's intervention. If the SC determines that its intervention is required, the SC will identify the problem or problems and propose and implement solutions. Solutions could range from ordering specific study personnel to be retrained or terminated from the study, to terminating enrollment at a specific Site, depending on the severity and chronicity of the violation.
If the problem persists, the next step is to refer the problem to NIDCR. A problem that reaches this stage will generally be of such gravity as to present a clear and present danger to the OPT Study's completion, requiring immediate and drastic action.
III.12. Incentive Payments (Gift Certificates)
Each gift certificates dispensed by the OPT Study is worth $20. Gift certificates can be for Target, Wal-Mart, or a similar discount store convenient for study participants.
III.12.1. Occasions on which subjects receive gift certificates
Subjects receive a gift certificate on these occasions:
• On enrollment (see Section II.1.3).

• At the Baseline/Randomization Visit (Visit 1), if it does not occur on the same day

as enrollment (see Section II.2.4).

• At each Essential Dental Care visit (see Section II.3).

• At each visit required to complete study periodontal therapy in the test group (see

Section II.4).

• At each study visit (i.e., Visits 2, 3, 4, 5, and 6) for both groups (see Section II.5).

• At each visit required to complete periodontal therapy in the control group (see

Section II.7).
III.12.2. Procedure for payment
For Enrollment Sites other than the Minneapolis Site (Hennepin County Medical Center), the following procedure is followed each time a gift certificate is dispensed.
The Study Coordinator hands the subject the gift certificate. The subject then signs an acknowledgement of payment form indicating that she has received a gift certificate. Each form records the date, the gift certificate's serial number (if applicable), the subject's name and signature and the signature of the staff member issuing the certificate.
For the Minneapolis Site (Hennepin County Medical Center), the procedure is identical except for gift certificates for Essential Dental Care. For the Minneapolis Site, Essential Dental Care is provided at the University of Minnesota Dental School and Clinics, so gift certificates dispensed after Essential Dental Care are dispensed by the General Dentist who delivers Essential Dental Care. Otherwise, the procedures are the same as above. The Minneapolis Site thus has two disbursement logs: one maintained by the Study Coordinator, and one by the dentist providing Essential Dental Care.
III.12.3. Managing and protecting the gift certificate inventory
The gift certificates are purchased by the Administrative Center at the University of Minnesota and sent to each Enrollment Site's Study Coordinator by registered mail monthly. Upon receiving the gift certificates, the Study Coordinator signs for the receipt of the gift certificates and verifies in writing the number of gift certificates received and the beginning and ending serial numbers. The latter written verification is faxed to the Study Chair at the University of Minnesota. Gift certificates distributed to the Minneapolis Site's Essential Dental Care clinic at the University of Minnesota are verified in writing directly rather than by fax.
Each month, a Site's Study Coordinator mails the Study Chair a copy of that month's signed payment receipts. Specifically, the payment receipts are copied with the subject names and signatures concealed for confidentiality, and the partly-obscured copy is mailed to the Study Chair. Payment receipts should not be faxed as this may pose a problem with confidentiality. The Minneapolis Site's Essential Dental Care clinic provides the obscured copy directly to the Study Chair rather than by fax.
The Study Chair maintains records of:
• gift certificates purchased,

• gift certificates distributed to Enrollment Sites,

• faxes from Study Coordinators verifying receipt of gift certificates, and

• copied payment receipts from the Enrollment Sites.


All records will be available for auditing and oversight by NIH staff.
Each Site's Study Coordinator is responsible for maintaining security of the gift certificates and for verifying disbursement of gift certificates to study subjects. At the Minneapolis Site's Essential Dental Care clinic, this responsibility is delegated to the dentist providing Essential Dental Care. Gift certificates must be kept under lock at all times except when being accessed. Training will emphasize protecting the gift certificates, which are as good as cash at the retailer that sold them.



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