Buffered Lidocaine for Loop Electrosurgical Excision Procedures (LEEPs)
|First Received Date ICMJE||July 28, 2011|
|Last Updated Date||July 12, 2013|
|Start Date ICMJE||July 2011|
|Primary Completion Date||October 2012 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Injection Pain Score [ Time Frame: immediately following procedure ] [ Designated as safety issue: No ]
A Likert visual analog scale will be used to document each study participant's level of pain experienced during injection of the cervical block.
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT01405768 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||Overall LEEP procedure pain (including procedural pain and cramping) [ Time Frame: immmediately following procedure ] [ Designated as safety issue: No ]
A likert visual analog scale will be used to determine the overall pain experienced by each study participant including injection pain, procedural pain, and cramping.
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Buffered Lidocaine for Loop Electrosurgical Excision Procedures (LEEPs)|
|Official Title ICMJE||A Randomized Trial of Buffered vs Nonbuffered Lidocaine With Epinephrine for Cervical Loop Excision|
Women undergoing a LEEP procedure who receive lidocaine buffered with sodium bicarbonate for their cervical block will experience less injection pain than women who receive plain lidocaine.
Although cervical cancer rates have been dramatically reduced by Pap test screening and the eradication of precursors, more than 100,000 U.S. women develop premalignant cervical lesions each year that require treatment (1). The cervical loop electrosurgical excision procedure (LEEP) is the most common therapy for CIN among U.S. gynecologists. LEEP is performed using one or more 1-2 cm electrosurgical diathermy loops to excise involved and at-risk cervical epithelium including underlying stroma containing glands. Destroying this tissue eliminates cells infected with human papillomavirus, the proximate cause of cervical cancer, and radically reduces the risk of later developing cervical cancer (2, 3).
LEEP is usually performed as an outpatient procedure using intracervical anesthesia, most commonly combining lidocaine as an anesthetic agent with epinephrine as a hemostatic agent; final hemostasis is achieved using electrosurgical fulguration and topical hemostatic agents (4). Prior literature has suggested that pain from LEEP has 3 components: pain from injection of the anesthetic combination, pain from the excision, and cramping from reflex uterine contractions (5). While cramping can be controlled with oral nonsteroidal anti-inflammatory agents, injection and procedural pain are not. Most women categorize the pain of LEEP as 3-7 on a 0-10 Likert scale (5, 6).
Studies of dermal and ocular anesthesia and bone marrow biopsy have found that buffering of acidic local anesthetic agents reduces injection pain (7-14), with up to 66% reduction in pain and significant results in randomized trials involving 30-50 participants. However, the use of buffered lidocaine has not yet been tested for LEEPs. The principal investigator has used both forms of anesthesia and considers both acceptable forms of therapy; he is unaware of any evidence to support the superiority of either arm.
Inclusion criteria 1. Subjects ≥ 18 years who meet any of the following indications for LEEP:
a. Antecedent biopsy read as i. cervical intraepithelial neoplasia (CIN) grade 2 or 3 or microinvasive cancer ii. adenocarcinoma in situ iii. persistent CIN1 b. Antecedent Pap read as i. high grade squamous intraepithelial lesion ii. atypical glandular cells iii. persistent low grade squamous intraepithelial lesion Exclusion criteria
Methods Eligible, consenting women who have either a negative pregnancy test or are postmenopausal women who present for LEEP in the Gynecologic Treatment Center in the Center for Advanced Medicine will be randomized to either buffered or nonbuffered lidocaine. The LEEP clinic is run by the PI, Dr. Leslie Massad, and as such this is the PI's patient population and clinic. Women will be asked about analgesics and antiplatelet or anticoagulant therapy, and records will be reviewed for a history of bleeding diathesis. Subjects will not be excluded for use of over the counter medications such as Ibuprofen or Tylenol. Subjects who have taken stronger prescription analgesics (ie codeine, or other narcotics) within 7 days of her scheduled LEEP procedure will be excluded.
Randomization will be by computerized random number generation by the Division of Clinical Research in the Department of Obstetrics & Gynecology at Washington University in St. Louis. Treatment assignments will be sequenced accordingly, and prepared, opaque envelopes will be opened in order by either the medical assistant (MA) or registered nurse (RN) responsible; neither the MA or the RN will perform the procedure or obtain pain scores. Only the RNs will prepare the study drug solution.
The randomization envelopes will be prepared by Dr. Peipert's team and, then will be submitted sealed to the LEEP clinic where they will be stored by the MAs. Only the MAs and the RNs will have access to these envelopes. Once randomization of the participant is noted by one of two gynecologic oncology RNs (Gina Vansickle, RN or Vanessa Thomas-Homes, RN), she will then fill syringes with either 10 ml 1% lidocaine with epinephrine 1:100,000 (control) vs 9 ml 1% lidocaine with epinephrine 1:100,000 and 1 ml of a 1mEq/ml (8.4%) solution of NaHCO3 (study) in a separate room adjacent to the LEEP procedure room. The RNs will prepare the anesthesia solution as if in standard clinical practice. Anesthetic will be carried immediately to the treatment area, so storage will not occur. Neither the treating clinicians performing LEEP nor the patient will be informed of allocation. Either the MA or RN will inform the study coordinator (Lynne Lippmann) of the treatment allocation once the participant has completed the post-procedure questionnaire and she is finished with her participation in the study. The principal investigator along with all members of the study team involved in data analysis will remained blinded to the study groups until the analyses are fully completed.
After informed consent for procedure and study, and after cervical visualization as per standard clinical care to determine suitable cervical anatomy for excision, the anesthetic solution will be injected intracervically. The injection technique will not differ from routine practice and will be done within 30 minutes of mixing the solution. The patient will be advised that pain experienced at this point is "injection pain." LEEP will be tailored to individual needs according to lesion size, lesion grade, and depth into the endocervical canal. Once the procedure begins, the patient will be informed that the subsequent cramping pain is distinct from the pain felt at the time of injection and is considered "procedural" pain.
Within 30 min of completion of the procedure and after instruction by the primary investigator, women will represent the intensity of their pain by marking single lines across 100mm Likert visual analog scales employed in prior nongynecologic studies of buffered lidocaine (5, 7-10) (See appendix). Scales will not include hashmarks or internal descriptors, as these have been shown to bias responses and diminish reliability (12). Separate scales will be marked to represent the previously identified domains of intensity of pain from injection, pain from LEEP, and cramping (3). Buffering will be assumed to have influenced pain for any of the three domains with a significant reduction in pain score. Self-designated ethnicity will be solicited to facilitate description of the study population to allow for generalization of results. This information will be obtained as part of the pain assessment questionnaire given to the participant post-procedure (See appendix).
Patient participation in the study will end on completion of the pain scoresheet. Clinical follow-up will continue as per usual standard care. The principal investigator will review charts for additional demographic information and procedural data, again to allow for generalization of results.
Risks No serious risks are likely. Less likely risks may include greater pain from a diluted lidocaine solution, though this has not been seen with buffered lidocaine used for other procedures, and increased bleeding from dilution of the epinephrine in the anesthetic solution. Alkalinization of epinephrine-containing local anesthetic solutions takes several hours; since buffered lidocaine with epinephrine will be injected within 30 min of mixing, this should not be relevant to the current study (13).
Statistical analysis Patient marks on 100mm Likert scale lines will be measured by the PI and a score defined by the length marked off in mm. We will first perform basic descriptive statistics on the baseline data of the two groups. We will then assess whether the randomization achieved balance of baseline characteristics using standard chi-square and Fisher Exact tests (for categorical variables), and t-tests or nonparametric tests for continuous data. We expect the pain scores will not approximate a Gaussian distribution, so we will use a Mann-Whitney non-parametric test to compare pain scores of the two groups. Assuming an alpha (type I error rate) of 0.05, a power of 80% (type II error rate of 0.20), a pain score of at least 5 for 80% of women in the standard treatment arm, and a 50% reduction in pain with buffering to 40% scoring pain above 5, with no loss to follow-up, 27 women will need to be accrued per group, or 54 women in the trial. This should be achievable within 2 years.
When a patient is found to be eligible for study, verbal and signed informed consent will be required by the managing physician. Nora Kizer, MD, physician and study team member, will contact the potential study participant by telephone to discuss the research project, evaluate eligibility criteria, and answer any questions. Information included in the consent form will be discussed. However, the potential participant will not view the actual consent document until the day of her scheduled LEEP. There will be an approximate 1-2 week wait period between the phone conversation and the date of the LEEP where the patient may discuss with study with family and friends, if desired. Individuals who agree to participate by phone, will be asked to sign a consent document in clinic at the time of their regularly scheduled LEEP. A paper copy of the consent form will be mailed to those individuals who agree to participate or remain undecided after the telephone conversation. The potential participant may to decline to participate at that time, even if she initially agreed to participate over the phone. An eligibility checklist will be submitted to the Contact Person/Data Manager at Washington University, Lynne Lippmann (FAX # 314-362-2893). Questions concerning eligibility may be addressed to the Study Chair(s), Contact Person, or Data Manager. A protocol number will be assigned and the designated study team member (Dr. Nora Kizer) will be informed of this number. All patient entries will also be reported to the Siteman Cancer Center by the Gynecologic Oncology Data Manager for entry into their database. The following forms will be completed in a timely fashion as per the schedule below and will be placed in the subject's study chart: Eligibility checklist, datasheet, patient scoresheet, consent.
Data Safety and Monitoring The principal investigator will supervise or perform all LEEPs. A separate research member (Dr. Nora Kizer) will complete all data entry sheets (including measurement of Likert scores and description of adverse events), and will enter de-identified data to a spreadsheet.
The frequency and severity of all toxicities will be tabulated on an ongoing basis and summarized for review under the Data Safety and Monitoring Plan for this study (DSMP) as per the guidelines for the Siteman Cancer Center at Washington University. Data for this study will be reviewed by L. Stewart Massad, M.D. (Gynecologic Oncology), Nora Kizer, M.D. (Gynecologic Oncology), and Lynne Lippmann, CCRP (Research Administrator) (Gynecologic Oncology). Statistical support will be provided by Jeffery Peipert, MD, MPH, MHA and Feng Gao, MD, PhD. Data will be reviewed every six months for toxicities and response, prior to the bi-annual report to the Quality Assurance and Safety Monitoring committee of the Siteman Cancer Center. All serious and/or unexpected events will be communicated to the Study Chair and reviewed within 2 working days for consideration of notification, amendment, or immediate study suspension.
The principal investigator will review all patient data at least every six months, and provide a semi-annual report to the Siteman Cancer Center Quality Assurance and Safety Monitoring (QASM) Committee. This report will include
Study Calendar Study Phase Recruitment Consent Research Participation Follow-up Time Frame 2 weeks prior to scheduled LEEP Day of LEEP Day of LEEP N/A Activity 1 Patient is called to discuss their potential participation in the study and review consent form. On day of procedure, the consent form is reviewed with the patient and signed. The participant undergoes LEEP in routine fashion. She receives either buffered or plain lidocaine for anesthesia. There is no follow-up specific to the study. Each patient will follow-up per routine clinical practice.
Activity 2 Paper copy of consent form is mailed. All questions and concerns are addressed. Post-procedure questionnaire is completed by the participant.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Supportive Care
|Condition ICMJE||Uterine Cervical Dysplasia|
|Intervention ICMJE||Drug: sodium bicarbonate buffered lidocaine
8.4% sodium bicarbonate will be mixed with lidocaine in a 1:10 ratio prior to mixing with epinephrine and injecting into the cervix.
|Study Arm (s)||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Completion Date||December 2012|
|Primary Completion Date||October 2012 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||18 Years and older|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Location Countries ICMJE||United States|
|NCT Number ICMJE||NCT01405768|
|Other Study ID Numbers ICMJE||201104269|
|Has Data Monitoring Committee||No|
|Responsible Party||Washington University School of Medicine|
|Study Sponsor ICMJE||Washington University School of Medicine|
|Collaborators ICMJE||Not Provided|
|Information Provided By||Washington University School of Medicine|
|Verification Date||July 2013|
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