Contemporary Clinical Trials Communications 22 (2021) 100806 Contents lists available at ScienceDirect Contemporary Clinical Trials Communications Efficacy and safety of preoperative preparation with Lugol's iodine solution in euthyroid patients with Graves’ disease (LIGRADIS Trial): Study protocol for a multicenter randomized trial José Luis Muñoz de Nova a, *, Guzmán Franch-Arcas b, Gina Paola Mejía-Abril c, María Eugenia Flores-Ruiz c, Nuria Muñoz-Pérez d, Elena Pintos-Sánchez c, Francisco Javier Guadarrama González e, Álvaro Valdés de Anca a, Enrique Mercader-Cidoncha f, Aitor de la Quintana-Basarrate g, Irene Osorio-Silla h, Susana Ros-López i, Lander Gallego-Otaegui j, Elena Santos-Molina c, Concepción Martínez-Nieto k, Elena Gamborino-Caramés l, Mariano Artés-Caselles m, Leyre Lorente-Poch n, Maitane García-Carrillo o, Pablo Moreno-Llorente p, Consuelo Marín-Velarde q, Joaquín Ortega-Serrano r, Juan Manuel Martos-Martínez s, Oscar Vidal-Pérez t, Patricia Luengo-Pierrard u, Jesús María Villar-del-Moral e a Department of General and Digestive Surgery, Hospital Universitario La Princesa, Instituto de Investigación Sanitaria La Princesa, Universidad Autónoma de Madrid, Diego de León 62, 28006, Madrid, Spain b Department of General and Digestive Surgery, Complejo Asistencial Universitario de Salamanca, Paseo San Vicente 58-182, 37007, Salamanca, Spain c Department of Clinical Pharmacology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria La Princesa, Universidad Autónoma de Madrid, Diego de León 62, 28006, Madrid, Spain d Department of General and Digestive Surgery, Hospital Universitario Virgen de las Nieves, Avda. de las Fuerzas Armadas 2, 18014, Granada, Spain e Department of General and Digestive Surgery. Hospital Universitario 12 de Octubre, Av. de Córdoba s/n, 28041, Madrid, Spain f Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Doctor Esquerdo 46, 28007, Madrid, Spain g Department of General and Digestive Surgery, Hospital Universitario de Cruces, Universidad del Pais Vasco, Plaza de Cruces S/N, 48903, Baracaldo, Vizcaya, Spain h Department of General and Digestive Surgery, Hospital Universitario Fundación Jiménez Díaz, Av. de los Reyes Católicos 2, 28040, Madrid, Spain i Department of General and Digestive Surgery, Hospital Clínico Universitario Lozano Blesa, Avda. San Juan Bosco 15, 50009, Zaragoza, Spain j Department of General and Digestive Surgery, Hospital Universitario Donostia, Begiristain Doktorea Pasealekua 109, 20014, San Sebastián, Guipúzcoa, Spain k Department of Pharmacy, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria La Princesa, Universidad Autónoma de Madrid, Diego de León 62, 28006, Madrid, Spain l Department of General and Digestive Surgery, Hospital Clínico Universitario, Rúa da Choupana s/n, 15706, Santiago de Compostela (La Coruña), Spain m Department of General and Digestive Surgery, Hospital Universitario Puerta de Hierro, Manuel de Falla 1, 28222, Majadahonda, Madrid, Spain n Department of General and Digestive Surgery. Hospital Universitario del Mar, Passeig Marítim de la Barceloneta 25-29, 08003, Barcelona, Spain o Department of General and Digestive Surgery, Hospital Universitario de Basurto, Montevideo Etorb 18, 48013, Bilbao, Vizcaya, Spain p Endocrine Surgery Unit, Hospital Universitario de Bellvitge, Feixa Llarga s/n, 08907, Hospitalet de Llobregat (Barcelona), Spain q Department of General and Digestive Surgery, Hospital Universitario Virgen Macarena, Dr. Fedriani 3, 41009, Sevilla, Spain r Department of General and Digestive Surgery, Hospital Clínico Universitario, Universidad de Valencia, Av. de Blasco Ibáñez 17, 46010, Valencia, Spain s Department of General and Digestive Surgery, Hospital Universitario Virgen del Rocío, Av. Manuel Siurot s/n, 41013, Sevilla, Spain t Department of General and Digestive Surgery, Hospital Clinic, Villarroel 170, 08036, Barcelona, Spain u Department of General and Digestive Surgery, Hospital Universitario Ramón y Cajal, Ctra. Colmenar Viejo km. 9,100, 28034, Madrid, Spain Corresponding author. Department of General and Digestive Surgery, Hospital Universitario La Princesa, Diego de Leon 62, 28006, Madrid, Spain. * E-mail addresses: jmunoz@salud.madrid.org (J.L. Muñoz de Nova), gfranch@saludcastillayleon.es (G. Franch-Arcas), ginapaola.mejia@salud.madrid.org (G.P. Mejía-Abril), mariaeugenia.flores@salud.madrid.org (M.E. Flores-Ruiz), numupe@gmail.com (N. Muñoz-Pérez), elena.pintos@scren.es (E. Pintos-Sánchez), fj avier.guadarrama@salud.madrid.org (F.J. Guadarrama González), alvaro.valdes@salud.madrid.org (Á. Valdés de Anca), enrique.mercader@salud.madrid.org (E. Mercader-Cidoncha), aitor.quintanadelabasarrate@osakidetza.eus (A. de la Quintana-Basarrate), irene.osorio@quironsalud.es (I. Osorio-Silla), susanaros44@gmail.com (S. Ros-López), lander.gallegootaegui@osakidetza.net (L. Gallego-Otaegui), cmartinezn@salud.madrid.org (C. Martínez-Nieto), elena.gam borino.carames@sergas.es (E. Gamborino-Caramés), mariano.artes@salud.madrid.org (M. Artés-Caselles), lorentepoch@live.com (L. Lorente-Poch), maitane.garcia carrillo@osakidetza.eus (M. García-Carrillo), pmoreno@bellvitgehospital.cat (P. Moreno-Llorente), consuelomarinvelarde@hotmail.com (C. Marín-Velarde), joaquin.ortega@uv.es (J. Ortega-Serrano), juan.martos.sspa@juntadeandalucia.es (J.M. Martos-Martínez), ovidal@clinic.cat (O. Vidal-Pérez), patypierrard@yahoo.es (P. Luengo-Pierrard), jesusm.villar.sspa@juntadeandalucia.es (J.M. Villar-del-Moral). https://doi.org/10.1016/j.conctc.2021.100806 Received 10 March 2021; Received in revised form 7 June 2021; Accepted 12 June 2021 Available online 15 June 2021 2451-8654/© 2021 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). J.L. Muñoz de Nova et al. Contemporary Clinical Trials Communications 22 (2021) 100806 ARTICLE INFO ABSTRACT Keywords: Background: Currently, both the American Thyroid Association and the European Thyroid Association recom- Thyroid surgery mend preoperative preparation with Lugol's Solution (LS) for patients undergoing thyroidectomy for Graves’ Graves' disease Disease (GD), but their recommendations are based on low-quality evidence. The LIGRADIS trial aims to pro- Lugol's solution vide evidence either to support or refute the systematic use of LS in euthyroid patients undergoing thyroidec- Hyperthyroidism tomy for GD. Methods: A multicenter randomized controlled trial will be performed. Patients ≥18 years of age, diagnosed with GD, treated with antithyroid drugs, euthyroid and proposed for total thyroidectomy will be eligible for inclusion. Exclusion criteria will be prior thyroid or parathyroid surgery, hyperparathyroidism that requires associated parathyroidectomy, thyroid cancer that requires adding a lymph node dissection, iodine allergy, consumption of lithium or amiodarone, medically unfit patients (ASA-IV), breastfeeding women, preoperative vocal cord palsy and planned endoscopic, video-assisted or remote access surgery. Between January 2020 and January 2022, 270 patients will be randomized for either receiving or not preoper- ative preparation with LS. Researchers will be blinded to treatment assignment. The primary outcome will be the rate of postoperative complications: hypoparathyroidism, recurrent laryngeal nerve injury, hematoma, surgical site infection or death. Secondary outcomes will be intraoperative events (Thyroidectomy Difficulty Scale score, blood loss, recurrent laryngeal nerve neuromonitoring signal loss), operative time, postoperative length of stay, hospital readmissions, permanent complications and adverse events associated to LS. Conclusions: There is no conclusive evidence supporting the benefits of preoperative treatment with LS in this set- ting. This trial aims to provide new insights into future Clinical Practice Guidelines recommendations. Trial registration: ClinicalTrials.gov identifier: NCT03980132. 1. Background Currently, both the American Thyroid Association [11] and the Eu- ropean Thyroid Association [1] recommend the use of LS in the prepa- Graves’ disease (GD) is the most common cause of hyperthyroidism. ration of patients undergoing surgery, but their recommendations are Most patients with GD are initially treated with antithyroid drugs (AT) based on low-quality evidence. Probably because of this lack of high- (thionamides), occasionally followed by surgery or radioactive iodine quality evidence its use has not been generalized. A recent survey esti- when failure, intolerance, or relapse after AT treatment [1]. As an alter- mates that less than a third of the European endocrine surgery units sys- native to radioiodine, surgical treatment offers important advantages tematically use it [12]. such as a low recurrence rate and a rapid resolution of hyperthy- The LIGRADIS trial (Lugol Iodine in GRAves’ DIsease Surgery) is the roidism, but its use has been hampered by fear of postoperative compli- first multicenter randomized controlled clinical trial addressing this cations (hypoparathyroidism, recurrent laryngeal nerve injury, topic and intends to provide adequate evidence to support future rec- hematoma, surgical site infection, etc.), whose overall incidence rate ommendations on the preoperative preparation with LS in patients un- ranges between 30 and 40%. Despite the initial controversy regarding dergoing TT for GD. the surgical technique, some meta-analysis and randomized clinical tri- als have established near-total/total thyroidectomy (TT) as the tech- 2. Methods/design nique of choice given that its complication rate is similar to that of more conservative procedures, with a lower recurrence rate [2]. 2.1. Objectives Lugol's solution (LS) was first described in 1829 and is composed by iodine and potassium iodide mixed with distilled water. It has a red- The primary objective is to analyze whether, in euthyroid patients dish-brown color, and a characteristic bitter and metallic taste. Its use undergoing TT for GD, no preoperative preparation with LS increases in the preoperative preparation of patients with GD was proposed by the rate of postoperative complications compared to prepared patients Plummer in 1923 with the aim of achieving euthyroidism before or not. surgery, reducing intraoperative bleeding and preventing the develop- The secondary objective is to evaluate the influence of preoperative ment of a perioperative thyroid storm due to the massive release of thy- preparation on surgical difficulty, intraoperative blood loss, surgical roid hormones during surgery [3]. However, since the introduction of time, intraoperative neuromonitoring results, postoperative length of AT, most patients achieve euthyroidism before surgery. In these cases, stay, hospital readmission rate, permanent complications and adverse the only benefit of LS is a theoretical decrease in surgical complexity events. due to less intraoperative bleeding caused by a drop in glandular vascu- larization. 2.2. Study design The few clinical trials [4–8] published on this subject only analyze intraoperative outcomes, wherein relationship with postoperative com- The LIGRADIS trial is a multicenter, randomized trial, blinded for plications is limited by the small sample size of the studies. All these the researchers. Patients will be randomized (1:1) to receiving or not studies published to date are single-center, which further limits their preoperative preparation with LS before TT (Fig. 1). Some 19 special- sample size, external validity and makes it difficult to obtain meaning- ized Endocrine Surgery Units in Spain are willing to participate. ful results. Only one prospective study [9] suggests a lower rate of com- plications in patients prepared with LS. A recent meta-analysis [10] has 2.3. Study population not been able to demonstrate any clinical benefit after the administra- tion of LS in euthyroid patients undergoing TT for GD and the authors, Patients who meet all of the following criteria will be eligible: even though they emphasize the high heterogeneity of the studies in- cluded, call into question the validity of the recommendations of the 1. Patients ≥18 years of age. clinical guidelines. 2 J.L. Muñoz de Nova et al. Contemporary Clinical Trials Communications 22 (2021) 100806 Fig. 1. Flowchart of the LIGRADIS trial. 2. Patients must be able to understand the nature of the study and 3. Thyroid carcinoma that requires to perform lymph node agree to participate in it, by signing the corresponding informed dissection (central and/or lateral neck compartments) during the consent document. same surgical act. 3. GD diagnosis, defined as the existence of hyperthyroidism (TSH 4. Iodine allergy. values < lower limit of laboratory normality associated with TSI 5. Consumption of lithium or amiodarone between randomization values > upper limit of laboratory normality) that present and administration of LS. ultrasonographic data (diffuse vascularization increase) and/or 6. Patients classified as category IV according to the American scintigraphy (diffuse uptake of the radioisotope) compatible with Society of Anesthesiologists (ASA) Physical Status Classification GD. System. 4. Euthyroid state (free T4 and/or free T3 within normal values) at the 7. Women breastfeeding during the administration of the LS or in the time of randomization, and under treatment with AT drugs following month. (propylthiouracil, carbimazole or methimazole). 8. Preoperative vocal cord palsy verified by laryngoscopy. 5. Total thyroidectomy planned through a transcervical approach. 9. Surgery performed by training specialists or by staff not specifically dedicated to endocrine surgery. Patients will be excluded if they meet any of the following criteria: 10. Surgery not performed under general anesthesia. 11. Endoscopic, video assisted or remote access surgery. 1. History of thyroid or parathyroid gland surgery. 12. Surgery performed in an outpatient setting. 2. Concurrent hyperparathyroidism that requires associated 13. Current illegal drug consumption or alcohol abuse. parathyroidectomy. 14. Participation in any other clinical trial with drugs in the month prior to randomization. 3 J.L. Muñoz de Nova et al. Contemporary Clinical Trials Communications 22 (2021) 100806 2.4. Recruitment procedure presence of iodine in its molecule, it is not feasible to obtain a placebo preparation without iodine with similar properties. The local investigators will check that the patient meets the eligibil- It is very likely that the evaluation of the results could be biased if ity criteria upon diagnosis and confirmation of the surgical indication. the surgeon-investigator knows the assigned group. Therefore, our de- Local investigators will explain to the patient the aim of the LIGRADIS sign has been made to keep the surgeon-investigator blinded about the trial, the procedure and the potential harms, and will discuss the possi- group assigned to each patient. For that purpose, the assignment made bility of being included in it. Patients will be provided with and infor- in the Hospital Pharmacy Department of each center will be hidden, mation sheet and informed consent document. If the patient agrees to emphasizing patients on the importance of not revealing to the surgeon participate, the Informed Consent will be signed both by the patient and whether they are in the LS arm or not, except if the unmasking assump- the investigator. The investigator will provide all the information re- tions apply. quested by the patient and allow as much time as needed to decide Given the safety profile of the LS, it is unlikely that a medical emer- whether to participate or not. Only when the patient agrees to partici- gency will occur so as to require urgent unmasking. However, the inves- pate, the randomization will be performed. tigator is authorized to proceed with it if he considers it necessary. If unmasking occurs, the investigator must record the reasons for it, as 2.5. Follow-up procedure well as the date and time of the accountable event. The corresponding information will be recorded in the Electronic Case Record Form After randomization (T2), the next meeting with the patient will be (ECRF) by the investigator. If it occurs before the second postoperative at hospital admission on the day of surgery (T3). Upon arrival, an un- day, it will be considered a withdrawal criteria. blinded member of the investigator team will assess the assigned group, the presence of adverse events (AE) and, in the LS group, will verify the 2.6. Trial interventions correct LS intake. This will be the only role of the un-blinded members, and they will not participate in any other evaluation or any further data Each Hospital Pharmacy Department will prepare the study drug collection during the study either. (5% LS) for its outpatient oral administration. This preparation will After surgery, follow-up will be programmed according to usual strictly follow the indications given in the Typified Master Formula pro- clinical practice. During hospital stay, patients will be evaluated on the vided by the Spanish Drugs and Sanitary Products Agency (AEMPS). Pa- first postoperative day (T4) and on the second day (T5) if he was not tients assigned to the LS arm will take 5 drops of LS dissolved in water discharged at day 1. After discharge, patients will be evaluated in an every 8 h, 10 days before surgery. Last dose will be on the night before outpatient basis at 1 week (T6), 1 month (T7) and 6 months (T8). T8 surgery. The LS will be stored in amber-glass light-resistant containers visit will be unnecessary if the patient is discharged at T7 in the absence between 10 and 30 °C. of postoperative complications or if they have been successfully re- All surgeries will be performed in reference Endocrine Surgery solved (Table 1). Units, all of which perform more than 100 thyroidectomies per year. All patients will be attended according to routinely clinical practice of each 2.5.1. Participants withdrawal center. Intraoperative laryngeal nerve monitoring will be done in all Patients are free to leave the study at any time for any reason, with- cases. out any consequences. Additionally, the investigator team can with- draw a patient for medical reasons or if there are any concerns about 2.7. Harms the blinding procedure. Patients’ withdrawal and its motivation will be registered. This study will be stopped if there is any suspicion that patients' health is put at risk because of their participation. The sponsor and the 2.5.2. Randomization and blinding investigators will carry out a continuous safety evaluation of the pa- Patients will be randomized to one of the two study groups using a tients according to Good Clinical Practice defined by the International system of centralized allocation, with a 1:1 randomization scheme be- Conference on Harmonization and current review of the Helsinki Decla- tween treatment arms. Subjects will be assigned by a random number ration. The sponsor will notify to the accredited Medical Ethical Board generator performed by a computerized system. This assignment se- any concerns about patients’ security without delay. quence will be hidden from researchers. An AE will be defined as a medical occurrence in a patient partici- For this study, it seems unlikely that the patients’ knowledge of the pating in the study, regardless of the causal relationship to the treat- treatment group assigned can influence the measured objectives. Fur- ment assigned. Any AE reported by the patients or those observed by thermore, due to the organoleptic properties of LS are conferred by the the investigator team will be recorded. Serious AE will be notified to the sponsor within 15 days, except those that are life-threatening or cause the death of the patient, which will be reported without delay. Typical posthyroidectomy complications, defined as the primary outcome, will Table 1 not be notified unless their severity is above the usual (intensive care Schedule interventions and assessments of the LIGRADIS trial. unit admission longer than 72 h, life-threatening or death). T1 T2 T3 T4 T5* T6 T7 T8* 2.8. Outcomes Eligibility screening X Informed consent X Clinical evaluation X X X X X* X X X* 2.8.1. Primary outcome Blood test X X X* X* X X* The primary outcome will be the development of at least one post- Cervical ultrasound X operative complication: hypoparathyroidism, inferior laryngeal nerve Laryngoscopy X X* X* injury, postoperative hematoma, surgical site infection or postoperative Allocation X death. Thyroidectomy X Hypoparathyroidism is defined by an albumin or protein corrected Complications assessment X X X* X X X* serum calcium <8 mg/dL the morning after surgery or the need for cal- T1 = Baseline; T2 = Allocation; T3 = Intervention; T4 = 1st postoperative cium or vitamin D supplementation between surgery and this determi- day; T5 = 2° postoperative day; T6 = 1 week after surgery; T7 = 1 month af- nation. Biochemical tests will be performed systematically the morning ter surgery; T8 = 6 month after surgery. * Depending on patients evolution. 4 J.L. Muñoz de Nova et al. Contemporary Clinical Trials Communications 22 (2021) 100806 after surgery, including at least total serum calcium, total proteins or al- The estimation of the effect between both treatment groups will be car- bumin, and PTH levels. ried out by calculating the relative risk (RR) and its 95% confidence in- Inferior laryngeal nerve injury is defined by a vocal cord palsy (uni terval. Univariate and multivariate logistic regression models adjusted or bilateral) confirmed by laryngoscopy after surgery. Laryngoscopy for confounding variables will be performed. The goodness of fit of the will be performed in the first postoperative week when laryngeal nerve regression formula will be measured by the Hosmer-Lemeshow statistic. injury is suspected due to dysphonia or loss of signal during intraopera- The correct classification percentage will also be calculated for the tive nerve monitoring. model. In all cases, the construction of the models will be done taking Postoperative hematoma will be considered only when surgical into account the parsimony principle to include a limited number of drainage is required. variables, although the main independent variable and the relevant Surgical site infection will be defined by the presence of any of the ones will always be included. following criteria: purulent drainage from the surgical wound, isolation The statistical significance was set at p < 0.05 with bilateral con- of pathogenic microorganisms in a culture obtained aseptically from trast hypothesis for all tests. A sequential evaluation procedure of sec- the surgical incision, signs or symptoms of infection (local pain, ondary outcomes will be used. warmth and/or erythema) associated with a positive surgical wound culture or diagnosis of SSI at the discretion of the surgical team. 2.12. Sample size Postoperative hematoma, surgical site infection and death will be evaluated until 30 days after surgery. Based on the limited data published on this subject, we estimate that 40% of patients undergoing a TT without preparation with LS could 2.8.2. Secondary outcomes have at least one postoperative complication, while this proportion Surgical difficulty will be intraoperatively evaluated by the Thy- could drop down to 20% with preparation. As the main outcome will be roidectomy Difficulty Scale [13]. Hemorrhage during the procedure measured in the early postoperative period, losses in this period are not will be calculated weighting the gauzes employed and measuring the likely to occur. Assuming an alpha error of 0.05 to find differences surgical field liquid aspirated. Regarding nerve monitoring, intraopera- among the two groups and a beta error of 0.05 to detect its absence, and tive loss of signal will be defined as a vagus signal <100microV at the using a two-sided χ2 test for two independent samples, minimum of 133 end of surgery, provided that the initial vagus signal (previous to recur- patients in each arm will be needed. Therefore, the sample size that has rent laryngeal nerve dissection) was ≥100 microV. If it happens, addi- been deemed necessary to recruit is 135 patients in each arm, 270 in to- tional information on its characteristics will be recorded (partial/ tal. global, side, permanent/temporary, time to recovery if temporary, and probable etiology). Surgical time will be defined as time between skin 2.13. Data management and protection incision and closure. Postoperative length of stay and hospital readmissions to treat post- Each participant will receive a unique alphanumeric code composed operative complications until postoperative day 30 will be recorded. by three letters that identify the center, and three numbers, consecu- Hypoparathyroidism or vocal cord palsy will be considered perma- tively assigned, that identify the patient. Only the investigator team, nent postoperative complications if they are still unresolved 6 months monitors, health care authorities and regulatory organisms will be able after surgery. Hypoparathyroidism resolution will be defined as a PTH to correlate the patients’ identity with the code. Every local investigator value above the lower reference laboratory limit and the absence of cal- will store, in the master file of the study, all the data, which will be kept cium or vitamin D supplementation to control hypocalcemic symptoms. for 25 years once the study is finished. Vocal cord palsy recovery must be confirmed by laryngoscopy. All details about the patients’ participation will be treated according to data protection regulation. 2.9. Data collection and processing 2.13.1. Data safety monitoring All the trial variables will be consigned by the investigator in an Study monitoring will be performed independently by the Clinical ECRF. Trials Unit of La Princesa University Hospital. It will include the verifi- The investigators will collect the data directly from interviews with cation of informed consent signature, the eligibility criteria, the authen- participants or from electronic patient files and reports or clinical test tication of the data collected in the ECRF and the AE monitoring. results. 2.13.2. Auditing of the participating medical centers 2.10. Funding source All the centers will receive a remote initiation visit, followed by re- mote monitoring based on the ECRF collected data, that will be audited This project is funded by the Spanish Association of Surgeons by a by an encoded patient reporting form submitted to the monitors by the competitive grant for multicenter studies. This Association has no influ- investigators. Additionally, there will be monitoring visits after the in- ence on any part of the design, data collection, analysis or interpreta- clusion of the 3rd, 7th, 11th and 15th patients. These visits could be on- tion of the results, all of which will be carried out by the main investiga- site or remote depending on the situation derived by the COVID-19 out- tors (JLMN and JMVM). break, but at least one will be on-site. Close-out visit will be also on-site. 2.11. Statistical analysis 2.14. Ethical approval The qualitative variables will be presented by frequencies and pro- The study has been approved by the Institutional Review Board and portions. For the comparison of qualitative variables, Pearson's chi- Ethics Committee of the La Princesa University Hospital (registration square test or Fisher's exact test will be used as appropriate. The quanti- code 2018–3750) and conforms in accordance with the provisions of tative variables will be presented by the mean±the standard deviation. the Helsinki Declaration as revised in 2013 and the confidentiality pro- The normal distribution of quantitative variables will be assessed with vided under the current Spanish State and European laws. the Shapiro-Wilk test and the equality of variances with the Levene's test. For quantitative variables, unpaired Student's t or the Mann- Whitney U tests will be used when applicable, for bivariate analysis. 5 J.L. Muñoz de Nova et al. Contemporary Clinical Trials Communications 22 (2021) 100806 3. Discussion tions to the conception and design of this study. All other authors par- ticipated in the design of the study and are local investigators at the To our knowledge, the LIGRADIS trial is the first multicenter ran- participating centers. All authors read and approved this manuscript. domized trial to evaluate the effect on postoperative complications of the preoperative preparation with LS before TT in euthyroid patients Declaration of competing interest with GD. The specific organoleptic features conferred by iodine content to the The authors declare that they have no known competing financial LS makes almost impossible to get a placebo with similar characteris- interests or personal relationships that could have appeared to influ- tics. Additionally, the primary outcome is defined by the development ence the work reported in this paper. of postoperative complications that could hardly be influenced by the The authors declare the following financial interests/personal rela- patient. For these reasons, we believe that the lack of placebo control tionships which may be considered as potential competing interests: will have minor consequences in the study conclusions. When calculating the sample size, we decided to rise the study References power to 95%, even if more patients will need to be recruited, in order [1] G.J. Kahaly, L. Bartalena, L. Hegedüs, L. Leenhardt, K. Poppe, S.H. Pearce, 2018 to achieve enough power to accept our results in case of not founding European thyroid association guideline for the management of graves’ differences between both groups. In order to reach this number, a mul- hyperthyroidism, Eur. Thyroid J. 7 (4) (2018) 167–186. ticenter design seems necessary, which will also be important to the ex- [2] L. Zw, L. Masterson, B. Fish, P. Jani, K. Chatterjee, Thyroid surgery for Graves ’ ternal validity of the trial. disease and Graves ’ ophthalmopathy, Cochrane Database Syst. Rev. 25 (2015) CD010576. [3] H.S. Plummer, Results of administering iodine to patients having exophtalmic Availability of the protocol goiter, J. Am. Med. Assoc. 80 (1923) 1955. [4] G. Whalen, M. Sullivan, L. Maranda, R. Quinlan, A. Larkin, Randomized trial of a short course of preoperative potassium iodide in patients undergoing thyroidectomy The full protocol can be obtained from: for Graves’ disease, Am. J. Surg. 213 (4) (2017) 805–809. [5] Y. Yilmaz, K.E. Kamer, O. Ureyen, E. Sari, T. Acar, O. Karahalli, The effect of - ClinicalTrials.gov:https://www.clinicaltrials.gov/ct2/show/ preoperative Lugol’s iodine on intraoperative bleeding in patients with hyperthyroidism, Ann. Med. Surg. 9 (2016) 53–57. NCT03980132?term=NCT03980132&draw=2&rank=1 [6] Y. Erbil, Y. Ozluk, M. Giriş, A. Salmaslioglu, H. Issever, U. Barbaros, et al., Effect of - Spanish Clinical Trials Registry: https://reec.aemps.es/reec/ lugol solution on thyroid gland blood flow and microvessel density in the patients estudio/2019-001237-14 with Graves’ disease, J. Clin. Endocrinol. Metab. 92 (6) (2007) 2182–2189. [7] S. Kaur, J.H. Parr, I.D. Ramsay, T.M. Hennebry, K.J. Jarvis, E. Lester, Effect of preoperative iodine in patients with Graves’ disease controlled with antithyroid Trial status drugs and thyroxine, Ann. R. Coll. Surg. Engl. 70 (3) (1988) 123–127. [8] P.J. Coyle, J.E. Mitchell, Thyroidectomy: is Lugol’s iodine necessary?, Ann. R. Coll. Surg. Engl. 64 (5) (1982) 334–335. Finally, the COVID-19 outbreak has affected the normal study devel- [9] R.W. Randle, M.F. Bates, K.L. Long, S.C. Pitt, D.F. Schneider, R.S. Sippel, Impact of opment from the beginning. Soon after recruitment began, the potassium iodide on thyroidectomy for Graves’ disease: implications for safety and LIGRADIS trial was almost stopped. Although recruitment process has operative difficulty, Surgery 163 (1) (2018) 68–72. [10] C.-H. Tsai, C.-Y. Kuo, P.-S. Yang, S.-P. Cheng, T.-P. Liu, J.-J. Lee, Effects of been resumed in all participating centers, the epidemiological situation preoperative iodine administration on thyroidectomy for hyperthyroidism: a makes this process very slow. We believe that most of the patients that systematic review and meta-analysis, Otolaryngol. Head Neck Surg. 160 (6) (2019) have not been recruited because of COVID-19 outbreak are still poten- 993–1002. tial participants of the study, but it is difficult to predict the global im- [11] D.S. Ross, H.B. Burch, D.S. Cooper, M.C. Greenlee, P. Laurberg, A.L. Maia, et al., 2016 American thyroid association guidelines for diagnosis and management of pact of the pandemic on the study. Given these circumstances, we esti- hyperthyroidism and other causes of thyrotoxicosis, Thyroid 26 (10) (2016) mate that the follow-up of the patients recruited will be completed by 1343–1421. the end of 2022. After analyzing the collected data, these could be pub- [12] L. Bartalena, H.B. Burch, K.D. Burman, G.J.A. Kahaly, 2013 European survey of clinical practice patterns in the management of Graves’ disease, Clin. Endocrinol. 84 lished in the second quarter of 2023. (1) (2016) 115–120. [13] D.F. Schneider, H. Mazeh, S.C. Oltmann, H. Chen, R.S. Sippel, Novel thyroidectomy Contributors difficulty scale correlates with operative times, World J. Surg. 38 (8) (2014) 1984–1989. JLMN, GFA, AVA and JMVM drafted the manuscript. JLMN, GFA, GPMD, MEFR, EPS, ESM, CMN and JMVM made substantial contribu- 6