Alterations in Muscle's Functional Characteristics After Parathyroid Surgery for Primary Hyperparathyroidism.
Alterations in Muscle's Functional Characteristics After Parathyroid Surgery for Primary Hyperparathyroidism.
Protocol title: Alterations in functional characteristics of the muscle tissue following
 surgery for primary hyperparathyroidism.

 Purpose: To detect any changes in functional characteristics of muscles in patients who
 undergo surgery for primary hyperparathyroidism compared to patients with primary
 hyperparathyroidism and conservative treatment, patients undergoing thyroid surgery and
 healthy subjects.

 Design: Prospective, multi-center observational study Patient Population: Male or female
 subjects 18 years of age or older scheduled for parathyroidectomy No. of Subjects: 50
 patients undergoing parathyroidectomy, 50 patients undergoing conservative follow up, 50
 patients undergoing thyroid surgery due to nontoxic multinodular goiter or solitary nontoxic
 thyroid adenoma and 50 healthy control subjects, estimated up to 12 months to enroll.

 Duration of Treatment: During the operation Duration of Follow-up: Follow-up will be
 performed daily during hospitalization and at 3, 6 and 12 months after the procedure
 Endpoints: To evaluate the changes in functional characteristics of all the type of muscles
 which occur after parathyroidectomy for primary hyperparathyroidism.
1.0 INTRODUCTION The association between parathyroidectomy and cardiovascular status
 improvement is still inconclusive. There is evidence to suggest that primary
 hyperparathyroidism (PHPT) is associated with hypertension, whereas few studies show that
 hypertension does not reverse after surgical care. Moreover, left ventricular hypertrophy
 (LVH) is considered to be linearly associated with parathyroid hormone (PTH) and independent
 of hypertension. In addition, inflammatory changes in the cardiovascular system, which are
 expected to occur after parathyroidectomy, can be evaluated by assessing the levels of
 inflammation biomarkers, such as high-sensitivity C reactive protein (hs-CRP), increased
 levels of which are associated with high cardiovascular event rate. The investigators will
 evaluate cardiovascular system before and after parathyroidectomy by appraising the levels of
 hs-CRP, measuring Left Ventricular Mass Index (LVMI) and monitoring patients' blood pressure
 (BP) for 24 hours.

 Primary hyperparathyroidism (PHPT) has also been associated with neuromuscular abnormalities.
 The typical symptoms are proximal muscle weakness and muscle atrophy, especially of type II
 fibers. Other symptoms are generalized fatigue, reduced well-being, hyperreflexia, abnormal
 gait and tongue fasciculations. Although, nowadays, most of the symptoms with which patients
 are presented are mild or completely absent probably because PHPT is detected at a
 preclinical stage. On the other hand, many "asymptomatic" patients preoperatively, report
 subjective amelioration after the surgery, with respect to muscle strength and function. The
 investigators will conduct clinical examination, focusing on neuromuscular status, assess
 motor nerve conduction velocity, using electroneurography (ENG) and muscle strength, using
 isokinetic dynamometers. Moreover, the investigators will evaluate neuromuscular junction
 with the help of electrodiagnostic techniques, such as electromyography (EMG). Finally, due
 to the fact that stapedius muscle is the smallest skeletal muscle in the human body, the
 investigators tend to measure stapedius reflex in order to test the hypothesis that there is
 association between acoustic reflex improvement and parathyroidectomy for PHPT.

 2.0 OBJECTIVES To detect and compare the changes in functional characteristics of muscles,
 which occur in patients who undergo surgery for primary hyperparathyroidism compared to
 patients with primary hyperparathyroidism and conservative treatment, patients undergoing
 thyroid surgery and healthy subjects.

 3.0 DESIGN AND STUDY POPULATION The study is designed as a prospective, multi-center,
 observational study. Any patient that has indication for a parathyroidectomy, as a
 therapeutic intervention, due to primary hyperparathyroidism will be considered eligible.

 3.1 Duration of the study The study will be conducted until all subjects of each category are
 included. It is estimated that it will take up to 12 months to enroll the patients and an
 additional 12 months to obtain the follow-up information

 4.0 STUDY PROCEDURE

 4.1 Pre-Surgery

 Procedures performed such as routine hospital examinations, antibiotic prophylactic
 treatment, anticoagulant treatment and diet will be according to the standard management
 protocol and will be recorded for the study. The following pre-surgery information will be
 recorded:

 1. Demographic information including: name, age, gender, ethnicity

 2. Height, weight, BMI and American Society of Anesthesiologists physical status
 classification system (I-VI)

 3. Behavioral history (Smoking, alcohol or drug use)

 4. Blood Pressure and Ultra Sound measurement of Left Ventricular Mass Index (LVMI)

 5. Neurological clinical examination

 6. Hearing and stapedius reflex assessment

 7. Electromyography and electroneurography

 8. Muscle strength status

 9. Preoperative labs [white blood cells (WBC), hematocrit (Ht), hemoglobin (Hgb), serum
 calcium (Ca2+), free triiodothyronine (fT3), free thyroxine (fT4), thyroid-stimulating
 hormone (TSH), PTH, vitamin D (VitD), creatine phosphokinase (CPK), lactate
 dehydrogenase (LDH), hs-CRP]

 10. Diagnosis including clinical observations and previous imaging results

 11. Pre-operative characteristics of the adenoma

 12. Medications

 13. Questionnaire assessing subjects' physical activity

 14. Current and past history of surgical and medical comorbidities

 4.2 Intra-operative

 The surgeon will perform the preplanned operation. The following intraoperative variables
 will be recorded for all patients:

 1. Surgery date

 2. Duration of surgery

 3. Operation performed

 4. Procedure related comments

 5. Intraoperative frozen section

 6. Quick intraoperative parathyroid assay (intact PTH intra-operative values)

 4.3 Pathology data form

 The following pathology data will be recorded for all patients:

 1. Post-operative diagnosis including pathology report

 2. Weight of the adenoma

 3. Dimensions of the adenoma

 4.4 Postoperative follow-up

 Follow-up evaluation will be performed during hospitalization, at the 3rd, 6th and 12th
 month. The following information will be recorded:

 1. Postoperative labs (WBC, Ht, Hgb, Ca2+, fT3, fT4, TSH, PTH, VitD, CPK, LDH, Hs- CRP)

 2. Blood Pressure and Ultra Sound measurement of Left Ventricular Mass Index (LVMI)

 3. Neurological clinical examination

 4. Hearing and stapedius reflex assessment

 5. Electromyography and electroneurography

 6. Muscle strength status

 7. Questionnaire assessing subjects' physical activity

 8. Comments

 5.0 COMPLICATIONS AND ADVERSE EVENTS

 The investigator is required to notify the Ethics Committee of any serious adverse events,
 according to local regulations and requirements. Serious Adverse Events include:

 1. Death regardless of cause

 2. Any-life-threatening event

 3. Any hospitalization or prolongation of existing hospitalization

 4. Any event that results in persistent or significant disability or incapacity to the
 patient.

 6.0 STATISTICAL ANALYSIS The objective of this study is to detect and compare the changes in
 functional characteristics of muscles, which occur in patients who undergo surgery for
 primary hyperparathyroidism comparing with patients who do not, patients undergoing thyroid
 surgery and healthy subjects. All the subject will be matched in race, gender and age.

 Four groups will be formed:

 1. Group A, which includes patients with PHPT, undergoing parathyroidectomy, as a
 therapeutic intervention.

 2. Group B, which includes patients with PHPT, not undergoing parathyroidectomy and
 receiving conservative treatment. This group will be considered as control group.

 3. Group C, which includes patients undergoing thyroid surgery due to nontoxic multinodular
 goiter or solitary nontoxic thyroid adenoma. This group will be considered as control
 group.

 4. Group D, which includes healthy subjects. This group will be considered as control
 group.

 In order to efficiently evaluate the contribution of parathyroidectomy for PHPT in the
 functional alterations occurring after it, the investigators will search for significant
 statistical differences in pre- and postoperative alterations in muscles' functional
 characteristics in Group A, using repeated measure ANOVA for continuous variables and
 Cochran's Q test for categorical data.

 Furthermore, differences in functional characteristics of muscles between the four groups
 will be explored using ANOVA for continuous data and Fischer's Exact Test for categorical
 data. Baseline characteristics will be summarized using appropriate descriptive statistics.
 Statistical significance will be set at 0.05.

 Since the study does not have pre-specified hypotheses all statistical analyses are
 exploratory and interpretation of results should be within this context.

 7.0 DATA MONITORING PLAN The investigators are going to monitor all data accrual.
 Furthermore, the investigators will review the progress of the clinical trial including
 safety data and ensure as possible that it is conducted, recorded and reported in accordance
 with the protocol, good clinical practice and the applicable regulatory requirements.

 8.0 DATA CONFIDENTIALITY Each patient will be identified by his/her initials and a unique
 patient identification number. Source data will be stored with source documents. Only
 personnel responsible for collecting data and transcribing it into the case report forms will
 have access to the data. Records will remain on site in secure areas.

 9.0 FUNDING No additional funding for the execution of the present protocol is necessary. The
 investigators are willing to execute the present study without any additional reimbursement.

 10.0 ETHICS Prior to study institution review board (IRB) approval should be obtained. Any
 changes in the study protocol, informed consent forms, or investigator must be re-approved by
 the IRB. All patients enrolled in the study will provide their consent prior to entering the
 study. An informed consent form shall be signed and dated by the patient. The investigator
 will retain the forms as part of the study records.

 This study will be executed in accordance with the Declaration of Helsinki, in agreement with
 the guidelines for conducting a clinical investigation in accordance with the principles of
 ICH (International Conference on Harmonization) GCP (Good Clinical Practice) outlined in the
 E6 document. By signing the present protocol, participants in the study commit themselves to
 carry it out in accordance with local legal requirements.

 11.0 INFORMED CONSENT All eligible patients should have the capacity to provide an informed
 consent. The above described inclusion and exclusion criteria were designed to ensure the
 entry of the appropriate population of patients to this study and will be approved by the
 local IRB. Screening for these criteria will be conducted by the coordinator. Eligible
 patients will be educated about the research proposal by a study investigator. To determine
 whether the patient has understood the issues, he/she will be asked to describe what the
 research entails and whether they have any questions. All questions will be addressed prior
 to enrollment. The patient can refuse participation in the study at any time. A written
 informed consent form will be generated. For each patient, a case report form (CRF) will be
 completed, providing general medical information and history.
Inclusion Criteria:

 1. Patient is over 18 years old

 2. Patient scheduled for a non-emergency operation

 3. Patients diagnosed with PHPT:

 i) one or more samples of total serum calcium above the upper limit of normal value
 for the laboratory (hypercalcemia) ii) serum albumin within the normal range iii)
 hypercalcemia with normal or elevated PTH levels iv) serum 25(OH) vitamin D more than
 20 ng/ml (50nmol/lt)

 4. Patient eligible for parathyroid surgery: PHPT with one or more of the following i)
 age less than 50 years ii) serum calcium level more than 1mg/dl above the upper limit
 of normal iii) T score of less than -2.5 at any site, or non traumatic osteoporotic
 fracture by history or VFA (Vertebral Fracture Assessment) iv) history of renal colic
 or evidence of lithiasis/calcinosis by x-Ray or ultrasound v) creatinine clearance of
 less than 60ml/min vi) hypercalciuria (more than 400mg/ day)

 5. Patient signs and dates a written informed consent form (ICF) and indicates an
 understanding of the study procedures

 Exclusion Criteria:

 1. Patient is participating in another clinical trial which may affect this study's
 outcomes

 2. Patient with recurrent hyperparathyroidism

 3. Previous operation at the thyroid and parathyroid glands or neck irradiation

 4. Noneuthyroid condition

 5. Primary hyperparathyroidism due to hyperplasia or multiple adenomas

 6. Secondary hyperparathyroidism

 7. Primary or secondary hypoparathyroidism

 8. Diabetes mellitus

 9. Chronic renal failure

 10. Systemic diseases (e.g. infections, neoplasms)

 11. Hypoalbuminemia

 12. Use of drugs that influences calcium metabolism (Vitamin D analogues, oral calcium
 supplements, bisphosphonates, teriparatide, thiazide diuretics, aromatase inhibitors)

 13. Known neuromuscular disorders due to other causes

 14. Factors affecting acoustic reflex:

 i) Conductive or sensorineural hearing loss (hearing threshold better than 80dBs
 (decibells) in every testing frequency) ii) Otosclerosis iii) Middle ear dysfunction
 (acute or chronic inflammation) iv) Facial nerve dysfunction v) Retrocochlear damage
 (acoustic neurinoma, vestibular Schwannoma) vi) Impaired stapedius muscle