Title: Near Infrared Fluorescence (NIRF) Imaging to prevent Post-surgical Hypoparathyroidism (PoSH) after Thyroid Surgery (NIFTy) - A phase II/III pragmatic, multicentre randomised controlled trial
Funder: Medical Research Council

Abstract: Background:Parathyroid glands are tiny glands in the neck behind the thyroid gland that control the level of calcium in the blood. More than 12,000 patients undergo thyroid surgery every year in England alone (HES dataset). A common complication of thyroid surgery is damage to or accidental removal of parathyroid glands. This causes a condition called hypoparathyroidism; this may be a temporary condition in ~25% of patients, but in up to 12% of cases, it is long-term requiring lifelong medication and care. It reduces blood parathyroid hormone and calcium levels resulting in a wide range of symptoms (such as tingling & numbness in the extremities, nausea and nocturnal cramps), longer hospital stays and requirement for frequent blood tests to monitor calcium levels & ongoing treatment. It has a significant impact on patients’ quality of life and the potential for kidney damage, accumulation of calcium in the tissues and seizures; this can be life threatening._x000D_ _x000D_ Recently, a new intraoperative technique using fluorescence (glow) from a dye called indocyanine green (ICG) has been shown in early studies to help in accurate identification and preservation of parathyroid glands during thyroid and parathyroid surgery. ICG has been used in humans for many years in evaluating blood supply of tissues and is considered very safe at the doses used. We are setting up a further study to determine if this technology will help reduce the risk and severity of hypoparathyroidism_x000D_ _x000D_ Aim:To find out how many patients develop short and long term parathyroid damage following the use of this technology compared to those who underwent surgery in the standard manner. The study will also determine if this new treatment will reduce hospital stay after surgery and improve quality of life for patients._x000D_ _x000D_ Design:The study will compare patients who undergo surgery in the standard manner with those where this technology is used. The risk of temporary and long term hypoparathyroidism will be evaluated as well as complications and quality of life. We aim to initially recruit 200 patients to determine whether there is enough early evidence of efficacy to justify recruiting a larger sample of patients for definitive analysis. If there is, then we aim to recruit to a total of 454 patients from 10 hospitals. Patients will be followed up at 1 and 6 months following surgery. If the study shows a clear benefit to patients, the technology will be widely implemented. Successful use of this technology will reduce the risk of low blood calcium and save many patients from suffering a long term, surgery induced, debilitating and life threatening condition. _x000D_ _x000D_ Patient & Public Involvement: Patient representatives have been involved in the development of the trial and help determine what outcomes are important from a patient’s point of view. We have also received input from the online PPI panel at Sheffield Teaching Hospital Trust in the use of lay language. We will be working closely with two patient charities, Hypopara UK &Butterfly UK and will include two additional patient reps to sit on the Trial Management Group and Steering Committee. _x000D_ _x000D_ Dissemination:Findings will be disseminated to professionals through national and international conferences, peer-reviewed journals and patient information websites (such as Butterfly Thyroid Cancer Trust & Hypopara UK). Results will also be disseminated through the British Association of Endocrine & Thyroid Surgeons to UK surgeons practising thyroid surgery in the UK.

Lay abstract: The primary objective of the study is to compare the incidence of hypoparathyroidism at 6 months after surgery in the intervention arm (patients undergoing thyroid surgery with NIRF+ICG) with that in the control arm (patients undergoing standard thyroid surgery)._x000D_ Secondary objectives are to compare the following in the two arms of the study:_x000D_ • Incidence of transient hypocalcaemia, defined as any adjusted calcium of <2.1 mmol/L 1-day after surgery (1) _x000D_ • Protracted hypoparathyroidism at one month after surgery_x000D_ • Intra- and post-operative complications within 6 months of surgery_x000D_ • Length of stay in hospital after surgery_x000D_ • Health related quality of life (HRQoL) _x000D_ • Re-admission within 6 months of surgery_x000D_ • Hypercalcaemia within 6 months of surgery_x000D_ _x000D_ Design: An unblinded, parallel group, multicentre, seamless phase II/III randomised controlled trial comparing surgery with near-infrared fluorescence (NIRF) and indocyanine green (ICG) against standard surgery to determine the effect on 6-month post-surgical hypoparathyroidism (PoSH) in patients undergoing thyroidectomy._x000D_ _x000D_ Population: Adult (18+ years) patients due to have completion or total thyroidectomy. Indications for thyroid surgery may include Graves’ disease, suspected or confirmed thyroid cancer, benign pathology e.g. colloid goitre. Excluding:_x000D_ • concomitant parathyroid or thoracic surgery_x000D_ • re-operative thyroid surgery (except completion thyroidectomy after previous contralateral lobectomy)_x000D_ • documented hypo or hypercalcaemia prior to thyroid surgery_x000D_ • patients on selective serotonin reuptake inhibitors_x000D_ _x000D_ Intervention - NIRF will be used with ICG using the Fluobeam® LX device during thyroidectomy. _x000D_ Control – Thyroid surgery as per standard protocol_x000D_ _x000D_ Phase II primary outcome: Transient hypocalcaemia (1-day post-surgery)_x000D_ Phase III primary outcome: Incidence of hypoparathyroidism (6 months post-surgery)._x000D_ Secondary outcomes (Phase III) include:_x000D_ • Transient hypocalcaemia _x000D_ • Protracted hypoparathyroidism_x000D_ • Intra- and post-operative complications_x000D_ • HRQoL (SF-36 and hypocalcaemia symptom score - HSS 0-12) at baseline, 1 month and 6 months post-op_x000D_ • Any episode of re-admission to hospital within 6 months of surgery_x000D_ _x000D_ Assessments: In addition to routine postoperative care including biochemical assesments for hypocalcaemia and hypoparathyroidism and determination of complications, quality of life will be evaluated by means of questionnaire surveys before and at various time periods (listed above) after surgery. _x000D_ _x000D_ Sample size: _x000D_ A sample size of 454 patients is sufficient to detect absolute reductions of 6-month PoSH rate of 7% or more at the 5% two-sided level of significance with 89% power, allowing for 10% attrition. _x000D_ An integral phase II design, which will determine an interim stop/go decision, will be performed once 200 patients have accrued primary endpoint data. _x000D_ _x000D_ Project timetable: Trial set-up + qualitative research (12 months), recruitment (32 months), follow-up (8 months- to allow time from randomisation to surgery plus 6 months follow-up post operation), analysis & dissemination (6 months). 10 sites will be required to recruit 454 over the recruitment period =~18 patients per site/year. Audit data from STHFT shows ~69 patients per year would meet the trial criteria (2).

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.4 SURGERY
Health categories: METABOLIC AND ENDOCRINE