Randomized crossover trial for the effect of sevelamer-hydrochloride as adjuvant on serum phosphate in patients with idiopathic-hypoparathyroidism hyperphosphatemia on standard conventional therapy

Idiopathic-hypoparathyroidism is a rare disorder with prevalence of 10-12 cases/million population manifesting with life-threatening hypocalcemia, tetany/seizure and chronic complications of cataract/intracranial-calcification. Lack of parathyroid hormone (PTH) mediated phosphaturic-effect leads to hyperphosphatemia. Hypoparathyroidism is conventionally managed with lifelong daily vitamin-D analogues/elemental-calcium to achieve serum-calcium of 8-8.5 mg/dL for symptomatic relief. Recently, in a randomised-control-trial (RCT), we demonstrated 100% efficacy of alphacalcidol/calcitriol for optimal calcemic control leading to withdrawal of oral calcium in 40% of them (JCEM-2021). Despite adequate therapy, serum-phosphate remains high in 60-70% patients. Our earlier study showed that such hyperphosphatemia was associated with intracranial-calcification, neuropsychiatric-dysfunction and vertebral-fractures (Clin-Endocrinol-2012). Phosphatemic control in hypoparathyroidism is an unmet clinical need. Novelty: We have managed the largest single-center-cohort of world comprising 300 idiopathic-hypoparathyroidism patients in Endocrinology-clinics of AIIMS-Delhi, since 1998. The present study is the first to assess role of phosphate binders ‘sevelamer-hydrochloride’ as an adjuvant for management of hyperphosphatemia in hypoparathyroidism. Objectives: To assess the effect of sevelamer hydrochloride as an adjuvant on serum-phosphate after four-months against conventional-therapy alone in idiopathic-hypoparathyroidism with hyperphosphatemia. Sample Size : The mean serum phosphate maintained by hypoparathyroid patients at optimal calcemic control in our earlier study was 5.0 ± 0.9 mg/dL. Sample size has been estimated assuming that addition of sevelamer hydrochloride to conventional therapy would lead to reduction of 0.5 mg/dl with SD of 0.9 mg/dl and bring their mean serum phosphate to at least upper normal of 4.5 ± 0.9 mg/dL. Calculation revealed that at 90% power, and 5% level of significance, each arm would require at least 20 patients which would become 30 in each arm considering the possibility of drop out of 25%. Altogether, we would have data for at least 40 subjects which can extend to a maximum of 60 hypoparathyroid patients (if there is no drop out) in each arm after cross-over. Methods:The study will be randomized crossover trial. Patients will be selected from the cohort of hypoparathyroid patients who are in our follow up in the endocrine Clinics at AIIMS, New Delhi. We have managed 300 such patients during last 24 years. Approximately 150 of them are in regular follow up. These patients visit clinic at an average interval of 2-3 months. At each visit, their biochemical investigations including serum total calcium, inorganic phosphorus, 25(OH)D, and urinary calcium, and phosphorus is assessed. Adequacy of the urine collection is checked by urinary creatinine. Patients who cannot afford regular intake of active vitamin D analogues and oral calcium are provided these medicines free of cost by the investigators. For the present study patients who have achieved optimal calcemic control on conventional-therapy but continue to demonstrate persistent significant hyperphosphatemia i.e serum phosphate at least 5.0 mg/dl on last three occasion during past one-year of follow-up visit will be considered eligible Only those patients who have serum total calcium value between 8.0-9.5 mg/dl i.e. an optimal calcemic control on conventional therapy will be considered as for participation in this study. Patents younger than 18 years or more than 75 years, pregnant, lactating, on steroid therapy for any reason, or have serious coexisting medical illness or unable to come for repeated follow-up at frequent interval (total 10 visits during study period of 10 months) will be excluded. After fulfilling all the inclusion and exclusion criteria, a list of all the hypoparathyroidism patients eligible for participation will be prepared in advance. A serial number will be assigned to each patient for entry to the trial in a consecutive manner on the basis of their previously assigned hypoparathyroid identification number in our cohort. Randomization and allocation of patients to sevelamer with conventional therapy and conventional therapy alone arms (group 1 and Group 2, respectively): A randomised list will be prepared from a computer generated software using a mixed block size (four and six) for block-randomization of the study subjects in two study arms i.e. group 1 and group 2. The sealed envelopes containing intervention to be allocated will be prepared in advance using a mixed block size to have a 1:1 ratio of allocation. The separate container for collection of urine would be provided to the study subject before the start of the study. One day prior to the allocation into two arms, subjects will be informed to come to the endocrine laboratory in the overnight fasting state for biochemical tests. They would also be instructed to bring 24 hour urine in the container for measurement of urinary calcium and phosphorus for phosphorus excretion index. The volume of 24 hour urine would be measured by a trained worker for accuracy of collection. Besides 24 hour urine creatinine would also be measured for accuracy of collection. On the day of randomization, serum will be drawn for all the biochemical parameters including serum total calcium, phosphorus, serum 25(OH)D, PTH, FGF23 and serum magnesium. The serum will be stored at �’20°C in multiple aliquots. After block randomization, Group 1 would receive sevelamer-hydrochloride along with on-going conventional therapy consisting of alfacalcidol, and oral elemental calcium as calcium carbonate. Group 2 would continue their usual conventional-therapy only, for four months. The dietary history of all the participants will be assessed at initial recruitment. Subjects will be asked to continue with their usual daily diet during the whole study period (Please see Figure 1 of the additional supplementary information). Intervention dose and duration: Patients in group 1 would receive sevelamer-hydrochloride 400 mg three times a day with meals. The onset of action of oral sevelamer is five days with peak action at two weeks. Therefore, a total of four months of intervention is planned to have stable serum phosphate levels for sufficient time. Sevelamer-hydrochloride would be procured directly from the manufacturer and same batch of medicine would be used for all the participants. Monitoring of serum total calcium, phosphorus, Serum 25(OH)D, fibroblast growth factor (FGF23) and urinary phosphate excretion and fractional excretion of phosphorus, would be carried out at monthly interval (Please Table 1). At each visit subjects would be given their one month quota of medicines including full dose of conventional therapy and sevelamer-hydrochloride. During follow-up alfacalcidol dose would be unchanged unless serum total calcium exceeds or fall below the desired range. If change of dose is requited for the conventional therapy, alfacalcidol would be added or reduced rather than oral calcium. The criteria for consideration of change of dose of alfacalcidol during study period is when their serum calcium levels goes below 8.0 mg/dl or 10.5 mg/dl on two occasions at one week interval. 60 idiopathic-hypoparathyroidism patients with persistent hyperphosphatemia ≥ 3 occasions during past one-year on conventional therapy will be randomised in two arms to receive sevelamer-hydrochloride with conventional-therapy versus conventional therapy alone for four months and cross-over for change of therapy with a washout period of two-months. Reduction of serum-phosphate by 0.5 mg/dL/normalisation will be an outcome. Wash-over period: Since the peak effect of sevelamer-hydrochloride is within two weeks, a wash over period of two month would be provided before crossing over the intervention in the two arms. In the present study, two months of wash out period is being planned to ensure complete wash out of sevelamer and rise of serum phosphorus to that of pre-sevelemer stage. During wash out period, the usual conventional therapy being taken by the study subjects will be continued. Cross-over: On the day before the cross over, all the biochemical parameters in the blood and urine would be assessed for all the participants in group 1 and group 2 of the two study arms. These parameters as described above would be serum total calcium, phosphorus, serum 25(OH)D, fibroblast growth factor (FGF23) and urinary phosphate excretion and fractional excretion of phosphorus, Following biochemical investigations, subjects in group 1 would be switched to the conventional therapy. The subjects earlier in group 2 will receive conventional therapy along with sevelamer-hydrochloride Safety and compliance: Side effects of sevelamer mainly pertain to the gastrointestinal system i.e. vomiting, nausea, diarrhoea and dyspepsia. Their frequency varies from 16-19%. Other side effects are abdominal pain, flatulence and constipation in 8%. Side effects would be monitored using a free WHO protocol (http://www. icssc.org/Documents/Resources/AEManual2003AppendicesFebruary062003%20final.pdf PAGE 71). Compliance with the therapy would be assessed by counting the left-over sevelamer and pills in the conventional therapy in each follow-up. Expected outcome: If effective in control of hyperphosphatemia, it will suggest sevelamer-hydrochloride as an adjuvant for phosphatemic control in hypoparathyroidism