| CTRI Number |
CTRI/2024/12/078414 [Registered on: 20/12/2024] Trial Registered Prospectively |
| Last Modified On: |
18/12/2024 |
| Post Graduate Thesis |
No |
| Type of Trial |
Interventional |
|
Type of Study
|
Drug |
| Study Design |
Randomized, Crossover Trial |
|
Public Title of Study
|
Effect of sevelamer-hydrochloride therapy on serum phosphate levels in idiopathic-hypoparathyroidism patients with hyperphosphatemia |
|
Scientific Title of Study
|
Randomized crossover trial for the effect of sevelamer-hydrochloride as adjuvant on serum phosphate in patients with idiopathic-hypoparathyroidism hyperphosphatemia on standard conventional therapy |
| Trial Acronym |
|
|
Secondary IDs if Any
|
| Secondary ID |
Identifier |
| NIL |
NIL |
|
|
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
|
| Name |
Ravinder Goswami |
| Designation |
Professor |
| Affiliation |
All India Institute of Sciences |
| Address |
Room no. 304, Third Floor,Department of Endocrinology and Metabolism, Biotechnology Block AIIMS, Ansari Nagar, New Delhi
AIIMS, Ansari Nagar, New Delhi
South
DELHI
110029
India |
| Phone |
09818130879 |
| Fax |
|
| Email |
gosravinder@hotmail.com |
|
Details of Contact Person
Scientific Query
|
| Name |
Ravinder Goswami |
| Designation |
Professor |
| Affiliation |
All India Institute of Sciences |
| Address |
Room no. 304, Third Floor,Department of Endocrinology and Metabolism, Biotechnology Block AIIMS, Ansari Nagar, New Delhi
AIIMS, Ansari Nagar, New Delhi
DELHI
110029
India |
| Phone |
09818130879 |
| Fax |
|
| Email |
gosravinder@hotmail.com |
|
Details of Contact Person
Public Query
|
| Name |
Ravinder Goswami |
| Designation |
Professor |
| Affiliation |
All India Institute of Sciences |
| Address |
Room no. 304, Third Floor,Department of Endocrinology and Metabolism, Biotechnology Block AIIMS, Ansari Nagar, New Delhi
AIIMS, Ansari Nagar, New Delhi
DELHI
110029
India |
| Phone |
09818130879 |
| Fax |
|
| Email |
gosravinder@hotmail.com |
|
|
Source of Monetary or Material Support
|
| Indian Council of Medical Research-ICMR |
|
|
Primary Sponsor
|
| Name |
Indian Council of Medical Research-ICMR |
| Address |
Indian Council of Medical Research, Ansari Nagar, New Delhi-110029 |
| Type of Sponsor |
Government funding agency |
|
|
Details of Secondary Sponsor
|
|
|
Countries of Recruitment
|
India |
|
Sites of Study
|
| No of Sites = 1 |
| Name of Principal
Investigator |
Name of Site |
Site Address |
Phone/Fax/Email |
| Dr Ravinder Goswami |
All India Institute of Medical Sciences, New Delhi |
Department of Endocrinology and Metabolism, Biotechnology Block AIIMS, Ansari Nagar, New Delhi
South
DELHI |
09818130879
gosravinder@hotmail.com |
|
|
Details of Ethics Committee
|
| No of Ethics Committees= 1 |
| Name of Committee |
Approval Status |
| Institute Ethics Committee, AIIMS, New Delhi |
Approved |
|
|
Regulatory Clearance Status from DCGI
|
|
|
Health Condition / Problems Studied
|
| Health Type |
Condition |
| Patients |
, (1) ICD-10 Condition: E200||Idiopathic hypoparathyroidism, |
|
|
Intervention / Comparator Agent
|
| Type |
Name |
Details |
| Comparator Agent |
Conventional therapy i.e, alphacalcidol and oral calcium only without sevelemar hydrochloride therapy |
In the first four months after randomization, group 2 patients will receive conventional therapy only, then after 2 months of wash-over period. they will be stwitched to intervention arm. Group 1 patients who are earlier in the intervention arm for first four month will be switched to conventional therapy only for next four months after a wash over period of 2 months. |
| Intervention |
Sevelamer-hydrochloride along with on-going conventional therapy i.e, alphacalcidol and oral calcium |
Patients with Idiopathic Hypoparathyroidism will be randomized into two arms: 1) Sevelamer hydrochloride with conventional therapy and 2) conventional therapy alone (Group 1 and Group 2, respectively): A randomised list will be prepared using a mixed block size (four and six) for block-randomization. After block randomization,for first 4 months, patients in group 1 would receive sevelamer-hydrochloride 400 mg three times a day with meals along with conventional therapy consisting of alfacalcidol, and oral elemental calcium and group 2 would receive conventional therapy alone. This will be followed by two months of washout period. After that, both groups would cross-over for change of therapy. Group 1 would be switched to the conventional therapy, while group 2 would receive sevelamer-hydrochloride 400 mg three times a day with meals along with conventional therapy for next four months. |
|
|
Inclusion Criteria
|
| Age From |
18.00 Year(s) |
| Age To |
75.00 Year(s) |
| Gender |
Both |
| Details |
Patients with idiopathic hypoparathyroidism with optimal calcium control i.e, serum total calcium value between 8.0-9.5 mg/dl on conventional therapy and have hyperphosphatemia i.e serum phosphate at least 5.0 mg/dl on last three visits during past one-year of follow-up will be considered eligible for the study. |
|
| ExclusionCriteria |
| Details |
1. Patients with idiopathic hypoparathyroidism younger than 18 years or more than 75 years
2. pregnant, lactating, on steroid therapy for any reason, or have serious coexisting medical illness 3. Patients who will be unable to come for repeat follow-up at frequent interval (total 10 visits during study period of 10 months) will be excluded. |
|
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Method of Generating Random Sequence
|
Computer generated randomization |
|
Method of Concealment
|
Sequentially numbered, sealed, opaque envelopes |
|
Blinding/Masking
|
Open Label |
|
Primary Outcome
|
| Outcome |
TimePoints |
| Reduction of serum-phosphate by 0.5 mg/dL and normalisation of hyperphosphatemia will be an expected outcome. |
After 4 months of sevelamer hydrochloride therapy |
|
|
Secondary Outcome
|
| Outcome |
TimePoints |
| Reduction in 24 hour urinary phosphate excretion & Fractional excretion of phosphorus (FEPh) after 4 months of sevelamer hydrochloride therapy |
After 4 months of sevelamer hydrochloride therapy |
|
|
Target Sample Size
|
Total Sample Size="60"
Sample Size from India="60"
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" |
|
Phase of Trial
|
Phase 3 |
|
Date of First Enrollment (India)
|
03/03/2025 |
| Date of Study Completion (India) |
Applicable only for Completed/Terminated trials |
| Date of First Enrollment (Global) |
Date Missing |
| Date of Study Completion (Global) |
Applicable only for Completed/Terminated trials |
|
Estimated Duration of Trial
|
Years="3"
Months="0"
Days="0" |
|
Recruitment Status of Trial (Global)
|
Not Yet Recruiting |
| Recruitment Status of Trial (India) |
Not Yet Recruiting |
|
Publication Details
|
N/A |
|
Individual Participant Data (IPD) Sharing Statement
|
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
|
|
Brief Summary
|
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 |