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Assessing Bone Calcium Content in Children With Kidney Disease Treated With Two Different Medicines (CAL-BAL)

Primary Purpose

Chronic Kidney Diseases

Status
Unknown status
Phase
Not Applicable
Locations
United Kingdom
Study Type
Interventional
Intervention
calcium carbonate
sevelamer carbonate
Sponsored by
University College, London
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Chronic Kidney Diseases focused on measuring Dialysis, chronic kidney disease stage 3b, 4-5, calcium isotope ratio, bone mineral content, Calcium isotope fractions δ44/42Ca

Eligibility Criteria

5 Years - 17 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age 5-17 years
  2. Must be in stable Chronic Kidney Disease (CKD) stage 3b-5 (as per the Kidney Disease Improving Global Outcomes classification) or on dialysis for at least 1 month
  3. Hyperphosphataemia defined as a serum P above the age-specific normal level as per the Kidney Disease Outcomes Quality Initiative (KDOQI) guideline, or high or normal P levels in a patient already on a P-binder in the preceding 4 weeks
  4. On a stable Ca and P diet as assessed by a dietitian and willing to avoid intentional changes in their dairy intake during the trial period
  5. Able to give fully informed consent/ assent as applicable.

Exclusion Criteria:

  1. Pre-existing inherited bone disease
  2. Glucocorticoid therapy in the preceding year, or a lifetime cumulative steroid exposure ≥6 months
  3. Bisphosphonate therapy at any time in the past
  4. On cinacalcet in the preceding 6-months
  5. Any acute illness in the preceding 2 weeks (when the child was unable to maintain their usual diet or had bed-rest)
  6. Living-donor renal transplant planned ≤6 months
  7. At screening the albumin-corrected serum calcium cannot be <2.0mMol/L or >2.8mMol/L
  8. Already participating in any interventional clinical trial or last trial completed less than 4 weeks previously
  9. Previously documented poor compliance with medications
  10. Any other contraindication to usual prescription of calcium carbonate or sevelamer carbonate
  11. Any other reason in the opinion of the Investigator that the participant may not be suitable
  12. Estimated GFR (eGFR) more than 45ml/min/1.73m2
  13. Pregnant or lactating
  14. Currently on sevelamer (includes sevelamer carbonate or sevelamer hydrochloride)

Sites / Locations

  • Great Ormond Street Hospital for Children

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Other

Arm Label

calcium carbonate

sevelamer carbonate

Arm Description

Calcium based P-binder - calcium carbonate: Typical dose is 500mg, orally, three times a day but this can be adjusted as per individual patient requirements at the clinician's discretion. All participants will be given sevelamer carbonate (Ca-free P-binder) for up to 16 weeks and then calcium carbonate (Ca-based P-binder) for 12 weeks, administered orally. No wash out period is possible as the children must always be on a P-binder. The Ca-free P-binder may be administered for less than 16 weeks if it is clinically necessary to resume the Ca-based P-binder early based on serial monitoring of serum Ca levels.

Calcium (Ca) free P-binder - sevelamer carbonate: Typical dose is 800mg, orally, three times a day but this can be adjusted as per individual patient requirements at the clinician's discretion. All participants will be given sevelamer carbonate (Ca-free P-binder) for up to 16 weeks and then calcium carbonate (Ca-based P-binder) for 12 weeks, administered orally. No wash out period is possible as the children must always be on a P-binder. The Ca-free P-binder may be administered for less than 16 weeks if it is clinically necessary to resume the Ca-based P-binder early based on serial monitoring of serum Ca levels.

Outcomes

Primary Outcome Measures

Ca isotope ratios in serum measured by dual-tracer stable isotope method (Ca isotope fractions δ44/42Ca) of a child after up to 12 weeks treatment with each of two P-binders (Ca based and Ca free).
Ca isotope ratios in serum measured by dual-tracer stable isotope method (Ca isotope fractions δ44/42Ca) of a child after up to 12 weeks treatment with each of two P-binders (Ca based and Ca free).

Secondary Outcome Measures

Ca isotope ratios in urine measured by dual-tracer stable Ca isotope method (Ca isotope fractions δ44/42Ca) of a child after up to 12 weeks treatment with each of two P-binders (Ca based and Ca free).
To evaluate the association between the change in δ44/42Ca in blood and urine during treatment with each P-binder with the following quantities (which will also be measured longitudinally):1. Dietary Ca and vitamin D intake (including Ca intake from phosphate binders) 2. Serum Ca, P, PTH, 25(OH)D and 1,25(OH)2D 3. Biomarkers of osteoblast (bone-specific alkaline phosphatase, P1NP), osteoclast (TRAP5b, carboxyterminal cross - linked telopeptide of type I collagen- CTX and NTX), and osteocyte activity (FGF23, sclerostin). 4.To determine the earliest detectable changes in Ca isotope ratios after changing therapy. In children on haemodialysis the Ca isotope ratios will be measured by dual-tracer stable Ca isotope method (Ca isotope fractions δ44/42Ca) in serum and urine (if available) at day 3, day 5, day 8 and day 10 (+/- 2 days) after starting sevelamer carbonate or calcium carbonate.

Full Information

First Posted
September 18, 2019
Last Updated
August 11, 2021
Sponsor
University College, London
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1. Study Identification

Unique Protocol Identification Number
NCT04120922
Brief Title
Assessing Bone Calcium Content in Children With Kidney Disease Treated With Two Different Medicines
Acronym
CAL-BAL
Official Title
The Effect of Calcium-based and Calcium-free Phosphate-binders on Bone Mineral Content, Measured by a Novel Technique of Dual-tracer Stable Calcium Isotope Method, in Children With Chronic Kidney Disease or on Dialysis - a Time Series Trial
Study Type
Interventional

2. Study Status

Record Verification Date
August 2021
Overall Recruitment Status
Unknown status
Study Start Date
January 7, 2020 (Actual)
Primary Completion Date
December 2021 (Anticipated)
Study Completion Date
April 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University College, London

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is an open label, time series trial. The trial is likely to be single centre (additional sites will only be opened if necessary) and will involve 25 children with chronic kidney disease (stage 3b, 4-5) or on dialysis. The overall aim of this trial is to explore the viability of the Ca isotope ratio measured by dual-tracer stable Ca isotope method as a measure of bone mineral (Ca) content, and to evaluate how it changes in response to two commonly used medications that either contain Ca (calcium carbonate) or do not (sevelamer carbonate). Both calcium carbonate and sevelamer carbonate are routinely used in children, but their effect on the bone mineral content (measured by the Ca isotope ratio) has not been studied. This short-term trial will provide proof-of-concept data to determine the utility of the Ca isotope fractionation technique in guiding medication usage in children with CKD and on dialysis. These data will inform a potential future randomised trial that utilises the calcium isotope fractionation technique to adjust the calcium intake (through diet and different medications, including vitamin D analogues) and monitor changes in important patient level outcomes such as fractures and bone mineral density on DXA scan. Participants will be administered sevelamer carbonate first for 16 weeks and then will switch to calcium carbonate for 12 weeks. Participants may need to change medication earlier than 16 weeks at the clinician's discretion based on their calcium levels on routine blood tests. Calcium isotope levels will be measured in blood and urine samples for up to 28 weeks. Isotopes levels in faeces and dialysis fluid samples may also be measured. This is not a Clinical Trial of an Investigational Medicinal Product (CTIMP).
Detailed Description
Lay Summary of Background and Rationale: The growing bones of children need calcium in order to mineralise (become strong). Children with kidney failure (called chronic kidney disease; CKD) or on dialysis can often be calcium deficient. They are given medications with extra calcium to help their bones mineralise. However, there is currently no practical way of measuring bone mineralisation. Doctors may perform special x-rays, but it takes many months before any bone structure problems become apparent on X-rays. Doctors giving children additional calcium do not know how much to give. Sometimes children are given too little and their bones do not mineralise adequately, or they are given too much, and the excess calcium is deposited in their arteries causing vascular calcification. Timely and practical ways of measuring bone mineralisation are needed so doctors can accurately determine the amount of calcium containing medicines they give. The CAL-BAL trial will evaluate a novel potential biomarker of bone mineralisation: the calcium isotope ratio (δ44/42Ca) which will be measured in blood and urine. The trial will collect information on δ44/42Ca for patients with CKD or on dialysis for 28 weeks. It will measure how δ44/42Ca changes when a patient switches from a medicine containing calcium to one not containing calcium. It will also evaluate the association between δ44/42Ca and established biomarkers of bone formation and repair. The data collected in CALBAL will not by itself allow doctors to decide whether δ44/42Ca is good biomarker of bone mineralisation. However, it will provide additional biological and clinical information that will further clarify its usefulness as biomarker for further research. Together with information from previous studies done by the Chief Investigator which measured the typical δ44/42Ca of healthy children and children with CKD and on dialysis, the data collected in CAL-BAL may inform the design of a future randomised trial of standard-of-care compared to an approach where δ44/42Ca results are used to prescribe the amount of medicine containing calcium children with CKD or on dialysis are given.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Kidney Diseases
Keywords
Dialysis, chronic kidney disease stage 3b, 4-5, calcium isotope ratio, bone mineral content, Calcium isotope fractions δ44/42Ca

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Model Description
A open label, time series trial
Masking
None (Open Label)
Masking Description
This is a time series open label trial so there is no randomisation or blinding to treatment. All analyses will be performed in a blinded manner and the treating clinicians will be blinded to the results of the calcium isotope ratios until after participants have completed their trial related administration of P-binder.
Allocation
Non-Randomized
Enrollment
21 (Actual)

8. Arms, Groups, and Interventions

Arm Title
calcium carbonate
Arm Type
Other
Arm Description
Calcium based P-binder - calcium carbonate: Typical dose is 500mg, orally, three times a day but this can be adjusted as per individual patient requirements at the clinician's discretion. All participants will be given sevelamer carbonate (Ca-free P-binder) for up to 16 weeks and then calcium carbonate (Ca-based P-binder) for 12 weeks, administered orally. No wash out period is possible as the children must always be on a P-binder. The Ca-free P-binder may be administered for less than 16 weeks if it is clinically necessary to resume the Ca-based P-binder early based on serial monitoring of serum Ca levels.
Arm Title
sevelamer carbonate
Arm Type
Other
Arm Description
Calcium (Ca) free P-binder - sevelamer carbonate: Typical dose is 800mg, orally, three times a day but this can be adjusted as per individual patient requirements at the clinician's discretion. All participants will be given sevelamer carbonate (Ca-free P-binder) for up to 16 weeks and then calcium carbonate (Ca-based P-binder) for 12 weeks, administered orally. No wash out period is possible as the children must always be on a P-binder. The Ca-free P-binder may be administered for less than 16 weeks if it is clinically necessary to resume the Ca-based P-binder early based on serial monitoring of serum Ca levels.
Intervention Type
Other
Intervention Name(s)
calcium carbonate
Intervention Description
See arm description
Intervention Type
Other
Intervention Name(s)
sevelamer carbonate
Intervention Description
See arm description
Primary Outcome Measure Information:
Title
Ca isotope ratios in serum measured by dual-tracer stable isotope method (Ca isotope fractions δ44/42Ca) of a child after up to 12 weeks treatment with each of two P-binders (Ca based and Ca free).
Description
Ca isotope ratios in serum measured by dual-tracer stable isotope method (Ca isotope fractions δ44/42Ca) of a child after up to 12 weeks treatment with each of two P-binders (Ca based and Ca free).
Time Frame
Measured over 12 weeks. N.B. Treatment changes from sevelamer carbonate to calcium carbonate after 16 weeks in the trial or earlier at the clinician's discretion based on serial monitoring of serum Ca levels.
Secondary Outcome Measure Information:
Title
Ca isotope ratios in urine measured by dual-tracer stable Ca isotope method (Ca isotope fractions δ44/42Ca) of a child after up to 12 weeks treatment with each of two P-binders (Ca based and Ca free).
Description
To evaluate the association between the change in δ44/42Ca in blood and urine during treatment with each P-binder with the following quantities (which will also be measured longitudinally):1. Dietary Ca and vitamin D intake (including Ca intake from phosphate binders) 2. Serum Ca, P, PTH, 25(OH)D and 1,25(OH)2D 3. Biomarkers of osteoblast (bone-specific alkaline phosphatase, P1NP), osteoclast (TRAP5b, carboxyterminal cross - linked telopeptide of type I collagen- CTX and NTX), and osteocyte activity (FGF23, sclerostin). 4.To determine the earliest detectable changes in Ca isotope ratios after changing therapy. In children on haemodialysis the Ca isotope ratios will be measured by dual-tracer stable Ca isotope method (Ca isotope fractions δ44/42Ca) in serum and urine (if available) at day 3, day 5, day 8 and day 10 (+/- 2 days) after starting sevelamer carbonate or calcium carbonate.
Time Frame
Measured over 12 weeks. N.B. Treatment changes from sevelamer carbonate to calcium carbonate after 16 weeks in the trial or earlier at the clinician's discretion based on serial monitoring of serum Ca levels.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
5 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 5-17 years Must be in stable Chronic Kidney Disease (CKD) stage 3b-5 (as per the Kidney Disease Improving Global Outcomes classification) or on dialysis for at least 1 month Hyperphosphataemia defined as a serum P above the age-specific normal level as per the Kidney Disease Outcomes Quality Initiative (KDOQI) guideline, or high or normal P levels in a patient already on a P-binder in the preceding 4 weeks On a stable Ca and P diet as assessed by a dietitian and willing to avoid intentional changes in their dairy intake during the trial period Able to give fully informed consent/ assent as applicable. Exclusion Criteria: Pre-existing inherited bone disease Glucocorticoid therapy in the preceding year, or a lifetime cumulative steroid exposure ≥6 months Bisphosphonate therapy at any time in the past On cinacalcet in the preceding 6-months Any acute illness in the preceding 2 weeks (when the child was unable to maintain their usual diet or had bed-rest) Living-donor renal transplant planned ≤6 months At screening the albumin-corrected serum calcium cannot be <2.0mMol/L or >2.8mMol/L Already participating in any interventional clinical trial or last trial completed less than 4 weeks previously Previously documented poor compliance with medications Any other contraindication to usual prescription of calcium carbonate or sevelamer carbonate Any other reason in the opinion of the Investigator that the participant may not be suitable Estimated GFR (eGFR) more than 45ml/min/1.73m2 Pregnant or lactating Currently on sevelamer (includes sevelamer carbonate or sevelamer hydrochloride)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rukshana Shroff, MD FRCPCH PhD
Organizational Affiliation
Great Ormond Street Hospital for Children NHS Foundation Trust
Official's Role
Principal Investigator
Facility Information:
Facility Name
Great Ormond Street Hospital for Children
City
London
ZIP/Postal Code
WC1N 3JH
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No

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Assessing Bone Calcium Content in Children With Kidney Disease Treated With Two Different Medicines

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