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Precision Medicine Approaches to Renal Osteodystrophy (PMaROD)

Primary Purpose

Renal Osteodystrophy, Chronic Kidney Diseases, CKD-MBD

Status
Recruiting
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
miRNAseq analysis
Standard treatment for bone disorder
Sponsored by
Thomas Nickolas, MD MS
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Renal Osteodystrophy focused on measuring Bone biopsy, microRNA, HR-pQCT, Bone biomarkers, Bone imaging

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Study participant has provided informed consent Age ≥ 18 years CKD Stages 3-5D regardless of kidney transplantation status CKD5D patients receiving maintenance hemodialysis for at least 3 months Clinically indicated treatment for renal hyperparathyroidism, renal osteodystrophy and/or Osteoporosis PTH, BSAP and CTX meets defined thresholds for low or high turnover ROD type or a Bone biopsy evidence of low or high turnover based Exclusion Criteria: Currently receiving treatment in an investigational device or drug study, or less than 30 days since ending treatment on an investigational device or drug study(s) Currently receiving investigational procedures/drugs from another study while participating in this study Use of etelcalcetide, bisphosphonate, denosumab, teriparatide, abaloparatide or romosozumab during the 6 months prior to study enrollment; however, participant can be included if being treated with bone active agent but will have class change to an agent that will result in a change in bone turnover from low to high or high to low New use of cinacalcet over the prior 6 months Use of Zoledronic Acid (Reclast) less than 24 months from study enrollment for patients with eGFR <30mL/minute Anticipated or scheduled kidney transplant during the study period or less than 1 year from receiving a kidney transplant For patients with a solid organ transplant, less than 1 year from receiving the transplant Patient has an unstable medical condition based on medical history, physical examination, and routine laboratory tests, or is otherwise unstable in the judgment of the Investigator Metabolic bone diseases not related to the kidney (e.g., Paget's, Osteogenesis Imperfecta) Endocrinopathy (e.g., untreated hyperthyroidism) Malignancy within the last 5 years (except non-melanoma skin cancers or cervical carcinoma in situ) Patient is pregnant or nursing Weight >300 pounds (scanner limitation) Allergy to tetracycline or demeclocycline Patients on non-aspirin anticoagulants that cannot be reasonably held for biopsy Patient unable to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the patient and Investigator's knowledge

Sites / Locations

  • Columbia University Irving Medical CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Bone-targeted management - prospective cohort

Arm Description

Participants diagnosed with a bone disorder related to chronic kidney disease (CKD) and undergoing a clinically indicated treatment for bone disease. Participants will have some questionnaires, research blood draws, bone scans and a bone biopsy. There will be a total of 4 visits over six months for data collection.

Outcomes

Primary Outcome Measures

Correlation between miRNA panel to discriminate changes in bone turnover.
To determine the utility of a miRNA panel to discriminate changes in bone turnover. miRNA sequencing libraries will be prepared using the QIASeq miRNA Library Kit (Qiagen). Total RNA extracted from human serum will be used as the starting material. After a final library cleanup, the miRNA libraries will be QC and quantified using an Agilent Bioanalyzer 2100 and Invitrogen Qubit Fluorometer. The resulting miRNA libraries will be sequenced on an Illumina NextSeq 500 (Illumina, San Diego, CA) with single-end 75 bp read length. The study will then confirm any novel or other miRNA that are present in serum from RNAseq by PCR using TaqMan miRNA Assays (TaqMan MGP probes, FAM dye-labeled) with Applied Biosystems ViiA 7 Real-Time PCR systems. The ΔΔCT method will be used to analyze relative changes in miRNA expression.
Correlation between a miRNA panel that identifies bone turnover type is able to also identify with bone quality.
To utilize the circulating miRNA panel to fully assess bone quality in patients with renal osteodystrophy; whether there is evidence that bone turnover directly affects bone strength through alterations in bone quality.

Secondary Outcome Measures

Number of instances where miRNAs in circulation reflect miRNAs in bone-tissue.
The miRNA panel that identifies turnover type in blood will be compared to the miRNAs that are expressed in bone tissue derived from iliac crest bone biopsy.
Number of instances where miRNAs in circulation reflect changes in bone, based on bone imaging.
Pre- and post-treatment changes in the circulating miRNA profile will be compared to changes in bone imaging by HR-pQCT.

Full Information

First Posted
May 19, 2023
Last Updated
July 14, 2023
Sponsor
Thomas Nickolas, MD MS
Collaborators
Indiana University School of Medicine, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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1. Study Identification

Unique Protocol Identification Number
NCT05880914
Brief Title
Precision Medicine Approaches to Renal Osteodystrophy
Acronym
PMaROD
Official Title
Precision Medicine Approaches to Renal Osteodystrophy
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 21, 2022 (Actual)
Primary Completion Date
August 17, 2026 (Anticipated)
Study Completion Date
June 30, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Thomas Nickolas, MD MS
Collaborators
Indiana University School of Medicine, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Treatment of renal osteodystrophy is impeded by the lack of practical and accurate tools to determine underlying bone turnover. Gold standard bone biopsy is not practical in the clinic for the vast majority of kidney disease patients and parathyroid hormone and bone alkaline phosphatase have insufficient accuracy for turnover type to safely and confidently guide treatment of renal osteodystrophy. In the present investigation, the investigators will study a microRNA approach as a novel non-invasive biomarker of turnover for renal osteodystrophy.
Detailed Description
Renal osteodystrophy (ROD) is a complex disorder of cortical bone quality and strength. Impaired cortical bone is due to the combined actions of elevated parathyroid hormone (PTH) levels and changes in bone hormones as a result of kidney failure. ROD affects nearly all patients with chronic kidney disease (CKD) and results in cortical bone loss, cortical-type fractures and cardiovascular events. The current goal of ROD treatment, to reduce high bone turnover due to renal hyperparathyroidism, is contraindicated in the presence of low turnover yet reliable ways to determine low turnover status are lacking. The Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend that treatment is guided by the biomarkers PTH and bone specific alkaline phosphatase (BSAP) and not to treat when turnover is low. However, despite these recommendations, cortical-type fracture incidence has doubled in dialysis patients over the past 25-years, a failure in fracture reduction due in part to PTH and BSAP being developed to identify turnover in trabecular rather than cortical bone. Furthermore, although KDIGO recommends tetracycline-labeled bone biopsy to define turnover and guide treatment, the histomorphometry is also based on analysis of trabecular and not cortical bone, the latter being the primary site of PTH action. Published preliminary data for this proposal suggest that trabecular turnover is a poor surrogate for cortical turnover, with only moderate correlations between bone compartments (R2 59%). Thus, there is an unmet need to identify biomarkers with high diagnostic accuracy and clinical utility for the identification of low cortical turnover, used without or without trabecular turnover, to guide treatment decisions and for use in clinical trials. In published data, the investigators hypothesized that an a priori defined subset of microRNAs (miRNA) that regulate osteoblast (miRNA-30c, 30b, 125b) and osteoclast (miRNA-155) development would be accurate biomarkers of low cortical turnover. In 23 CKD patients with bone biopsies, the areas under the curve for discrimination of low from non- low turnover were 0.866, 0.813, 0.813, and 0.723 for miRNAs-30b, 30c, 125b and 155 respectively, 0.925 for a panel of the 4 four miRNAs combined, while PTH and BSAP, individually and together, did not discriminate in this population. Based on these findings, the central hypothesis is that circulating miRNAs discriminate ROD cortical bone subtype. In a cohort of 90 CKD patients with low, normal, and high turnover (30/group; Aim 1) we will use miRNAseq to identify novel miRNAs that correlate with ROD type and determine if their combination with the preliminary panel enhances discrimination. In 40 ROD patients managed with strategies that change turnover from high to low or low to high (n=20/group; Aim 2), the investigators will determine if changes in histology-based turnover are reflected by changes in the optimized panel and if the circulating miRNA panel mirrors bone-tissue miRNA expression. Then, the investigators will determine if the panel is related to bone quality and strength (Aim 3). The study results will determine if the circulating panel can serve as a biomarker for guiding ROD management. This high impact proposal has the potential to result in a paradigm shift in the non-invasive diagnosis and management of ROD.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Renal Osteodystrophy, Chronic Kidney Diseases, CKD-MBD, Bone Turnover Rate Disorder, Secondary Hyperparathyroidism
Keywords
Bone biopsy, microRNA, HR-pQCT, Bone biomarkers, Bone imaging

7. Study Design

Primary Purpose
Other
Study Phase
Early Phase 1
Interventional Study Model
Single Group Assignment
Model Description
Patients with kidney disease and requiting treatment for osteoporosis will be managed as per clinical indications. The bone turnover response, measured by bone biopsy, will be compared to circulating levels of miRNAs and bone turnover markers.
Masking
None (Open Label)
Allocation
N/A
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Bone-targeted management - prospective cohort
Arm Type
Other
Arm Description
Participants diagnosed with a bone disorder related to chronic kidney disease (CKD) and undergoing a clinically indicated treatment for bone disease. Participants will have some questionnaires, research blood draws, bone scans and a bone biopsy. There will be a total of 4 visits over six months for data collection.
Intervention Type
Procedure
Intervention Name(s)
miRNAseq analysis
Intervention Description
Identify miRNA in serum and prepare a miRNA sequencing library for novel analysis.
Intervention Type
Drug
Intervention Name(s)
Standard treatment for bone disorder
Other Intervention Name(s)
Clinically indicated treatment for bone disease
Intervention Description
Participants will be prescribed a clinically indicated bone-targeted treatment for osteoporosis or bone disorder related to CKD. (non-experimental)
Primary Outcome Measure Information:
Title
Correlation between miRNA panel to discriminate changes in bone turnover.
Description
To determine the utility of a miRNA panel to discriminate changes in bone turnover. miRNA sequencing libraries will be prepared using the QIASeq miRNA Library Kit (Qiagen). Total RNA extracted from human serum will be used as the starting material. After a final library cleanup, the miRNA libraries will be QC and quantified using an Agilent Bioanalyzer 2100 and Invitrogen Qubit Fluorometer. The resulting miRNA libraries will be sequenced on an Illumina NextSeq 500 (Illumina, San Diego, CA) with single-end 75 bp read length. The study will then confirm any novel or other miRNA that are present in serum from RNAseq by PCR using TaqMan miRNA Assays (TaqMan MGP probes, FAM dye-labeled) with Applied Biosystems ViiA 7 Real-Time PCR systems. The ΔΔCT method will be used to analyze relative changes in miRNA expression.
Time Frame
Five years
Title
Correlation between a miRNA panel that identifies bone turnover type is able to also identify with bone quality.
Description
To utilize the circulating miRNA panel to fully assess bone quality in patients with renal osteodystrophy; whether there is evidence that bone turnover directly affects bone strength through alterations in bone quality.
Time Frame
Five Years
Secondary Outcome Measure Information:
Title
Number of instances where miRNAs in circulation reflect miRNAs in bone-tissue.
Description
The miRNA panel that identifies turnover type in blood will be compared to the miRNAs that are expressed in bone tissue derived from iliac crest bone biopsy.
Time Frame
Five Years
Title
Number of instances where miRNAs in circulation reflect changes in bone, based on bone imaging.
Description
Pre- and post-treatment changes in the circulating miRNA profile will be compared to changes in bone imaging by HR-pQCT.
Time Frame
Five Years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Study participant has provided informed consent Age ≥ 18 years CKD Stages 3-5D regardless of kidney transplantation status CKD5D patients receiving maintenance hemodialysis for at least 3 months Clinically indicated treatment for renal hyperparathyroidism, renal osteodystrophy and/or Osteoporosis PTH, BSAP and CTX meets defined thresholds for low or high turnover ROD type or a Bone biopsy evidence of low or high turnover based Exclusion Criteria: Currently receiving treatment in an investigational device or drug study, or less than 30 days since ending treatment on an investigational device or drug study(s) Currently receiving investigational procedures/drugs from another study while participating in this study Use of etelcalcetide, bisphosphonate, denosumab, teriparatide, abaloparatide or romosozumab during the 6 months prior to study enrollment; however, participant can be included if being treated with bone active agent but will have class change to an agent that will result in a change in bone turnover from low to high or high to low New use of cinacalcet over the prior 6 months Use of Zoledronic Acid (Reclast) less than 24 months from study enrollment for patients with eGFR <30mL/minute Anticipated or scheduled kidney transplant during the study period or less than 1 year from receiving a kidney transplant For patients with a solid organ transplant, less than 1 year from receiving the transplant Patient has an unstable medical condition based on medical history, physical examination, and routine laboratory tests, or is otherwise unstable in the judgment of the Investigator Metabolic bone diseases not related to the kidney (e.g., Paget's, Osteogenesis Imperfecta) Endocrinopathy (e.g., untreated hyperthyroidism) Malignancy within the last 5 years (except non-melanoma skin cancers or cervical carcinoma in situ) Patient is pregnant or nursing Weight >300 pounds (scanner limitation) Allergy to tetracycline or demeclocycline Patients on non-aspirin anticoagulants that cannot be reasonably held for biopsy Patient unable to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the patient and Investigator's knowledge
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Maria Aponte, MD
Phone
212-342-4678
Email
maa2308@cumc.columbia.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Thomas L Nickolas, MD, MS
Phone
212-305-9847
Email
tln2001@cumc.columbia.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Thomas Nickolas, MD, MS
Organizational Affiliation
Professor of Medicine at the Columbia University Medical Center, Dept of Medicine Nephrology
Official's Role
Principal Investigator
Facility Information:
Facility Name
Columbia University Irving Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Thomas L Nickolas, MD MS
Phone
212-305-9847
Email
tln2001@cumc.columbia.edu
First Name & Middle Initial & Last Name & Degree
Maria A Aponte, MD
Phone
212-342-4678
Email
maa2308@cumc.columbia.edu
First Name & Middle Initial & Last Name & Degree
Thomas L Nickolas, MD, MS

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
The investigator is currently not planning on providing IPD to other researchers but may modify his plans in the future. All IPD would be de-identified and provided after justification from the corresponding investigator.
Citations:
PubMed Identifier
32490328
Citation
Nickolas TL, Chen N, McMahon DJ, Dempster D, Zhou H, Dominguez J 2nd, Aponte MA, Sung J, Evenepoel P, D'Haese PC, Mac-Way F, Moyses R, Moe S. A microRNA Approach to Discriminate Cortical Low Bone Turnover in Renal Osteodystrophy. JBMR Plus. 2020 Mar 25;4(5):e10353. doi: 10.1002/jbm4.10353. eCollection 2020 May.
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Precision Medicine Approaches to Renal Osteodystrophy

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