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Hypophosphatemic Rickets

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All Drugs and Chemicals

Cinacalcet

Mitogens

Rachel I Gafni, M.D.

Background:

* Hypophosphatemia is a condition where a person has low levels of phosphorus in the blood. Low blood phosphorus can cause muscle and bone weakness (such as rickets) and teeth problems. One cause of the condition is having too much fibroblast growth factor 23 (FGF23). FGF23 is a hormone that causes the kidney to get rid of phosphorus in the urine. It can also prevent the body from making vitamin D, which helps the body absorb phosphorus in food.
* Many people with low blood phosphorus take high doses of phosphorus and calcium medications. However, one side effect of these drugs is increased blood levels of parathyroid hormone (PTH). The drug cinacalcet can help lower PTH levels, which may decrease the amount of phosphorus lost in the urine and increase the phosphorus levels in the blood. Researchers want to see if cinacalcet can help blood phosphorus and decrease the amount of phosphorus supplements that people need to take.

Objectives:

- To see if cinacalcet can be a safe and effective treatment for people with low phosphorus conditions due to high FGF23.

Eligibility:

- Individuals between 18 and 70 years of age who have different forms of hypophosphatemic rickets and tumor-induced hypophosphatemia

Design:

* Participants will have up to 25 study visits over about 28 weeks.
* Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected.
* Up to three more lab visits for blood and urine tests will be required before treatment. Imaging studies of the bones, spine, and kidneys will be performed.
* Participants will have a 3-night hospital stay to start treatment. They will take cinacalcet once a day. Treatment will be monitored with frequent blood tests and imaging studies.
* Participants will continue to take cinacalcet once a day for 3 weeks. They will have regular study visits to monitor the treatment.
* There will be up to two other overnight hospital stays (1 to 3 nights) to adjust cinacalcet doses. The dose will increase until the maximum dose is reached, or side effects develop.
* After the end of the cinacalcet study, participants will have several more followup visits to monitor the effects of treatment.

OBJECTIVES:

The primary objective of this protocol is to evaluate the tolerability of cinacalcet in individuals with fibroblast growth factor 23 (FGF23)-mediated hypophosphatemia, using an open-label, dose-titration study of once-daily dosing. Secondary objectives are to evaluate the pharmacodynamics of cinacalcet in this subject population and to explore the efficacy of cinacalcet by comparing a) level of oral phosphate required at baseline to the level required at maximum tolerated dose (MTD) and b) change in renal phosphate handling from baseline to MTD. Tertiary objectives are to evaluate tolerability, pharmacodynamics, and efficacy of twice daily dosing of each subject s MTD of cinacalcet after completion of the once-daily dose-titration phase. A final objective is to determine the length of time it takes for subjects to return to their pre-treatment steady state once treatment is complete.

STUDY POPULATION:

Up to 17 subjects with FGF23-mediated hypophosphatemia will be treated.

DESIGN:

This study is an open-label, dose-titration study of once-daily dosing of cinacalcet, with up to 4 escalating doses given at approximately 3 week intervals. After an initial standard of care optimization period of 2-9 weeks, subjects will proceed to the cinacalcet dose-titration period. Subjects who experience extended toxicity or study drug related serious adverse events or other related, intolerable adverse events will be down titrated to a lower dose of study medication. After subjects have achieved their own maximum tolerated dose (MTD) and completed the once-daily dosing phase, they will continue the study medication for approximately 3 additional weeks with twice daily dosing at their MTD. At the end of the cinacalcet treatment phase of the study, cinacalcet will be discontinued and standard of care (SOC) medications will be adjusted/restarted on an individualized basis. Subjects will continue in this final SOC safety follow-up period for up to 4 weeks until their SOC medications have been re-equilibrated.

OUTCOME MEASURES:

Primary safety:

Whether or not a subject discontinued the study due to a toxicity, related serious adverse event (SAE), or related intolerable adverse event (AE).

Secondary safety:

* \<TAB\>Maximum tolerated dose of cinacalcet
* \<TAB\>Serum calcium levels
* \<TAB\>Urine calcium levels
* \<TAB\>Adverse events
* \<TAB\>Time from cinacalcet discontinuation to return to pre-treatment standard of care dosage levels

Secondary efficacy:

* \<TAB\>Pharmacodynamic assessments
* \<TAB\>Serum: FGF23, intact parathyroid hormone, calcium, creatinine, phosphorus
* \<TAB\>Urine: phosphorus, creatinine, calcium.
* \<TAB\>Tubular maximum reabsorption of phosphate/glomerular filtration rate
* \<TAB\>Tubular reabsorption of phosphate
* \<TAB\>Other
* \<TAB\>Change in oral phosphate and calcitriol intake required to maintain adequate phosphorus and calcium serum levels
* \<TAB\>Serum osteocalcin and alkaline phosphatase
* \<TAB\>Serum intact parathyroid hormone (PTH)

Tertiary efficacy:

* \<TAB\>Twice-Daily Dosing at MTD
* \<TAB\>Time from cinacalcet discontinuation of twice-daily dosing to return to pre-treatment standard of care dosage levels
* \<TAB\>Dental Evaluation
* \<TAB\>Visible Plaque Index (VPI)
* \<TAB\>Gingival Bleeding Index (GBI)
* \<TAB\>Position of Gingival Margin (PGM)
* \<TAB\>Relative Attachment Level (RAL)
* \<TAB\>Periodontal Probing Pocket Depth (PPD)
* \<TAB\>Gingival Crevicular Fluid (GCF) Biomarkers

Cinacalcet for Fibroblast Growth Factor 23 (FGF23)-Mediated Hypophosphatemia (Hypophosphatemic Rickets)

Open-label Dose-titration Study of the Tolerability and Efficacy of Cinacalcet to Treat Fibroblast Growth Factor 23 (FGF23)-Mediated Hypophosphatemia

National Institute of Dental and Craniofacial Research (NIDCR)

This study will use a procedure called selective venous catheterization in patients with tumor-induced osteomalacia (TIO) or oncogenic osteomalacia (OOM) to try to locate very small tumors that produce proteins called phosphatonins. Too much phosphatonin in the blood causes the kidneys to allow large amounts of phosphorus to be excreted in the urine, leading to low blood levels of phosphorus and, in turn, to osteomalacia (a condition of soft bones). Osteomalacia can cause bone fractures requiring many surgical procedures that can leave patients in pain. Patients may also feel weak and can lose height from massive bone loss. Selective venous catheterization is a way to measure the amount of phosphatonin in the blood and may be used as a way to locate phosphatonin-producing tumors that cannot be found using standard imaging techniques.

Patients with TIO or OOM are screened under NIDR Protocol 01-D-0184 with a medical history, review of medical records and routine physical examination. Other procedures may include blood tests, urine tests, and imaging tests, such as x-rays, bone densitometry, bone scan, computed tomography (CT) and magnetic resonance imaging (MRI). This study will include mostly patients whose tumors were not able to be located through imaging procedures, but also a few patients whose tumors were located.

All participants, regardless of whether or not their tumor was located, undergo selective venous catheterization. For this procedure, a radiologist inserts a catheter (thin flexible tube) into the body and uses fluoroscopy (a type of x-ray) to guide the tip of the catheter to different places in the body to collect small amounts of blood from the different areas. After the procedure, the patient lies flat for 2 hours and avoids moving his or her leg on the side where the catheter was placed.

The blood is analyzed to measure the amount phosphatonin is in each sample, and the amounts are compared to the average amount of phosphatonin in the general blood circulation. If a higher level of phosphatonin is found in one area and the location of the tumor is unknown, the patient undergoes imaging in that area. If a tumor is found and it is in an area where it can be removed surgically, the patient is given the option to have the surgery. If the tumor is not found by imaging done after the first catheterization procedure, the patient has the option to have a second catheterization, taking samples of blood only from the area where the phosphatonin was found to be the highest during the sampling procedure.

Phosphaturic mesenchymal tumors elaborate phosphate lowering factors (phosphatonins) which lead to tumor induced osteomalacia/osteogenic osteomalacia (TIO/OOM). Patients with TIO/OOM suffer years of significant morbidity and debilitation unless their tumors, which are notoriously difficult to locate, are removed.

Selective venous catheterization has been used to localize hormonally active neoplasms by demonstrating a gradient in the concentration of the hormone of interest between the vessel immediately draining the tumor site and the peripheral circulation. The primary objective of this protocol is to evaluate the utility of combining selective venous catheterization with biochemical assays that identify phosphatonins in the serum as a way to identify phosphatonin gradients and thereby localize phosphaturic tumors.

Our study population will consist of TIO/OOM patients with non-localized phosphaturic tumors as well as five patients whose lesions have been identified with some certainty by conventional imaging techniques. These individuals will undergo selective venous catheterization during which blood samples will be obtained and processed for the presence of phosphatonins. The primary endpoint will be met if a gradient indicating a possible tumor is found, focused clinical imaging in the appropriate anatomical sub-region identifies a lesion, and the lesion is confirmed to be a phosphaturic mesenchymal tumor upon surgical removal.

Catheterization to Locate Mesenchymal Tumors in Patients With Tumor-Induced Osteomalacia or Oncogenic Osteomalacia

Selective Venous Catheterization for the Localization of Phosphaturic Mesenchymal Tumors

Osteoporosis

Calcinosis

Familial Tumoral Calcinosis

Subjects with known or suspected bone disease and disorder of mineral metabolism.

Karen A Pozo, R.N.

For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)

This study has four objectives: 1) to provide investigators the opportunity to study bone specimens from patients with various skeletal diseases; 2) to treat patients with skeletal diseases at the NIH; 3) to expose NIH trainees to certain skeletal diseases; and 4) to gain more knowledge about skeletal diseases and stimulate further study of bone biology.

Anyone with a disease that affects the skeleton may be eligible for this study.

All evaluations, tests, procedures and treatments given study participants are used in the standard care of skeletal diseases. No experimental evaluations or treatments are offered. Patient evaluations include a medical history, review of medical records and routine physical examination. Based on the findings, other procedures may be recommended, including blood tests, urine tests, and imaging tests, such as X-rays, bone densitometry, bone scan, computed tomography (CT) and magnetic resonance imaging (MRI).

Bone specimens from participants will be collected for research use. Specimens will be obtained from bone removed during a patient s planned surgical procedure performed for medical care, or patients may be requested to have a bone biopsy removal of a small piece of bone tissue as part of the patient evaluation procedure.

Study Description:

To evaluate participants with bone and mineral disorders at the NIH Clinical Center and obtain tissue and clinical specimens from outside institutions

Objectives:

Primary Objective:

Provide a protocol within which participants with common and rare disorders of bone and mineral metabolism can be studied, evaluated and treated at NIH.

Secondary Objectives:

To obtain tissue and clinical specimens (including but not limited to blood, urine, nucleic acids, skin and bone) and data collected at outside institutions and the NIH Clinical Center from participants with various bone and mineral disorders.

Tertiary/Exploratory Objective:

Generate a pool of participants with bone and mineral disorders, from which research questions could arise and future clinical research studies may be generated.

Endpoints:

Primary Endpoint:

Medical evaluation with clinical assessments performed at time points specific to each participant s diagnosis. Analysis of research and participant outcome data will be performed.

Secondary Endpoint:

Genetic and/or biochemical assessments of surgical waste material from the NIH Clinical Center or other medical facilities.

Tertiary/Exploratory Endpoint:

Development of a database containing information from enrolled participants with bone and mineral disorders and annotated specimens and data.

A Natural History Study of Bone and Mineral Disorders

.As this study enrolls participants with a myriad of disorders and research specimens are not collected in a systematic manner, sharing of IPD is not meaningful.

Specimens will be collected for creating better understanding of the disorders seen and for generating future research studies.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cinacalcet for Fibroblast Growth Factor 23 (FGF23)-Mediated Hypophosphatemia (Hypophosphatemic Rickets)	NCT01748812	Osteomalacia	Osteomalacia	18 Years - 70 Years	National Institutes of Health Clinical Center (CC)
Catheterization to Locate Mesenchymal Tumors in Patients With Tumor-Induced Osteomalacia or Oncogenic Osteomalacia	NCT00099762	Osteomalacia Neoplasms		8 Years - 100 Years	National Institutes of Health Clinical Center (CC)
A Natural History Study of Bone and Mineral Disorders	NCT00024804	Tumor Induced O... Osteomalacia Familial Tumora...		1 Day -	National Institutes of Health Clinical Center (CC)
A Natural History Study of Bone and Mineral Disorders	NCT00024804	Tumor Induced O... Osteomalacia Familial Tumora...		1 Day -	National Institutes of Health Clinical Center (CC)
A Natural History Study of Bone and Mineral Disorders	NCT00024804	Tumor Induced O... Osteomalacia Familial Tumora...		1 Day -	National Institutes of Health Clinical Center (CC)
A Natural History Study of Bone and Mineral Disorders	NCT00024804	Tumor Induced O... Osteomalacia Familial Tumora...		1 Day -	National Institutes of Health Clinical Center (CC)

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