Cinacalcet for Fibroblast Growth Factor 23 (FGF23)-Mediated Hypophosphatemia (Hypophosphatemic Rickets)
| Status: | Terminated |
|---|---|
| Conditions: | Other Indications, Metabolic |
| Therapuetic Areas: | Pharmacology / Toxicology, Other |
| Healthy: | No |
| Age Range: | 18 - 70 |
| Updated: | 6/2/2017 |
| Start Date: | November 16, 2012 |
| End Date: | December 31, 2016 |
Open-label Dose-titration Study of the Tolerability and Efficacy of Cinacalcet to Treat Fibroblast Growth Factor 23 (FGF23)-Mediated Hypophosphatemia
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.
- 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:
-Maximum tolerated dose of cinacalcet
-Serum calcium levels
-Urine calcium levels
-Adverse events
-Time from cinacalcet discontinuation to return to pre-treatment standard of care
dosage levels
Secondary efficacy:
-Pharmacodynamic assessments
-Serum: FGF23, intact parathyroid hormone, calcium, creatinine, phosphorus
-Urine: phosphorus, creatinine, calcium.
-Tubular maximum reabsorption of phosphate/glomerular filtration rate
-Tubular reabsorption of phosphate
-Other
-Change in oral phosphate and calcitriol intake required to maintain adequate
phosphorus and calcium serum levels
-Serum osteocalcin and alkaline phosphatase
-Serum intact parathyroid hormone (PTH)
Tertiary efficacy:
-Twice-Daily Dosing at MTD
-Time from cinacalcet discontinuation of twice-daily dosing to return to
pre-treatment standard of care dosage levels
-Dental Evaluation
-Visible Plaque Index (VPI)
-Gingival Bleeding Index (GBI)
-Position of Gingival Margin (PGM)
-Relative Attachment Level (RAL)
-Periodontal Probing Pocket Depth (PPD)
-Gingival Crevicular Fluid (GCF) Biomarkers
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:
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dosage levels
Secondary efficacy:
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phosphorus and calcium serum levels
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Tertiary efficacy:
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pre-treatment standard of care dosage levels
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- INCLUSION CRITERIA:
1.
2.
1.
2.
3.
Or, diagnosis of a non-genetic form of FGF23-mediated hypophosphatemia, i.e.
tumor-induced osteomalacia (TIO)
3.
4.
regimen
5.
ligation, bilateral oophorectomy or hysterectomy, or who are not postmenopausal
for greater than or equal to 1 year) must agree to practice adequate
contraception that may include, but is not limited to, abstinence, monogamous
relationship with vasectomized partner, barrier methods such as condoms,
diaphragms, spermicides, intrauterine devices, and licensed hormonal methods for
the duration of the treatment portion of the study.
EXCLUSION CRITERIA:
1.
mmol/L)
2.
above the upper limit of normal
3.
4.
conventional therapy (as determined during SOC optimization phase)
5.
and serum albumin < 3 g/dL and International Normalized Ratio (INR) >2 OR presence of
ascites or hepatic encephalopathy.
6.
7.
8.
9.
10.
diuretics or medications that may have a significant drug interaction with cinacalcet
11.
12.
13.
use of an investigational product that may have impact on the study) within the last
3 months
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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