Open-label Dose-titration Study of the Tolerability and Efficacy of Cinacalcet to Treat Fibroblast Growth Factor 23 (FGF23)-Mediated Hypophosphatemia
18 Years
70 Years
Both
Osteomalacia
Trial Information
Open-label Dose-titration Study of the Tolerability and Efficacy of Cinacalcet to Treat Fibroblast Growth Factor 23 (FGF23)-Mediated Hypophosphatemia
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
Inclusion Criteria
- INCLUSION CRITERIA:
1. Chronological age: 18-70 years
2. Diagnosis of a genetic form of FGF23-mediated hypophosphatemia:
1. X-linked hypophosphatemic rickets (XLH)
2. Autosomal dominant hypophosphatemic rickets (ADHR)
3. Autosomal recessive hypophosphatemic rickets (ARHR)
Or, diagnosis of a non-genetic form of FGF23-mediated hypophosphatemia, i.e.
tumor-induced osteomalacia (TIO)
3. Ability to understand and provide informed consent
4. Ability to complete the protocol scheduled assessments and medication regimen
5. Women of child-bearing potential (not surgically sterile via tubal 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. Chronic or recurrent hypocalcemia defined by a serum calcium < 8.4 mg/dL (2.1
mmol/L)
2. Tertiary hyperparathyroidism as evidenced by concurrent PTH and calcium levels above
the upper limit of normal
3. History of parathyroid surgery and/or hypoparathyroidism
4. Hypercalciuria as defined as > 4 mg/kg/day (0.1 mmol/kg/day) on optimized
conventional therapy (as determined during SOC optimization phase)
5. Moderate to severe hepatic insufficiency as defined by total bilirubin > 2 mg/dL and
serum albumin < 3 g/dL and International Normalized Ratio (INR) > 2 OR presence of
ascites or hepatic encephalopathy.
6. A calculated eGFR < 50 mL/min/1.73 m(2), using the CKD-EPI equation
7. History of a non-febrile seizure disorder
8. History of a clinically significant cardiac arrhythmia
9. History of chronic gastrointestinal disease
10. Current therapy (at the time of informed consent) bisphosphonates, calcitonin,
diuretics or medications that may have a significant drug interaction with cinacalcet
11. Known hypersensitivity to cinacalcet or any of its constituents
12. Positive pregnancy test or lactation
13. Use of another investigational agent (i.e., in the context of a clinical trial, use
of an investigational product that may have impact on the study) within the last 3
months
Type of Study:
Interventional
Study Design:
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Evaluate the tolerability of cinacalcet in individuals with FGF23-mediated hypophosphatemia
Outcome Time Frame:
4 years
Principal Investigator
Rachel I Gafni, M.D.
Investigator Role:
Principal Investigator
Investigator Affiliation:
National Institute of Dental and Craniofacial Research (NIDCR)
Authority:
United States: Federal Government
Study ID:
130025
NCT ID:
NCT01748812
Start Date:
November 2012
Completion Date:
October 2015
Related Keywords:
- Osteomalacia
- Tumor Induced Osteomalacia
- Hypophosphatemic Rickets
- Osteomalacia
- Hypophosphatemia
- Hypophosphatemic Rickets, X-Linked Dominant
Name | Location |
|---|---|
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda, Maryland 20892 |
