Clinical Trial: Calcitonin for Treating X-linked Hypophosphatemia

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Calcitonin for Treating X-linked Hypophosphatemia

Brief Summary:

X-linked hypophosphatemia (XLH) is the most common form of inherited rickets in the United States. It also causes bone disease in adults. XLH is caused by overproduction of a hormone call FGF23, which makes the body waste phosphate. This study is designed to determine if nasal calcitonin, an already approved drug in the US, can lower blood levels of FGF23 and reduce phosphate wasting in patients with XLH. In this study the investigators will:

1. Determine whether nasal calcitonin significantly lowers integrated 24-hour blood levels of FGF23 in patients with XLH.
2. Evaluate whether nasal calcitonin improves serum phosphate levels in XLH.
3. Assess whether nasal calcitonin improves blood levels of the active form of vitamin D and calcium absorption from the intestine.
4. Make sure that nasal calcitonin is safe and well tolerated.

Detailed Summary:

The pathophysiology of X-linked hypophosphatemia (XLH) was clarified with the report in 1995 by the HYP Consortium led by Dr. Michael Econs, that mutations in the neutral endopeptidase PHEX, are the genetic basis for this disorder (Nature Genetics 11:130). By a pathway that remains unclear, loss-of-function mutations in PHEX lead to elevated circulating levels of FGF23. It is now well established that FGF23 is the proximate biological mediator of this syndrome. FGF23 suppresses renal tubular phosphate reabsorption by inhibiting transcription of the major sodium phosphate co-transporters in the proximal renal tubule. In addition, it suppresses 1-α hydroxylase activity leading low to low-normal serum levels of 1,25(OH)2vitamin D. This in turn impairs intestinal phosphate and calcium absorption. These combined biochemical abnormalities lead to persistent defects in skeletal mineralization manifested as rickets in children and osteomalacia in adults. Conventional therapy for XLH consists of oral therapy with phosphate supplements and calcitriol and requires ingestion of medications 4-6 times daily. There are several limitations to conventional therapy including its inability to correct growth retardation in children or the enthesopathy so frequently seen in adults. Furthermore, it is now clear that this therapeutic approach causes a further rise in circulating levels of FGF23 in XLH. Thus, there is an urgent need for more appropriate therapy directed at the basic pathophysiology of this disorder. As detailed in the Research Strategy, we have identified calcitonin as a novel suppressor of FGF23 production in XLH. A single, subcutaneous injection of calcitonin results in a sustained fall in FGF23 levels that persists for 16 hours after drug administration; a change not observed in control subjects. The fall in serum FGF23 is associated with a rise in serum phosphate and circulating levels of 1,25(OH)2vitamin D. These data
Sponsor: Yale University

Current Primary Outcome:

• Area under the curve for FGF23 [ Time Frame: Time 0 ]
  FGF23 will be measured serially during a 24 hour admission and AUC calculated.
• Area under the curve for FGF23 [ Time Frame: 3 months ]
  FGF23 will be measured serially during a 24 hour admission at 3 months and AUC calculated and compared to baseline.

Original Primary Outcome: Same as current

Current Secondary Outcome:

• Area under the curve for serum phosphate and fasting TmP/GFR [ Time Frame: Time 0 ]
  Serum phosphate will be measured serially during a 24 hr admission, AUC calculated, and fasting Tmp/GFR calculated.
• Area under the curve for 1,25(OH)2vitamin D [ Time Frame: Time 0 ]
  Serum 1,25(OH)2vitamin D will be measured serially during a 24 hr admission and AUC calculated.
• Nasal congestion [ Time Frame: Time 0 ]
  This symptom will be assessed at baseline
• Area under the curve for serum phosphate and fasting TmP/GFR [ Time Frame: Time 3 months ]
  Serum phosphate will be measured serially during a 24 hr admission at 3 months and AUC calculated and compared to baseline. Fasting Tmp/GFR will be measured at 3 months and compared to baseline.
• Area under the curve for 1,25(OH)2vitamin D [ Time Frame: Time 3 months ]
  Serum 1,25(OH)2vitamin D will be measured serially during a 24 hr admission and AUC calculated and results will be compared to baseline values.
• Nasal congestion [ Time Frame: Time 1 month ]
  This symptom will be assessed.
• Nasal congestion [ Time Frame: Time 2 months ]
  This symptom will be assessed.
• Nasal congestion [ Time Frame: Time 3 months ]
  This symptom will be assessed.
• Nasal ulceration [ Time Frame: Time 0 ]
  This symptom will be assessed at baseline
• Allergic reactions [ Time Frame: Time 0 ]
  This symptom will be assessed at baseline
• Nasal ulceration [ Time Frame: Time 1 month ]
  This symptom will be assessed.
• Allergic reactions [ Time Frame: Time 1 month ]
  This symptom will be assessed.
• Nasal ulceration [ Time Frame: Time 2 months ]
  This symptom will be assessed.
• Allergic reactions [ Time Frame: Time 2 months ]
  This symptom will be assessed.
• Nasal ulceration [ Time Frame: Time 3 months ]
  This symptom will be assessed.
• Allergic reactions [ Time Frame: Time 3 months ]
  This symptom will be assessed.

Original Secondary Outcome: Same as current

Information By: Yale University

Dates:
Date Received: July 23, 2012
Date Started: March 2011
Date Completion:
Last Updated: May 24, 2016
Last Verified: May 2016