Calcitonin for Treating X-linked Hypophosphatemia

Hypophosphatemic Rickets, X Linked Dominant Clinical Trial

Official title:

Calcitonin for Treating X-linked Hypophosphatemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01652573
• Other study ID #: 1010007548
• Secondary ID: R21AR061818
• Status: Completed
• Phase: N/A
• First received: July 23, 2012
• Last updated: May 24, 2016
• Start date: March 2011
• Est. completion date: September 2015

Study information

• Verified date: May 2016
• Source: Yale University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review BoardUnited States: Federal Government
• Study type: Interventional

Clinical Trial 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.

Description:

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 are very exciting as they suggest a novel therapy for XLH. This exploratory clinical trial seeks to establish the efficacy of calcitonin in improving the biochemical abnormalities in untreated adults with XLH. We will test the hypothesis that calcitonin, by lowering circulating levels of FGF23 and raising serum levels of 1,25(OH)2vitamin D, will improve phosphate homeostasis in patients with XLH. To test this hypothesis we will pursue the following specific aims: 1. Determine whether 3 months of nasal calcitonin administered at a dose of 400 IU/day significantly lowers integrated 24-hour serum levels of FGF23 in patients with XLH. 2. Evaluate whether nasal calcitonin improves phosphate homeostasis by raising the TmP/GFR and integrated 24 hr. serum phosphate concentrations. 3. Assess whether nasal calcitonin improves calcium metabolism in patients with XLH by increasing integrated 24 hr. serum levels of 1,25(OH)2vitamin D and enhancing intestinal calcium absorption, as estimated by 24-hour urine calcium. 4. Confirm that nasal calcitonin is well tolerated by quantifying side effects and nasal irritation during the trial.

If successful, this study will provide proof-of-principal for the novel use of an FDA-approved drug in treating XLH. This approach, unlike conventional treatment, addresses the underlying pathophysiology in this disorder and would represent the first therapeutic advance for XLH in 30 years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: September 2015
• Est. primary completion date: September 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• age =18 or greater

• an established diagnosis of XLH

• fasting serum calcium =10.5 mg/dl

• fasting PTH at time of screen </= 1.7 times the upper limit of normal

Exclusion Criteria:

• estimated creatinine clearance < 60 cc/min and/or serum creatinine > 1.5 mg/dl;

• serum 25(OH)vitamin D < 30 ng/ml. Potential study subjects who have a serum 25(OH)vitamin D < 30 ng/ml will be supplemented with 25(OH)vitamin D to achieve a serum value > 30 ng/ml and then re- screened

• inability to comply with instructions and appropriate follow up visits

• treatment with agents that may skeletal metabolism such as glucocorticoids, bisphosphonates, denosumab, teriparatide, estrogen and anticonvulsants.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Familial Hypophosphatemic Rickets
• Hypophosphatemia
• Hypophosphatemic Rickets, X Linked Dominant

Intervention

Drug:
• nasal salmon calcitonin
400 IU daily in two sprays (one to each nares)
• Saline Nasal Spray Placebo

Locations

Country	Name	City	State
United States	Yale School of Medicine	New Haven	Connecticut

Sponsors (2)

Lead Sponsor	Collaborator
Yale University	National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area under the curve for FGF23	FGF23 will be measured serially during a 24 hour admission and AUC calculated.	Time 0	No
Primary	Area under the curve for FGF23	FGF23 will be measured serially during a 24 hour admission at 3 months and AUC calculated and compared to baseline.	3 months	No
Secondary	Area under the curve for serum phosphate and fasting TmP/GFR	Serum phosphate will be measured serially during a 24 hr admission, AUC calculated, and fasting Tmp/GFR calculated.	Time 0	No
Secondary	Area under the curve for 1,25(OH)2vitamin D	Serum 1,25(OH)2vitamin D will be measured serially during a 24 hr admission and AUC calculated.	Time 0	No
Secondary	Nasal congestion	This symptom will be assessed at baseline	Time 0	Yes
Secondary	Area under the curve for serum phosphate and fasting TmP/GFR	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.	Time 3 months	No
Secondary	Area under the curve for 1,25(OH)2vitamin D	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.	Time 3 months	No
Secondary	Nasal congestion	This symptom will be assessed.	Time 1 month	Yes
Secondary	Nasal congestion	This symptom will be assessed.	Time 2 months	Yes
Secondary	Nasal congestion	This symptom will be assessed.	Time 3 months	Yes
Secondary	Nasal ulceration	This symptom will be assessed at baseline	Time 0	Yes
Secondary	Allergic reactions	This symptom will be assessed at baseline	Time 0	Yes
Secondary	Nasal ulceration	This symptom will be assessed.	Time 1 month	Yes
Secondary	Allergic reactions	This symptom will be assessed.	Time 1 month	Yes
Secondary	Nasal ulceration	This symptom will be assessed.	Time 2 months	Yes
Secondary	Allergic reactions	This symptom will be assessed.	Time 2 months	Yes
Secondary	Nasal ulceration	This symptom will be assessed.	Time 3 months	Yes
Secondary	Allergic reactions	This symptom will be assessed.	Time 3 months	Yes