Calcitonin for Treating X-linked Hypophosphatemia

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.

Study Overview

• Status: Completed
• Conditions: Hypophosphatemic Rickets, X Linked Dominant
• Intervention / Treatment: Drug: nasal salmon calcitonin; Drug: Saline Nasal Spray Placebo

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520-0820
      • Yale School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nasal calictonin; Subjects will received nasal calcitonin once daily	Drug: nasal salmon calcitonin; 400 IU daily in two sprays (one to each nares); Other Names: Miacalcin; Fortical
Placebo Comparator: Saline Nasal spray; Patients will receive saline nasal spray once daily	Drug: Saline Nasal Spray Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve for FGF23	FGF23 will be measured 0 to 24 hours post dose during a 24 hour admission and AUC calculated.	Time 0
Area Under the Curve for FGF23	FGF23 will be measured 0 to 24 hours post dose during a 24 hour admission at 3 months and AUC calculated and compared to baseline.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve for TmP/GFR	Serum phosphate will be measured 0 to 24 hours postdose during a 24 hr admission, AUC calculated, and fasting Tmp/GFR calculated.	Time 0
Area Under the Curve for 1,25(OH)2vitamin D	Serum 1,25(OH)2vitamin D will be measured 0 to 24 hours post dose during a 24 hr admission and AUC calculated.	Time 0
Number of Patients With Nasal Congestion at Baseline	This symptom will be assessed at baseline	Time 0
Area Under the Curve for TmP/GFR	TmP/GFR will be measured 0 to 24 hours postdose during a 24 hr admission at 3 months and AUC calculated and compared to baseline.	Time 3 months
Area Under the Curve for 1,25(OH)2vitamin D	Serum 1,25(OH)2vitamin D will be measured 0 to 24 hours post dose during a 24 hr admission and AUC calculated and results will be compared to baseline values.	Time 3 months
Number of Participants With Nasal Congestion at 1 Month	This symptom will be assessed.	Time 1 month
Number of Participants With Nasal Congestion at 2 Months	This symptom will be assessed.	Time 2 months
Number of Participants With Nasal Congestion at 3 Months	This symptom will be assessed.	Time 3 months
Number of Participants With Nasal Ulcerations at Baseline	This symptom will be assessed at baseline	Time 0
Number of Participants With Allergic Reactions at Baseline	This symptom will be assessed at baseline	Time 0
Number of Participants With Nasal Ulceration at 1 Month	This symptom will be assessed.	Time 1 month
Number of Participants With Allergic Reactions at 1 Month	This symptom will be assessed.	Time 1 month
Number of Participants With Nasal Ulceration at 2 Months	This symptom will be assessed.	Time 2 months
Number of Participants With Allergic Reactions at 2 Months	This symptom will be assessed.	Time 2 months
Number of Participants With Nasal Ulcerations at 3 Months	This symptom will be assessed.	Time 3 months
Number of Participants With Allergic Reactions at 3 Months	This symptom will be assessed.	Time 3 months

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• Investigators: Principal Investigator: Karl L Insogna, MD, Profossor of Medicine, Yale School of Medicine

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (Actual): September 1, 2015
• Study Completion (Actual): September 1, 2015

Study Registration Dates

• First Submitted: July 23, 2012
• First Submitted That Met QC Criteria: July 27, 2012
• First Posted (Estimate): July 30, 2012

Study Record Updates

• Last Update Posted (Actual): May 31, 2017
• Last Update Submitted That Met QC Criteria: April 25, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: X linked hypophosphatemia; calcitonin; FGF twenty three
• Additional Relevant MeSH Terms: Metabolic Diseases; Kidney Diseases; Urologic Diseases; Nutrition Disorders; Genetic Diseases, Inborn; Musculoskeletal Diseases; Avitaminosis; Deficiency Diseases; Malnutrition; Bone Diseases; Metabolism, Inborn Errors; Bone Diseases, Metabolic; Renal Tubular Transport, Inborn Errors; Calcium Metabolism Disorders; Metal Metabolism, Inborn Errors; Phosphorus Metabolism Disorders; Vitamin D Deficiency; Hypophosphatemia, Familial; Rickets; Familial Hypophosphatemic Rickets; Hypophosphatemia; Rickets, Hypophosphatemic; Physiological Effects of Drugs; Vasodilator Agents; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Calcitonin; Salmon calcitonin; Calcitonin Gene-Related Peptide; Katacalcin
• Other Study ID Numbers: 1010007548; R21AR061818 (U.S. NIH Grant/Contract)