Calcitonin for Treating X-linked Hypophosphatemia

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Yale University
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Karl Insogna, Yale University
ClinicalTrials.gov Identifier:
NCT01652573
First received: July 23, 2012
Last updated: June 12, 2014
Last verified: June 2014
  Purpose

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.

Condition Intervention
Hypophosphatemic Rickets, X Linked Dominant
Drug: nasal salmon calcitonin
Drug: Saline Nasal Spray Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Calcitonin for Treating X-linked Hypophosphatemia

Resource links provided by NLM:


Further study details as provided by Yale University:

Primary Outcome Measures:
  • Area under the curve for FGF23 [ Time Frame: Time 0 ] [ Designated as safety issue: No ]
    FGF23 will be measured serially during a 24 hour admission and AUC calculated.

  • Area under the curve for FGF23 [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    FGF23 will be measured serially during a 24 hour admission at 3 months and AUC calculated and compared to baseline.


Secondary Outcome Measures:
  • Area under the curve for serum phosphate and fasting TmP/GFR [ Time Frame: Time 0 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Serum 1,25(OH)2vitamin D will be measured serially during a 24 hr admission and AUC calculated.

  • Nasal congestion [ Time Frame: Time 0 ] [ Designated as safety issue: Yes ]
    This symptom will be assessed at baseline

  • Area under the curve for serum phosphate and fasting TmP/GFR [ Time Frame: Time 3 months ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    This symptom will be assessed.

  • Nasal congestion [ Time Frame: Time 2 months ] [ Designated as safety issue: Yes ]
    This symptom will be assessed.

  • Nasal congestion [ Time Frame: Time 3 months ] [ Designated as safety issue: Yes ]
    This symptom will be assessed.

  • Nasal ulceration [ Time Frame: Time 0 ] [ Designated as safety issue: Yes ]
    This symptom will be assessed at baseline

  • Allergic reactions [ Time Frame: Time 0 ] [ Designated as safety issue: Yes ]
    This symptom will be assessed at baseline

  • Nasal ulceration [ Time Frame: Time 1 month ] [ Designated as safety issue: Yes ]
    This symptom will be assessed.

  • Allergic reactions [ Time Frame: Time 1 month ] [ Designated as safety issue: Yes ]
    This symptom will be assessed.

  • Nasal ulceration [ Time Frame: Time 2 months ] [ Designated as safety issue: Yes ]
    This symptom will be assessed.

  • Allergic reactions [ Time Frame: Time 2 months ] [ Designated as safety issue: Yes ]
    This symptom will be assessed.

  • Nasal ulceration [ Time Frame: Time 3 months ] [ Designated as safety issue: Yes ]
    This symptom will be assessed.

  • Allergic reactions [ Time Frame: Time 3 months ] [ Designated as safety issue: Yes ]
    This symptom will be assessed.


Estimated Enrollment: 20
Study Start Date: March 2011
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01652573

Contacts
Contact: Karl L Insogna, MD 203-737-2871 karl.insogna@yale.edu
Contact: Elizabeth O'lear, MS 203-785-3759 elizabeth.olear@yale.edu

Locations
United States, Connecticut
Yale School of Medicine Recruiting
New Haven, Connecticut, United States, 06520-0820
Contact: Karl Insogna, MD    203-737-2871    karl.insogna@yale.edu   
Contact: Alice Abraham, MD    917-257-8916    alice.abraham@yale.edu   
Principal Investigator: Karl L Insogna, MD         
Sub-Investigator: Alice Abraham, MD         
Sponsors and Collaborators
Yale University
Investigators
Principal Investigator: Karl L Insogna, MD Profossor of Medicine, Yale School of Medicine
  More Information

No publications provided

Responsible Party: Karl Insogna, Professor of Medicine, Yale University
ClinicalTrials.gov Identifier: NCT01652573     History of Changes
Other Study ID Numbers: 1010007548, R21AR061818
Study First Received: July 23, 2012
Last Updated: June 12, 2014
Health Authority: United States: Institutional Review Board
United States: Federal Government

Keywords provided by Yale University:
X linked hypophosphatemia
calcitonin
FGF twenty three

Additional relevant MeSH terms:
Rickets
Hypophosphatemic Rickets, X-Linked Dominant
Hypophosphatemia
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Calcium Metabolism Disorders
Metabolic Diseases
Vitamin D Deficiency
Avitaminosis
Deficiency Diseases
Malnutrition
Nutrition Disorders
Phosphorus Metabolism Disorders
Hypophosphatemia, Familial
Renal Tubular Transport, Inborn Errors
Kidney Diseases
Urologic Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Metal Metabolism, Inborn Errors
Metabolism, Inborn Errors
Salmon calcitonin
Calcitonin
Calcitonin Gene-Related Peptide
Bone Density Conservation Agents
Physiological Effects of Drugs
Pharmacologic Actions
Vasodilator Agents
Cardiovascular Agents

ClinicalTrials.gov processed this record on July 23, 2014