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Calcitonin for Treating X-linked Hypophosphatemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01652573
Recruitment Status : Completed
First Posted : July 30, 2012
Results First Posted : May 31, 2017
Last Update Posted : May 31, 2017
Sponsor:
Collaborator:
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Information provided by (Responsible Party):
Karl Insogna, Yale University

Tracking Information
First Submitted Date  ICMJE July 23, 2012
First Posted Date  ICMJE July 30, 2012
Results First Submitted Date  ICMJE March 6, 2017
Results First Posted Date  ICMJE May 31, 2017
Last Update Posted Date May 31, 2017
Study Start Date  ICMJE March 2011
Actual Primary Completion Date September 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 25, 2017)
  • Area Under the Curve for FGF23 [ Time Frame: Time 0 ]
    FGF23 will be measured 0 to 24 hours post dose during a 24 hour admission and AUC calculated.
  • Area Under the Curve for FGF23 [ Time Frame: 3 months ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 27, 2012)
  • 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.
Change History Complete list of historical versions of study NCT01652573 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 25, 2017)
  • Area Under the Curve for TmP/GFR [ Time Frame: Time 0 ]
    Serum phosphate will be measured 0 to 24 hours postdose 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 0 to 24 hours post dose during a 24 hr admission and AUC calculated.
  • Number of Patients With Nasal Congestion at Baseline [ Time Frame: Time 0 ]
    This symptom will be assessed at baseline
  • Area Under the Curve for TmP/GFR [ Time Frame: Time 3 months ]
    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.
  • Area Under the Curve for 1,25(OH)2vitamin D [ Time Frame: Time 3 months ]
    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.
  • Number of Participants With Nasal Congestion at 1 Month [ Time Frame: Time 1 month ]
    This symptom will be assessed.
  • Number of Participants With Nasal Congestion at 2 Months [ Time Frame: Time 2 months ]
    This symptom will be assessed.
  • Number of Participants With Nasal Congestion at 3 Months [ Time Frame: Time 3 months ]
    This symptom will be assessed.
  • Number of Participants With Nasal Ulcerations at Baseline [ Time Frame: Time 0 ]
    This symptom will be assessed at baseline
  • Number of Participants With Allergic Reactions at Baseline [ Time Frame: Time 0 ]
    This symptom will be assessed at baseline
  • Number of Participants With Nasal Ulceration at 1 Month [ Time Frame: Time 1 month ]
    This symptom will be assessed.
  • Number of Participants With Allergic Reactions at 1 Month [ Time Frame: Time 1 month ]
    This symptom will be assessed.
  • Number of Participants With Nasal Ulceration at 2 Months [ Time Frame: Time 2 months ]
    This symptom will be assessed.
  • Number of Participants With Allergic Reactions at 2 Months [ Time Frame: Time 2 months ]
    This symptom will be assessed.
  • Number of Participants With Nasal Ulcerations at 3 Months [ Time Frame: Time 3 months ]
    This symptom will be assessed.
  • Number of Participants With Allergic Reactions at 3 Months [ Time Frame: Time 3 months ]
    This symptom will be assessed.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 27, 2012)
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Calcitonin for Treating X-linked Hypophosphatemia
Official Title  ICMJE 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 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  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Hypophosphatemic Rickets, X Linked Dominant
Intervention  ICMJE
  • Drug: nasal salmon calcitonin
    400 IU daily in two sprays (one to each nares)
    Other Names:
    • Miacalcin
    • Fortical
  • Drug: Saline Nasal Spray Placebo
Study Arms  ICMJE
  • Experimental: Nasal calictonin
    Subjects will received nasal calcitonin once daily
    Intervention: Drug: nasal salmon calcitonin
  • Placebo Comparator: Saline Nasal spray
    Patients will receive saline nasal spray once daily
    Intervention: Drug: Saline Nasal Spray Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 24, 2016)
21
Original Estimated Enrollment  ICMJE
 (submitted: July 27, 2012)
20
Actual Study Completion Date  ICMJE September 2015
Actual Primary Completion Date September 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01652573
Other Study ID Numbers  ICMJE 1010007548
R21AR061818 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Karl Insogna, Yale University
Study Sponsor  ICMJE Yale University
Collaborators  ICMJE National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Investigators  ICMJE
Principal Investigator: Karl L Insogna, MD Profossor of Medicine, Yale School of Medicine
PRS Account Yale University
Verification Date April 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP