Examining the Effect of Burosumab on Muscle Function

X-linked Hypophosphatemia Clinical Trial

Official title:

Examining the Effect of Burosumab on Muscle Function Using MR Spectroscopy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04146935
• Other study ID #: 2000026400
• Status: Completed
• Phase: Phase 4
• Start date: November 13, 2019
• Est. completion date: August 25, 2022

Study information

• Verified date: August 2023
• Source: Yale University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Patients with X-linked hypophosphatemia (XLH) often report symptoms of fatigue and weakness particularly after exertion, in addition to their skeletal complaints. In previous trials using KRN23 (same drug as burosumab/Crysvita®), patients report these symptoms improve. The investigators wish to test this hypothesis directly by measuring muscle energy when patients begin treatment with Crysvita® for the first time.

Description:

X-linked hypophosphatemia is a skeletal dysplasia. The mineralized tissue complications of XLH have been the focus of investigative studies seeking to understand its pathogenesis, as well as studies directed at new therapies. However, in addition to their skeletal complaints, patients with XLH have among their most frequent symptoms, fatigue and weakness, which manifest as both a generalized sense of a lack of energy as well as a more specific feeling that their muscular function is impaired. Objectively, patients complain of fatigue after exertion, when otherwise they do not think they should expect to feel so spent. These symptoms occur in individuals who otherwise have good cardiovascular and respiratory health, so co-morbidities are unlikely to explain these pervasive complaints. Anecdotally, the investigators open-label trial data using KRN23 suggest that these symptoms are dramatically ameliorated by treatment with the drug. In a recent study¹, the investigators found that when stressed by a low-phosphate diet, rates of insulin-stimulated myocyte Adenosine triphosphate (ATP) flux were reduced by 50% in an experimental model of systemic hypophosphatemia (the NaPi2a knockout mouse). Moreover, ATP synthetic flux correlated directly with cellular and mitochondrial phosphate uptake in two rodent myocyte cell lines, as well as in freshly isolated myocyte mitochondria. As direct evidence that these preclinical findings are relevant to human hypophosphatemic genetic syndromes we studied a patient with Heredity Hypophosphatemic Rickets with Hypercalciuria (HHRH) who was not being treated at the time of our experiment. In this patient who had a 50% reduction in serum phosphate, muscle ATP content was also significantly reduced ¹. Both of these parameters normalized completely with oral phosphate repletion ¹. These data strongly support the hypothesis that reduced muscle ATP flux may underlie the myopathy seen in patients with XLH. The investigators propose to directly test this hypothesis, in patients about to begin treatment with Crysvita® for the first time.

Muscle tissue phosphorus concentration and ATP flux rates will be assessed in the right gastrocnemius of the lower leg using 31P-NMR (nuclear magnetic resonance) spectroscopy over the course of the 3 month study. The study consists of 5 visits total over 3 months. At visits 1,4 and 5, patients will undergo magnetic resonance (MR) spectroscopy assessments and functional testing along with blood and urine analysis. At visits 1,2 and 3 patients will receive Burosumab/Crysvita® by subcutaneous injection.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: August 25, 2022
• Est. primary completion date: August 25, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

1. 18-65 years of age

2. Diagnosis of XLH

3. eGFR = 50 (estimated glomerular filtration rate)

4. Normal serum calcium

5. Phosphate = 2.5 mg/dl

6. Deemed clinically appropriate for starting therapy with Burosumab/Crysvita® (based on the treating physician's evaluation)

7. Deemed appropriate for MR Spectroscopy

Exclusion Criteria:

1. Patients with fixed skeletal abnormalities which would prevent them from successfully completing study-related functional assessments

2. Patients unwilling to stop therapy with supplemental phosphate and calcitriol 2 weeks prior to enrollment.

3. Patients who have undergone an orthopaedic procedure within the previous 6 months involving implantation of metal hardware

Related Conditions & MeSH terms

• Familial Hypophosphatemic Rickets
• Hypophosphatemia
• X-linked Hypophosphatemia

Intervention

Drug:
• Burosumab Injection [Crysvita]
Burosumab/Crysvita SC injection monthly

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Yale University

Country where clinical trial is conducted

United States, 

References & Publications (1)

Pesta DH, Tsirigotis DN, Befroy DE, Caballero D, Jurczak MJ, Rahimi Y, Cline GW, Dufour S, Birkenfeld AL, Rothman DL, Carpenter TO, Insogna K, Petersen KF, Bergwitz C, Shulman GI. Hypophosphatemia promotes lower rates of muscle ATP synthesis. FASEB J. 2016 Oct;30(10):3378-3387. doi: 10.1096/fj.201600473R. Epub 2016 Jun 23. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Six-minute Walk Test	functional testing outcome measured in meters	2.5 months
Other	Sit to Stand	functional testing outcome measured in the number completed in 30 seconds	2.5 months
Other	Timed up and go Test	functional testing outcome measured in seconds	2.5 months
Primary	Skeletal Muscle Adenosine Triphosphate (ATP) Synthesis Rate	Rates of mitochondrial phosphorylation activity were assessed in the soleus/gastrocnemius muscle complex of the right calf by 31P magnetic resonance spectroscopy saturation transfer technique (micro-mol/g/min)	2.5 months
Secondary	Serum Phosphate	measured in mg/dl	2.5 months
Secondary	Intracellular Phosphate Concentration in Umol/g Muscle	Intracellular phosphorus concentration in skeletal muscle (umol/g muscle)	2.5 months