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A randomized, double-blind, placebo-controlled study to assess the efficacy and safety of cinacalcet in pediatric patients with chronic kidney disease and secondary hyperparathyroidism receiving dialysis

  • Bradley A. Warady
  • Janet N. Iles
  • Gema Ariceta
  • Bastian Dehmel
  • Guillermo Hidalgo
  • Xun Jiang
  • Benjamin Laskin
  • Shahnaz Shahinfar
  • Johan Vande Walle
  • Franz Schaefer
Original Article
Part of the following topical collections:
  1. What’s New in Chronic Kidney Disease

Abstract

Background

This randomized phase 3 study evaluated the efficacy and safety of cinacalcet in children with secondary hyperparathyroidism (SHPT) receiving dialysis.

Methods

This study had double-blind and open-label phases. Eligible patients aged 6–< 18 years were randomized to cinacalcet (starting dose ≤ 0.20 mg/kg) or placebo. The primary endpoint was ≥ 30% reduction from baseline in mean intact parathyroid hormone (iPTH). Secondary endpoints included mean iPTH ≤ 300 pg/mL; percentage change from baseline in corrected total serum calcium, phosphorus, and calcium phosphorus product (Ca × P); and safety.

Results

The double-blind phase comprised 43 patients (cinacalcet, n = 22; placebo, n = 21). Nineteen months into the study, regulatory authorities were notified of a fatality; the study was subsequently terminated after a 14-month clinical hold. Before the hold, 12 patients (55%) on cinacalcet and four (19%) on placebo achieved the primary endpoint (p = 0.017), and 27% and 24%, respectively, achieved iPTH ≤ 300 pg/mL. The between-group differences (95% CI) in percentage changes for total serum calcium, phosphorus, and Ca × P were − 4% (− 9 to 1%), − 6% (− 21 to 8%), and − 10% (− 23 to 3%). The mean maximum actual weight-adjusted daily cinacalcet dosage administered was 0.99 mg/kg/day. Overall, 82% of patients on cinacalcet and 86% on placebo had ≥ 1 treatment-emergent adverse event; the most common were vomiting (32%, 24%, respectively), hypocalcemia (23%, 19%), nausea (18%, 14%), and hypertension (14%, 24%).

Conclusions

Despite early termination, efficacy and safety outcomes observed with cinacalcet in children with SHPT on dialysis were consistent with adult observations, suggesting cinacalcet may meet an unmet medical need for this population.

Keywords

Calcimimetics Chronic kidney disease Cinacalcet Parathyroid hormone Pediatric patients Secondary hyperparathyroidism 

Notes

Acknowledgments

The authors acknowledge Meghan Johnson, PhD, and James Balwit, MS, CMPP (Complete Healthcare Communications, LLC, a CHC Group company, North Wales, PA), whose work was funded by Amgen Inc., as well as Holly Tomlin, MPH, CMPP (Amgen Inc. at time of writing, currently Tomlin Health Sciences Communications), and William W. Stark, Jr., PhD (Amgen employee and stockholder), for the assistance in writing this manuscript.

Funding

This study was funded by Amgen Inc.

Compliance with ethical standards

Conflicts of interest

BAW and SS have served as consultants for Amgen Inc. JNI was an employee and stockholder of Amgen Inc. at the time the work was done. BD was an employee of Amgen Europe GmbH at the time the work was done. GH has received grant funding from Amgen Inc. XJ is an employee and stockholder of Amgen Inc. BL was the principal investigator for a clinical study site for the study described in this manuscript. JVW is a member of the Ferring Safety Board, Astellas Safety and Investigator Board for Solifenacin, Mitsubishi Safety Board, and Alexion Registry Review Board and receives research funding and is on the speakers bureau for Alexion Pharmaceuticals, Inc. FS has received personal fees from Amgen Inc. GA declares no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

The study protocol was approved by the institutional review board or independent ethics committee of each study center.

Informed consent

Informed consent or assent, when applicable, because the youngest participants cannot consent, was obtained from all individual participants included in the study and/or their parent or legally acceptable representative.

Data sharing

There is a plan to share data. This may include de-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request, also related data dictionaries, study protocol, statistical analysis plan, informed consent form, and/or clinical study report. Data sharing requests relating to data in this manuscript will be considered after the publication date and (1) this product and indication (or other new use) have been granted marketing authorization in both the USA and Europe, or (2) clinical development discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for these data. Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labeling. A committee of internal advisors reviews requests. If not approved, requests may be further arbitrated by a Data Sharing Independent Review Panel. Requests that pose a potential conflict of interest or an actual or potential competitive risk may be declined at Amgen’s sole discretion and without further arbitration. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the following: http://www.amgen.com/datasharing.

Supplementary material

467_2018_4116_MOESM1_ESM.pdf (202 kb)
ESM 1 (PDF 201 kb)

References

  1. 1.
    Cunningham J, Locatelli F, Rodriguez M (2011) Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options. Clin J Am Soc Nephrol 6(4):913–921CrossRefGoogle Scholar
  2. 2.
    Sanchez CP (2003) Secondary hyperparathyroidism in children with chronic renal failure: pathogenesis and treatment. Paediatr Drugs 5(11):763–776CrossRefGoogle Scholar
  3. 3.
    Kuizon BD, Salusky IB (1999) Growth retardation in children with chronic renal failure. J Bone Miner Res 14(10):1680–1690CrossRefGoogle Scholar
  4. 4.
    Salusky IB, Fine RN, Kangarloo H, Gold R, Paunier L, Goodman WG, Brill JE, Gilli G, Slatopolsky E, Coburn JW (1987) “High-dose” calcitriol for control of renal osteodystrophy in children on CAPD. Kidney Int 32(1):89–95CrossRefGoogle Scholar
  5. 5.
    Oh J, Wunsch R, Turzer M, Bahner M, Raggi P, Querfeld U, Mehls O, Schaefer F (2002) Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure. Circulation 106(1):100–105CrossRefGoogle Scholar
  6. 6.
    Schmitt CP, Mehls O (2011) Mineral and bone disorders in children with chronic kidney disease. Nat Rev Nephrol 7(11):624–634CrossRefGoogle Scholar
  7. 7.
    Sensipar® (cinacalcet) (2017) Full prescribing information. Amgen Inc., Thousand OaksGoogle Scholar
  8. 8.
    Palmer SC, Nistor I, Craig JC, Pellegrini F, Messa P, Tonelli M, Covic A, Strippoli GF (2013) Cinacalcet in patients with chronic kidney disease: a cumulative meta-analysis of randomized controlled trials. PLoS Med 10(4):e1001436CrossRefGoogle Scholar
  9. 9.
    Ballinger AE, Palmer SC, Nistor I, Craig JC, Strippoli GF (2014) Calcimimetics for secondary hyperparathyroidism in chronic kidney disease patients. Cochrane Database Syst Rev 12:CD006254Google Scholar
  10. 10.
    KDIGO 2017 Clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD-MBD). Kidney International Supplements. http://kdigo.org/wp-content/uploads/2017/02/2017-KDIGO-CKD-MBD-GL-Update.pdf. Accessed 5 Oct 2017
  11. 11.
    Alharthi AA, Kamal NM, Abukhatwah MW, Sherief LM (2015) Cinacalcet in pediatric and adolescent chronic kidney disease: a single-center experience. Medicine 94(2):e401CrossRefGoogle Scholar
  12. 12.
    Silverstein DM, Kher KK, Moudgil A, Khurana M, Wilcox J, Moylan K (2008) Cinacalcet is efficacious in pediatric dialysis patients. Pediatr Nephrol 23(10):1817–1822CrossRefGoogle Scholar
  13. 13.
    Platt C, Inward C, McGraw M, Dudley J, Tizard J, Burren C, Saleem MA (2010) Middle-term use of Cinacalcet in paediatric dialysis patients. Pediatr Nephrol 25(1):143–148CrossRefGoogle Scholar
  14. 14.
    Dotis J, Printza N, Ghogha C, Papachristou F (2013) Short- and middle-term continuous use of cinacalcet in children on peritoneal dialysis. J Pediatr Endocrinol Metab 26(1–2):39–43PubMedGoogle Scholar
  15. 15.
    Holm S (1979) A simple sequentially rejective multiple test procedure. Scand J Stat 6(2):65–70Google Scholar
  16. 16.
    US Department of Health and Human Services (2010) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Accessed 25 Sept 2017
  17. 17.
    Block GA, Martin KJ, de Francisco AL, Turner SA, Avram MM, Suranyi MG, Hercz G, Cunningham J, Abu-Alfa AK, Messa P, Coyne DW, Locatelli F, Cohen RM, Evenepoel P, Moe SM, Fournier A, Braun J, McCary LC, Zani VJ, Olson KA, Drueke TB, Goodman WG (2004) Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 350(15):1516–1525CrossRefGoogle Scholar
  18. 18.
    Lindberg JS, Moe SM, Goodman WG, Coburn JW, Sprague SM, Liu W, Blaisdell PW, Brenner RM, Turner SA, Martin KJ (2003) The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in secondary hyperparathyroidism. Kidney Int 63(1):248–254CrossRefGoogle Scholar
  19. 19.
    Quarles LD, Sherrard DJ, Adler S, Rosansky SJ, McCary LC, Liu W, Turner SA, Bushinsky DA (2003) The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease. J Am Soc Nephrol 14(3):575–583CrossRefGoogle Scholar
  20. 20.
    Muscheites J, Wigger M, Drueckler E, Fischer DC, Kundt G, Haffner D (2008) Cinacalcet for secondary hyperparathyroidism in children with end-stage renal disease. Pediatr Nephrol 23(10):1823–1829CrossRefGoogle Scholar
  21. 21.
    Mimpara® (cinacalcet) (2017) Summary of product characteristics. Amgen Inc., Thousand OaksGoogle Scholar
  22. 22.
    Kakajiwala A, Jemielita TO, Copelovitch L, Leonard MB, Furth SL, York A, Benton M, Hoofnagle AN, Windt K, Merrigan K, Lederman A, Denburg MR (2017) Variability in measures of mineral metabolism in children on hemodialysis: impact on clinical decision-making. Pediatr Nephrol 32(12):2311–2318CrossRefGoogle Scholar

Copyright information

© IPNA 2018

Authors and Affiliations

  • Bradley A. Warady
    • 1
  • Janet N. Iles
    • 2
  • Gema Ariceta
    • 3
  • Bastian Dehmel
    • 4
  • Guillermo Hidalgo
    • 5
  • Xun Jiang
    • 2
  • Benjamin Laskin
    • 6
  • Shahnaz Shahinfar
    • 6
    • 7
  • Johan Vande Walle
    • 8
  • Franz Schaefer
    • 9
  1. 1.Division of Pediatric NephrologyChildren’s Mercy Kansas CityKansas CityUSA
  2. 2.Amgen Inc.Thousand OaksUSA
  3. 3.University Hospital Vall d’ HebronBarcelonaSpain
  4. 4.Amgen Europe GmbHZugSwitzerland
  5. 5.Brody School of MedicineEast Carolina UniversityGreenvilleUSA
  6. 6.Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  7. 7.S. Shahinfar Consulting Inc.Newtown SquareUSA
  8. 8.Ghent UniversityGhentBelgium
  9. 9.Heidelberg University HospitalHeidelbergGermany

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