Cinacalcet in Paediatric Secondary Hyperparathyroidism (SHPT) Due to Chronic Kidney Disease (CKD)

Twelve-month, multicenter, intra-subject controlled (retrospective-prospective), open-label, active-treatment study to evaluate the dose-response and pharmacokinetics (PK) of cinacalcet HCl for the treatment of Secondary Hyperparathyroidism (SHPT) in paediatric subjects with chronic kidney disease (CKD) on dialysis, followed by 12-month study extension.

This multicenter, intra-subject controlled, open-label, active-treatment study will assess in children affected by Secondary Hyperparathyroidism, aged 2-18 years on chronic dialysis not responsive to standard of care (SoC) therapy, the response after 6-month cinacalcet compared intra-subject to SoC alone at screening visit 6 months prior to cinacalcet start. Secondary objectives are to evaluate effects on growth over 18 months and PK profile. At baseline children have PTH levels\>300 pg/mL, plasma P\<6 mg/dL, and Ca 8.4-10.5 mg/dL, or Ca x P product\>60 not responsive to SoC. Initial dosing of cinacalcet will be 0.5-0.75 mg/Kg per os OD to be adjusted up to a max of 180mg OD for target PTH values\<180 pg/mL in absence of hypocalcemia. Thirty children will be enrolled at 12 centres participating in a national paediatric dialysis registry, corresponding to an α=0.05 and a power of 80% using the McNemar test, with an expected % of responders to cinacalcet or SoC of 40% or 5% respectively, with a drop-out rate of 15. Primary study endpoint (EP) will be the % of children who will have a reduction from baseline \>25% in mean PTH levels during the 6-mo efficacy-assessment period. Among secondary EPs over 18 mos will be the % of patients with mean PTH levels\<300 pg/mL; the % change in PTH, Ca, P values, and the Ca x P product; PK profile (or population profile by age) and its correlation with PTH and testosterone levels; auxological indices and growth velocity; % of children with treatment-emergent adverse events and lab abnormalities; retention on treatment and reasons of treatment withdrawal. The study will evaluate whether cinacalcet represents a safe and effective therapeutic option for SHPT children.

Eligibility Criteria:
Inclusion Criteria:

* Parents'/guardian written informed consent, and child's assent
* Age \> 2 and \<18 years;
* A dry body weight (BW) \>10.49 Kg in males and \>9.95 Kg in females, respectively;
* Inpatient or outpatient status at the time of enrolment;
* Males or females. Female subjects sexually active must be neither pregnant nor breastfeeding, and must lack childbearing potential from screening visit to the end of the safety follow-up
* On stable hemodialysis (HD) or peritoneal dialysis (PD) for their CKD for at least one month before entering the 6-month pre-treatment period;
* Plasma iPTH levels \> 300 pg/mL, AND
* Plasma Ca levels \> 9.4 mg/dL (with normal serum albumin level), AND
* Plasma P levels \<6.5 mg/dL in patients younger than 6 years, or \<6.0mg/dL in older patients, OR
* Ca x P product \> 60;
* Records' availability for the following parameters 6 months prior to study entry: demographic information, physical examination, height and dry weight, auxological/anthropometric indices, blood pressure values, Kt/V urea, plasma iPTH, calcium, phosphorus, and alkaline phosphatise levels, blood pH and bicarbonate, serum creatinine/urea, C reactive protein (CRP) levels, liver function tests, blood count, blood 25(OH) vitamin D3 level.

Exclusion Criteria:

* The following laboratory values: Hb\<9.0 g/dL, WBC\<2000/mm3 (2x109/L), platelets \<150,000/mm3 (150x109/L) only in subjects who are otherwise eligible for PK/PD assessments; abnormal liver function, defined by a total bilirubin ≥2 times the upper limit of normal values, ASAT, ALAT, γ-GT levels ≥2 times the ULN values.
* Any other lab values that in the opinion of the investigator might place the subject at unacceptable risk for participation in the study.
* History of malignancy (active malignancy, or off therapy since less than 1 year)
* History of diseases causing hypercalcemia
* Chronic inflammatory diseases (C-Reactive Protein-CRP \>2 times the upper limit of normal values) requiring a concomitant corticosteroid or immunosuppressive therapy
* History of infectious diseases (including opportunistic infections) within 4 weeks prior to study entry
* Evidence as assessed by the Investigator of active or latent bacterial, viral or fungal infections at the time of potential enrollment, including subjects with evidence of HIV infection.
* Hepatitis-B surface antigen-positive subjects only in subjects who are otherwise eligible for PK/PD assessments
* Hepatitis C antibody-positive subjects who are also PCR-positive or RIBA positive only in subjects who are otherwise eligible for PK/PD assessments
* Use of recombinant human growth hormone therapy
* Use of drugs that interact with cinacalcet disposition
* Previous use of cinacalcet