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.

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