E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hypercalcemia in renal transplant recipients with autonomous hyperparathyroidism |
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E.1.1.1 | Medical condition in easily understood language |
High calcium levels in the blood in patients with hyperparathyroidism after a kidney transplant |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10020583 |
E.1.2 | Term | Hypercalcaemia |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate the efficacy of cinacalcet for correcting hypercalcemia in
kidney transplant recipients with autonomous hyperparathyroidism (HPT) |
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E.2.2 | Secondary objectives of the trial |
Key:
To assess the efficacy of cinacalcet for increasing bone mineral density at the femoral
neck
To evaluate the efficacy of cinacalcet for raising serum phosphorus levels
Other:
To evaluate the impact of cinacalcet on kidney transplant function
To evaluate the efficacy of cinacalcet for reducing corrected total serum calcium levels
To evaluate the efficacy of cinacalcet for reducing plasma intact parathyroid hormone (iPTH) levels
To assess the impact of cinacalcet on urinary calcium and phosphorus excretion
To assess the safety and tolerability of cinacalcet (including evaluations of adverse events, acute rejection, kidney transplant failure, incidence of parathyroidectomy and hypocalcemia) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Received a kidney transplant ≥ 9 weeks at time of Screening and ≤ 24 months before first dose (ie, subjects may receive first dose of investigational product no sooner than 12 weeks post-transplant and no later than 24 months post-transplant); may be the first kidney transplant or a repeat kidney transplant.
Subjects with a functional, stable kidney transplant, defined as MDRD estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 (CKD Stage 3 or better) at Screening.
Estimated GFR (mL/min/1.73 m2) will be calculated by the Interactive Voice Response System (IVRS) using the MDRD equation:
SI Units:
eGFRMDRD = 175 x [SCr/88.4]−1.154 x [age]−0.203 x [0.742 if subject is female] x [1.212 if subject is African American]
Conventional Units:
eGFRMDRD = 175 x [SCr]−1.154 x [age]−0.203 x [0.742 if subject is female] x [1.212 if subject is African American]
where SCr is the serum creatinine.
Men or women ≥ 18 years at the start of Screening (ie, time of informed consent).
Corrected total serum calcium > 10.5 mg/dL (2.63 mmol/L), defined as the mean of 2 values during the Screening period.
iPTH > 100 pg/mL (10.6 pmol/L), during the Screening period (obtained at Screen 1 or Screen 2). |
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E.4 | Principal exclusion criteria |
Received cinacalcet therapy for more than 14 days cumulatively posttransplant.
If cinacalcet therapy was received for a total of 14 days or less posttransplant, there must be a 4 week washout before subject is eligible for screening in this study (Note: This does not exclude pre-transplant use of cinacalcet).
Anticipated parathyroidectomy within 6 to12 months after Randomization.
Ongoing therapy with bisphosphonates or use within 6 months prior to
Screening.
Ongoing use of 1,25-dihydroxyvitamin D3 (including other active vitamin D metabolites or analogues) or use within 30 days prior to Screening.
Ongoing use of calcium supplements or use within 30 days prior to Screening.
Ongoing use of phosphate binders (calcium or non-calcium containing) or use within 30 days prior to Screening.
Ongoing use of a thiazide diuretic.
Current enrollment in, or fewer than 30 days has passed since subject has completed, another investigational device or drug study(s); or subject is receiving other investigational agent(s) [ie, less than 30 days prior to Randomization].
Refuse to use highly effective contraceptive measures (as determined by the investigator) throughout the study.
Evidently pregnant (eg, positive HCG test) or is breast feeding.
Known sensitivity to any of the products to be administered during dosing.
Current gastrointestinal disorder that may be associated with impaired absorption of orally administered medications or an inability to swallow tablets.
Will not be available for follow-up assessment.
Any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures.
Subjects with a history of seizures who had a seizure within the 3 months prior to Randomization, which required adjustments to the seizure medication.
Acute Kidney Injury (AKI) or renal biopsy within 6 weeks prior to Screening, unless it is an institutional protocol-driven biopsy. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Correction of hypercalcemia, defined as achievement of a mean corrected total serum calcium value < 10.2 mg/dL (2.55 mmol/L), during the EAP (weeks 21 to 26)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Key:
Percent change in the bone mineral density at the femoral neck measured by dual X-ray absorptiometry (DXA) scan from baseline to week 52
Absolute change in mean serum phosphorus from baseline to the EAP
Other:
Absolute change in kidney transplant function assessed using MDRD-estimated glomerular filtration rate (eGFR) from baseline to week 52
Absolute change in mean corrected total serum calcium from baseline to the EAP
Absolute change in mean iPTH from baseline to the EAP
Absolute change in urine phosphorus levels from baseline to the EAP
Subject incidence of parathyroidectomy
Time to parathyroidectomy after enrollment |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Key:
Percent change in the bone mineral density at the femoral neck measured by DXA scan from baseline to week 52 - day 1 and week 52
Absolute change in mean serum phosphorus from baseline to the EAP: Day 1, wks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 and 26
Other:
Absolute change in kidney transplant function assessed using MDRD-estimated glomerular filtration rate (eGFR) from baseline to week 52: Screen 1, Day 1, wks 12, 26, 34, 42 and 52
Absolute change in mean corrected total serum calcium from baseline to the EAP: Screen 1, Screen 2, wks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 and 26
Absolute change in mean iPTH from baseline to the EAP: Screen 1, Screen 2, wks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 and 26
For remaining time points, please see the protocol
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
Switzerland |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of study is defined as the date on which the last subject completes the last study assessment |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 12 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 12 |