Evaluation of the Effectiveness of Paricalcitol Versus Cinacalcet With Low-Dose Vitamin D

During a 4-week washout period, participants stopped taking cinacalcet or other vitamin D receptor activators (VDRAs). (Participants who were naive to cinacalcet or VDRAs did not have to wash out). At randomization, participants entered a 28-week open-label treatment period, during which they received either cinacalcet or paricalcitol. Participants who were assigned to receive paricalcitol were dosed according to the approved label in their respective geographic regions (i.e., IV at sites in the US and Russia and oral at sites in Europe). Supplemental cinacalcet was administered to participants in the paricalcitol arms who developed hypercalcemia (defined as >= 10.5 mg/dL). The evaluation period was from Weeks 21 to 28.

• Paricalcitol (Drug), also known as ABT-358, Zemplar: Paricalcitol dosed per label by region (participants were to receive cinacalcet if they developed hypercalcemia)
• Cinacalcet (Drug), also known as Sensipar, Mimpara, Hectorol: On-label oral cinacalcet by region with low dose vitamin D receptor activator (VDRA) (either doxercalciferol at US sites or alfacalcidol at non-US sites)

Primary outcomes

• The Number of Participants Who Achieve a Mean Intact Parathyroid Hormone (iPTH) Value Between 150 to 300 pg/mL During the Evaluation Period (Weeks 21 to 28). [Weeks 21 to 28]: iPTH values obtained during the evaluation period (Weeks 21 to 28) were averaged for each participant with at least 2 iPTH values. Participants whose average iPTH value was between 150 to 300 pg/mL were counted.

Secondary outcomes

• Number of Participants Who Achieve at Least 30% Reduction From Baseline in Intact Parathyroid Hormone (iPTH) as Assessed by the Mean iPTH Obtained During the Evaluation Period (Weeks 21 to 28). [Weeks 21 to 28]: iPTH values obtained during the evaluation period (Weeks 21 to 28) were averaged for each participant with both a baseline iPTH value and at least 2 iPTH values. Participants whose average iPTH value showed a 30% reduction from Baseline were counted.
• Number of Participants Who Achieve at Least 50% Reduction From Baseline in iPTH as Assessed by the Mean iPTH Obtained During the Evaluation Period (Weeks 21 to 28). [Weeks 21 to 28]: iPTH values obtained during the evaluation period (Weeks 21 to 28) were averaged for each participant with both a baseline iPTH value and at least 2 iPTH values. Participants whose average iPTH value showed a 50% reduction from Baseline were counted.
• Analysis of the Number of Participants Who Achieve a Mean iPTH Value Between 150 and 300 pg/mL During the Evaluation Period (Weeks 21 to 28) Using a Cochran-Mantel-Haenszel Test Controlling for IV and Oral Site Randomization Strata [Weeks 21 to 28]: iPTH values obtained during the evaluation period (Weeks 21 to 28) were averaged for each participant with at least 2 iPTH values. Participants whose average iPTH value was between 150 to 300 pg/mL were counted. Data from both the IV and oral strata were analyzed together.
• Number of Participants With Hypocalcemia Defined as < 8.4 mg/dL and Based on the Mean of at Least 2 Values Obtained During the Evaluation Period (Weeks 21 to 28) [Weeks 21 to 28]: Calcium values obtained during the evaluation period (Weeks 21 to 28) were averaged for each participant with at least 2 calcium values. Participants whose average calcium value was < 8.4 mg/dL were counted.
• Number of Participants With Hypercalcemia Defined as Calcium > 10.5 mg/dL and Based on the Mean of at Least 2 Values Obtained During the Evaluation Period (Weeks 21 to 28) [Weeks 21 to 28]: Calcium values obtained during the evaluation period (Weeks 21 to 28) were averaged for each participant with at least 2 calcium values. Participants whose average calcium value was > 10.5 mg/dL were counted.

Sex: All, ages: 18 Years to any

Inclusion Criteria

1. Male or female patients >= 18 years old.
2. Patient was diagnosed with Stage 5 chronic kidney disease (CKD) and had been receiving intravenous (IV) or oral vitamin D receptor activators (VDRAs) or cinacalcet during the 8 weeks prior to the screening period or naïve patients who had not received VDRA or cinacalcet within 8 weeks of screening.
3. Patient was on maintenance HD (hemodialysis) 3 times weekly (TIW) for at least 3 months prior to screening and was expected to remain on HD for the duration of the study.
4. For entry into the Pre-Treatment Washout Period (for patients who were not naïve to VDRAs and cinacalcet), the patient had to have screening laboratory values of:

   * iPTH level 130 to 700 pg/mL
   * Serum Total Alkaline Phosphatase level >= 40 U/L
   * Calcium level <= 10.0 mg/dL (2.49 mmol/L)
   * Calcium-phosphorus product (CaxP) <= 75 mg2/dL2 (US) and <= 70 mg2/dL2 (non-US)

Exclusion Criteria

1. Patient had a history of parathyroidectomy.
2. Patient had a current malignancy (with the exception of basal or squamous cell carcinoma of the skin), or clinically significant liver disease, in the opinion of the investigator.
3. Use of known inhibitors (i.e., ketoconazole) or inducers (i.e., carbamazepine) of cytochrome P450 (including grapefruit and/or grapefruit juice) 3A (CYP3A) or drugs metabolized by cytochrome P450 2D6 (CYP2D6) (e.g., flecainide, vinblastine, thioridazine, and most tricyclic antidepressants) within 2 weeks prior to study drug administration. Commonly used beta blockers such as metoprolol and carvedilol are allowed but are metabolized by CYP2D6; thus, an adjustment to a lower dose may have been required.
4. Patient was known to be human immunodeficiency (HIV) positive.

Participant flow

Outcome results

• The Number of Participants Who Achieve a Mean Intact Parathyroid Hormone (iPTH) Value Between 150 to 300 pg/mL During the Evaluation Period (Weeks 21 to 28). (Primary), Number, Participants: IV Paricalcitol in the IV Stratum 30; Cinacalcet in the IV Stratum 16; Oral Paricalcitol in the Oral Stratum 31; Cinacalcet in the Oral Stratum 23 (p 0.016)
• Number of Participants Who Achieve at Least 30% Reduction From Baseline in Intact Parathyroid Hormone (iPTH) as Assessed by the Mean iPTH Obtained During the Evaluation Period (Weeks 21 to 28). (Secondary), Number, Participants: IV Paricalcitol in the IV Stratum 44; Cinacalcet in the IV Stratum 24; Oral Paricalcitol in the Oral Stratum 39; Cinacalcet in the Oral Stratum 30 (p <0.001)
• Number of Participants Who Achieve at Least 50% Reduction From Baseline in iPTH as Assessed by the Mean iPTH Obtained During the Evaluation Period (Weeks 21 to 28). (Secondary), Number, Participants: IV Paricalcitol in the IV Stratum 34; Cinacalcet in the IV Stratum 11; Oral Paricalcitol in the Oral Stratum 26; Cinacalcet in the Oral Stratum 22 (p <0.001)
• Analysis of the Number of Participants Who Achieve a Mean iPTH Value Between 150 and 300 pg/mL During the Evaluation Period (Weeks 21 to 28) Using a Cochran-Mantel-Haenszel Test Controlling for IV and Oral Site Randomization Strata (Secondary), Number, Participants: IV Paricalcitol in the IV Stratum 30; Cinacalcet in the IV Stratum 16; Oral Paricalcitol in the Oral Stratum 31; Cinacalcet in the Oral Stratum 23 (p 0.010)
• Number of Participants With Hypocalcemia Defined as < 8.4 mg/dL and Based on the Mean of at Least 2 Values Obtained During the Evaluation Period (Weeks 21 to 28) (Secondary), Number, Participants: IV Paricalcitol in the IV Stratum 0; Cinacalcet in the IV Stratum 23; Oral Paricalcitol in the Oral Stratum 2; Cinacalcet in the Oral Stratum 29 (p <0.001)
• Number of Participants With Hypercalcemia Defined as Calcium > 10.5 mg/dL and Based on the Mean of at Least 2 Values Obtained During the Evaluation Period (Weeks 21 to 28) (Secondary), Number, Participants: IV Paricalcitol in the IV Stratum 4; Cinacalcet in the IV Stratum 0; Oral Paricalcitol in the Oral Stratum 0; Cinacalcet in the Oral Stratum 0 (p 0.118)

Adverse events

Time frame: Treatment-emergent adverse events were reported. These include all adverse events that began on or after the first dose of study drug through 30 days after the last dose of study drug.

Serious adverse events by term

32 more terms not shown.

Other adverse events by term

11 more terms not shown.

Limitations and caveats: Using a fixed dosing algorithm based on biochemical criteria may affect interpretation of the results. In the future, the risk/benefit profile of these interventions should be assessed by longer-term clinical outcomes.

• Results publication: Cozzolino M, Ketteler M, Martin KJ, Sharma A, Goldsmith D, Khan S. Paricalcitol- or cinacalcet-centred therapy affects markers of bone mineral disease in patients with secondary hyperparathyroidism receiving haemodialysis: results of the IMPACT-SHPT study. Nephrol Dial Transplant. 2014 Apr;29(4):899-905. doi: 10.1093/ndt/gfu011. Epub 2014 Feb 4. PMID 24500308
• Results publication: Sharma A, Marshall TS, Khan SS, Johns B. Cost effectiveness of paricalcitol versus cinacalcet with low-dose vitamin D for management of secondary hyperparathyroidism in haemodialysis patients in the USA. Clin Drug Investig. 2014 Feb;34(2):107-15. doi: 10.1007/s40261-013-0151-4. PMID 24214232
• Results publication: Ketteler M, Martin KJ, Wolf M, Amdahl M, Cozzolino M, Goldsmith D, Sharma A, Marx S, Khan S. Paricalcitol versus cinacalcet plus low-dose vitamin D therapy for the treatment of secondary hyperparathyroidism in patients receiving haemodialysis: results of the IMPACT SHPT study. Nephrol Dial Transplant. 2012 Aug;27(8):3270-8. doi: 10.1093/ndt/gfs018. Epub 2012 Mar 2. PMID 22387567

• Samina Khan, MD, Study director, Abbott

NIH grants: 2009