Chronic Kidney Disease, Hemodialysis, Secondary Hyperparathyroidism
Conditions
Keywords
Zemplar, paricalcitol, IMPACT SHPT, Hemodialysis, Chronic Kidney Disease Stage 5
Brief summary
Evaluates the effectiveness of on-label Paricalcitol versus Cinacalcet with Low-Dose Vitamin D.
Detailed description
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.
Interventions
DRUGParicalcitol
Paricalcitol dosed per label by region (participants were to receive cinacalcet if they developed hypercalcemia)
DRUGCinacalcet
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)
Sponsors
Abbott
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Czechia, Denmark, Germany, Greece, Italy, Netherlands, Portugal, Russia, Spain, Sweden, United Kingdom, United States
Participant flow
Pre-assignment details
Of the 272 participants enrolled in the study, 4 did not receive study drug and were not included in the population analyzed.
Participants by arm
| Arm | Count |
|---|---|
| IV Paricalcitol in the IV Stratum IV stratum | 62 |
| Cinacalcet in the IV Stratum IV stratum | 64 |
| Oral Paricalcitol in the Oral Stratum Oral stratum | 72 |
| Cinacalcet in the Oral Stratum Oral stratum | 70 |
| Total | 268 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 7 | 7 | 7 |
| Overall Study | Calcium < 7.5 mg/dL on 3 draws | 0 | 0 | 0 | 1 |
| Overall Study | Noncompliance | 0 | 2 | 1 | 0 |
| Overall Study | Protocol Violation | 7 | 3 | 4 | 3 |
| Overall Study | Required kidney transplantation | 1 | 3 | 3 | 1 |
| Overall Study | Travel for family reasons | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 5 | 1 | 5 |
Baseline characteristics
| Characteristic | IV Paricalcitol in the IV Stratum | Cinacalcet in the IV Stratum | Oral Paricalcitol in the Oral Stratum | Cinacalcet in the Oral Stratum | Total |
|---|---|---|---|---|---|
| Age Continuous | 61.2 years STANDARD_DEVIATION 12.71 | 59.9 years STANDARD_DEVIATION 12.04 | 65.7 years STANDARD_DEVIATION 13.48 | 65.1 years STANDARD_DEVIATION 12.5 | 63.1 years STANDARD_DEVIATION 12.89 |
| History of angina No | 54 Participants | 62 Participants | 61 Participants | 63 Participants | 240 Participants |
| History of angina Yes | 8 Participants | 2 Participants | 11 Participants | 7 Participants | 28 Participants |
| History of coronary artery disease No | 37 Participants | 45 Participants | 61 Participants | 64 Participants | 207 Participants |
| History of coronary artery disease Yes | 25 Participants | 19 Participants | 11 Participants | 6 Participants | 61 Participants |
| History of left ventricular hypertrophy No | 50 Participants | 60 Participants | 65 Participants | 64 Participants | 239 Participants |
| History of left ventricular hypertrophy Yes | 12 Participants | 4 Participants | 7 Participants | 6 Participants | 29 Participants |
| History of myocardial infarction No | 50 Participants | 56 Participants | 62 Participants | 62 Participants | 230 Participants |
| History of myocardial infarction Yes | 12 Participants | 8 Participants | 10 Participants | 8 Participants | 38 Participants |
| History of type 1 diabetes mellitus No | 56 Participants | 63 Participants | 71 Participants | 68 Participants | 258 Participants |
| History of type 1 diabetes mellitus Yes | 6 Participants | 1 Participants | 1 Participants | 2 Participants | 10 Participants |
| History of type 2 diabetes mellitus No | 25 Participants | 30 Participants | 44 Participants | 61 Participants | 160 Participants |
| History of type 2 diabetes mellitus Yes | 37 Participants | 34 Participants | 28 Participants | 9 Participants | 108 Participants |
| Sex: Female, Male Female | 24 Participants | 26 Participants | 23 Participants | 27 Participants | 100 Participants |
| Sex: Female, Male Male | 38 Participants | 38 Participants | 49 Participants | 43 Participants | 168 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 48 / 62 | 46 / 64 | 59 / 72 | 54 / 70 |
| serious Total, serious adverse events | 22 / 62 | 28 / 64 | 22 / 72 | 15 / 70 |
Outcome results
Primary
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).
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.
Time frame: Weeks 21 to 28
Population: Randomized participants who received at least 1 dose of study drug and who had both a baseline iPTH value and at least 2 iPTH values during the evaluation period (Weeks 21 to 28)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IV Paricalcitol in the IV Stratum | 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). | 30 Participants |
| Cinacalcet in the IV Stratum | 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). | 16 Participants |
| Oral Paricalcitol in the Oral Stratum | 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). | 31 Participants |
| Cinacalcet in the Oral Stratum | 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). | 23 Participants |
Comparison: With a sample size of 49 participants in each treatment group in the IV stratum, a Fisher's exact test with a 0.050 2-sided significance level will have 81% power to detect a 30% difference in the percentage of participants who achieve iPTH between 150 and 300 pg/mL, assuming the cinacalcet percentage is 36% and the paricalcitol percentage is 66%.p-value: 0.016Fisher Exact
Comparison: With a sample size of 49 participants in each treatment group in the oral stratum, a Fisher's exact test with a 0.050 2-sided significance level will have 81% power to detect a 30% difference in the percentage of participants who achieve iPTH between 150 and 300 pg/mL, assuming the cinacalcet percentage is 36% and the paricalcitol percentage is 66%.p-value: 0.26Fisher Exact
Secondary
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
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.
Time frame: Weeks 21 to 28
Population: Randomized participants who received at least 1 dose of study drug and who had both a baseline iPTH value and at least 2 iPTH values during the evaluation period (Weeks 21 to 28)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IV Paricalcitol in the IV Stratum | 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 | 30 Participants |
| Cinacalcet in the IV Stratum | 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 | 16 Participants |
| Oral Paricalcitol in the Oral Stratum | 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 | 31 Participants |
| Cinacalcet in the Oral Stratum | 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 | 23 Participants |
p-value: 0.01Cochran-Mantel-Haenszel
Secondary
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).
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.
Time frame: Weeks 21 to 28
Population: Randomized participants who received at least 1 dose of study drug and who had both a baseline iPTH value at least 2 iPTH values during the evaluation period (Weeks 21 to 28)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IV Paricalcitol in the IV Stratum | 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). | 44 Participants |
| Cinacalcet in the IV Stratum | 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). | 24 Participants |
| Oral Paricalcitol in the Oral Stratum | 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). | 39 Participants |
| Cinacalcet in the Oral Stratum | 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). | 30 Participants |
p-value: <0.001Fisher Exact
p-value: 0.239Fisher Exact
Secondary
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).
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.
Time frame: Weeks 21 to 28
Population: Randomized participants who received at least 1 dose of study drug and who had both a baseline iPTH value and at least 2 iPTH values during the evaluation period (Weeks 21 to 28)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IV Paricalcitol in the IV Stratum | 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). | 34 Participants |
| Cinacalcet in the IV Stratum | 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). | 11 Participants |
| Oral Paricalcitol in the Oral Stratum | 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). | 26 Participants |
| Cinacalcet in the Oral Stratum | 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). | 22 Participants |
p-value: <0.001Fisher Exact
p-value: 0.704Fisher Exact
Secondary
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)
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.
Time frame: Weeks 21 to 28
Population: Randomized participants who received at least 1 dose of study drug and who had at least 2 calcium values during the evaluation period (Weeks 21 to 28)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IV Paricalcitol in the IV Stratum | 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) | 4 Participants |
| Cinacalcet in the IV Stratum | 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) | 0 Participants |
| Oral Paricalcitol in the Oral Stratum | 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) | 0 Participants |
| Cinacalcet in the Oral Stratum | 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) | 0 Participants |
p-value: 0.118Fisher Exact
p-value: 1Fisher Exact
Secondary
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)
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.
Time frame: Weeks 21 to 28
Population: Randomized participants who received at least 1 dose of study drug and who had at least 2 calcium values during the evaluation period (Weeks 21 to 28)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IV Paricalcitol in the IV Stratum | 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) | 0 Participants |
| Cinacalcet in the IV Stratum | 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) | 23 Participants |
| Oral Paricalcitol in the Oral Stratum | 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) | 2 Participants |
| Cinacalcet in the Oral Stratum | 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) | 29 Participants |
p-value: <0.001Fisher Exact
p-value: <0.001Fisher Exact