A Phase 1 interventional study of Denosumab in Renal Impairment, sponsored by Amgen. Completed at 7 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2016-02-19.
Sponsored by Amgen · Phase 1, Interventional, and Treatment
The primary objective was to evaluate the incidence of clinically significant hypocalcemia following multiple 120 mg subcutaneous doses of denosumab in patients with severe chronic kidney disease (CKD) and CKD on dialysis
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Exclusion Criteria:
Participants received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.
Drug: Denosumab
Adminstered by subcutaneous injection
Also known as: XGEVA, AMG 162
Number of Participants With Clinically Significant Hypocalcemia
Clinically significant hypocalcemia is defined as albumin-adjusted calcium \< 7.0 mg/dL or symptomatic hypocalcemia. Symptomatic hypocalcemiais is defined as both a clinical adverse event of hypocalcemia and a concomitant symptom of hypocalcemia (e.g., hypoesthesia, paresthesia, muscle cramps, seizure, prolonged QT interval) that occurred along with the hypocalcemia event or decreased serum calcium levels.
Time frame: 113 days
Number of Participants With Hypocalcemia Determined by CTCAE v.4.0 Criteria
The severity of hypocalcemia (a low concentration of calcium, corrected for albumin, in the blood) was graded according to the common terminology criteria for adverse events (CTCAE) v.4.0 criteria: Grade 1: albumin-adjusted serum calcium \< lower limit of normal (LLN; 9.2 mg/dL) to 8.0 mg/dL; Grade 2: albumin-adjusted serum calcium \< 8.0 to 7.0 mg/dL; Grade 3: albumin-adjusted serum calcium \< 7.0 to 6.0 mg/dL; Grade 4: albumin-adjusted serum calcium \< 6.0 mg/dL.
Time frame: 113 days
Number of Participants With Hypophosphatemia Determined by CTCAE v.4.0 Criteria
The severity of hypophosphatemia (a low concentration of phosphates in the blood) was graded according to the common terminology criteria for adverse events (CTCAE) v.4.0 criteria: Grade 1: \< LLN (3 mg/dL) - 2.5 mg/dL; Grade 2: \< 2.5 - 2.0 mg/dL; Grade 3: \< 2.0 - 1.0 mg/dL; Grade 4: \< 1.0 mg/dL.
Time frame: 113 days
Number of Participants With Hypomagnesemia Determined by CTCAE v.4.0 Criteria
The severity of hypomagnesemia (a low concentration of magnesium in the blood) was graded according to the common terminology criteria for adverse events (CTCAE) v.4.0 criteria: Grade 1: \< LLN (1.5 mg/dL) - 1.2 mg/dL; Grade 2: \< 1.2 - 0.9 mg/dL; Grade 3: \< 0.9 - 0.7 mg/dL; Grade 4: \< 0.7 mg/dL.
Time frame: 113 days
Percent Change From Baseline in Albumin-adjusted Serum Calcium Over Time
Time frame: Baseline and Days 2, 3, 6, 8, 11, 15, 22, 29, 30, 31, 34, 36, 39, 43, 57, 71, 85, and 113
Percent Change From Baseline in Serum Phosphorus Over Time
Time frame: Baseline and Days 2, 3, 6, 8, 11, 15, 22, 29, 30, 31, 34, 36, 39, 43, 57, 71, 85, and 113
Percent Change From Baseline in Serum Magnesium Over Time
Time frame: Baseline and Days 2, 3, 6, 8, 11, 15, 22, 29, 30, 31, 34, 36, 39, 43, 57, 71, 85, and 113
Number of Participants With Adverse Events
The severity of each adverse event (AE) was graded using the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. The investigator assessed whether AEs were possibly related to study drug by answering the question: "Is there a reasonable possibility that the event may have been caused by the investigational product?" Abnormal laboratory findings without clinical significance (based on the investigator's judgment) were not recorded as AEs, however, laboratory value changes that required treatment or adjustment in current therapy were considered AEs. A serious adverse event is defined as an adverse event that meets at least 1 of the following serious criteria: • fatal, • life-threatening (places the participant at immediate risk of death), • requires in-patient hospitalization or prolongation of existing hospitalization, • results in persistent or significant disability/incapacity, • congenital anomaly/birth defect, and/or • other medically important serious event.
Time frame: 113 days
Maximum Observed Serum Denosumab Concentration (Cmax)
Serum concentrations of denosumab were measured by an enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 20 ng/mL.
Time frame: Days 1 and 29 (predose), and on Days 8, 15, 36, 43, 57, 71, 85, and 113
Time to Maximum Observed Serum Denosumab Concentration (Tmax)
Serum concentrations of denosumab were measured by an enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 20 ng/mL.
Time frame: Days 1 and 29 (predose), and on Days 8, 15, 36, 43, 57, 71, 85, and 113
Area Under the Serum Concentration-time Curve From Time 0 to 4 Weeks (AUC0-4wks) After Dose 1
Estimated using the linear trapezoidal method.
Time frame: Days 1, 8, 15, and 29 (predose)
Area Under the Serum Concentration-time Curve From Time 0 to 12 Weeks (AUC0-12wks) After Dose 2
Estimated using the linear trapezoidal method.
Time frame: Days 29 (predose), 36, 43, 57, 71, and 85
Percent Change From Baseline in Serum C-Telopeptide Over Time
Time frame: Baseline and Days 1 and 29 (predose), and on Days 8, 15, 36, 43, 57, 71, 85, and 113
Number of Participants Who Developed Anti-denosumab Antibodies
Time frame: From Day 1 (predose) to Day 113
| Milestone | Severe CKD | ESRD |
|---|---|---|
| Started | 16 | 16 |
| Completed | 15 | 16 |
| Not completed | 1 | 0 |
| Withdrew: Withdrawal by subject | 1 | 0 |
Clinically significant hypocalcemia is defined as albumin-adjusted calcium \< 7.0 mg/dL or symptomatic hypocalcemia. Symptomatic hypocalcemiais is defined as both a clinical adverse event of hypocalcemia and a concomitant symptom of hypocalcemia (e.g., hypoesthesia, paresthesia, muscle cramps, seizure, prolonged QT interval) that occurred along with the hypocalcemia event or decreased serum calcium levels.
| participants | Severe CKD | ESRD |
|---|---|---|
| Number of Participants With Clinically Significant Hypocalcemia | 1 | 2 |
The severity of hypocalcemia (a low concentration of calcium, corrected for albumin, in the blood) was graded according to the common terminology criteria for adverse events (CTCAE) v.4.0 criteria: Grade 1: albumin-adjusted serum calcium \< lower limit of normal (LLN; 9.2 mg/dL) to 8.0 mg/dL; Grade 2: albumin-adjusted serum calcium \< 8.0 to 7.0 mg/dL; Grade 3: albumin-adjusted serum calcium \< 7.0 to 6.0 mg/dL; Grade 4: albumin-adjusted serum calcium \< 6.0 mg/dL.
| participants | Severe CKD | ESRD |
|---|---|---|
| Grade 1 | 12 | 6 |
| Grade 2 | 3 | 9 |
| Grade 3 | 0 | 1 |
| Grade 4 | 0 | 0 |
The severity of hypophosphatemia (a low concentration of phosphates in the blood) was graded according to the common terminology criteria for adverse events (CTCAE) v.4.0 criteria: Grade 1: \< LLN (3 mg/dL) - 2.5 mg/dL; Grade 2: \< 2.5 - 2.0 mg/dL; Grade 3: \< 2.0 - 1.0 mg/dL; Grade 4: \< 1.0 mg/dL.
| participants | Severe CKD | ESRD |
|---|---|---|
| Grade 1 | 0 | 0 |
| Grade 2 | 2 | 1 |
| Grade 3 | 0 | 5 |
| Grade 4 | 0 | 0 |
The severity of hypomagnesemia (a low concentration of magnesium in the blood) was graded according to the common terminology criteria for adverse events (CTCAE) v.4.0 criteria: Grade 1: \< LLN (1.5 mg/dL) - 1.2 mg/dL; Grade 2: \< 1.2 - 0.9 mg/dL; Grade 3: \< 0.9 - 0.7 mg/dL; Grade 4: \< 0.7 mg/dL.
| participants | Severe CKD | ESRD |
|---|---|---|
| Grade 1 | 2 | 0 |
| Grade 2 | 0 | 0 |
| Grade 3 | 0 | 0 |
| Grade 4 | 0 | 0 |
| percent change | Severe CKD | ESRD |
|---|---|---|
| Day 2 (N=16, 16) | -0.55 ± 3.56 | 1.21 ± 4.66 |
| Day 3 (N=16, 16) | -3.20 ± 5.99 | -1.86 ± 5.82 |
| Day 6 (N=16, 16) | -4.27 ± 7.42 | -7.34 ± 8.75 |
| Day 8 (N=15, 16) | -3.11 ± 5.77 | -9.75 ± 9.88 |
| Day 11 (N=16, 16) | -5.10 ± 5.07 | -5.51 ± 6.78 |
| Day 15 (N=16, 16) | -0.49 ± 5.19 | -6.36 ± 9.79 |
| Day 22 (N=14, 15) | -3.74 ± 7.28 | -4.26 ± 8.57 |
| Day 29 (N=15, 16) | -1.17 ± 3.77 | -5.87 ± 12.34 |
| Day 30 (N=15, 16) | -1.08 ± 3.64 | -2.17 ± 9.73 |
| Day 31 (N=15, 16) | -1.03 ± 4.76 | -2.29 ± 10.16 |
| Day 34 (N=15, 16) | 0.00 ± 6.07 | -2.85 ± 13.42 |
| Day 36 (N=14, 16) | -1.08 ± 6.94 | -1.11 ± 7.39 |
| Day 39 (N=16, 15) | -0.60 ± 5.15 | -1.93 ± 7.79 |
| Day 43 (N=15, 15) | -1.04 ± 7.91 | -0.82 ± 6.78 |
| Day 57 (N=15, 16) | -2.08 ± 5.52 | -1.64 ± 11.11 |
| Day 71 (N=15, 16) | 2.06 ± 5.56 | -4.98 ± 9.38 |
| Day 85 (N=14, 15) | 1.06 ± 6.37 | -6.87 ± 10.81 |
| Day 113 (N=15, 16) | 0.00 ± 9.48 | -4.88 ± 7.94 |
| percent change | Severe CKD | ESRD |
|---|---|---|
| Day 2 (N=16, 15) | -5.97 ± 10.42 | -20.00 ± 15.51 |
| Day 3 (N=16, 15) | -10.37 ± 15.25 | -25.93 ± 24.26 |
| Day 6 (N=16, 15) | -19.09 ± 15.81 | -24.56 ± 26.43 |
| Day 8 (N=15, 16) | -13.46 ± 14.96 | -31.16 ± 35.81 |
| Day 11 (N=16, 14) | -19.38 ± 10.93 | -33.29 ± 29.13 |
| Day 15 (N=16, 16) | -10.00 ± 9.15 | -27.64 ± 26.62 |
| Day 22 (N=15, 16) | -15.38 ± 17.27 | -25.89 ± 34.20 |
| Day 29 (N=15, 16) | -5.13 ± 13.22 | -21.64 ± 22.06 |
| Day 30 (N=15, 15) | -5.71 ± 13.63 | -31.25 ± 20.94 |
| Day 31 (N=15, 15) | -7.14 ± 13.20 | -19.30 ± 20.69 |
| Day 34 (N=15, 15) | -5.41 ± 14.23 | -15.00 ± 28.53 |
| Day 36 (N=14, 16) | -4.84 ± 13.80 | -19.38 ± 18.77 |
| Day 39 (N=16, 14) | -8.30 ± 11.72 | -18.89 ± 21.00 |
| Day 43 (N=15, 15) | -6.82 ± 16.53 | -6.25 ± 30.76 |
| Day 57 (N=15, 16) | -11.43 ± 11.65 | -7.18 ± 30.00 |
| Day 71 (N=15, 16) | -3.45 ± 16.32 | -0.05 ± 45.15 |
| Day 85 (N=15, 16) | -7.69 ± 14.51 | -6.04 ± 30.74 |
| Day 113 (N=15, 16) | -7.14 ± 10.07 | -8.99 ± 33.92 |
| percent change | Severe CKD | ESRD |
|---|---|---|
| Day 2 (N=16, 15) | 0.00 ± 7.54 | -3.85 ± 7.47 |
| Day 3 (N=16, 15) | 0.00 ± 10.94 | 0.00 ± 6.65 |
| Day 6 (N=16, 15) | 2.50 ± 8.58 | 4.00 ± 14.39 |
| Day 8 (N=15, 16) | 4.76 ± 7.47 | 0.00 ± 10.46 |
| Day 11 (N=16, 14) | 2.38 ± 10.29 | 0.00 ± 6.12 |
| Day 15 (N=16, 16) | 0.00 ± 10.78 | 0.00 ± 7.88 |
| Day 22 (N=15, 16) | 10.53 ± 9.14 | 0.00 ± 9.24 |
| Day 29 (N=15, 16) | 0.00 ± 9.87 | 2.27 ± 12.57 |
| Day 30 (N=15, 15) | 0.00 ± 16.15 | -4.55 ± 8.87 |
| Day 31 (N=15, 15) | 0.00 ± 12.46 | 0.00 ± 7.94 |
| Day 34 (N=15, 15) | 0.00 ± 7.79 | 0.00 ± 7.85 |
| Day 36 (N=14, 16) | 0.00 ± 9.79 | -4.45 ± 7.47 |
| Day 39 (N=16, 14) | 0.00 ± 12.06 | -4.35 ± 8.68 |
| Day 43 (N=15, 15) | 0.00 ± 8.31 | 3.45 ± 9.00 |
| Day 57 (N=15, 16) | 5.00 ± 15.87 | 0.00 ± 8.50 |
| Day 71 (N=15, 16) | 0.00 ± 9.15 | 0.00 ± 11.74 |
| Day 85 (N=15, 16) | 0.00 ± 9.21 | 4.12 ± 12.40 |
| Day 113 (N=15, 16) | 0.00 ± 11.87 | 1.92 ± 9.46 |
The severity of each adverse event (AE) was graded using the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. The investigator assessed whether AEs were possibly related to study drug by answering the question: "Is there a reasonable possibility that the event may have been caused by the investigational product?" Abnormal laboratory findings without clinical significance (based on the investigator's judgment) were not recorded as AEs, however, laboratory value changes that required treatment or adjustment in current therapy were considered AEs. A serious adverse event is defined as an adverse event that meets at least 1 of the following serious criteria: • fatal, • life-threatening (places the participant at immediate risk of death), • requires in-patient hospitalization or prolongation of existing hospitalization, • results in persistent or significant disability/incapacity, • congenital anomaly/birth defect, and/or • other medically important serious event.
| participants | Severe CKD | ESRD |
|---|---|---|
| Any adverse event (AE) | 10 | 15 |
| Adverse events Grade >=3 | 3 | 7 |
| Serious adverse events | 1 | 2 |
| Leading to discontinuation of study drug | 0 | 0 |
| Leading to discontinuation from study | 0 | 0 |
| Fatal adverse events | 0 | 0 |
| Hypocalcemia adverse events | 3 | 10 |
| Hypomagnesemia adverse events | 0 | 0 |
| Hypophosphatemia adverse events | 0 | 1 |
| Treatment-related adverse events (TRAE) | 2 | 10 |
| Treatment-related adverse events Grade >=3 | 0 | 2 |
| Treatment-related serious adverse events | 0 | 0 |
| TRAE leading to discontinuation of study drug | 0 | 0 |
| TRAE leading to study discontinuation | 0 | 0 |
Serum concentrations of denosumab were measured by an enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 20 ng/mL.
| μg/mL | Severe CKD - Dose 1 | ESRD - Dose 1 | Severe CKD - Dose 2 | ESRD - Dose 2 |
|---|---|---|---|---|
| Maximum Observed Serum Denosumab Concentration (Cmax) | 10.5 ± 3.6 | 8.17 ± 4.22 | 16.1 ± 5.2 | 14.5 ± 7.4 |
Serum concentrations of denosumab were measured by an enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 20 ng/mL.
| days | Severe CKD - Dose 1 | ESRD - Dose 1 | Severe CKD - Dose 2 | ESRD - Dose 2 |
|---|---|---|---|---|
| Time to Maximum Observed Serum Denosumab Concentration (Tmax) | 14 ± 3.6 | 14 ± 4.22 | 14 ± 5.2 | 7.0 ± 7.4 |
Estimated using the linear trapezoidal method.
| μg*day/mL | Severe CKD - Dose 1 | ESRD - Dose 1 |
|---|---|---|
| Area Under the Serum Concentration-time Curve From Time 0 to 4 Weeks (AUC0-4wks) After Dose 1 | 233 ± 75 | 177 ± 91 |
Estimated using the linear trapezoidal method.
| μg*day/mL | Severe CKD - Dose 2 | ESRD - Dose 2 |
|---|---|---|
| Area Under the Serum Concentration-time Curve From Time 0 to 12 Weeks (AUC0-12wks) After Dose 2 | 853 ± 260 | 607 ± 262 |
| percent change | Severe CKD | ESRD |
|---|---|---|
| Day 8 (N=15, 16) | -63.0 ± 24.3 | -79.1 ± 13.6 |
| Day 15 (N=16, 16) | -60.7 ± 23.6 | -79.3 ± 11.9 |
| Day 29 (N=15, 16) | -58.4 ± 24.7 | -81.5 ± 12.3 |
| Day 36 (N=15, 16) | -63.0 ± 24.2 | -79.4 ± 13.1 |
| Day 43 (N=15, 15) | -58.4 ± 24.5 | -77.7 ± 13.4 |
| Day 57 (N=15, 16) | -58.4 ± 24.0 | -81.7 ± 11.7 |
| Day 71 (N=15, 16) | -58.4 ± 24.0 | -76.4 ± 13.8 |
| Day 85 (N=15, 16) | -57.4 ± 24.0 | -75.9 ± 12.0 |
| Day 113 (N=15, 16) | -50.2 (-75.0 to -39.4) | -75.6 (-88.5 to -63.3) |
| participants | Severe CKD | ESRD |
|---|---|---|
| Number of Participants Who Developed Anti-denosumab Antibodies | 0 | 0 |
Collected over 113 days. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Denosumab 120 mg - Severe | — | 1/16 (6.3%) | 10/16 (62.5%) |
| Denosumab 120 mg - ESRD | — | 2/16 (12.5%) | 15/16 (93.8%) |
| Denosumab 120 mg - All Subjects | — | 3/32 (9.4%) | 25/32 (78.1%) |
| Event | Denosumab 120 mg - Severe | Denosumab 120 mg - ESRD | Denosumab 120 mg - All Subjects |
|---|---|---|---|
| IleitisGastrointestinal disorders | 0/16 | 1/16 | 1/32 |
| AstheniaGeneral disorders | 1/16 | 0/16 | 1/32 |
| Non-cardiac chest painGeneral disorders | 0/16 | 1/16 | 1/32 |
| Event | Denosumab 120 mg - Severe | Denosumab 120 mg - ESRD | Denosumab 120 mg - All Subjects |
|---|---|---|---|
| HypocalcaemiaMetabolism and nutrition disorders | 2/16 | 10/16 | 12/32 |
| HypercalcaemiaMetabolism and nutrition disorders | 2/16 | 3/16 | 5/32 |
| DiarrhoeaGastrointestinal disorders | 2/16 | 1/16 | 3/32 |
| Upper respiratory tract infectionInfections and infestations | 0/16 | 2/16 | 2/32 |
| AnaemiaBlood and lymphatic system disorders | 1/16 | 0/16 | 1/32 |
| Angina pectorisCardiac disorders | 0/16 | 1/16 | 1/32 |
| PericarditisCardiac disorders | 0/16 | 1/16 | 1/32 |
| Sinus tachycardiaCardiac disorders | 0/16 | 1/16 | 1/32 |
| Ventricular extrasystolesCardiac disorders | 0/16 | 1/16 | 1/32 |
| Hearing impairedEar and labyrinth disorders | 0/16 | 1/16 | 1/32 |
| Age, Continuous(years) | Severe CKD | ESRD | Total |
|---|---|---|---|
| Mean | 79.2 ± 9.5 | 65.9 ± 12.4 | 72.5 ± 12.8 |
| Sex: Female, Male(Participants) | Severe CKD | ESRD | Total |
|---|---|---|---|
| Female | 9 | 7 | 16 |
| Male | 7 | 9 | 16 |
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