Trial Outcomes & Findings for Multiple Dose Study to Evaluate the Safety of Multiple Doses of Denosumab 120 mg in Adults With Severe Chronic Kidney Disease (CKD) and CKD on Dialysis (NCT NCT01464931)

Last Updated: 2016-02-19

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

32 participants

Primary outcome timeframe

113 days

Results posted on

2016-02-19

Participant Flow

Participant milestones

Participant milestones
Measure	Severe CKD Participants with severe chronic kidney disease (CKD; defined as creatinine clearance \< 30 mL/min) received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	ESRD Participants with end-stage renal disease (ESRD) requiring dialysis received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.
Overall Study STARTED	16	16
Overall Study COMPLETED	15	16
Overall Study NOT COMPLETED	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Severe CKD Participants with severe chronic kidney disease (CKD; defined as creatinine clearance \< 30 mL/min) received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	ESRD Participants with end-stage renal disease (ESRD) requiring dialysis received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.
Overall Study Withdrawal by Subject	1	0

Baseline Characteristics

Multiple Dose Study to Evaluate the Safety of Multiple Doses of Denosumab 120 mg in Adults With Severe Chronic Kidney Disease (CKD) and CKD on Dialysis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Severe CKD n=16 Participants Participants with severe chronic kidney disease (CKD; defined as creatinine clearance \< 30 mL/min) received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	ESRD n=16 Participants Participants with end-stage renal disease (ESRD) requiring dialysis received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	Total n=32 Participants Total of all reporting groups
Age, Continuous	79.2 years STANDARD_DEVIATION 9.5 • n=5 Participants	65.9 years STANDARD_DEVIATION 12.4 • n=7 Participants	72.5 years STANDARD_DEVIATION 12.8 • n=5 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	7 Participants n=7 Participants	16 Participants n=5 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	9 Participants n=7 Participants	16 Participants n=5 Participants

PRIMARY outcome

Timeframe: 113 days

Population: Safety Analysis Set (all participants who received at least 1 dose of denosumab)

Outcome measures

Outcome measures
Measure	Severe CKD n=16 Participants Participants with severe chronic kidney disease (CKD; defined as creatinine clearance \< 30 mL/min) received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	ESRD n=16 Participants Participants with end-stage renal disease (ESRD) requiring dialysis received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	Severe CKD - Dose 2 Participants with severe CKD received 120 mg denosumab administered subcutaneously on Day 29.	ESRD - Dose 2 Participants with ESRD requiring dialysis received 120 mg denosumab administered subcutaneously on Day 29.
Number of Participants With Clinically Significant Hypocalcemia	1 participants	2 participants	—	—

SECONDARY outcome

Timeframe: 113 days

Population: Safety analysis set

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.

Outcome measures

Outcome measures
Measure	Severe CKD n=16 Participants Participants with severe chronic kidney disease (CKD; defined as creatinine clearance \< 30 mL/min) received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	ESRD n=16 Participants Participants with end-stage renal disease (ESRD) requiring dialysis received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	Severe CKD - Dose 2 Participants with severe CKD received 120 mg denosumab administered subcutaneously on Day 29.	ESRD - Dose 2 Participants with ESRD requiring dialysis received 120 mg denosumab administered subcutaneously on Day 29.
Number of Participants With Hypocalcemia Determined by CTCAE v.4.0 Criteria Grade 1	12 participants	6 participants	—	—
Number of Participants With Hypocalcemia Determined by CTCAE v.4.0 Criteria Grade 2	3 participants	9 participants	—	—
Number of Participants With Hypocalcemia Determined by CTCAE v.4.0 Criteria Grade 3	0 participants	1 participants	—	—
Number of Participants With Hypocalcemia Determined by CTCAE v.4.0 Criteria Grade 4	0 participants	0 participants	—	—

SECONDARY outcome

Timeframe: 113 days

Population: Safety analysis set

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.

Outcome measures

Outcome measures
Measure	Severe CKD n=16 Participants Participants with severe chronic kidney disease (CKD; defined as creatinine clearance \< 30 mL/min) received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	ESRD n=16 Participants Participants with end-stage renal disease (ESRD) requiring dialysis received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	Severe CKD - Dose 2 Participants with severe CKD received 120 mg denosumab administered subcutaneously on Day 29.	ESRD - Dose 2 Participants with ESRD requiring dialysis received 120 mg denosumab administered subcutaneously on Day 29.
Number of Participants With Hypophosphatemia Determined by CTCAE v.4.0 Criteria Grade 1	0 participants	0 participants	—	—
Number of Participants With Hypophosphatemia Determined by CTCAE v.4.0 Criteria Grade 2	2 participants	1 participants	—	—
Number of Participants With Hypophosphatemia Determined by CTCAE v.4.0 Criteria Grade 3	0 participants	5 participants	—	—
Number of Participants With Hypophosphatemia Determined by CTCAE v.4.0 Criteria Grade 4	0 participants	0 participants	—	—

SECONDARY outcome

Timeframe: 113 days

Population: Safety analysis set

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.

Outcome measures

Outcome measures
Measure	Severe CKD n=16 Participants Participants with severe chronic kidney disease (CKD; defined as creatinine clearance \< 30 mL/min) received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	ESRD n=16 Participants Participants with end-stage renal disease (ESRD) requiring dialysis received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	Severe CKD - Dose 2 Participants with severe CKD received 120 mg denosumab administered subcutaneously on Day 29.	ESRD - Dose 2 Participants with ESRD requiring dialysis received 120 mg denosumab administered subcutaneously on Day 29.
Number of Participants With Hypomagnesemia Determined by CTCAE v.4.0 Criteria Grade 1	2 participants	0 participants	—	—
Number of Participants With Hypomagnesemia Determined by CTCAE v.4.0 Criteria Grade 2	0 participants	0 participants	—	—
Number of Participants With Hypomagnesemia Determined by CTCAE v.4.0 Criteria Grade 3	0 participants	0 participants	—	—
Number of Participants With Hypomagnesemia Determined by CTCAE v.4.0 Criteria Grade 4	0 participants	0 participants	—	—

SECONDARY outcome

Timeframe: Baseline and Days 2, 3, 6, 8, 11, 15, 22, 29, 30, 31, 34, 36, 39, 43, 57, 71, 85, and 113

Population: Safety analysis set with available data at each time point

Outcome measures

Outcome measures
Measure	Severe CKD n=16 Participants Participants with severe chronic kidney disease (CKD; defined as creatinine clearance \< 30 mL/min) received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	ESRD n=16 Participants Participants with end-stage renal disease (ESRD) requiring dialysis received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	Severe CKD - Dose 2 Participants with severe CKD received 120 mg denosumab administered subcutaneously on Day 29.	ESRD - Dose 2 Participants with ESRD requiring dialysis received 120 mg denosumab administered subcutaneously on Day 29.
Percent Change From Baseline in Albumin-adjusted Serum Calcium Over Time Day 34 (N=15, 16)	0.00 percent change Inter-Quartile Range 6.07 • Interval -3.92 to 2.94	-2.85 percent change Inter-Quartile Range 13.42 • Interval -8.48 to 3.57	—	—
Percent Change From Baseline in Albumin-adjusted Serum Calcium Over Time Day 36 (N=14, 16)	-1.08 percent change Inter-Quartile Range 6.94 • Interval -3.92 to 3.11	-1.11 percent change Inter-Quartile Range 7.39 • Interval -6.55 to 2.18	—	—
Percent Change From Baseline in Albumin-adjusted Serum Calcium Over Time Day 2 (N=16, 16)	-0.55 percent change Inter-Quartile Range 3.56 • Interval -1.28 to 0.51	1.21 percent change Inter-Quartile Range 4.66 • Interval -54.0 to 4.52	—	—
Percent Change From Baseline in Albumin-adjusted Serum Calcium Over Time Day 3 (N=16, 16)	-3.20 percent change Inter-Quartile Range 5.99 • Interval -6.88 to 0.19	-1.86 percent change Inter-Quartile Range 5.82 • Interval -7.11 to 2.38	—	—
Percent Change From Baseline in Albumin-adjusted Serum Calcium Over Time Day 6 (N=16, 16)	-4.27 percent change Inter-Quartile Range 7.42 • Interval -7.77 to -0.9	-7.34 percent change Inter-Quartile Range 8.75 • Interval -13.62 to 4.15	—	—
Percent Change From Baseline in Albumin-adjusted Serum Calcium Over Time Day 8 (N=15, 16)	-3.11 percent change Inter-Quartile Range 5.77 • Interval -6.9 to -1.01	-9.75 percent change Inter-Quartile Range 9.88 • Interval -12.18 to 1.06	—	—
Percent Change From Baseline in Albumin-adjusted Serum Calcium Over Time Day 11 (N=16, 16)	-5.10 percent change Inter-Quartile Range 5.07 • Interval -7.34 to -0.78	-5.51 percent change Inter-Quartile Range 6.78 • Interval -12.92 to -1.73	—	—
Percent Change From Baseline in Albumin-adjusted Serum Calcium Over Time Day 15 (N=16, 16)	-0.49 percent change Inter-Quartile Range 5.19 • Interval -5.91 to 1.08	-6.36 percent change Inter-Quartile Range 9.79 • Interval -15.92 to -0.21	—	—
Percent Change From Baseline in Albumin-adjusted Serum Calcium Over Time Day 22 (N=14, 15)	-3.74 percent change Inter-Quartile Range 7.28 • Interval -8.25 to 0.0	-4.26 percent change Inter-Quartile Range 8.57 • Interval -13.13 to 2.3	—	—
Percent Change From Baseline in Albumin-adjusted Serum Calcium Over Time Day 29 (N=15, 16)	-1.17 percent change Inter-Quartile Range 3.77 • Interval -4.12 to 1.14	-5.87 percent change Inter-Quartile Range 12.34 • Interval -9.62 to 3.0	—	—
Percent Change From Baseline in Albumin-adjusted Serum Calcium Over Time Day 30 (N=15, 16)	-1.08 percent change Inter-Quartile Range 3.64 • Interval -2.08 to 1.01	-2.17 percent change Inter-Quartile Range 9.73 • Interval -4.61 to 1.98	—	—
Percent Change From Baseline in Albumin-adjusted Serum Calcium Over Time Day 31 (N=15, 16)	-1.03 percent change Inter-Quartile Range 4.76 • Interval -6.45 to 2.08	-2.29 percent change Inter-Quartile Range 10.16 • Interval -6.17 to 3.71	—	—
Percent Change From Baseline in Albumin-adjusted Serum Calcium Over Time Day 39 (N=16, 15)	-0.60 percent change Inter-Quartile Range 5.15 • Interval -4.6 to 2.66	-1.93 percent change Inter-Quartile Range 7.79 • Interval -10.11 to 3.19	—	—
Percent Change From Baseline in Albumin-adjusted Serum Calcium Over Time Day 43 (N=15, 15)	-1.04 percent change Inter-Quartile Range 7.91 • Interval -4.12 to 2.15	-0.82 percent change Inter-Quartile Range 6.78 • Interval -9.27 to 2.96	—	—
Percent Change From Baseline in Albumin-adjusted Serum Calcium Over Time Day 57 (N=15, 16)	-2.08 percent change Inter-Quartile Range 5.52 • Interval -6.86 to 2.27	-1.64 percent change Inter-Quartile Range 11.11 • Interval -9.92 to 2.59	—	—
Percent Change From Baseline in Albumin-adjusted Serum Calcium Over Time Day 71 (N=15, 16)	2.06 percent change Inter-Quartile Range 5.56 • Interval -3.41 to 5.21	-4.98 percent change Inter-Quartile Range 9.38 • Interval -15.07 to 1.88	—	—
Percent Change From Baseline in Albumin-adjusted Serum Calcium Over Time Day 85 (N=14, 15)	1.06 percent change Inter-Quartile Range 6.37 • Interval -6.86 to 4.55	-6.87 percent change Inter-Quartile Range 10.81 • Interval -15.06 to 4.49	—	—
Percent Change From Baseline in Albumin-adjusted Serum Calcium Over Time Day 113 (N=15, 16)	0.00 percent change Inter-Quartile Range 9.48 • Interval -4.12 to 4.67	-4.88 percent change Inter-Quartile Range 7.94 • Interval -8.71 to 1.12	—	—

SECONDARY outcome

Timeframe: Baseline and Days 2, 3, 6, 8, 11, 15, 22, 29, 30, 31, 34, 36, 39, 43, 57, 71, 85, and 113

Population: Safety analysis set with available data at each time point

Outcome measures

Outcome measures
Measure	Severe CKD n=16 Participants Participants with severe chronic kidney disease (CKD; defined as creatinine clearance \< 30 mL/min) received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	ESRD n=16 Participants Participants with end-stage renal disease (ESRD) requiring dialysis received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	Severe CKD - Dose 2 Participants with severe CKD received 120 mg denosumab administered subcutaneously on Day 29.	ESRD - Dose 2 Participants with ESRD requiring dialysis received 120 mg denosumab administered subcutaneously on Day 29.
Percent Change From Baseline in Serum Phosphorus Over Time Day 2 (N=16, 15)	-5.97 percent change Inter-Quartile Range 10.42 • Interval -12.14 to -2.41	-20.00 percent change Inter-Quartile Range 15.51 • Interval -28.07 to -15.63	—	—
Percent Change From Baseline in Serum Phosphorus Over Time Day 3 (N=16, 15)	-10.37 percent change Inter-Quartile Range 15.25 • Interval -14.72 to -1.72	-25.93 percent change Inter-Quartile Range 24.26 • Interval -35.71 to 2.27	—	—
Percent Change From Baseline in Serum Phosphorus Over Time Day 6 (N=16, 15)	-19.09 percent change Inter-Quartile Range 15.81 • Interval -25.47 to -8.22	-24.56 percent change Inter-Quartile Range 26.43 • Interval -42.5 to -3.13	—	—
Percent Change From Baseline in Serum Phosphorus Over Time Day 8 (N=15, 16)	-13.46 percent change Inter-Quartile Range 14.96 • Interval -22.5 to -5.13	-31.16 percent change Inter-Quartile Range 35.81 • Interval -40.92 to -7.81	—	—
Percent Change From Baseline in Serum Phosphorus Over Time Day 11 (N=16, 14)	-19.38 percent change Inter-Quartile Range 10.93 • Interval -26.14 to -12.86	-33.29 percent change Inter-Quartile Range 29.13 • Interval -40.48 to -15.63	—	—
Percent Change From Baseline in Serum Phosphorus Over Time Day 15 (N=16, 16)	-10.00 percent change Inter-Quartile Range 9.15 • Interval -14.39 to -4.11	-27.64 percent change Inter-Quartile Range 26.62 • Interval -40.0 to -16.75	—	—
Percent Change From Baseline in Serum Phosphorus Over Time Day 22 (N=15, 16)	-15.38 percent change Inter-Quartile Range 17.27 • Interval -28.21 to -3.57	-25.89 percent change Inter-Quartile Range 34.20 • Interval -44.35 to -2.98	—	—
Percent Change From Baseline in Serum Phosphorus Over Time Day 29 (N=15, 16)	-5.13 percent change Inter-Quartile Range 13.22 • Interval -21.21 to 3.13	-21.64 percent change Inter-Quartile Range 22.06 • Interval -27.5 to -10.0	—	—
Percent Change From Baseline in Serum Phosphorus Over Time Day 30 (N=15, 15)	-5.71 percent change Inter-Quartile Range 13.63 • Interval -20.51 to 3.45	-31.25 percent change Inter-Quartile Range 20.94 • Interval -35.56 to -17.54	—	—
Percent Change From Baseline in Serum Phosphorus Over Time Day 31 (N=15, 15)	-7.14 percent change Inter-Quartile Range 13.20 • Interval -17.31 to 2.22	-19.30 percent change Inter-Quartile Range 20.69 • Interval -22.5 to -9.38	—	—
Percent Change From Baseline in Serum Phosphorus Over Time Day 34 (N=15, 15)	-5.41 percent change Inter-Quartile Range 14.23 • Interval -15.38 to 3.57	-15.00 percent change Inter-Quartile Range 28.53 • Interval -30.0 to 2.27	—	—
Percent Change From Baseline in Serum Phosphorus Over Time Day 36 (N=14, 16)	-4.84 percent change Inter-Quartile Range 13.80 • Interval -12.5 to 6.25	-19.38 percent change Inter-Quartile Range 18.77 • Interval -36.61 to -11.0	—	—
Percent Change From Baseline in Serum Phosphorus Over Time Day 39 (N=16, 14)	-8.30 percent change Inter-Quartile Range 11.72 • Interval -14.45 to 0.94	-18.89 percent change Inter-Quartile Range 21.00 • Interval -33.33 to 0.0	—	—
Percent Change From Baseline in Serum Phosphorus Over Time Day 43 (N=15, 15)	-6.82 percent change Inter-Quartile Range 16.53 • Interval -10.26 to 9.38	-6.25 percent change Inter-Quartile Range 30.76 • Interval -40.48 to 7.5	—	—
Percent Change From Baseline in Serum Phosphorus Over Time Day 57 (N=15, 16)	-11.43 percent change Inter-Quartile Range 11.65 • Interval -21.15 to -3.45	-7.18 percent change Inter-Quartile Range 30.00 • Interval -41.01 to 8.94	—	—
Percent Change From Baseline in Serum Phosphorus Over Time Day 71 (N=15, 16)	-3.45 percent change Inter-Quartile Range 16.32 • Interval -18.18 to 2.27	-0.05 percent change Inter-Quartile Range 45.15 • Interval -30.95 to 32.5	—	—
Percent Change From Baseline in Serum Phosphorus Over Time Day 85 (N=15, 16)	-7.69 percent change Inter-Quartile Range 14.51 • Interval -25.64 to 3.13	-6.04 percent change Inter-Quartile Range 30.74 • Interval -23.15 to 7.81	—	—
Percent Change From Baseline in Serum Phosphorus Over Time Day 113 (N=15, 16)	-7.14 percent change Inter-Quartile Range 10.07 • Interval -18.18 to 0.0	-8.99 percent change Inter-Quartile Range 33.92 • Interval -19.87 to 25.0	—	—

SECONDARY outcome

Timeframe: Baseline and Days 2, 3, 6, 8, 11, 15, 22, 29, 30, 31, 34, 36, 39, 43, 57, 71, 85, and 113

Population: Safety analysis set with available data at each time point

Outcome measures

Outcome measures
Measure	Severe CKD n=16 Participants Participants with severe chronic kidney disease (CKD; defined as creatinine clearance \< 30 mL/min) received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	ESRD n=16 Participants Participants with end-stage renal disease (ESRD) requiring dialysis received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	Severe CKD - Dose 2 Participants with severe CKD received 120 mg denosumab administered subcutaneously on Day 29.	ESRD - Dose 2 Participants with ESRD requiring dialysis received 120 mg denosumab administered subcutaneously on Day 29.
Percent Change From Baseline in Serum Magnesium Over Time Day 2 (N=16, 15)	0.00 percent change Inter-Quartile Range 7.54 • Interval -4.76 to 5.01	-3.85 percent change Inter-Quartile Range 7.47 • Interval -7.41 to 4.55	—	—
Percent Change From Baseline in Serum Magnesium Over Time Day 3 (N=16, 15)	0.00 percent change Inter-Quartile Range 10.94 • Interval -5.26 to 8.2	0.00 percent change Inter-Quartile Range 6.65 • Interval -4.55 to 0.0	—	—
Percent Change From Baseline in Serum Magnesium Over Time Day 6 (N=16, 15)	2.50 percent change Inter-Quartile Range 8.58 • Interval -4.65 to 9.52	4.00 percent change Inter-Quartile Range 14.39 • Interval 0.0 to 9.09	—	—
Percent Change From Baseline in Serum Magnesium Over Time Day 8 (N=15, 16)	4.76 percent change Inter-Quartile Range 7.47 • Interval -4.55 to 9.52	0.00 percent change Inter-Quartile Range 10.46 • Interval -8.15 to 4.55	—	—
Percent Change From Baseline in Serum Magnesium Over Time Day 11 (N=16, 14)	2.38 percent change Inter-Quartile Range 10.29 • Interval -4.77 to 10.53	0.00 percent change Inter-Quartile Range 6.12 • Interval -4.35 to 3.45	—	—
Percent Change From Baseline in Serum Magnesium Over Time Day 15 (N=16, 16)	0.00 percent change Inter-Quartile Range 10.78 • Interval -4.65 to 10.03	0.00 percent change Inter-Quartile Range 7.88 • Interval -4.76 to 2.27	—	—
Percent Change From Baseline in Serum Magnesium Over Time Day 22 (N=15, 16)	10.53 percent change Inter-Quartile Range 9.14 • Interval 0.0 to 11.76	0.00 percent change Inter-Quartile Range 9.24 • Interval -2.0 to 4.45	—	—
Percent Change From Baseline in Serum Magnesium Over Time Day 29 (N=15, 16)	0.00 percent change Inter-Quartile Range 9.87 • Interval -4.76 to 4.76	2.27 percent change Inter-Quartile Range 12.57 • Interval -8.47 to 11.03	—	—
Percent Change From Baseline in Serum Magnesium Over Time Day 30 (N=15, 15)	0.00 percent change Inter-Quartile Range 16.15 • Interval -5.26 to 10.0	-4.55 percent change Inter-Quartile Range 8.87 • Interval -13.64 to 0.0	—	—
Percent Change From Baseline in Serum Magnesium Over Time Day 31 (N=15, 15)	0.00 percent change Inter-Quartile Range 12.46 • Interval -5.26 to 5.88	0.00 percent change Inter-Quartile Range 7.94 • Interval -9.09 to 0.0	—	—
Percent Change From Baseline in Serum Magnesium Over Time Day 34 (N=15, 15)	0.00 percent change Inter-Quartile Range 7.79 • Interval -5.26 to 4.76	0.00 percent change Inter-Quartile Range 7.85 • Interval -6.9 to 5.26	—	—
Percent Change From Baseline in Serum Magnesium Over Time Day 36 (N=14, 16)	0.00 percent change Inter-Quartile Range 9.79 • Interval -5.88 to 4.76	-4.45 percent change Inter-Quartile Range 7.47 • Interval -9.9 to 0.0	—	—
Percent Change From Baseline in Serum Magnesium Over Time Day 39 (N=16, 14)	0.00 percent change Inter-Quartile Range 12.06 • Interval -4.55 to 4.88	-4.35 percent change Inter-Quartile Range 8.68 • Interval -13.64 to 0.0	—	—
Percent Change From Baseline in Serum Magnesium Over Time Day 43 (N=15, 15)	0.00 percent change Inter-Quartile Range 8.31 • Interval -4.76 to 5.88	3.45 percent change Inter-Quartile Range 9.00 • Interval -8.7 to 4.76	—	—
Percent Change From Baseline in Serum Magnesium Over Time Day 57 (N=15, 16)	5.00 percent change Inter-Quartile Range 15.87 • Interval 0.0 to 9.52	0.00 percent change Inter-Quartile Range 8.50 • Interval -6.02 to 7.99	—	—
Percent Change From Baseline in Serum Magnesium Over Time Day 71 (N=15, 16)	0.00 percent change Inter-Quartile Range 9.15 • Interval -5.0 to 5.88	0.00 percent change Inter-Quartile Range 11.74 • Interval -8.19 to 9.52	—	—
Percent Change From Baseline in Serum Magnesium Over Time Day 85 (N=15, 16)	0.00 percent change Inter-Quartile Range 9.21 • Interval -9.09 to 5.88	4.12 percent change Inter-Quartile Range 12.40 • Interval -8.39 to 9.31	—	—
Percent Change From Baseline in Serum Magnesium Over Time Day 113 (N=15, 16)	0.00 percent change Inter-Quartile Range 11.87 • Interval -9.09 to 15.0	1.92 percent change Inter-Quartile Range 9.46 • Interval -4.45 to 8.55	—	—

SECONDARY outcome

Timeframe: 113 days

Population: Safety analysis set

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.

Outcome measures

Outcome measures
Measure	Severe CKD n=16 Participants Participants with severe chronic kidney disease (CKD; defined as creatinine clearance \< 30 mL/min) received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	ESRD n=16 Participants Participants with end-stage renal disease (ESRD) requiring dialysis received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	Severe CKD - Dose 2 Participants with severe CKD received 120 mg denosumab administered subcutaneously on Day 29.	ESRD - Dose 2 Participants with ESRD requiring dialysis received 120 mg denosumab administered subcutaneously on Day 29.
Number of Participants With Adverse Events Any adverse event (AE)	10 participants	15 participants	—	—
Number of Participants With Adverse Events Hypocalcemia adverse events	3 participants	10 participants	—	—
Number of Participants With Adverse Events Hypomagnesemia adverse events	0 participants	0 participants	—	—
Number of Participants With Adverse Events Adverse events Grade >=3	3 participants	7 participants	—	—
Number of Participants With Adverse Events Serious adverse events	1 participants	2 participants	—	—
Number of Participants With Adverse Events Leading to discontinuation of study drug	0 participants	0 participants	—	—
Number of Participants With Adverse Events Leading to discontinuation from study	0 participants	0 participants	—	—
Number of Participants With Adverse Events Fatal adverse events	0 participants	0 participants	—	—
Number of Participants With Adverse Events Hypophosphatemia adverse events	0 participants	1 participants	—	—
Number of Participants With Adverse Events Treatment-related adverse events (TRAE)	2 participants	10 participants	—	—
Number of Participants With Adverse Events Treatment-related adverse events Grade >=3	0 participants	2 participants	—	—
Number of Participants With Adverse Events Treatment-related serious adverse events	0 participants	0 participants	—	—
Number of Participants With Adverse Events TRAE leading to discontinuation of study drug	0 participants	0 participants	—	—
Number of Participants With Adverse Events TRAE leading to study discontinuation	0 participants	0 participants	—	—

SECONDARY outcome

Timeframe: Days 1 and 29 (predose), and on Days 8, 15, 36, 43, 57, 71, 85, and 113

Population: Pharmacokinetic (PK) Parameter Analysis Set (all participants who received at least 1 dose of denosumab and for whom PK parameter estimates could be derived)

Serum concentrations of denosumab were measured by an enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 20 ng/mL.

Outcome measures

Outcome measures
Measure	Severe CKD n=14 Participants Participants with severe chronic kidney disease (CKD; defined as creatinine clearance \< 30 mL/min) received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	ESRD n=16 Participants Participants with end-stage renal disease (ESRD) requiring dialysis received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	Severe CKD - Dose 2 n=15 Participants Participants with severe CKD received 120 mg denosumab administered subcutaneously on Day 29.	ESRD - Dose 2 n=16 Participants Participants with ESRD requiring dialysis received 120 mg denosumab administered subcutaneously on Day 29.
Maximum Observed Serum Denosumab Concentration (Cmax)	10.5 μg/mL Standard Deviation 3.6	8.17 μg/mL Standard Deviation 4.22	16.1 μg/mL Standard Deviation 5.2	14.5 μg/mL Standard Deviation 7.4

SECONDARY outcome

Timeframe: Days 1 and 29 (predose), and on Days 8, 15, 36, 43, 57, 71, 85, and 113

Population: PK Parameter Analysis Set

Serum concentrations of denosumab were measured by an enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 20 ng/mL.

Outcome measures

Outcome measures
Measure	Severe CKD n=14 Participants Participants with severe chronic kidney disease (CKD; defined as creatinine clearance \< 30 mL/min) received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	ESRD n=16 Participants Participants with end-stage renal disease (ESRD) requiring dialysis received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	Severe CKD - Dose 2 n=15 Participants Participants with severe CKD received 120 mg denosumab administered subcutaneously on Day 29.	ESRD - Dose 2 n=16 Participants Participants with ESRD requiring dialysis received 120 mg denosumab administered subcutaneously on Day 29.
Time to Maximum Observed Serum Denosumab Concentration (Tmax)	14 days Full Range 3.6 • Interval 7.0 to 28.0	14 days Full Range 4.22 • Interval 7.0 to 28.0	14 days Full Range 5.2 • Interval 7.0 to 14.0	7.0 days Full Range 7.4 • Interval 7.0 to 28.0

SECONDARY outcome

Timeframe: Days 1, 8, 15, and 29 (predose)

Population: PK Parameter Analysis Set

Estimated using the linear trapezoidal method.

Outcome measures

Outcome measures
Measure	Severe CKD n=14 Participants Participants with severe chronic kidney disease (CKD; defined as creatinine clearance \< 30 mL/min) received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	ESRD n=16 Participants Participants with end-stage renal disease (ESRD) requiring dialysis received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	Severe CKD - Dose 2 Participants with severe CKD received 120 mg denosumab administered subcutaneously on Day 29.	ESRD - Dose 2 Participants with ESRD requiring dialysis received 120 mg denosumab administered subcutaneously on Day 29.
Area Under the Serum Concentration-time Curve From Time 0 to 4 Weeks (AUC0-4wks) After Dose 1	233 μg*day/mL Standard Deviation 75	177 μg*day/mL Standard Deviation 91	—	—

SECONDARY outcome

Timeframe: Days 29 (predose), 36, 43, 57, 71, and 85

Population: PK Parameter Analysis Set

Estimated using the linear trapezoidal method.

Outcome measures

Outcome measures
Measure	Severe CKD n=15 Participants Participants with severe chronic kidney disease (CKD; defined as creatinine clearance \< 30 mL/min) received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	ESRD n=16 Participants Participants with end-stage renal disease (ESRD) requiring dialysis received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	Severe CKD - Dose 2 Participants with severe CKD received 120 mg denosumab administered subcutaneously on Day 29.	ESRD - Dose 2 Participants with ESRD requiring dialysis received 120 mg denosumab administered subcutaneously on Day 29.
Area Under the Serum Concentration-time Curve From Time 0 to 12 Weeks (AUC0-12wks) After Dose 2	853 μg*day/mL Standard Deviation 260	607 μg*day/mL Standard Deviation 262	—	—

SECONDARY outcome

Timeframe: Baseline and Days 1 and 29 (predose), and on Days 8, 15, 36, 43, 57, 71, 85, and 113

Population: Pharmacodynamic Analysis Set (all participants who received at least 1 dose of denosumab and from whom baseline and at least 1 postbaseline value was collected)

Outcome measures

Outcome measures
Measure	Severe CKD n=16 Participants Participants with severe chronic kidney disease (CKD; defined as creatinine clearance \< 30 mL/min) received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	ESRD n=16 Participants Participants with end-stage renal disease (ESRD) requiring dialysis received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	Severe CKD - Dose 2 Participants with severe CKD received 120 mg denosumab administered subcutaneously on Day 29.	ESRD - Dose 2 Participants with ESRD requiring dialysis received 120 mg denosumab administered subcutaneously on Day 29.
Percent Change From Baseline in Serum C-Telopeptide Over Time Day 8 (N=15, 16)	-63.0 percent change Inter-Quartile Range 24.3 • Interval -75.0 to -39.4	-79.1 percent change Inter-Quartile Range 13.6 • Interval -87.8 to -68.8	—	—
Percent Change From Baseline in Serum C-Telopeptide Over Time Day 15 (N=16, 16)	-60.7 percent change Inter-Quartile Range 23.6 • Interval -73.0 to -38.3	-79.3 percent change Inter-Quartile Range 11.9 • Interval -87.1 to -69.8	—	—
Percent Change From Baseline in Serum C-Telopeptide Over Time Day 29 (N=15, 16)	-58.4 percent change Inter-Quartile Range 24.7 • Interval -74.7 to -39.4	-81.5 percent change Inter-Quartile Range 12.3 • Interval -87.0 to -67.8	—	—
Percent Change From Baseline in Serum C-Telopeptide Over Time Day 36 (N=15, 16)	-63.0 percent change Inter-Quartile Range 24.2 • Interval -75.0 to -39.4	-79.4 percent change Inter-Quartile Range 13.1 • Interval -88.2 to -69.9	—	—
Percent Change From Baseline in Serum C-Telopeptide Over Time Day 43 (N=15, 15)	-58.4 percent change Inter-Quartile Range 24.5 • Interval -75.0 to -39.4	-77.7 percent change Inter-Quartile Range 13.4 • Interval -87.0 to -69.3	—	—
Percent Change From Baseline in Serum C-Telopeptide Over Time Day 57 (N=15, 16)	-58.4 percent change Inter-Quartile Range 24.0 • Interval -75.0 to -39.4	-81.7 percent change Inter-Quartile Range 11.7 • Interval -87.2 to -68.0	—	—
Percent Change From Baseline in Serum C-Telopeptide Over Time Day 71 (N=15, 16)	-58.4 percent change Inter-Quartile Range 24.0 • Interval -75.0 to -39.4	-76.4 percent change Inter-Quartile Range 13.8 • Interval -87.9 to -68.2	—	—
Percent Change From Baseline in Serum C-Telopeptide Over Time Day 85 (N=15, 16)	-57.4 percent change Inter-Quartile Range 24.0 • Interval -75.0 to -39.4	-75.9 percent change Inter-Quartile Range 12.0 • Interval -85.9 to -68.1	—	—
Percent Change From Baseline in Serum C-Telopeptide Over Time Day 113 (N=15, 16)	-50.2 percent change Interval -75.0 to -39.4	-75.6 percent change Interval -88.5 to -63.3	—	—

SECONDARY outcome

Timeframe: From Day 1 (predose) to Day 113

Population: Safety analysis set

Outcome measures

Outcome measures
Measure	Severe CKD n=16 Participants Participants with severe chronic kidney disease (CKD; defined as creatinine clearance \< 30 mL/min) received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	ESRD n=16 Participants Participants with end-stage renal disease (ESRD) requiring dialysis received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	Severe CKD - Dose 2 Participants with severe CKD received 120 mg denosumab administered subcutaneously on Day 29.	ESRD - Dose 2 Participants with ESRD requiring dialysis received 120 mg denosumab administered subcutaneously on Day 29.
Number of Participants Who Developed Anti-denosumab Antibodies	0 participants	0 participants	—	—

Adverse Events

Denosumab 120 mg - Severe

Serious events: 1 serious events

Other events: 10 other events

Deaths: 0 deaths

Denosumab 120 mg - ESRD

Serious events: 2 serious events

Other events: 15 other events

Deaths: 0 deaths

Denosumab 120 mg - All Subjects

Serious events: 3 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Denosumab 120 mg - Severe n=16 participants at risk Participants with severe chronic kidney disease (CKD; defined as creatinine clearance \< 30 mL/min) received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	Denosumab 120 mg - ESRD n=16 participants at risk Participants with end-stage renal disease (ESRD) requiring dialysis received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.	Denosumab 120 mg - All Subjects n=32 participants at risk Participants received two 120 mg doses of denosumab administered subcutaneously on Day 1 and Day 29.
Gastrointestinal disorders Ileitis	0.00% 0/16 • 113 days Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold. Summary of Adverse Events includes only those subjects who received at least one dose of investigational product. ESRD = End stage renal disease requiring dialysis.	6.2% 1/16 • 113 days Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold. Summary of Adverse Events includes only those subjects who received at least one dose of investigational product. ESRD = End stage renal disease requiring dialysis.	3.1% 1/32 • 113 days Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold. Summary of Adverse Events includes only those subjects who received at least one dose of investigational product. ESRD = End stage renal disease requiring dialysis.
General disorders Asthenia	6.2% 1/16 • 113 days Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold. Summary of Adverse Events includes only those subjects who received at least one dose of investigational product. ESRD = End stage renal disease requiring dialysis.	0.00% 0/16 • 113 days Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold. Summary of Adverse Events includes only those subjects who received at least one dose of investigational product. ESRD = End stage renal disease requiring dialysis.	3.1% 1/32 • 113 days Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold. Summary of Adverse Events includes only those subjects who received at least one dose of investigational product. ESRD = End stage renal disease requiring dialysis.
General disorders Non-cardiac chest pain	0.00% 0/16 • 113 days Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold. Summary of Adverse Events includes only those subjects who received at least one dose of investigational product. ESRD = End stage renal disease requiring dialysis.	6.2% 1/16 • 113 days Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold. Summary of Adverse Events includes only those subjects who received at least one dose of investigational product. ESRD = End stage renal disease requiring dialysis.	3.1% 1/32 • 113 days Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold. Summary of Adverse Events includes only those subjects who received at least one dose of investigational product. ESRD = End stage renal disease requiring dialysis.

Other adverse events

Additional Information

Study Director

Amgen Inc.

Phone: 866-572-6436

Results disclosure agreements

Principal investigator is a sponsor employee The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
Publication restrictions are in place

Restriction type: OTHER