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

An Open-label Study to Evaluate the Safety of Multiple Doses of Denosumab 120 mg Administered Subcutaneously in Subjects With Severe Chronic Kidney Disease (CKD) and CKD on Dialysis

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01464931

Enrollment

Registered

2011-11-04

Start date

2011-11-30

Completion date

2013-03-31

Last updated

2016-02-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Renal Impairment

Brief summary

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

Interventions

DRUGDenosumab

Adminstered by subcutaneous injection

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Subjects at least 18 years old with severe CKD (defined as creatinine clearance \< 30 mL/min at both screening assessments) and CKD requiring hemodialysis * Additional inclusion criteria apply

Exclusion criteria

* Subjects must have calcium, phosphate, and magnesium levels appropriate for their condition and must not have other uncontrolled co-morbidities. * Additional

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Clinically Significant Hypocalcemia	113 days	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.

Secondary

Measure	Time frame	Description
Number of Participants With Hypophosphatemia Determined by CTCAE v.4.0 Criteria	113 days	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.
Number of Participants With Hypomagnesemia Determined by CTCAE v.4.0 Criteria	113 days	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.
Percent Change From Baseline in Albumin-adjusted Serum Calcium Over Time	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	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	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	113 days	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.
Number of Participants With Hypocalcemia Determined by CTCAE v.4.0 Criteria	113 days	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 to Maximum Observed Serum Denosumab Concentration (Tmax)	Days 1 and 29 (predose), and on Days 8, 15, 36, 43, 57, 71, 85, and 113	Serum concentrations of denosumab were measured by an enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 20 ng/mL.
Area Under the Serum Concentration-time Curve From Time 0 to 4 Weeks (AUC0-4wks) After Dose 1	Days 1, 8, 15, and 29 (predose)	Estimated using the linear trapezoidal method.
Area Under the Serum Concentration-time Curve From Time 0 to 12 Weeks (AUC0-12wks) After Dose 2	Days 29 (predose), 36, 43, 57, 71, and 85	Estimated using the linear trapezoidal method.
Percent Change From Baseline in Serum C-Telopeptide Over Time	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	From Day 1 (predose) to Day 113	—
Maximum Observed Serum Denosumab Concentration (Cmax)	Days 1 and 29 (predose), and on Days 8, 15, 36, 43, 57, 71, 85, and 113	Serum concentrations of denosumab were measured by an enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 20 ng/mL.

Countries

United States

Participant flow

Participants by arm

Arm	Count
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.	16
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.	16
Total	32

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Withdrawal by Subject	1	0

Baseline characteristics

Characteristic	Severe CKD	ESRD	Total
Age, Continuous	79.2 years STANDARD_DEVIATION 9.5	65.9 years STANDARD_DEVIATION 12.4	72.5 years STANDARD_DEVIATION 12.8
Sex: Female, Male Female	9 Participants	7 Participants	16 Participants
Sex: Female, Male Male	7 Participants	9 Participants	16 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	10 / 16	15 / 16	25 / 32
serious Total, serious adverse events	1 / 16	2 / 16	3 / 32

Outcome results

Primary

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

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

Arm	Measure	Value (NUMBER)
Severe CKD	Number of Participants With Clinically Significant Hypocalcemia	1 participants
ESRD	Number of Participants With Clinically Significant Hypocalcemia	2 participants

Secondary

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

Population: PK Parameter Analysis Set

Arm	Measure	Value (MEAN)	Dispersion
Severe CKD	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
ESRD	Area Under the Serum Concentration-time Curve From Time 0 to 12 Weeks (AUC0-12wks) After Dose 2	607 μg*day/mL	Standard Deviation 262

Secondary

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)

Population: PK Parameter Analysis Set

Arm	Measure	Value (MEAN)	Dispersion
Severe CKD	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
ESRD	Area Under the Serum Concentration-time Curve From Time 0 to 4 Weeks (AUC0-4wks) After Dose 1	177 μg*day/mL	Standard Deviation 91

Secondary

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

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)

Arm	Measure	Value (MEAN)	Dispersion
Severe CKD	Maximum Observed Serum Denosumab Concentration (Cmax)	10.5 μg/mL	Standard Deviation 3.6
ESRD	Maximum Observed Serum Denosumab Concentration (Cmax)	8.17 μg/mL	Standard Deviation 4.22
Severe CKD - Dose 2	Maximum Observed Serum Denosumab Concentration (Cmax)	16.1 μg/mL	Standard Deviation 5.2
ESRD - Dose 2	Maximum Observed Serum Denosumab Concentration (Cmax)	14.5 μg/mL	Standard Deviation 7.4

Secondary