Clinical Trial Results:
A Single-arm, Multicenter, Proof-of-concept Study of Denosumab in the Treatment of Hypercalcemia of Malignancy in Subjects with Elevated Serum Calcium Despite Recent Treatment with IV Bisphosphonates.
Summary
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EudraCT number |
2009-009756-21 |
Trial protocol |
PL FR IT |
Global end of trial date |
21 Aug 2013
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Results information
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Results version number |
v1(current) |
This version publication date |
20 Jun 2016
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First version publication date |
24 Jul 2015
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
20070315
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00896454 | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Amgen Inc.
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Sponsor organisation address |
One Amgen Center Drive, Thousand Oaks, United States, 91320
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Public contact |
IHQ Medical Info – Clinical Trials, Amgen (EUROPE) GmbH, MedinfoInternational@amgen.com
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Scientific contact |
IHQ Medical Info – Clinical Trials, Amgen (EUROPE) GmbH, MedinfoInternational@amgen.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
21 Aug 2013
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
21 Aug 2013
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the potential for denosumab to treat hypercalcemia of malignancy that does not respond to recent treatment with Intravenous (IV) bisphosphonates by lowering corrected serum calcium (CSC) ≤ 11.5 mg/dL (2.9 mmol/L) by study day 10.
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Protection of trial subjects |
This study was conducted in accordance with the current version of the Declaration of Helsinki and the FDA and International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations. The study protocol, subject information, and informed consent form were reviewed and approved by the independent ethics committee (IEC) or institutional review board (IRB) for each study center. All subjects provided written informed consent after the aims, methods, and potential hazards of the study were adequately explained; the appropriate informed consent was obtained before any protocol-specific screening procedures or any investigational products were administered.
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Background therapy |
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Evidence for comparator |
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Actual start date of recruitment |
16 Nov 2009
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
12 Months | ||
Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 1
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Country: Number of subjects enrolled |
France: 8
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Country: Number of subjects enrolled |
Italy: 1
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Country: Number of subjects enrolled |
United States: 23
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Worldwide total number of subjects |
33
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EEA total number of subjects |
10
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
19
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From 65 to 84 years |
13
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85 years and over |
1
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Recruitment
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Recruitment details |
First patient was enrolled on 16 November 2009 and the last patient enrolled on 02 July 2012. The primary analysis cut-off date was 13 September 2012; the last subject completed follow-up 21 August 2013. | ||||||||||||||||||||||
Pre-assignment
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Screening details |
Eligible subjects were adults ≥ 18 years of age who had hypercalcemia of malignancy (HCM), defined as documented histologically or cytologically confirmed cancer and a corrected serum calcium (CSC) > 12.5 mg/dL (3.1 mmol/L) despite IV bisphosphonates administered ≥ 7 days and ≤ 30 days prior to the screening CSC. | ||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||
Arms
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Arm title
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Denosumab | ||||||||||||||||||||||
Arm description |
Participants received denosumab at a dose of 120 mg subcutaneously (SC) every 4 weeks (Q4W) with a loading dose of 120 mg SC on study Days 8 and 15. | ||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||
Investigational medicinal product name |
Denosumab
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Investigational medicinal product code |
AMG 162
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Other name |
XGEVA
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Denosumab was administered at a dose of 120 mg SC Q4W with loading doses of 120 mg SC being administered on study days 8 and 15.
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Baseline characteristics reporting groups
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Reporting group title |
Denosumab
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Reporting group description |
Participants received denosumab at a dose of 120 mg subcutaneously (SC) every 4 weeks (Q4W) with a loading dose of 120 mg SC on study Days 8 and 15. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Denosumab
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Reporting group description |
Participants received denosumab at a dose of 120 mg subcutaneously (SC) every 4 weeks (Q4W) with a loading dose of 120 mg SC on study Days 8 and 15. |
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End point title |
Percentage of Participants With a Response Within 10 Days of First Dose of Denosumab [1] | ||||||||
End point description |
Response is defined as corrected serum calcium (CSC) ≤ 11.5 mg/dL, within 10 days after the first dose of denosumab. For all CSC values, if albumin was < 4 g/dL, the following formula was used to calculate CSC: CSC = Total serum calcium [mg/dL] + (0.8 x (4 – serum albumin [g/dL])).
The Response Analysis Subset included all participants who received at least 1 dose of denosumab and had a screening CSC (from local lab) > 12.5 mg/dL (3.1 mmol/L).
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End point type |
Primary
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End point timeframe |
10 days
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal hypothesis was tested. |
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Notes [2] - Reponse analysis subset |
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No statistical analyses for this end point |
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End point title |
Percentage of Participants With a Response by Visit | ||||||||||||||||||||||||||||||||
End point description |
Response is defined as corrected serum calcium (CSC) ≤ 11.5 mg/dL, within 10 days after the first dose of denosumab. For all CSC values, if albumin was < 4 g/dL, the following formula was used to calculate CSC: CSC = Total serum calcium [mg/dL] + (0.8 x (4 – serum albumin [g/dL])) .
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End point type |
Secondary
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End point timeframe |
Days 2, 4, 8, 10, 15, 19, 23, 29, 36, 43, 50 and 57
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No statistical analyses for this end point |
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End point title |
Percentage of Participants With a Complete Response by Visit | ||||||||||||||||||||||||||||||||
End point description |
Response is defined as corrected serum calcium (CSC) ≤ 10.8 mg/dL (2.7 mmol/L). For all CSC values, if albumin was < 4 g/dL, the following formula was used to calculate CSC: CSC = Total serum calcium [mg/dL] + (0.8 x (4 – serum albumin [g/dL])).
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End point type |
Secondary
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End point timeframe |
Days 2, 4, 8, 10, 15, 19, 23, 29, 36, 43, 50 and 57
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Notes [3] - Response Analysis Subset |
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No statistical analyses for this end point |
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End point title |
Time to Response | ||||||||
End point description |
Time to Response was defined as the time period from study Day 1 to the first time post-baseline corrected serum calcium (CSC) ≤ 11.5 mg/dL. Participants were censored on the last CSC assessment day if no response was observed. If there was no post-baseline CSC assessment, time to response was censored on study Day 1.
Time to response was analyzed using Kaplan–Meier methods. The confidence interval was calculated using bootstrap method.
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End point type |
Secondary
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End point timeframe |
From Day 1 until the end of study date or primary data cutoff date (13 September 2012), whichever occured first; median time on study was 1.8 months.
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Notes [4] - Response Analysis Subset |
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No statistical analyses for this end point |
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End point title |
Time to Complete Response | ||||||||
End point description |
Time to complete response was defined as the time period from study Day 1 to the first time post-baseline corrected serum calcium (CSC) was ≤ 10.8 mg/dL (2.7 mmol/L). Participants were censored on the last CSC assessment day if no complete response was observed. If there was no post-baseline CSC assessment, time to complete response was censored on study Day 1. Time to complete response was analyzed using Kaplan–Meier methods. The confidence interval is calculated using bootstrap method.
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End point type |
Secondary
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End point timeframe |
From Day 1 until the end of study date or primary data cutoff date (13 September 2012), whichever occured first; median time on study was 1.8 months.
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Notes [5] - Response Analysis Subset |
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No statistical analyses for this end point |
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End point title |
Duration of Response | ||||||||
End point description |
Duration of response is defined as the number of days from the first day of corrected serum calcium ≤ 11.5 mg/dL (2.9 millimoles/L) to the last day of corrected serum calcium ≤ 11.5 mg/dL. Participants were censored on the last CSC assessment day if their CSC level never reached > 11.5 mg/dL after the first response. If a participant had no CSC assessment after the first response, duration of response was set to zero and censored. Duration of response was summarized for participants who achieved a response using the Kaplan-Meier method. "99999" indicates values were not estimable due to the low number of events.
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End point type |
Secondary
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End point timeframe |
From Day 1 until the end of study date or primary data cutoff date (13 September 2012), whichever occured first; median time on study was 1.8 months.
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Notes [6] - Participants with a response in the Response Analysis Subset |
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No statistical analyses for this end point |
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End point title |
Duration of Complete Response | ||||||||
End point description |
Duration of complete response is defined as the number of days from the first day of of corrected serum calcium ≤ 10.8 mg/dL (2.7 millimoles/L) to the last day of corrected serum calcium ≤ 10.8 mg/dL. Participants were censored on the last CSC assessment day if their CSC level never reached > 10.8 mg/dL after the complete response. If a participant had no CSC assessment after the complete response, duration of complete response was set to zero and censored. Duration of complete response was summarized for participants who achieved a complete response using the Kaplan-Meier method.
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End point type |
Secondary
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End point timeframe |
From Day 1 until the end of study date or primary data cutoff date (13 September 2012), whichever occured first; median time on study was 1.8 months.
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Notes [7] - Participants with a complete response in the Response Analysis Subset |
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No statistical analyses for this end point |
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End point title |
Time to Relapse/Nonresponse of Hypercalcemia of Malignancy | ||||||||
End point description |
Time to relapse/nonresponse was defined as the number of days from study Day 1 until the last day of CSC ≤ 11.5 mg/dL for all particiipants with relapse after the first response. Participants were censored on the last CSC assessment day if their CSC level never reached > 11.5 mg/dL after first response. For participants who never achieved response, time to relapse/nonresponse was set to zero. Otherwise, if there was no post-baseline CSC assessment, time to relapse/nonresponse was censored on study Day 1. Time to relapse/nonresponse was estimated using the Kaplan-Meier method.
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End point type |
Secondary
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End point timeframe |
From Day 1 until the end of study date or primary data cutoff date (13 September 2012), whichever occured first; median time on study was 1.8 months.
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Notes [8] - Response Analysis Subset |
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Corrected Serum Calcium | ||||||||||||||||||||||||||||||||
End point description |
The Efficacy Analysis Subset included all participants who received at least 1 dose of denosumab. n = the number of participants who had non-missing data at Baseline and the time point of interest.
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End point type |
Secondary
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End point timeframe |
Baseline and Days 2, 4, 8, 10, 15, 19, 23, 29, 36, 43, 50 and 57
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Notes [9] - Efficacy Analysis Subset |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Participants were followed for up to 6 months after last dose for serious adverse events. Median time on study was 1.8 months, maximum was 23 months.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15.1
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Reporting groups
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Reporting group title |
Denosumab
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Reporting group description |
Participants received denosumab at a dose of 120 mg subcutaneously (SC) every 4 weeks (Q4W) with a loading dose of 120 mg SC on study Days 8 and 15. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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14 May 2010 |
The primary reason for this amendment was to delete the exclusion of a prior history or current evidence of ONJ, and related factors. Subjects who qualified for this protocol, ie, HCM that is relapsed or refractory to bisphosphonate treatment, could have been previously treated with long-term bisphosphonates for their underlying malignancy, which has been shown to be associated with ONJ.
HCM is a serious and potentially life-threatening condition that requires immediate treatment. Excluding bisphosphonate-refractory subjects with prior or current ONJ or related factors would deny them treatment with another anti-resorptive agent that could potentially reduce their serum calcium levels.
Additional changes included the following:
-deleted the exclusion criterion of previous treatment with denosumab
-modified the contraceptive exclusion criteria
-clarified that screening chemistry and pregnancy testing was to be performed at a local laboratory
-changed the criteria for denosumab discontinuation, such that after 4 doses of denosumab or by study day 57, denosumab could be discontinued if CSC ≥ 12.5 mg/dL instead of ≥ 11.6 mg/dL
-modified the informed consent to be consistent with the protocol and updated safety information
-made minor wording changes and clarifications |
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05 May 2011 |
-Modified the eligibility criteria and informed consent to include 2 methods of highly effective contraception during treatment and for 7 months after the last dose of denosumab
-Modified the prestudy window for treatment with other therapeutic agents for hypercalcemia such that the determination for evaluating the expected potentially effective therapeutic window of these agents was at the discretion of the physician
-Made minor revisions to definitions of subsets, objectives, and endpoints |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |