Clinical Trial Results:
A single-arm, open-label, phase 2 clinical trial evaluating disease response following treatment with intravenous BHQ880, a fully human, anti-Dickkopf1 (DKK1) neutralizing antibody in previously untreated patients with high-risk, smoldering multiple myeloma
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Summary
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EudraCT number |
2010-022029-13 |
Trial protocol |
DE |
Global end of trial date |
27 Nov 2013
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Jul 2016
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First version publication date |
23 Jul 2015
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Other versions |
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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 |
CBHQ880A2204
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01302886 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Novartis Pharma AG
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Sponsor organisation address |
CH-4002, Basel, Switzerland,
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Public contact |
Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
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Scientific contact |
Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
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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 |
27 Nov 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 |
27 Nov 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 assess the overall response rate after BHQ880 treatment in previously untreated patients with high-risk smoldering multiple myeloma (SMM).
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
Since there are no specific rescue medications for BHQ880, acute allergic reactions or infusion-related reactions could be treated as clinically indicated using accepted guidelines. This included, in the event of anaphylactic reactions, any and all therapies necessary to restore normal cardiopulmonary status. Prophylactic pre-medication could be added if a patient experienced an infusion reaction and sites could then use their own institutional standard of care.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
25 May 2011
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Long term follow-up planned |
No
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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 |
France: 4
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Country: Number of subjects enrolled |
Germany: 7
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Country: Number of subjects enrolled |
United States: 30
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Worldwide total number of subjects |
41
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EEA total number of subjects |
11
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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) |
24
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From 65 to 84 years |
17
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||
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Pre-assignment
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Screening details |
Patients were screened for eligibility over a period of 28 days. | ||||||||||||||||
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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 | ||||||||||||||||
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Arms
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Arm title
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BHQ880 10mg/kg | ||||||||||||||||
Arm description |
Subjects received BHQ880 for a maximum of twelve 28-day cycles. | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
BHQ880
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
BHQ880 was administered at 10 mg/kg in 250 mL of a 5% Dextrose Injection United States Pharmacopeia (USP) or equivalent over 2 hours on Day 1 of a 28-day treatment cycle. The actual body weight in kilograms (kg) recorded at screening was used to calculate the dose for all patients.
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Baseline characteristics reporting groups
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Reporting group title |
BHQ880 10mg/kg
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Reporting group description |
Subjects received BHQ880 for a maximum of twelve 28-day cycles. | |||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
BHQ880 10mg/kg
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Reporting group description |
Subjects received BHQ880 for a maximum of twelve 28-day cycles. | ||
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End point title |
Number of Subjects With Overall Response (OR) of Minor Response (MR) or Better After 6 Months of Treatment with BHQ880 [1] | ||||||
End point description |
The Overall Response (OR) was defined as MR or better, with better being partial, very good partial, or complete response. Multiple myeloma (MM) response was evaluated by using modified international multiple myeloma working group (IMWG) criteria. This assessment included M-protein quantification and serum free light chain (FLC) assay following administration of BHQ880. Additionally, urine specimens for M-protein quantification and urine immunofixation, serum samples for serum immunofixation, bone marrow biopsy and aspirate, skeletal surveys, and magnetic resonance imaging (MRI) of the spine were also collected.
This endpoint analyzed the Full Analysis Set (FAS), defined as all patients who received at least one dose (full or partial) of BHQ880.
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End point type |
Primary
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End point timeframe |
Six 28-day treatment cycles
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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 statistical analysis was planned for this primary outcome measure. |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Subjects With Overall Response (OR) of Minor Response (MR) or Better After 12 Months of Treatment with BHQ880 | ||||||
End point description |
The Overall Response (OR) was defined as MR or better, with better being partial, very good partial, or complete response. Multiple myeloma (MM) response was evaluated by using modified international multiple myeloma working group (IMWG) criteria. This assessment included M-protein quantification and serum free light chain (FLC) assay following administration of BHQ880. Additionally, urine specimens for M-protein quantification and urine immunofixation, serum samples for serum immunofixation, bone marrow biopsy and aspirate, skeletal surveys, and magnetic resonance imaging (MRI) of the spine were also collected.
This endpoint analyzed the FAS, defined as all patients who received at least one dose (full or partial) of BHQ880.
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End point type |
Secondary
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End point timeframe |
Twelve 28-day treatment cycles
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| No statistical analyses for this end point | |||||||
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End point title |
Percent of Subjects with Disease Progression After 12 Months of Treatment with BHQ880 | ||||||||
End point description |
Progression was defined as progression to active multiple myeloma (PAMM), progressive disease (PD) but not evaluable for PAMM (NEPAMM) and discontinue for clinical PD (UNKPAMM). Assessments of PD included M-protein quantification and serum free light chain (FLC) assay following administration of BHQ880. Additionally, urine specimens for M-protein quantification and urine immunofixation, serum samples for serum immunofixation, bone marrow biopsy and aspirate, skeletal surveys, and magnetic resonance imaging (MRI) of the spine were also collected.
This endpoint analyzed the FAS, defined as all patients who received at least one dose (full or partial) of BHQ880.
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End point type |
Secondary
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End point timeframe |
Twelve 28-day treatment cycles
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under The Concentration-Time Curve (AUC) From Time Zero Up To The Last Measurable Concentration Sampling Time (0-tlast) of BHQ880 | ||||||||||||
End point description |
Pharmacokinetic (PK) parameters were determined for BHQ880 by using non-compartmental methods from the serum concentrations. Blood samples for PK evaluation were drawn pre-infusion and at 2 (±5 minutes), 24 (±1hour), 168 , 336 , 504, and 672 hours post-infusion during Cycles 1 and 4 and pre-infusion on Day 1 of Cycle 3. Blood samples for BHQ880 serum concentration-time profiles were collected from 15 patients for full PK profiling. Sample volume was 5 mL. Parameters are summarized for a single dose (Cycle 1) and after repeated dosing (Cycle 4).
This endpoint analyzed the Pharmacokinetic Analysis Set (PAS), defined as all patients in the Full Analysis Set (FAS) who had at least one blood sample providing evaluable PK data from either Cycle 1 or 4. The FAS was defined as all patients who received at least one dose (full or partial) of BHQ880.
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End point type |
Secondary
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End point timeframe |
Through four 28-day treatment cycles
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Time to Maximal Concentration (Tmax) of BHQ880 | ||||||||||||
End point description |
Pharmacokinetic (PK) parameters were determined for BHQ880 by using non-compartmental methods from the serum concentrations. Blood samples for PK evaluation were drawn pre-infusion and at 2 (±5 minutes), 24 (±1hour), 168 , 336 , 504, and 672 hours post-infusion during Cycles 1 and 4 and pre-infusion on Day 1 of Cycle 3. Blood samples for BHQ880 serum concentration-time profiles were collected from 15 patients for full PK profiling. Sample volume was 5 mL. Parameters are summarized for a single dose (Cycle 1) and after repeated dosing (Cycle 4).
This endpoint analyzed the PAS, defined as all patients in the FAS who had at least one blood sample providing evaluable PK data from either Cycle 1 or 4. The FAS was defined as all patients who received at least one dose (full or partial) of BHQ880.
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End point type |
Secondary
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End point timeframe |
Through four 28-day treatment cycles
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Time to Last Measurable Concentration (Tlast) of BHQ880 | ||||||||||||
End point description |
Pharmacokinetic (PK) parameters were determined for BHQ880 by using non-compartmental methods from the serum concentrations. Blood samples for PK evaluation were drawn pre-infusion and at 2 (±5 minutes), 24 (±1hour), 168 , 336 , 504, and 672 hours post-infusion during Cycles 1 and 4 and pre-infusion on Day 1 of Cycle 3. Blood samples for BHQ880 serum concentration-time profiles were collected from 15 patients for full PK profiling. Sample volume was 5 mL. Parameters are summarized for a single dose (Cycle 1) and after repeated dosing (Cycle 4).
This endpoint analyzed the PAS, defined as all patients in the FAS who had at least one blood sample providing evaluable PK data from either Cycle 1 or 4. The FAS was defined as all patients who received at least one dose (full or partial) of BHQ880.
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End point type |
Secondary
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End point timeframe |
Through four 28-day treatment cycles
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Maximum Concentration (Cmax) of BHQ880 | ||||||||||||
End point description |
Pharmacokinetic (PK) parameters were determined for BHQ880 by using non-compartmental methods from the serum concentrations. Blood samples for PK evaluation were drawn pre-infusion and at 2 (±5 minutes), 24 (±1hour), 168 , 336 , 504, and 672 hours post-infusion during Cycles 1 and 4 and pre-infusion on Day 1 of Cycle 3. Blood samples for BHQ880 serum concentration-time profiles were collected from 15 patients for full PK profiling. Sample volume was 5 mL. Parameters are summarized for a single dose (Cycle 1) and after repeated dosing (Cycle 4).
This endpoint analyzed the PAS, defined as all patients in the FAS who had at least one blood sample providing evaluable PK data from either Cycle 1 or 4. The FAS was defined as all patients who received at least one dose (full or partial) of BHQ880.
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End point type |
Secondary
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End point timeframe |
Through four 28-day treatment cycles
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Elimination Half-Life (T1/2) of BHQ880 | ||||||||||||
End point description |
Pharmacokinetic (PK) parameters were determined for BHQ880 by using non-compartmental methods from the serum concentrations. Blood samples for PK evaluation were drawn pre-infusion and at 2 (±5 minutes), 24 (±1hour), 168 , 336 , 504, and 672 hours post-infusion during Cycles 1 and 4 and pre-infusion on Day 1 of Cycle 3. Blood samples for BHQ880 serum concentration-time profiles were collected from 15 patients for full PK profiling. Sample volume was 5 mL. Parameters are summarized for a single dose (Cycle 1) and after repeated dosing (Cycle 4).
This endpoint analyzed the PAS, defined as all patients in the FAS who had at least one blood sample providing evaluable PK data from either Cycle 1 or 4. The FAS was defined as all patients who received at least one dose (full or partial) of BHQ880.
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End point type |
Secondary
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End point timeframe |
Through four 28-day treatment cycles
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Total Body Clearance (CL) of BHQ880 | ||||||||||||
End point description |
Pharmacokinetic (PK) parameters were determined for BHQ880 by using non-compartmental methods from the serum concentrations. Blood samples for PK evaluation were drawn pre-infusion and at 2 (±5 minutes), 24 (±1hour), 168 , 336 , 504, and 672 hours post-infusion during Cycles 1 and 4 and pre-infusion on Day 1 of Cycle 3. Blood samples for BHQ880 serum concentration-time profiles were collected from 15 patients for full PK profiling. Sample volume was 5 mL. Parameters are summarized for a single dose (Cycle 1) and after repeated dosing (Cycle 4).
This endpoint analyzed the PAS, defined as all patients in the FAS who had at least one blood sample providing evaluable PK data from either Cycle 1 or 4. The FAS was defined as all patients who received at least one dose (full or partial) of BHQ880.
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End point type |
Secondary
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End point timeframe |
Through four 28-day treatment cycles
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Apparent Volume of Distribution of BHQ880 During The Terminal Phase (V) | ||||||||||||
End point description |
Pharmacokinetic (PK) parameters were determined for BHQ880 by using non-compartmental methods from the serum concentrations. Blood samples for PK evaluation were drawn pre-infusion and at 2 (±5 minutes), 24 (±1hour), 168 , 336 , 504, and 672 hours post-infusion during Cycles 1 and 4 and pre-infusion on Day 1 of Cycle 3. Blood samples for BHQ880 serum concentration-time profiles were collected from 15 patients for full PK profiling. Sample volume was 5 mL. Parameters are summarized for a single dose (Cycle 1) and after repeated dosing (Cycle 4).
This endpoint analyzed the PAS, defined as all patients in the FAS who had at least one blood sample providing evaluable PK data from either Cycle 1 or 4. The FAS was defined as all patients who received at least one dose (full or partial) of BHQ880.
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End point type |
Secondary
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End point timeframe |
Through four 28-day treatment cycles
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Accumulation Ratio (AR) of BHQ880 After 4 Cycles of Therapy | ||||||||
End point description |
Pharmacokinetic (PK) parameters were determined for BHQ880 by using non-compartmental methods from the serum concentrations. Blood samples for PK evaluation were drawn pre-infusion and at 2 (±5 minutes), 24 (±1hour), 168 , 336 , 504, and 672 hours post-infusion during Cycles 1 and 4 and pre-infusion on Day 1 of Cycle 3. Blood samples for BHQ880 serum concentration-time profiles were collected from 15 patients for full PK profiling. Sample volume was 5 mL.
This endpoint analyzed the PAS, defined as all patients in the FAS who had at least one blood sample providing evaluable PK data from either Cycle 1 or 4. The FAS was defined as all patients who received at least one dose (full or partial) of BHQ880.
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End point type |
Secondary
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End point timeframe |
Through four 28-day treatment cycles
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Subjects With Positive Immunogenicity For BHQ880 After Treatment with BHQ880 | ||||||||||||||||
End point description |
Blood sampling for BHQ880 immunogenicity was collected from all patients within 3 hours before the BHQ880 infusion began on Day 1 of Cycles 1, 3, 6, 9, and 12. The samples were analyzed by using a validated Biomolecular Interaction Analysis binding method. Sample volume at each collection was 2 mL. Positive immunogenicity was defined as a value greater than the lower limit of quantification.
This endpoint analyzed the FAS, defined as all patients who received at least one dose (full or partial) of BHQ880.
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End point type |
Secondary
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End point timeframe |
Twelve 28-day treatment cycles
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change From Baseline in The Concentration of Dickkopf 1 (DKK1) After Treatment With BHQ880 | ||||||||||||
End point description |
Determination of total DKK1 levels in serum was done by using a validated DKK1 assay. Baseline values were defined as the last non-missing value before the first BHQ dose. A positive value indicates that the concentration has increased.
This endpoint analyzed the FAS, defined as all patients who received at least one dose (full or partial) of BHQ880.
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End point type |
Secondary
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End point timeframe |
Through four 28-day treatment cycles 672 hours post dose
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percent Change From Baseline in Bone Mineral Density After 6 Months of Treatment with BHQ880 | ||||||||||||||
End point description |
Dual energy x-ray absorptiometry scans were performed to evaluate bone metabolism and explore the anabolic effect of BHQ880 on bone by measuring bone density. A negative value indicates that bone density has decreased.
This endpoint analyzed the FAS, defined as all patients who received at least one dose (full or partial) of BHQ880.
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End point type |
Secondary
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End point timeframe |
Six 28-day treatment cycles
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| Notes [2] - n for lumbar spine = 39; n for hip = 37; n for forearm = 31 |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Percent Change From Baseline in Bone Mineral Density After 12 Months of Treatment with BHQ880 | ||||||||||||||
End point description |
Dual energy x-ray absorptiometry scans were performed to evaluate bone metabolism and explore the anabolic effect of BHQ880 on bone by measuring bone density. A negative value indicates that bone density has decreased.
This endpoint analyzed the FAS, defined as all patients who received at least one dose (full or partial) of BHQ880.
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End point type |
Secondary
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End point timeframe |
Twelve 28-day treatment cycles
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| Notes [3] - n for lumbar spine = 30; n for hip = 30; n for forearm = 23 |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Percent Change From Baseline in The Concentration of Osteocalcin After Treatment With BHQ880 | ||||||||
End point description |
The concentration of osteocalcin in serum was determined to evaluate bone metabolism and explore the anabolic effect of BHQ880 on bone. A positive value indicates that the concentration has increased.
This endpoint analyzed the FAS, defined as all patients who received at least one dose (full or partial) of BHQ880.
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End point type |
Secondary
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End point timeframe |
Twelve 28-day treatment cycles
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| No statistical analyses for this end point | |||||||||
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End point title |
Percent Change From Baseline in The Concentration of Procollagen Type 1 N-terminal Polypeptide (P1NP) After Treatment With BHQ880 | ||||||||
End point description |
The concentration of P1NP in serum was determined to evaluate bone metabolism and explore the anabolic effect of BHQ880 on bone. A positive value indicates that the concentration has increased.
This endpoint analyzed the FAS, defined as all patients who received at least one dose (full or partial) of BHQ880.
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End point type |
Secondary
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End point timeframe |
Twelve 28-day treatment cycles
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| No statistical analyses for this end point | |||||||||
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End point title |
Percent Change From Baseline in The Concentration of N-terminal Telopeptide of Type 1 Collagen (NTx) After Treatment With BHQ880 | ||||||||
End point description |
The concentration of NTx in urine, corrected for creatinine, was determined to evaluate bone metabolism and explore the anabolic effect of BHQ880 on bone. A positive value indicates that the concentration has increased.
This endpoint analyzed the FAS, defined as all patients who received at least one dose (full or partial) of BHQ880.
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End point type |
Secondary
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End point timeframe |
Twelve 28-day treatment cycles
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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 |
Serious Adverse Events are monitored from date of First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All other adverse events are monitored from First Patient First Treatment until Last Patient Last Visit.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 |
BHQ880 10mg/kg
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Reporting group description |
BHQ880 10mg/kg | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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25 Jan 2012 |
This amendment introduced the following important changes:
The main purpose of the amendment was to modify the prohibition on concomitant hormone replacement therapy for patients who have been receiving that therapy for at least 6 months. Patients who had been receiving long-term hormone replacement therapy and for whom those effects on bone would be considered stable could be enrolled in the study without having to discontinue that therapy.
In addition, the analyses of several serum bone biomarkers which supported a secondary endpoint were removed. The requirement for assessment of vital signs during and after drug infusion was also removed, based on the data and safety profile from Phase I studies.
For improved site and patient compliance and protocol execution, time windows around laboratory assessments were added and redundant laboratory testing was removed. |
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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 | |||
