E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028228 |
E.1.2 | Term | Multiple myeloma |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine if denosumab is non-inferior to zoledronic acid with respect to the first on-study occurrence of a skeletal related event (SRE) in subjects with multiple myeloma |
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E.2.2 | Secondary objectives of the trial |
- To determine if denosumab is superior to zoledronic acid with respect to the first on-study SRE;
- To determine if denosumab is superior to zoledronic acid with respect to the first and subsequent on-study SRE (multiple event analysis);
- To assess the treatment effects of denosumab and zoledronic acid on overall survival
- To assess the safety and tolerability of denosumab compared with zoledronic acid. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacokinetic sub-study, 11 February 2013: Samples for measurement of serum denosumab concentration levels and associated urine samples will be obtained on a subset of approximately 150 subjects prior to administration of the investigational products on study day 1, then weeks 5, 9, 13, 25, 49, and the end of treatment phase visit. The centers that will participate in this part of the study will be determined at the time of site selection, on the basis of center interest, site ability to obtain and process serum denosumab concentration samples, and recruitment capacity.
The purpose of this sub-study is to evaluate the pharmacokinetic profile of denosumab when given at a dose of 120 mg every 4 weeks (Q4W) to newly diagnosed subjects with multiple myeloma. |
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E.3 | Principal inclusion criteria |
- Adults with documented evidence of multiple myeloma (per local assessment);
- Radiographic evidence of at least 1 bone lesion;
- Plan to receive or is receiving primary frontline anti-myeloma therapies;
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2;
- Adequate organ function;
- Written informed consent. |
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E.4 | Principal exclusion criteria |
- Nonsecretory multiple myeloma (unless baseline serum free light chain level is elevated);
- Plasma cell leukemia;
- Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome;
- More than 30 days of previous treatment (before screening) with anti-myeloma therapy (does not include radiotherapy or a single short course of steroid [ie, less than or equal to the equivalent of dexamethasone 60 mg/day for 4 days]).
- Planned radiation therapy or surgery to bone (does not include procedures;
performed before randomization)
- Prior administration of denosumab;
- More than 1 previous dose of IV bisphosphonate administration;
- Use of oral bisphosphonates with a cumulative exposure of more than 1 year;
- Prior history or current evidence of osteonecrosis/ osteomyelitis of the jaw. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time to the first on-study SRE (non-inferiority)
SRE is an aggregate endpoint that includes pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary analysis cut-off date is event-driven (i.e. when approximately 676 subjects have experienced at least one on-study SRE) |
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E.5.2 | Secondary end point(s) |
- Time to the first on-study SRE (superiority);
- Time to the first-and-subsequent on-study SRE (superiority, using multiple event analysis);
Additional Secondary Endpoints:
- Overall survival (OS);
Safety Endpoints:
- Subject incidence of treatment emergent adverse events;
- Changes in laboratory values;
- Incidence of anti-denosumab antibody (binding and neutralizing) formation. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Primary analysis cut-off date is event-driven (i.e. when approximately 676 subjects have experienced at least one on-study SRE) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 113 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
European Union |
Hong Kong |
Japan |
Korea, Republic of |
Malaysia |
New Zealand |
Russian Federation |
Singapore |
Switzerland |
Taiwan |
Turkey |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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If denosumab is determined to have a positive benefit/risk profile
compared with zoledronic acid, the end of the study is defined as approximately 4 weeks after the last dose of denosumab in the open-label treatment phase. If the benefit/risk profile is not positive, the end of the clinical study is defined as approximately 4 weeks after the last subject’s follow-up assessment, or withdrawal from study, in the survival follow-up phase. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |