Clinical Trial Results:
Denosumab for high risk SMM and SLiM CRAB positive, early myeloma patients- a randomized, placebo controlled phase II trial “DEFENCE” (DEnosumab For the rEductioN of the smoldering myeloma transformatioN inCidence ratE)
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Summary
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EudraCT number |
2018-000924-32 |
Trial protocol |
AT DE GB GR |
Global end of trial date |
14 Sep 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
07 Sep 2024
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First version publication date |
07 Sep 2024
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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 |
AGMT_MM-3
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03792763 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
AGMT
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Sponsor organisation address |
Gentzgasse 60/21, Vienna, Austria, 1180
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Public contact |
Daniela Wolkersdorfer, AGMT, 0043 6626404412, d.wolkersdorfer@agmt.at
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Scientific contact |
Richard Greil, AGMT, 0043 6626404412, r.greil@salk.at
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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 |
07 Aug 2024
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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 |
14 Sep 2023
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
Effectiveness of denosumab in delaying transformation to symptomatic, active MM or progression of disease.
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Protection of trial subjects |
There was no dose adjustments for the SC investigational product.
Administration of investigational product and placebo was withheld for any subject who experienced a grade 3 or 4 adverse event reported by the investigator as related to investigational product, or osteonecrosis of the jaw (ONJ) as determined by the investigator. Re-exposure to investigational product or placebo occured only when the event was resolved to grade 1 or less or to the subject’s baseline and if the investigator and sponsor agreed subject safety was not compromised.
Denosumab is not recommended for use in pregnant women and women of child-bearing potential (WOCBP) not using contraception. The inclusion of women of childbearing potential had to follow specific recommendations for contraception and pregnancy testing. Women were advised not to become pregnant during and for at least 5 months after treatment with denosumab. Male participants were not required to use birth control during exposure to denosumab. If female partners of male participants were pregnant or become pregnant while he was taking denosumab, or within 5 months after stopping denosumab, the sponsor had to be informed.
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Background therapy |
Supplements of Calcium and Vitamin D were mandatory (at least 500 mg calcium und 400 IE vitamin D daily, unless hypercalcaemia was present, according to SmPC) and were provided by the sponsor. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
30 Sep 2019
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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 |
Austria: 8
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Worldwide total number of subjects |
8
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EEA total number of subjects |
8
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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) |
5
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From 65 to 84 years |
3
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85 years and over |
0
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Recruitment
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Recruitment details |
Between 30-Sep-2019 and 29-Jan-2021, 8 patients were enrolled at 5 sites in Austria. | |||||||||||||||||||||
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Pre-assignment
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Screening details |
Due to Covid-19 pandemic contact with target population was massively hampered as most of these patients are belonging to vulnerable groups and study treatment was not defined as “urgent” or “essential”. A targeted interim number of 20 patients by end of 2020 could not be reached and the study was prematurely closed. | |||||||||||||||||||||
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Period 1
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Period 1 title |
Overall (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor | |||||||||||||||||||||
Blinding implementation details |
For each registered patient, the documentation system automatically assigned a patient number per study site, ascending in the order of registration. The combination of study site number and patient number was unique throughout the whole study. The patient was assigned to the treatment group according to a randomizationplan.
In case of emergencies or regulatory requirements the unblinded persons were contacted, unblinding of random numbers and kits was also possible via the eCRF.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Arm A - denosumab | |||||||||||||||||||||
Arm description |
Treatment with denosumab 120 mg SC every 4 weeks (Q4W) for 6 months, then every 3 months (Q3M) for a total of 3 years or until progression to active, symptomatic MM | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Denosumab
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Investigational medicinal product code |
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Other name |
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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 |
120mg, subcutaneous use Q4W (6 months) followed by Q3M
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Arm title
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Arm B- placebo | |||||||||||||||||||||
Arm description |
Treatment with placebo SC every 4 weeks (Q4W) for 6 months then every 3 months (Q3M) for a total of 3 years or until progression to active, symptomatic MM | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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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 |
subcutaneous use Q4W (6 months) followed by Q3M
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Baseline characteristics reporting groups
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Reporting group title |
Overall
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Reporting group description |
- | ||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Arm A - denosumab
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Reporting group description |
Treatment with denosumab 120 mg SC every 4 weeks (Q4W) for 6 months, then every 3 months (Q3M) for a total of 3 years or until progression to active, symptomatic MM | ||
Reporting group title |
Arm B- placebo
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Reporting group description |
Treatment with placebo SC every 4 weeks (Q4W) for 6 months then every 3 months (Q3M) for a total of 3 years or until progression to active, symptomatic MM | ||
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End point title |
Patients with transformation or progression [1] | ||||||||||||||||||
End point description |
Number of subjects with transformation to symptomatic, active MM (defined as progression to active multiple myeloma according to IMWG diagnosis criteria 2014) or progression of disease according to IMWG response criteria 2016.
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End point type |
Primary
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End point timeframe |
The timepoints for the evaluation of this endpoint are: monthly during the first 6 months and 3-monthly until a maximum of 3 years.
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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: Due to very small reduced sample size, no statistical analysis was planned. |
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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 |
All patients having received at least one dose of the study medication were followed for adverse events for at least 28 days after discontinuing study treatment or completion of study treatment.
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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 |
25.1
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Reporting groups
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Reporting group title |
Overall
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Reporting group description |
The safety analysis was conducted for a total of 7 subjects, including all subjects receiving at least one dose of the IMP denosumab or placebo. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Date |
Amendment |
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20 Jul 2020 |
Mainly due to Covid-19 pandemic recruitment of target population was massively hampered as most of these patients have been belonging to vulnerable groups (e.g. higher age and underlying pre-myeloma disease with higher infection risk).
Only 8 patients could be randomized between date of first-patient-in on 01-Oct-2019 and end of January 2021. Therefore, recruitment was stopped on 29-Jan-2021.
Treatment of all included patients will be unblinded.
• Patients in denosumab group (verum group) will further be treated according to protocol until 3 years after treatment start, progressive disease or intolerability.
• Patients who were randomized in the placebo group will be asked to further participate in study at least for 3-monthly follow-ups but will not receive further study treatment with placebo or mandatory concomitant medication (calcium, vitamin D). Further treatment of these patients is up to the discretion of the responsible physicians and not determinate by protocol specifications.
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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. | |||
| Recruitment of the trial was stopped on 29-Jan-2021 as covid-19 pandemic circumstances hampered enrollment. | |||
