Clinical Trial Results:
Randomized, Open Label, Multicenter Study Assessing The Clinical Benefit Of Isatuximab Combined With Carfilzomib (Kyprolis®) And Dexamethasone Versus Carfilzomib With Dexamethasone In Patients With Relapse And/Or Refractory Multiple Myeloma Previously Treated With 1 to 3 Prior Lines
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Summary
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EudraCT number |
2017-001940-37 |
Trial protocol |
GB CZ HU ES GR IT |
Global end of trial date |
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Results information
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Results version number |
v1(current) |
This version publication date |
11 May 2023
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First version publication date |
11 May 2023
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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 |
EFC15246
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03275285 | ||
WHO universal trial number (UTN) |
U1111-1195-5957 | ||
Other trial identifiers |
IND Number: 103217 | ||
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Sponsors
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Sponsor organisation name |
Sanofi Aventis Recherche & Développement
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Sponsor organisation address |
1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
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Public contact |
Trial Transparency Team, Sanofi Aventis Recherche & Développement, Contact-US@sanofi.com
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Scientific contact |
Trial Transparency Team, Sanofi Aventis Recherche & Développement, Contact-US@sanofi.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 |
Interim
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Date of interim/final analysis |
14 Jan 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
14 Jan 2022
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Global end of trial reached? |
No
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General information about the trial
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Main objective of the trial |
To demonstrate the benefit of isatuximab in combination with carfilzomib and dexamethasone in the prolongation of progression free survival (PFS) using International Myeloma Working Group (IMWG) as compared to carfilzomib and dexamethasone in subjects with relapsed and/or refractory multiple myeloma (MM) previously treated with 1 to 3 lines of therapy.
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Protection of trial subjects |
Subjects were fully informed of all pertinent aspects of the clinical trial, as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
25 Oct 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
Australia: 37
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Country: Number of subjects enrolled |
Brazil: 33
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Country: Number of subjects enrolled |
Canada: 8
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Country: Number of subjects enrolled |
Czechia: 34
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Country: Number of subjects enrolled |
France: 39
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Country: Number of subjects enrolled |
Greece: 20
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Country: Number of subjects enrolled |
Hungary: 13
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Country: Number of subjects enrolled |
Italy: 6
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Country: Number of subjects enrolled |
Japan: 19
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Country: Number of subjects enrolled |
Korea, Republic of: 27
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Country: Number of subjects enrolled |
New Zealand: 6
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Country: Number of subjects enrolled |
Russian Federation: 10
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Country: Number of subjects enrolled |
Spain: 24
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Country: Number of subjects enrolled |
Turkey: 14
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Country: Number of subjects enrolled |
United Kingdom: 9
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Country: Number of subjects enrolled |
United States: 3
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Worldwide total number of subjects |
302
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EEA total number of subjects |
136
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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) |
154
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From 65 to 84 years |
146
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85 years and over |
2
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Recruitment
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Recruitment details |
Study conducted at 69 active centers in 16 countries. 341 subjects screened between 25 Oct 2017 & 21 Mar 2019, 39 subjects were screen failure - not met eligibility criteria. Randomisation - stratified by number of prior lines (1 vs >1) & revised international staging system (R-ISS) I/II vs III vs not classified. 302 subjects enrolled & randomised. | ||||||||||||||||||
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Pre-assignment
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Screening details |
Study ongoing, data cut-off date for result analysis reported 07 Feb 2020: efficacy outcomes, 14 Jan 2022: CR, MRD, PFS2. PFS data reported at 07 Feb 2020 & 14 Jan 2022. Primary analysis of PFS refer to interim analysis planned to be conducted at 103 events (07Feb20) & final analysis of PFS planned to be conducted at 159 events (14Jan22). | ||||||||||||||||||
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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 |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Carfilzomib + Dexamethasone (Kd) | ||||||||||||||||||
Arm description |
Subjects received carfilzomib 20 milligrams per meter square (mg/m^2), intravenous (IV) infusion on Days 1, and 2 in Cycle 1, and then escalated to 56 mg/m^2 on Days 8, 9, 15 and 16 of Cycle 1 on Days 1, 2, 8, 9, 15 and 16 of each subsequent 28-day treatment cycles plus dexamethasone 20 milligrams (mg), orally (PO) or IV on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day treatment cycles until disease progression or unacceptable adverse event or subject’s decision to discontinue the study treatment or any other reason, whichever comes first (maximum exposure: 208 weeks). | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Carfilzomib
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Investigational medicinal product code |
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Other name |
Kyprolis
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Carfilzomib 20 mg/m^2, was administered as an IV infusion on Days 1, and 2 in Cycle 1, and then escalated to 56 mg/m^2 on Days 8, 9, 15 and 16 of Cycle 1 and then on Days 1, 2, 8, 9, 15 and 16 of each subsequent 28-day treatment cycle along with dexamethasone 20 mg, PO or IV on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day treatment cycle.
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Investigational medicinal product name |
Dexamethasone
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection, Tablet
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Routes of administration |
Intravenous use, Oral use
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Dosage and administration details |
Dexamethasone 20 mg was administered PO or IV on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day treatment cycle along with Carfilzomib.
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Arm title
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Isatuximab + Carfilzomib + Dexamethasone (IKd) | ||||||||||||||||||
Arm description |
Subjects received isatuximab 10 mg/kg, IV infusion on Days 1, 8, 15 and 22 in Cycle 1, then on Day 1 and Day 15 of each 28-day treatment cycles plus carfilzomib 20 mg/m^2, IV on Days 1, and 2 in Cycle 1, and then escalated to 56 mg/m^2 on Days 8, 9, 15 and 16 of Cycle 1 and on Days 1, 2, 8, 9, 15 and 16 of each subsequent 28-day treatment cycles and dexamethasone 20 mg, PO or IV on Day 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day treatment cycles until disease progression or unacceptable adverse event or subject’s decision to discontinue the study treatment or any other reason, whichever comes first (maximum exposure: 215 weeks). | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Carfilzomib
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Investigational medicinal product code |
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Other name |
Kyprolis
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Carfilzomib 20 (mg/m^2, was administered as an IV infusion on Days 1, and 2 in Cycle 1, and then escalated to 56 mg/m^2 on Days 8, 9, 15 and 16 of Cycle 1 and then on Days 1, 2, 8, 9, 15 and 16 of each subsequent 28-day treatment cycle along in combination with carfilzomib and dexamethasone.
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Investigational medicinal product name |
Isatuximab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Isatuximab 10 mg/kg, was administered as an IV infusion on Days 1, 8, 15 and 22 in Cycle 1, and then on Days 1 and 15 of each 28-day treatment cycle in combination with carfilzomib and dexamethasone.
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Investigational medicinal product name |
Dexamethasone
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection, Tablet
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Routes of administration |
Intravenous use, Oral use
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Dosage and administration details |
Dexamethasone 20 mg was administered PO or IV on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day treatment cycle along with carfilzomib and isatuximab.
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Baseline characteristics reporting groups
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Reporting group title |
Carfilzomib + Dexamethasone (Kd)
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Reporting group description |
Subjects received carfilzomib 20 milligrams per meter square (mg/m^2), intravenous (IV) infusion on Days 1, and 2 in Cycle 1, and then escalated to 56 mg/m^2 on Days 8, 9, 15 and 16 of Cycle 1 on Days 1, 2, 8, 9, 15 and 16 of each subsequent 28-day treatment cycles plus dexamethasone 20 milligrams (mg), orally (PO) or IV on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day treatment cycles until disease progression or unacceptable adverse event or subject’s decision to discontinue the study treatment or any other reason, whichever comes first (maximum exposure: 208 weeks). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Isatuximab + Carfilzomib + Dexamethasone (IKd)
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Reporting group description |
Subjects received isatuximab 10 mg/kg, IV infusion on Days 1, 8, 15 and 22 in Cycle 1, then on Day 1 and Day 15 of each 28-day treatment cycles plus carfilzomib 20 mg/m^2, IV on Days 1, and 2 in Cycle 1, and then escalated to 56 mg/m^2 on Days 8, 9, 15 and 16 of Cycle 1 and on Days 1, 2, 8, 9, 15 and 16 of each subsequent 28-day treatment cycles and dexamethasone 20 mg, PO or IV on Day 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day treatment cycles until disease progression or unacceptable adverse event or subject’s decision to discontinue the study treatment or any other reason, whichever comes first (maximum exposure: 215 weeks). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Carfilzomib + Dexamethasone (Kd)
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Reporting group description |
Subjects received carfilzomib 20 milligrams per meter square (mg/m^2), intravenous (IV) infusion on Days 1, and 2 in Cycle 1, and then escalated to 56 mg/m^2 on Days 8, 9, 15 and 16 of Cycle 1 on Days 1, 2, 8, 9, 15 and 16 of each subsequent 28-day treatment cycles plus dexamethasone 20 milligrams (mg), orally (PO) or IV on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day treatment cycles until disease progression or unacceptable adverse event or subject’s decision to discontinue the study treatment or any other reason, whichever comes first (maximum exposure: 208 weeks). | ||
Reporting group title |
Isatuximab + Carfilzomib + Dexamethasone (IKd)
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Reporting group description |
Subjects received isatuximab 10 mg/kg, IV infusion on Days 1, 8, 15 and 22 in Cycle 1, then on Day 1 and Day 15 of each 28-day treatment cycles plus carfilzomib 20 mg/m^2, IV on Days 1, and 2 in Cycle 1, and then escalated to 56 mg/m^2 on Days 8, 9, 15 and 16 of Cycle 1 and on Days 1, 2, 8, 9, 15 and 16 of each subsequent 28-day treatment cycles and dexamethasone 20 mg, PO or IV on Day 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day treatment cycles until disease progression or unacceptable adverse event or subject’s decision to discontinue the study treatment or any other reason, whichever comes first (maximum exposure: 215 weeks). | ||
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End point title |
Progression Free Survival (PFS) As Determined by Independent Response Committee (IRC): Primary Analysis | ||||||||||||
End point description |
Time from randomisation to date of 1st documentation of progressive disease (PD)/date of death, whichever 1st. If PD & death not observed before cut-off date/date of initiation of further anti-myeloma treatment, PFS censored at date of last valid disease assessment not showing PD performed prior to initiation of further anti-myeloma treatment/cut-off date, whichever 1st. PD:any 1 of following: increase(inc) >=25% serum M-component from nadir; serum M component inc >=1 g/dL in 2 consecutive assessment, if starting M component >=5 g/dL; and/or inc >=25% in urine M-component from nadir and/or development of new bone lesion/soft tissue extramedullary disease/inc >=50% from nadir in sum of perpendicular diameter of existing soft tissue extramedullary disease lesion if >1 lesion/ >=50% increase in longest diameter of previous soft tissue extramedullary disease lesion >1 cm in short axis. ITT population. Kaplan-Meier method.99999=value could not be calculated as <50% subjects had PFS events.
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End point type |
Primary
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End point timeframe |
From randomisation until the primary analysis data cut-off date of 7 Feb 2020 (median duration of follow-up was 20.73 months)
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Statistical analysis title |
PFS per IRC: Primary Analysis | ||||||||||||
Statistical analysis description |
Statistical analysis for comparison of PFS between the Kd and IKd arms based on primary analysis.
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Comparison groups |
Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
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Number of subjects included in analysis |
302
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
= 0.0007 [2] | ||||||||||||
Method |
Stratified Log-Rank test | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.531
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Confidence interval |
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level |
99% | ||||||||||||
sides |
2-sided
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lower limit |
0.318 | ||||||||||||
upper limit |
0.889 | ||||||||||||
| Notes [1] - For PFS, the nominal significance levels at primary analysis was determined using alpha-spending function in order to control overall 1-sided type 1 error at 2.5%. The 1-sided nominal significance level to declare overwhelming efficacy at primary analysis (103 PFS events) was 0.005. Because the median PFS was not reached at the primary analysis, it was described at the final analysis. [2] - One-sided p-value based on Stratified log-rank test. Threshold for significance=0.005. Stratified on number of prior lines of therapy(1 vs >1) & revised international staging system (I/II vs III vs not classified) per interactive response technology. |
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End point title |
Progression Free Survival as Determined by Independent Response Committee: Final Analysis | ||||||||||||
End point description |
PFS: time (in months) from randomisation to date of first documentation of PD or date of death from any cause, whichever comes first. If PD and death was not observed before analysis cut-off date or date of initiation of further anti-myeloma treatment, PFS was censored at date of last valid disease assessment or analysis cut-off date, whichever comes first. PD as per IMWG criteria: any 1 of following: Inc of >=25% in Serum M-component from nadir; serum M component increase >=1 g/dL in 2 consecutive assessment, if starting M component was >=5 g/dL; and/or inc of >=25% in Urine M-component from nadir and/or development of new bone lesion/soft tissue extramedullary disease/inc >=50% from nadir in sum of perpendicular diameters of existing soft tissue extramedullary disease lesion if >1 lesion/ >=50% inc in longest diameter of previous soft tissue extramedullary disease lesion >1 cm in short axis. Analysis was performed on ITT population and estimated by Kaplan-Meier method.
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End point type |
Primary
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End point timeframe |
From randomisation until the final analysis data cut-off date of 14 January 2022 (the median duration of follow-up was 43.96 months)
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Statistical analysis title |
PFS per IRC: Final Analysis | ||||||||||||
Statistical analysis description |
Statistical Analysis Progression Free Survival: Final Analysis between Carfilzomib - Dexamethasone (Kd) and Isatuximab, Carfilzomib and Dexamethasone (IKd) arms.
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Comparison groups |
Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
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Number of subjects included in analysis |
302
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||
Method |
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Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.576
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Confidence interval |
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level |
95.4% | ||||||||||||
sides |
2-sided
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lower limit |
0.418 | ||||||||||||
upper limit |
0.792 | ||||||||||||
| Notes [3] - Hazard Ratio was stratified on number of prior lines of therapy (1 vs. >1) and R-ISS stage (I or II vs. III vs. not classified) according to IRT. |
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End point title |
Progression Free Survival as Determined by Independent Response Committee: (Event Censored if Occurred >8 Weeks From Last Disease Assessment): Primary Analysis | ||||||||||||
End point description |
Time from randomisation to date of 1st PD documentation/death, whichever 1st. If PD & death not observed before cut-off date/date of further anti-myeloma treatment, PFS censored at date of last disease assessment not showing PD performed prior to initiation of further anti-myeloma treatment/cut-off date, whichever 1st. Progression/death occurring >8 week after last disease assessment censored at earliest date of last disease assessment without evidence of progression before initiation of anti-myeloma treatment & cut-off date. PD:meeting any 1: Inc >=25% in Serum M-component from nadir; serum M component inc >=1 g/dL in 2 consecutive assessment; and/or inc >=25% in Urine M-component from nadir and/or development of new bone lesion/soft tissue extramedullary disease/inc >=50% from nadir in sum of perpendicular diameter of existing soft tissue extramedullary disease lesion. ITT population. Kaplan-Meier method. 99999=value could not be calculated as <50% subjects had PFS events.
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End point type |
Primary
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End point timeframe |
From randomisation until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)
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Statistical analysis title |
PFS: Event Censored: Primary Analysis | ||||||||||||
Statistical analysis description |
Statistical analysis for comparison of PFS between the Kd and IKd arm based on primary analysis.
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Comparison groups |
Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
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Number of subjects included in analysis |
302
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Analysis specification |
Pre-specified
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Analysis type |
superiority [4] | ||||||||||||
P-value |
= 0.0016 [5] | ||||||||||||
Method |
Stratified Log-Rank test | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.548
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Confidence interval |
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level |
99.2% | ||||||||||||
sides |
2-sided
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lower limit |
0.317 | ||||||||||||
upper limit |
0.948 | ||||||||||||
| Notes [4] - The 1-sided nominal significance level to declare overwhelming efficacy at primary analysis was 0.004. Because the median PFS was not reached at the primary analysis, it was described at the final analysis. [5] - One-sided p-value based on Stratified log-rank test. Threshold for statistical significance at 0.004. Stratified on number of prior lines of therapy (1 vs >1) & revised international staging system stage (I/II vs III vs not classified) as per IRT. |
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End point title |
Progression Free Survival as Determined by Independent Response Committee (Event Censored if Occurred >8 Weeks From Last Disease Assessment): Final Analysis | ||||||||||||
End point description |
Time from randomisation to date of 1st documentation of PD/date of death any cause, whichever come 1st. If PD & death not observed before cut-off date/date of initiation of further anti-myeloma treatment, PFS censored at date of last valid disease assessment not showing PD/cut-off date, whichever is 1st. Progressions/deaths occurring >8 weeks after last disease assessment censored at earliest date of last valid disease assessment not showing PD before initiation of further anti-myeloma treatment & cut-off date. PD: meeting any 1 criteria: Inc of >=25% in serum M-component from nadir; serum M component inc >=1 g/dL in 2 consecutive assessment; and/or inc of >=25% in urine M-component from nadir and/or development of new bone lesion/soft tissue extramedullary disease/inc >=50% from nadir in sum of perpendicular diameters of existing soft tissue extramedullary disease lesion. ITT population. Kaplan-Meier method. 99999=value could not be calculated as <50% subjects had PFS events.
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End point type |
Primary
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End point timeframe |
From randomisation until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months)
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Statistical analysis title |
PFS: Event Censored: Final Analysis | ||||||||||||
Comparison groups |
Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
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Number of subjects included in analysis |
302
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Analysis specification |
Pre-specified
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Analysis type |
superiority [6] | ||||||||||||
Method |
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Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.594
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Confidence interval |
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level |
95.4% | ||||||||||||
sides |
2-sided
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lower limit |
0.424 | ||||||||||||
upper limit |
0.832 | ||||||||||||
| Notes [6] - Hazard Ratio was stratified on number of prior lines of therapy (1 vs. >1) and R-ISS stage (I or II vs. III vs. not classified) according to IRT. |
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End point title |
Percentage of Subjects With Overall Response (OR) as Determined by Independent Response Committee: Primary Analysis | ||||||||||||
End point description |
OR: subjects with sCR, CR, VGPR & partial response (PR) as best overall response assessed using IMWG response criteria (from start of treatment until disease progression, death, initiation of further anti-myeloma treatment/cutoff date, whichever is 1st). sCR: negative immunofixation on serum & urine, disappearance of soft tissue plasmacytoma, <5% plasma cells in bone marrow aspirate (BMA) + normal FLC ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum & urine, disappearance of soft tissue plasmacytoma, <5% plasma cells in BMA. VGPR: serum & urine M-protein detectable by immunofixation, not on electrophoresis/,>=90% reduction in serum M-protein + urine M-protein level <100mg/24h/,>=90% decrease in SPD compared to baseline in plasmacytoma. PR:>=50% reduction of serum M-protein & decrease in 24h urinary M-protein by >=90%/<200mg/24h, if present at baseline,>=50% decrease in SPD of soft tissue plasmacytoma. Analysis on ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomisation until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Percentage of Subjects with OR | ||||||||||||
Statistical analysis description |
Statistical analysis for comparison of Overall Response between the Kd and IKd arms based on primary analysis.
|
||||||||||||
Comparison groups |
Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
|
||||||||||||
Number of subjects included in analysis |
302
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [7] | ||||||||||||
P-value |
= 0.193 [8] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Confidence interval |
|||||||||||||
| Notes [7] - A closed test procedure was used to control the Type I error rate from the primary efficacy endpoints sequentially through the secondary efficacy endpoints. No further testing would be performed unless the significance level had been reached on PFS and testing on subsequent endpoints were continued only if the null hypothesis for the previously tested endpoint was rejected. [8] - One-sided p-value based on Stratified Cochran-Mantel-Haenszel test. One sided p-value was stratified based on randomisation factors according to IRT. Threshold for statistical significance level at 0.025. |
|||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects With VGPR or Better with Minimal Residual Disease (MRD) Negativity: Primary Analysis | ||||||||||||
End point description |
Percentage of subjects with sCR, CR and VGPR for whom MRD assessed by sequencing was negative at any time after first dose of study treatment. MRD was assessed centrally by next-generation sequencing in bone marrow aspiration samples from subjects who achieve VGPR or better, to determine depth of response at molecular level. VGPR or better: percentage of subjects with sCR, CR and VGPR. sCR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in BMAs plus normal FLC ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in BMAs. VGPR: serum and urine M-protein detectable by immunofixation, not on electrophoresis/,>=90% reduction in serum M-protein plus urine M-protein level <100mg/24h/,>=90% decrease in SPD compared to baseline in soft tissue plasmacytoma. Analysis was performed on ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomisation until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects With Very Good Partial Response (VGPR) or Better as Determined by Independent Response Committee: Primary Analysis | ||||||||||||
End point description |
VGPR or better: defined as subjects with sCR, CR and VGPR as the best overall response (defined as best response from start of treatment until disease progression, death, initiation of further anti-myeloma treatment or cut-off date whichever occurs first) as per IRC. As per IMWG response criteria: sCR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in BMAs plus normal free light chain (FLC) ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in BMAs. VGPR: serum and urine M-protein detectable by immunofixation, not on electrophoresis/,>=90% reduction in serum M-protein plus urine M-protein level <100mg/24h/,>=90% decrease in SPD compared to baseline in soft tissue plasmacytoma. ITT population: subjects who gave their informed consent & for whom there was confirmed randomisation number by IRT.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomisation until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects With VGPR or Better With Minimal Residual Disease (MRD) Negativity: Final Analysis | ||||||||||||
End point description |
Percentage of subjects with sCR, CR and VGPR for whom MRD assessed by sequencing was negative at any time after first dose of study treatment. MRD was assessed centrally by next-generation sequencing in BM aspiration samples from subjects who achieve VGPR/better, to determine depth of response at molecular level. VGPR or better: percentage of subjects with sCR, CR and VGPR. sCR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates plus normal FLC ratio, absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum & urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates. VGPR: serum & urine M-protein detectable by immunofixation, not on electrophoresis/,>=90% reduction in serum M-protein plus urine M-protein level <100mg/24h/,>=90% decrease in SPD compared to baseline in soft tissue plasmacytoma. Analysis was performed on ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomisation until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects With Complete Response With MRD Negativity: Final Analysis | ||||||||||||
End point description |
MRD negativity: percentage of subjects for whom MRD was negative by next-generation sequencing at any timepoint after 1st dose of study treatment. Threshold for negativity is 10^-5. MRD status in a subject was negative if at least 1 result of assessment was negative in subject otherwise MRD was considered as positive (MRD status reported as positive, missing or unevaluable). CR: subjects with sCR and CR. IMWG response criteria for sCR: negative immunofixation on serum & urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates plus normal FLC ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum & urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates. Complete response at time of the final analysis was assessed with Hydrashift isatuximab IFE assay, which separated IgG isatuximab from IgG M protein. Analysis was performed on ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomisation until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects with Complete Response (CR) as per Independent Response Committee: Final Analysis | ||||||||||||
End point description |
Complete response was defined as the subjects with sCR and CR. IMWG response criteria for sCR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates plus normal FLC ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates. Complete response at the time of the final analysis was assessed with hydrashift isatuximab immunofixation electrophoresis (IFE) assay, which separated immunoglobulin G (IgG) isatuximab from IgG M protein. Analysis was performed on ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomisation until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Duration of Response (DOR): Primary Analysis | ||||||||||||
End point description |
Time from date of 1st IRC determined response for subject achieving PR/better to date of 1st documented PD determined by IRC/death, whichever is 1st. If disease progression/death before analysis cut-off date not observed, DOR censored at date of last valid disease assessment performed prior to initiation of further anti-myeloma treatment/data cut-off date, whichever 1st. PD:inc >=25% from lowest confirmed value in any 1 of following criteria: serum M-protein (absolute inc >=0.5 g/dL), serum M-protein inc >=1g/dL if lowest M component >=5g/dL; urine M-component (absolute inc >=200mg/24 hour),appearance of new lesion, >=50% inc from nadir in SPD of >1 lesion, >=50% inc in longest diameter of previous lesion >1 cm in short axis. PR: >=50% reduction of serum M-protein & reduction in 24h urinary M-protein by >=90%/<200mg/24 h. Analysis on subset of subjects with PR/better in ITT population by Kaplan Meier method. 99999=value not calculated as <50% subject reaching PR/better with PFS event.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomisation until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis for DOR: Primary Analysis | ||||||||||||
Comparison groups |
Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
|
||||||||||||
Number of subjects included in analysis |
257
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [9] | ||||||||||||
Method |
|||||||||||||
Parameter type |
Stratified Hazard Ratio | ||||||||||||
Point estimate |
0.425
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.269 | ||||||||||||
upper limit |
0.672 | ||||||||||||
| Notes [9] - Stratification was done on the number of prior lines of therapy (1 vs. >1) and R-ISS stage (I or II vs. III vs. not classified) according to IRT. |
|||||||||||||
|
|||||||||||||
End point title |
Overall Survival (OS): Final Analysis | ||||||||||||
End point description |
Data for this endpoint will be reported at the time of anticipated last subject last visit results posting (February 2024) as the study is still ongoing.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 6 years
|
||||||||||||
|
|||||||||||||
| Notes [10] - Data for this endpoint will be reported at time of last subject last visit. [11] - Data for this endpoint will be reported at time of last subject last visit. |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Time to Progression (TTP): Primary Analysis | ||||||||||||
End point description |
Time from randomisation to date of 1st documentation of PD. If progression not observed before analysis cut-off date/date of initiation of further anti-myeloma treatment, TTP censored at date of last valid disease assessment not showing disease progression performed prior to initiation of a further anti-myeloma treatment (if any)/analysis cut-off date, whichever 1st. As per IMWG criteria, PD was defined for subjects with inc of >= 25% from lowest confirmed value in any one of the following criteria: serum M-protein (the absolute inc must be >= 0.5 g/dL), serum M-protein inc >=1 g/dL if the lowest M component was >=5 g/dL; urine M-component (the absolute inc must be >=200 mg/24hour), appearance of new lesion(s), >=50% inc from nadir in SPD of >1 lesion, or >=50% inc in the longest diameter of a previous lesion >1 centimeter in short axis. Analysis performed on ITT population using Kaplan-Meier method. 99999 = value not calculated due to less number of subjects with progression events.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomisation until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis TTP: Primary Analysis | ||||||||||||
Comparison groups |
Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
|
||||||||||||
Number of subjects included in analysis |
302
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [12] | ||||||||||||
Method |
|||||||||||||
Parameter type |
Stratified Hazard Ratio | ||||||||||||
Point estimate |
0.495
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.324 | ||||||||||||
upper limit |
0.757 | ||||||||||||
| Notes [12] - Stratification was done on the number of prior lines of therapy (1 vs. >1) and R-ISS stage (I or II vs. III vs. not classified) according to IRT. |
|||||||||||||
|
|||||||||||||
End point title |
Time to First Response (TFR): Primary Analysis | ||||||||||||
End point description |
Time to first response was defined as the time (in months) from randomisation to the date of first IRC determined response (PR or better) that is subsequently confirmed. In the absence of response, subjects were censored at the earliest of the date of the last valid disease assessment before disease progression or death, the date of the last valid disease assessment before initiation of a further anti-myeloma treatment (if any) or the analysis cut-off date, whichever comes first. PR per IMWG criteria was defined as >=50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by >=90% or to <200 mg/24 h. In addition to the above listed criteria, if present at baseline, a >=50% reduction in the size (SPD) of soft tissue plasmacytomas was also required. Analysis was performed on ITT population. Analysis was performed by Kaplan-Meier method.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomisation until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis for TFR: Primary Analysis | ||||||||||||
Comparison groups |
Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
|
||||||||||||
Number of subjects included in analysis |
302
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [13] | ||||||||||||
Method |
|||||||||||||
Parameter type |
Stratified Hazard Ratio | ||||||||||||
Point estimate |
1.143
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.888 | ||||||||||||
upper limit |
1.471 | ||||||||||||
| Notes [13] - Stratification was done on the number of prior lines of therapy (1 vs. >1) and R-ISS stage (I or II vs. III vs. not classified) according to IRT. |
|||||||||||||
|
|||||||||||||
End point title |
Time to Best Response (TBR): Primary Analysis | ||||||||||||
End point description |
Time to best response: time (in months) from randomisation to date of 1st occurrence of IRC determined as best overall response (PR/better) that is subsequently confirmed. In absence of response, subjects were censored at earliest date of last valid disease assessment before disease progression/death, date of last valid disease assessment before initiation of further anti-myeloma treatment (if any)/ analysis cut-off date, whichever was 1st. PR (IMWG criteria) was defined as >=50% reduction of serum M-protein & reduction in 24 hours urinary M-protein by >=90% or to <200 mg/24 h. Additionally, if present at baseline, a >=50% reduction in size (SPD) of soft tissue plasmacytomas was also required. Best Overall Response defined as best response, using IRC’s assessment of response, from start of treatment until disease progression, death, initiation of further anti-myeloma treatment or cut-off date, whichever occurs 1st. Analysis was performed on ITT population using Kaplan-Meier method.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomisation until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Stat Analysis for TBR: Primary Analysis | ||||||||||||
Comparison groups |
Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
|
||||||||||||
Number of subjects included in analysis |
302
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [14] | ||||||||||||
Method |
|||||||||||||
Parameter type |
Stratified Hazard Ratio | ||||||||||||
Point estimate |
0.955
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.74 | ||||||||||||
upper limit |
1.233 | ||||||||||||
| Notes [14] - Stratification was done on the number of prior lines of therapy (1 vs. >1) and R-ISS stage (I or II vs. III vs. not classified) according to IRT. |
|||||||||||||
|
|||||||||||||
End point title |
Second Progression Free Survival (PFS2): Final Analysis | ||||||||||||
End point description |
Time from date of randomisation to date of 1st documentation of PD (assessed by investigator) after initiation of further anti-myeloma treatment /death (any cause), whichever 1st. Subjects alive without progression after initiation of further anti-myeloma treatment before analysis cut-off date, PFS2 censored at date of last follow-up visit not showing disease progression after initiation of further anti-myeloma treatment/analysis cut-off date, whichever 1st. Per IMWG,PD: defined for subjects with increase (inc) of >= 25% from lowest confirmed value in any 1 of criteria: serum M-protein (absolute inc must be >= 0.5 g/dL), serum M-protein inc >=1 g/dL if lowest M component was >=5 g/dL; urine M-component (absolute inc >=200 mg/24hour), appearance of new lesion(s), >=50% inc from nadir in SPD of >1 lesion, or >=50% inc in longest diameter of previous lesion >1 centimeter short axis. ITT population, Kaplan-Meier method, 99999 = value not calculated as not enough subjects with PFS2 events.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomisation until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis for PFS2: Final Analysis | ||||||||||||
Comparison groups |
Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
|
||||||||||||
Number of subjects included in analysis |
302
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [15] | ||||||||||||
Method |
|||||||||||||
Parameter type |
Stratified Hazard Ratio | ||||||||||||
Point estimate |
0.683
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.496 | ||||||||||||
upper limit |
0.941 | ||||||||||||
| Notes [15] - Stratification was done on the number of prior lines of therapy (1 vs. >1) and R-ISS stage (I or II vs. III vs. not classified) according to IRT. |
|||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Health Related Quality of Life (HRQL): Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 30 Items (EORTC QLQ-C30): Global Health Status Score at Specified Timepoints | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
EORTC QLQ-C30 is a cancer-specific instrument that contains 30 items & provides multidimensional assessment of HRQL. EORTC QLQ-C30 includes global health status/quality of life (GHS/QOL), functional scales (physical, role, cognitive, emotional, social), symptom scales (fatigue, pain, nausea/vomiting), and 6 single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, financial difficulties). Most questions from QLQ-C30 are 4-point scale (1/Not at All to 4/Very Much), except Items 29-30, which comprise GHS scale & are 7-point scale (1/Very Poor to 7/Excellent). GHS total score is calculated as ([{Q29+Q30}/2]-1)/6*100. Answers are converted into grading scale, with values between 0 (worse outcome) to100 (best outcome). High score represents a favorable outcome with best quality of life for subject. Results reported for primary analysis with data cut-off date 7-Feb-2020. Analysis was performed on ITT population. 'n' signifies subjects with available data for each category.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
HRQL: Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Disease Symptoms Domain Score at Specified Timepoints: Primary Analysis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in subjects with multiple myeloma. It is used in conjunction with the EORTC QLQ-C30 to assess symptoms and side effects due to treatment or the disease. Disease symptoms domain is one of the four domain scores. Disease symptoms domain consist of 6 questions and the score uses 4-point scale (1 'Not at All' to 4 'Very Much'). Disease Symptoms Domain Score is calculated as ([{Q31+Q32+Q33+Q34+Q35+Q36}/6]-1)/3*100. Scores are averaged, and transformed to 0-100 scale, where higher scores = more symptoms and lower HRQL. Analysis was performed on ITT population. Here, ‘n’ signifies subjects with available data for each specified category.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
HRQL: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Side Effects of Treatment at Specified Timepoints: Primary Analysis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in subjects with multiple myeloma. Side effects of treatment domain is one of the four domain scores. Side effects of treatment domain consists of 10 questions and the score uses a 4-point scale (1 'Not at All' to 4 'Very Much'). Side Effects of Treatment Score (MYSE) is calculated as ([{Q37+Q38+Q39+Q40+Q41+Q42+Q43+Q44+Q45+Q46}/10]-1)/3*100. Scores are averaged, and transformed to 0-100 scale, where higher scores = more side effects and lower HRQL and lower scores = less side effects and better HRQL. Analysis was performed on ITT population. Here, ‘n’ signifies subjects with available data for each specified category.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
HRQL: Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Body Image Score at Specified Timepoints: Primary Analysis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in subjects with multiple myeloma. It is used in conjunction with the EORTC QLQ-C30 to assess symptoms and side effects due to treatment or the disease. It consists of one question and scores are based on the 4-point Likert scale ranging from 'Not at all' to 'Very much'. Body image score is calculated as: (1 – [Q47-1]/3)*100. Scores are averaged, and transformed to scale ranging from 0 to 100. A higher score represents a better quality of life. Analysis was performed on ITT population. Here, ‘n’ signifies subjects with available data for each specified category.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
HRQL: Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Future Perspective at Specified Timepoints: Primary Analysis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in subjects with multiple myeloma. It is used in conjunction with the EORTC QLQ-C30 to assess symptoms and side effects due to treatment or the disease. It consists of three questions and the scores are based on the 4-point Likert scale ranging from 'Not at all' to 'Very much'. Future Perspective score is calculated as (1 - ([{Q48+Q49+Q50}/3] -1)/3)*100. Scores are averaged and transformed to scale ranging from 0 to 100. A higher score represents a better quality of life. Analysis was performed on ITT population. Here, ‘n’ signifies subjects with available data for each specified category.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
HRQL: Change from Baseline in European Quality of Life Group Questionnaire with 5 dimensions and 5 levels per dimension (EQ-5D-5L): Health State Utility Index Value at Specified Timepoints: Primary Analysis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The EQ-5D-5L is a standardized measure of health status that provides a general assessment of health utility and consist in 2 sections a descriptive system comprising 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and Visual Analog Scale (VAS). Each dimension has a 5-level response: no problems, slight problems, moderate problems, severe problems, and extreme problems. Response options are measured with a 5-point Likert scale. The 5D-5L systems are converted into a single index utility score between 0 to 1, where higher score indicates a better health state and lower score indicate worse health state. Analysis was performed on ITT population. Here, ‘n’ signifies subjects with available data for each specified category.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
HRQL: Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) Score: Visual Analogic Scale (VAS) at Specified Timepoints: Primary Analysis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The EQ-5D-5L is a standardised measure of health status that provides a general assessment of health utility and consist of 2 sections; descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and a VAS. The VAS records the respondent’s self-rated health on a 20 centimeter (cm) vertical VAS; the scale went from 0 (worst imaginable health state) to 100 (best imaginable health state). This information can be used as a quantitative measure of health as judged by the individual respondents. Analysis was performed on ITT population. Here, ‘n’ signifies subjects with available data for each specified category.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||
End point title |
Pharmacokinetics: Plasma Concentration at End of infusion (Ceoi) of Isatuximab: Primary Analysis [16] | ||||||||||||||
End point description |
Ceoi is the plasma concentration observed at the end of intravenous infusion. Analysis was performed on pharmacokinetic (PK) population which included subjects who received at least 1 dose of Isatuximab, with data for at least 1 PK parameter available. Here, ‘n' signifies number of subjects with available data for each specified category.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
End of infusion on Cycle 1 Day 1 and Cycle 1 Day 15; Cycle 2 Day 1
|
||||||||||||||
| Notes [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm. |
|||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||||||||||||||||||||||
End point title |
Pharmacokinetics: Plasma concentration of Isatuximab at Ctrough: Primary Analysis [17] | ||||||||||||||||||||||||||||||||||
End point description |
Ctrough was the plasma concentration observed just before treatment administration during repeated dosing. Analysis was performed on PK population. Here, ‘n’ signifies number of subjects with available data for each specified category.
|
||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||
End point timeframe |
Pre-infusion on Cycle 1 Day 1, Day 8, Day 15 and Day 22, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, Cycle 7 Day 1, Cycle 8 Day 1, Cycle 9 Day 1 and Cycle 10 Day 1
|
||||||||||||||||||||||||||||||||||
| Notes [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm. |
|||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||
|
|||||||||
End point title |
Pharmacokinetics: tmax of Carfilzomib: Primary Analysis [18] | ||||||||
End point description |
Tmax was defined as the time to reach Cmax, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15
|
||||||||
| Notes [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Pharmacokinetics: tlast of Carfilzomib: Primary Analysis [19] | ||||||||
End point description |
Tlast was defined as the time of last concentration observed above the lower limit of quantification, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15
|
||||||||
| Notes [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Pharmacokinetics: Clast of Carfilzomib: Primary Analysis [20] | ||||||||
End point description |
Clast was defined as the last concentration observed above the lower limit of quantification. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15
|
||||||||
| Notes [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Pharmacokinetics: Maximum Observed Concentration (Cmax) of Carfilzomib: Primary Analysis [21] | ||||||||
End point description |
Cmax was defined as the maximum concentration observed after the first infusion calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Cycle 1: pre-dose (0 hour), 30 minutes (min), 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15
|
||||||||
| Notes [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Pharmacokinetics: Area under the Plasma concentration time curve from time 0 to last quantifiable concentration (AUClast) of Carfilzomib: Primary Analysis [22] | ||||||||
End point description |
AUClast was defined as area under the plasma concentration versus time curve calculated from time 0 to last quantifiable concentration. AUClast was calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15
|
||||||||
| Notes [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Pharmacokinetics: Area Under the Plasma Concentration Time Curve (AUC) of Carfilzomib: Primary Analysis [23] | ||||||||
End point description |
AUC was defined as area under the plasma concentration-time curve extrapolated to infinity according to the equation: AUC= AUClast + Clast/λz. AUC was calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15
|
||||||||
| Notes [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Pharmacokinetics: Volume of Distribution at Steady State (Vss) of Carfilzomib: Primary Analysis [24] | ||||||||
End point description |
Volume of Distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss is the apparent volume of distribution at steady-state, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15
|
||||||||
| Notes [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Pharmacokinetics: Terminal Half-life (t1/2z) of Carfilzomib: Primary Analysis [25] | ||||||||
End point description |
T1/2 was defined as the time required for the concentration of the drug to reach half of its original value, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15
|
||||||||
| Notes [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Pharmacokinetics: Percentage of extrapolation of AUC (AUCext) of Carfilzomib: Primary Analysis [26] | ||||||||
End point description |
AUCext was defined as the percentage of the extrapolation of AUC, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15
|
||||||||
| Notes [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Pharmacokinetics: Clearance at Steady State (CLss) of Carfilzomib: Primary Analysis [27] | ||||||||
End point description |
CLss was defined as a quantitative measure of the rate at which a drug substance is removed from the body at steady state, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15
|
||||||||
| Notes [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
||||||||||||||||
End point title |
Number of Subjects with Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs): Final Analysis | |||||||||||||||
End point description |
Adverse Event (AE) was defined as any untoward medical occurrence in a subject who received study drug and did not necessarily had a causal relationship with the treatment. TEAEs were defined as AEs that developed, worsened, or became serious during the treatment period (time from the first dose of study treatments up to 30 days after last dose of study treatments). An SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalisation or prolongation of existing hospitalization, resulted in persistent or significant disability / incapacity, was a congenital anomaly/birth defect, was a medically important event. Analysis was performed on safety population which included all subjects who gave their informed consent and for whom there was confirmation of successful allocation of a randomisation number by the IRT and received at least one dose or a part of a dose of the study treatments.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 208 weeks for Kd arm and 215 weeks for IKd arm)
|
|||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
|||||||||||||
End point title |
Number of Subjects with Anti-Drug Antibodies (ADA): Primary Analysis [28] | ||||||||||||
End point description |
ADA were categorised as: pre-existing, treatment induced, and treatment boosted response. Pre-existing ADA was defined as ADA that were present in samples drawn during the pretreatment period (i.e., before the first isatuximab administration). Treatment-induced ADA was defined as ADA that developed at any time during the ADA on-study observation period in subjects without pre-existing ADA, including subjects without pretreatment samples. Treatment boosted ADA was defined as pre-existing ADA with an increase in titer during the ADA on-study observation period. Analysis was performed on ADA evaluable population which included subjects who received at least one dose of study drug from the IKd arm with at least one ADA assessment during the ADA on-study observation period with a reportable result.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: 111 weeks)
|
||||||||||||
| Notes [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||
End point title |
Number of Subjects with Renal Response (RR): Primary Analysis | ||||||||||||||||||
End point description |
RR comprises of complete RR (CR renal), partial RR (PR renal) & minor RR (MR renal). CR renal: improvement in estimated glomerular filtration rate (eGFR) from <50 mL/min/1.73m^2 at Baseline to >=60 mL/min/1.73m^2 in at least 1 assessment during treatment period (time from 1st dose of study treatment [ST] up to 30 days after last dose of ST); PR renal: improvement in eGFR from <15 mL/min/1.73m^2 at baseline to at least 1 assessment in range of 30 to 60 mL/min/1.73m^2 during on treatment-period (OTP) & MR renal: improvement in eGFR from <15 mL/min/1.73m^2 at baseline to at least 1 assessment in range of 15-30 mL/min/1.73m^2 during OTP/from 15-30 mL/min/1.73m^2 at
Baseline to at least 1 assessment in range of 30 to 60 mL/min/1.73m^2 during OTP. Analysis on ITT population. 'Number of subjects analysed' = subjects with available data for the endpoint & ‘n’ = subjects with available data for each category. 99999 signifies no subjects available for assessment at specified timepoint.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
From the first dose of study treatment to 30 days following the last administration of study treatment (maximum duration: up to 114 weeks)
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
AE data was collected from the time of first dose of study treatment to 30 days following the last administration of study treatment (up to 208 weeks for Kd arm and 215 weeks for IKd arm)
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||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Reported AEs & deaths are TEAEs that developed, worsened/became serious during treatment period (time from the 1st dose of study treatments up to 30 days after last dose of study treatment). Analysis was done for safety population.
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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 |
24.1
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Reporting groups
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Reporting group title |
Carfilzomib + Dexamethasone (Kd)
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Reporting group description |
Subjects received isatuximab 10 mg/kg, IV infusion on Days 1, 8, 15 and 22 in Cycle 1, then on Days 1 and Day 15 of each 28-day treatment cycles plus carfilzomib 20 mg/m^2, IV on Days 1, and 2 in Cycle 1, and then escalated to 56 mg/m^2 on Days 8, 9, 15 and 16 of Cycle 1 and on Days 1, 2, 8, 9, 15 and 16 of each subsequent 28-day treatment cycles and dexamethasone 20 mg, PO or IV on Day 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day treatment cycles until disease progression or unacceptable adverse event or subject’s decision to discontinue the study treatment or any other reason, whichever comes first (maximum exposure: 208 weeks). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Isatuximab + Carfilzomib + Dexamethasone (IKd)
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||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received isatuximab 10 mg/kg, IV infusion on Days 1, 8, 15 and 22 in Cycle 1, then on Days 1 and Day 15 of each 28-day treatment cycles plus carfilzomib 20 mg/m^2, IV on Days 1, and 2 in Cycle 1, and then escalated to 56 mg/m^2 on Days 8, 9, 15 and 16 of Cycle 1 and on Days 1, 2, 8, 9, 15 and 16 of each subsequent 28-day treatment cycles and dexamethasone 20 mg, PO or IV on Day 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day treatment cycles until disease progression or unacceptable adverse event or subject’s decision to discontinue the study treatment or any other reason, whichever comes first (maximum exposure: 215 weeks). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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21 Aug 2017 |
Infusion time of carfilzomib changed from 10 to 30 minutes to be consistent with SMPC/PI. |
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08 Feb 2018 |
Added objective to evaluate rate of VGPR/better in subjects who were MRD negative, Removed local laboratory testing for response to reduce number of blood samples drawn, Added Coombs test after treatment was initiated to assess assay interference, Changed frequency of pregnancy testing & added appendix with additional pregnancy testing requirements, Allowed urine pregnancy test. Added Grade 5 IARs & symptomatic NIMP overdose as AESIs, HR estimate & corresponding 95% CI was changed to HR & corresponding (1-2α)% (α: 1-sided nominal significance level: α=0.023 at final analysis & 0.005 at PFS interim analysis), Added serologic definition of active hepatitis B & C, Clarified instructions for duration of contraceptive measures, Clarified that further anti myeloma therapies be collected until OS analysis, Clarified that hydration prior carfilzomib could be <500 mL (but >250 mL) during 2 first infusions for subjects at risk of cardiac decompensation, G-CSF use no longer limited to 1st 3 cycles, Added treatment delays for subject convenience be avoided during 1st cycles, Modified recommended actions for low ANC & platelet count, Added delay for carfilzomib infusion if Grade 3-4 IR occurred during isatuximab infusion, Added Appendix with description of low dose body CT scan, Added PFS2 be assessed by Investigator, Added when confirmatory disease assessments be repeated at 3 month intervals, Added subjects with history of hypertension had to have controlled BP before dosing, Added hydration requirements predose if TLS observed at prior infusion. |
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02 Jul 2018 |
BMA is an invasive procedure and study allows up to 6 BMAs. To limit the number of BMAs, wording to trigger BMA was clarified, In absence of radiological and M protein progression, if clinical and biological data together provided clear evidence of clinical progression based on IRC judgement, the IRC could consider clinical progression as a PFS event, Czech Republic added to appendix list of countries with increased pregnancy testing, For exclusion criterion 12: Clarified that only curative radiotherapy was allowed within 14 days prior to randomization, Clarified that any therapy (not just chemotherapy) for other cancer should have been completed at least 5 years prior to enrollment, Allowed oral diphenhydramine or equivalent in country where there is no longer IV formulation, Added possibility of keeping the same hydration volume and lengthening the administration time in case of cardiac decompensation risk, Clarified rules for dose modifications, Added protocol recommendations regarding antibacterial prophylaxis and thromboprophylaxis, and added caution regarding cotreatment of dexamethasone with CYP3A inhibitor. |
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11 Jun 2019 |
Contraception duration after end of isatuximab changed from 3 months (12 weeks) to 5 months, Change in frequency of pregnancy test per country requirement for women with childbearing potential; pregnancy test was to be performed before each cycle and then monthly during the follow-up period up to 3 months (12 weeks) in the Kd arm and up to 5 months in the IKd arm. |
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11 Sep 2019 |
Implemented safety monitoring measures following identification of 2 new risks related to carfilzomib - Carfilzomib may increase risk of progressive multifocal leukoencephalopathy & Carfilzomib may increase risk of hepatitis B virus reactivation.
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13 Nov 2019 |
Based on Health Authority feedback, censoring rules for the primary PFS analysis were changed; PFS2 was also updated according to the change. Hepatitis B virus DNA testing by polymerase chain reaction was added for patients with a positive hepatitis B surface antigen test and/or anti-Hepatitis B core antibody test, Added that any second primary malignancies during the follow-up period will be reported, Statistical sections were updated to match Statistical Analysis Plan amendment of July 2019 and changes to the PFS definition. |
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10 Aug 2020 |
Instruction for collecting hospitalization report and exams reports in case of serious adverse events section was updated. Switch to the approved Isatuximab administration mode with fixed volume. Option of direct supplies of oral investigational medicinal products (IMPs) was added in case of regional or national emergency declared by a governmental agency that resulted in travel restrictions, confinement, or restricted site access. |
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11 Mar 2021 |
Based on the positive interim PFS data, the treatment effect of IKd was expected to be better than initially anticipated in comparison to Kd. A descriptive PFS analysis was added when approximately 180 PFS events were reached. Based on more PFS events accumulated, this additional analysis would help to better characterize the distribution of PFS in a descriptive way for the IKd arm. With approximately 180 PFS events planned, the possibility of observing the median PFS time for the IKd arm was expected to be increased.
Clarification of accidental or intentional overdose of isatuximab and carfilzomib was defined by each administration and dexamethasone defined by cycle. Appendix N was added for contingency measures for a regional or national emergency declared by a governmental agency. |
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14 Sep 2021 |
Addition of the possibility to omit carfilzomib dosing on Days 8 and 9 if a subject asked for a more convenient schedule and Investigator agreed because she/he judges that the maximum benefit was reached. If dexamethasone dosing was maintained on Days 8 and 9 while carfilzomib on Days 8 and 9 was omitted, possibility to re-increase the dose of dexamethasone if dose previously reduced, based on Investigator judgement. |
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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 | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/34097854 http://www.ncbi.nlm.nih.gov/pubmed/36372355 http://www.ncbi.nlm.nih.gov/pubmed/36239134 |
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