Clinical Trial Results:
A Phase 3 Single Arm Study Evaluating the Efficacy and Safety of Gene Therapy in Subjects with Transfusion-dependent β-Thalassemia, by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo with a Lentiviral βA-T87Q Globin Vector in Subjects <=50 Years of Age
|
Summary
|
|
EudraCT number |
2016-003611-35 |
Trial protocol |
GB DE GR FR IT |
Global end of trial date |
15 Nov 2022
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
28 May 2023
|
First version publication date |
28 May 2023
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
HGB-212
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT03207009 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
bluebird bio, Inc.
|
||
Sponsor organisation address |
455 Grand Union Blvd, Somerville, MA , United States, 02145
|
||
Public contact |
Clinical Trials Operations, bluebird bio, Inc., 001 3394999300, clinicaltrials@bluebirdbio.com
|
||
Scientific contact |
Clinical Trials Operations, bluebird bio, Inc., 001 3394999300, clinicaltrials@bluebirdbio.com
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
|
||
EMA paediatric investigation plan number(s) |
EMEA-000166-PIP01-14 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
26 Jan 2023
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
15 Nov 2022
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
15 Nov 2022
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
The primary purpose of this study was to evaluate the efficacy of treatment with LentiGlobin BB305 Drug Product (beti-cel) in subjects less than or equal to (<=) 50 years of age with transfusion-dependent beta-thalassemia (TDT), who have a beta0/beta0, beta0/IVS-I-110, or IVS-I-110/IVS-I-110 genotype at the HBB gene.
|
||
Protection of trial subjects |
This study was performed in accordance with Title 21, United States (US) Code of Federal Regulations (CFR) Parts 50, 54, 56, and 312 Subpart D; the International Council for Harmonisation (ICH) Guideline on Good Clinical Practice (GCP; E6); and the ethical principles outlined in the Declaration of Helsinki; and/or, where applicable, the European Directive 2001/20/EC relating to implementation of GCP in the conduct of clinical trials on medicinal products for human use and Directive 2005/28/EC on GCP for investigational medicinal products for human use.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
08 Jun 2017
|
||
Long term follow-up planned |
Yes
|
||
Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
13 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
United Kingdom: 1
|
||
Country: Number of subjects enrolled |
France: 1
|
||
Country: Number of subjects enrolled |
Germany: 2
|
||
Country: Number of subjects enrolled |
Greece: 2
|
||
Country: Number of subjects enrolled |
Italy: 3
|
||
Country: Number of subjects enrolled |
United States: 10
|
||
Worldwide total number of subjects |
19
|
||
EEA total number of subjects |
8
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
8
|
||
Adolescents (12-17 years) |
6
|
||
Adults (18-64 years) |
5
|
||
From 65 to 84 years |
0
|
||
85 years and over |
0
|
||
|
|||||||||||
|
Recruitment
|
|||||||||||
Recruitment details |
The study was conducted at 9 study centers in France, Germany, Greece, Italy, United Kingdom, and United States, of which 8 had enrolled subjects from 08 June 2017 to 15 November 2022. | ||||||||||
|
Pre-assignment
|
|||||||||||
Screening details |
A total of 19 subjects were enrolled, of which 18 subjects aged <=50 years were treated with LentiGlobin BB305 Drug Product. | ||||||||||
|
Period 1
|
|||||||||||
Period 1 title |
Overall Study (overall period)
|
||||||||||
Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Not applicable
|
||||||||||
Blinding used |
Not blinded | ||||||||||
|
Arms
|
|||||||||||
|
Arm title
|
LentiGlobin BB305 Drug Product | ||||||||||
Arm description |
Subjects <=50 years of age received a single intravenous (IV) infusion of LentiGlobin BB305 Drug Product at a dose of >=5.0 × 10^6 CD34+ cells/kilogram (kg) body weight on Day 1 after myeloablative conditioning with busulfan (4 days of conditioning followed by at least 48 hours of washout) (termed the Transplant population). | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
LentiGlobin BB305 Drug Product
|
||||||||||
Investigational medicinal product code |
|||||||||||
Other name |
betibeglogene autotemcel, beti-cel
|
||||||||||
Pharmaceutical forms |
Dispersion for infusion
|
||||||||||
Routes of administration |
Intravenous use
|
||||||||||
Dosage and administration details |
Subjects received a single IV infusion of >=5.0 x 10^6 CD34+ cells/kg body weight of LentiGlobin BB305 Drug Product.
|
||||||||||
|
|||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Overall Study
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects <= 50 years of age received a single intravenous (IV) infusion of LentiGlobin BB305 Drug Product at a dose of >= 5.0 × 10^6 CD34+ cells/kilogram (kg) body weight on Day 1 after myeloablative conditioning with busulfan (4 days of conditioning followed by at least 48 hours of washout) (termed the Transplant population). As appropriate, data are analysed at times based on Intent-to-Treat (ITT) population which included all 19 subjects who initiated any study procedures, beginning with mobilization by G-CSF and/or plerixafor. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
LentiGlobin BB305 Drug Product
|
||
Reporting group description |
Subjects <=50 years of age received a single intravenous (IV) infusion of LentiGlobin BB305 Drug Product at a dose of >=5.0 × 10^6 CD34+ cells/kilogram (kg) body weight on Day 1 after myeloablative conditioning with busulfan (4 days of conditioning followed by at least 48 hours of washout) (termed the Transplant population). | ||
|
|||||||||
End point title |
Percentage of Subjects who have Achieved Transfusion Independence (TI) [1] | ||||||||
End point description |
TI was defined as a weighted average hemoglobin (Hb) >= 9 grams per deciliter (g/dL) without any packed red blood cell (pRBC) transfusions for a continuous period of >= 12 months at any time during the study after drug product infusion. Transplant Population (TP) included all subjects who received beti-cel. Subjects evaluable for TI are defined as subjects who have achieved TI, have not achieved TI in their parent study, or completed their parent study.
|
||||||||
End point type |
Primary
|
||||||||
End point timeframe |
From 12 to 24 months post-transplant
|
||||||||
| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were performed; no inferential statistical analyses were performed. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Percentage of Subjects who have Achieved Transfusion Independence (TI) at Month 24 | ||||||||
End point description |
TI was defined as a weighted average hemoglobin (Hb) >= 9 grams per deciliter (g/dL) without any packed red blood cell (pRBC) transfusions for a continuous period of >= 12 months at any time during the study after drug product infusion. TP included all subjects who received beti-cel. Subjects evaluable for TI are defined as subjects who have achieved TI, have not achieved TI in their parent study, or completed their parent study. Here, “number of subjects analysed” signifies those subjects who achieved TI.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
At Month 24 post-transplant
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Duration of Transfusion Independence (TI) | ||||||||
End point description |
Duration of TI was calculated as the time from the start of TI (i.e. first Hb >=9 with no transfusions in the preceding 60 days) up to the last available Hb at which the TI criteria are still met using Kaplan-Meier methodology. TP included all subjects who received beti-cel. Subjects evaluable for TI are defined as subjects who have achieved TI, have not achieved TI in their parent study, or completed their parent study. Here, “number of subjects analysed” signifies those subjects who achieved TI. Data are presented through the Month 24 Visit based on calendar dates and including visit windows.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From start of TI up to Month 24 (actual maximum time frame of up to approximately 25 months due to visit window)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Time From Drug Product Infusion to Achievement of Transfusion Independence (TI) | ||||||||
End point description |
Time from drug product infusion to achievement of TI was calculated as the time from drug product infusion to the first hemoglobin at which a subject can be declared as TI (that is to 'start of TI + >= 12 months', dependent on Hb lab schedule). TP included all subjects who received beti-cel. Subjects evaluable for TI are defined as subjects who have achieved TI, have not achieved TI in their parent study, or completed their parent study. Here, “number of subjects analysed” signifies those subjects who achieved TI. Data are presented through the Month 24 Visit based on calendar dates and including visit windows.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From 14 months post-drug product infusion through Month 24 (actual maximum time frame of up to approximately 25 months due to visit window)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Weighted Average Hemoglobin (Hb) During Transfusion Independence (TI) | ||||||||
End point description |
Weighted average Hb was defined as the weighted average of Hb values without any pRBC transfusions in the proceeding 60 days. Ratio of the time between two Hb values and the time between the first and the last Hb values was used as the weight for calculation. TP included all subjects who received beti-cel. Subjects evaluable for TI are defined as subjects who have achieved TI, have not achieved TI in their parent study, or completed their parent study. Here, “number of subjects analysed” signifies those subjects who achieved TI.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From 60 days after the last pRBC transfusion through Month 24
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Percentage of Subjects who meet the Definition of Transfusion Reduction (TR) | ||||||||
End point description |
TR was defined as demonstration of a 60 percent (%) reduction in the annualized volume of pRBC transfusion requirements (in milliliter per kilogram [mL/kg]) in the post-treatment time period from 12 Months post-drug product infusion through Month 24 compared to the annualized mL/kg pRBC transfusion requirement during the 24 months prior to study enrollment. Here, “number of subjects analysed” signifies those subjects who were evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From 12 to 24 months post-transplant
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||
End point title |
Percentage of Subjects who had a Reduction of At least 50%, 60%, 75%, 90% or 100% in the Annualized pRBCs Transfusion Volume | ||||||||||||||||||
End point description |
Percentage of subjects with a reduction in the annualized mL/kg pRBCs transfused from 12 months post-drug product infusion through Month 24 (approximately a 12-month period) of at least 50%, 60%, 75%, 90% or 100% compared to the annualized mL/kg pRBC transfusion requirement during the 24 months prior to enrollment. TP included all subjects who received beti-cel.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
12 months post-drug product infusion through Month 24
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||
End point title |
Annualized Number of pRBC Transfusions | ||||||||
End point description |
Annualized number of pRBC transfusions from 12 months post-drug product infusion through Month 24 was reported. TP included all subjects who received beti-cel.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From 12 months post-drug product infusion through Month 24
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Annualized Volume of pRBC Transfusions | ||||||||
End point description |
Annualized volume of pRBC transfusions from 12 months post-drug product infusion through Month 24 compared to the annualized volume of transfusions during the 24 months prior to enrollment. TP included all subjects who received beti-cel.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From 12 to 24 months post-transplant
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Time From Drug Product Infusion to Last pRBC Transfusion | ||||||||
End point description |
Time from drug product infusion to last pRBC transfusion was reported. TP included all subjects who received beti-cel.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From start of drug product infusion up to Month 24
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Time From Last pRBC Transfusion to 24 Months | ||||||||
End point description |
Time From Last pRBC Transfusion to the Month 24 was reported. TP included all subjects who received beti-cel. Data are presented through the Month 24 Visit based on calendar dates and including visit windows.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From last pRBC Transfusion up to Month 24 (actual maximum time frame of up to approximately 27 months due to visit window)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Weighted Average Nadir Hemoglobin (Hb) | ||||||||
End point description |
The weighted average nadir Hb was defined as the most recent Hb prior to each pRBC transfusion, on the day of transfusion or within 3 days and, if there was a period of more than 60 days without transfusion, all Hb records between Day 61 and last follow-up or next transfusion (inclusive) was included. The weighted average nadir Hb during the period of 12 months post-drug product infusion to Month 24 was compared to the weighted average nadir Hb during the 24 months prior to enrollment. TP included all subjects who received beti-cel.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
12 months post-drug product infusion through Month 24
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||
End point title |
Unsupported Total Hb Levels at Month 6, 9, 12, 18 and 24 | ||||||||||||||||||
End point description |
Unsupported total Hb level was defined as the total Hb measurement level without any acute or chronic pRBC transfusions within 60 days prior to the measurement date. TP consisted of subjects who received LentiGlobin BB305 Drug Product infusion. Here, “number of subjects analysed” signifies those subjects who were evaluable for this endpoint and “n” signifies those subjects who were evaluable at specific timepoint.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
At Month 6, 9, 12, 18 and 24
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of Subjects With Unsupported Total Hb Levels (>=10 g/dL, >=11 g/dL, >=12 g/dL, >=13 g/dL, and >=14 g/dL) at Months 6, 9, 12, 18 and 24 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Number of subjects with unsupported total Hb levels (>=10 g/dL, >=11 g/dL, >=12 g/dL, >=13 g/dL, and >=14 g/dL) meeting the thresholds were reported at Months 6, 9, 12, 18 and 24. TP included all subjects who received beti-cel. Subjects were evaluable if they had an unsupported total Hb measurement at the specific timepoint, where unsupported total Hb level is defined as the total Hb measurement level without any acute or chronic pRBC transfusions within 60 days prior to the measurement date. Here, “number of subjects analysed” signifies those subjects who were evaluable for this endpoint and “n” signifies those subjects who were evaluable at specific timepoint.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
At Months 6, 9, 12, 18 and 24
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||
End point title |
Percentage of Subjects Who Have Not Received Chelation Therapy for At Least 6 Months Following Drug Product Infusion | ||||||||
End point description |
Percentage of subjects who have not received chelation therapy for at least 6 months following drug product infusion were reported. TP included all subjects who received beti-cel.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From 6 to 24 months
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Time From Last Iron Chelation Use to Last Follow-up | ||||||||
End point description |
Time from last iron chelation use to last follow-up to 24 months was reported. TP included all subjects who received beti-cel. Subjects were evaluable for this endpoint if they had not received iron chelation therapy for at least 6 months following drug product infusion. Here, “number of subjects analysed” signifies those subjects who were evaluable for this endpoint. Data are presented through the Month 24 Visit based on calendar dates and including visit windows.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From last Iron Chelation up to Month 24 (actual maximum time frame of up to approximately 29 months due to visit window)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||
End point title |
Number of Subjects who Used Therapeutic Phlebotomy Post DP infusion | ||||||
End point description |
Therapeutic phlebotomy could be used in lieu of chelation in subjects who had Hb consistently >= 11 g/dL and who were no longer receiving regular transfusions, at the discretion of the investigator. Number of subjects who used therapeutic phlebotomy post DP infusion for up to Month 24 were reported. TP included all subjects who received beti-cel.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
Up to Month 24
|
||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||||||||
End point title |
Change From Baseline in Liver Iron Content by Magnetic Resonance Imaging (MRI) | ||||||||||||
End point description |
Change From Baseline in Liver Iron Content by MRI at Months 12 and 24 were reported.TP included all subjects who received beti-cel. Subjects were evaluable for TI if they had completed the study (i.e., completed the Month 24 Visit), achieved TI, or did not achieve TI during the study. Baseline is defined as value closest to but prior to conditioning. Here, “n” signifies those subjects who were evaluable at specific timepoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Month 12 and 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change From Baseline in Cardiac T2* on MRI | ||||||||||||
End point description |
Change From Baseline in Cardiac T2* on MRI from baseline, month 12 and 24 was reported. TP included all subjects who received beti-cel. Subjects were evaluable for TI if they had completed the study (i.e., completed the Month 24 Visit), achieved TI, or did not achieve TI during the study. Here, “n” signifies those subjects who were evaluable at specific timepoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Months 12 and 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change From Baseline in Serum Ferritin | ||||||||||||
End point description |
Serum ferritin was commonly used for an indirect estimation of body iron stores. Although sensitive, it is not specific for iron overload as it can be elevated in a variety of infectious and inflammatory states, and in the presence of cytolysis. Subjects are evaluable for TI if they had completed the study (i.e., completed the Month 24 Visit), achieved TI, or did not achieve TI during the study. Here, “n” signifies those subjects who were evaluable at specific timepoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Month 12 and 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Total Scores at Months 12 and 24 | ||||||||||||||||
End point description |
PedsQL GCS designed to measure health-related quality of life in pediatric and adolescents (2-18 years). It encompassed 4 dimensions of functioning (physical [8 items], emotional [5 items], social [5 items], school [3 items]). Age groups: Toddler (2-4 years), Young pediatric (5-7 years), Pediatric (8-12 years), Teens (13-18 years). The questionnaire was also completed by parent/caregiver to assess parents' perceptions of their children's quality of life. The Toddler group consisted of 21 items, using a 5-point Likert scale (0 to 4); all other groups consisted of 23 items, with a 3-point Likert scale (0, 2, 4) for young pediatric, a 5-point Likert scale for pediatric and teens groups. All reported scores were transformed on a scale from 0 to 100 for each domain where 0=100, 1=75, 2=50, 3=25, and 4=0. Higher scores correspond with higher quality of life. TP population. “Number of subjects analysed”=subjects who were evaluable for this endpoint; “n”=subjects were at specific timepoint.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Month 12 and 24
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||
End point title |
Change From Baseline in EuroQol Quality of Life 5-Dimension Youth Scale (EQ-5D-Y) VAS Health Status at Months 12 and 24 | ||||||||||||
End point description |
EQ-5D is a validated, standardized, generic instrument that was most widely used preference based health related quality of life questionnaire in cost effectiveness and health technologies assessment. EQ-5D-Y was a version of instrument specifically developed and validated for use by youths aged 12 through 17 years. The EQ-5D-Y visual analog scale (VAS) consisted of a 20-cm vertical VAS, with anchors of 0 ("worst imaginable health state") and 100 ("best imaginable health state"). Respondents were asked to rate their own health state today by drawing a line from a box containing these words to the point on the scale that they felt most accurately reflected their current health state. The VAS was reported (raw data) on a scale of 0-100 where 0= death and 100= perfect health. Higher scores equated to better outcomes. TP population. Here, “number of subjects analysed” signifies those subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Months 12 and 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change From Baseline in EuroQol Quality of Life 5-Dimension Adult Scale (EQ-5D-3L) VAS Heath Status Score at Months 12 and 24 | ||||||||||||
End point description |
EQ-5D is a validated, standardized, generic instrument that was most widely used preference based health related quality of life (HRQoL) questionnaire in cost effectiveness and health technologies assessment. Participants age >=18 at time of informed consent were eligible to complete the EQ-5D-3L which is a visual analog scale (VAS) which consists of a 20-cm vertical VAS, with anchors of 0 ("worst imaginable health state") and 100 ("best imaginable health state"). Respondents were asked to rate their own health state today by drawing a line from a box containing these words to the point on the scale that they feel most accurately reflects their current health state. TP population. Number of subjects analysed signifies subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Months 12 and 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change From Baseline in Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Questionnaire Score | ||||||||||||
End point description |
FACT-BMT is assessed bone marrow transplant related quality of life in adults. It. Total score was sum of sub-scale scores for 5 domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, Functional Well-Being, and Bone Marrow Transplantation Subscale. Each item scored on a 5-point Likert scale based on participant agreement with each statement: 0 for "not at all," 1 for "a little bit," 2 for "somewhat," 3 for "quite a bit," and 4 for "very much. Reported scores were transformed as follows: After taking into account reverse scores for questions constructed in negative form, subscale score for each domain was calculated by multiplying sum of item scores by number of items in subscale, then dividing by number of items answered. Total score was sum of subscale total added together and ranges from 0-148. Higher scores corresponded with higher quality of life. TP population. Number of subjects analysed signifies those subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Months 12 and 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline in Short Form-36 Health Survey (SF-36), Version 2, Acute (Physical and Mental Component Summary Scores) at Months 12 and 24 | ||||||||||||||||
End point description |
SF-36 was designed to measure health-related quality of life in adults. The instrument consisted of 36 items, were aggregated into 8 multi-item scales (physical functioning [1=yes, limited a lot-3=no, not limited at all], role-physical [1=all of time-5=none of time], bodily pain [1=very severe to 6=none], general health [1=poor-5=excellent], vitality [1=none of time-5=all of time], social functioning [1=all of time-5=none of time], role emotional [1=all of time-5=none of time] and mental health [1=all of time-5=none of the time]). 4 domains comprised PCS score (physical functioning, role-physical, bodily pain, general health) and remaining 4 domains comprised MCS score (vitality, social functioning, role-emotional, mental health). Reported summary scores were transformed on a scale from 0-100. Higher scores corresponded with higher quality of life. TP population. Number of subjects analysed signifies those subjects who were evaluable for this endpoint.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Months 12 and 24
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||
End point title |
Annualized Phlebotomy Therapy Usage Following Drug Product Infusion | ||||||||
End point description |
Annualized phlebotomy therapy usage (number of procedures per year, calculated from DP infusion through last follow-up) were reported. TP included all subjects who received beti-cel. Here, “number of subjects analysed” signifies those subjects who received therapeutic phlebotomy.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to Month 24
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From date of informed consent up to Month 24
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
ITT population included all subjects who initiated any study procedures, beginning with mobilization by G-CSF and/or plerixafor.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
LentiGlobin BB305 Drug Product
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects <=50 years of age received a single IV infusion of LentiGlobin BB305 Drug Product at a dose of >= 5.0 × 10^6 CD34+ cells/kilogram (kg) body weight on Day 1 after myeloablative conditioning with busulfan (4 days of conditioning followed by at least 48 hours of washout) (termed the Transplant population). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
19 Jun 2018 |
Amendment version 2.0:
Part 1: • Target average daily busulfan AUC reduced from 4500 (range 4000 to 5000) mcM*min to 4200 (range 3800 to 4500) mcM*min. Children and adolescents were recommended to follow a q6h dosing regimen, with a target AUC of 1050 (range 950 to 1125) mcM*min. Prophylaxis with ursodeoxycholic acid (preferred) or defibrotide is required before initiation of conditioning to help prevent the occurrence of VOD/SOS.
•Modified select secondary efficacy endpoints: Added secondary efficacy endpoints for weighted average Hb during TI, time from drug product infusion to achievement of TI, and number of days hospitalized; data were already collected as part of the study. Rephrased the parameters used to assess transfusion-free periods, added under characterization of TR to be assessed for all subjects. Added secondary efficacy endpoints for total Hb over time and at specific levels to provide additional analysis of hematological parameters. Updated secondary efficacy endpoints for weighted average nadir Hb and volume of pRBC transfusions from Month 12 through Month 24; transfusion volume data had already been collected and used to calculate the primary endpoint. Added secondary efficacy endpoint for the use of phlebotomy and removed parameter for iron chelation usage as it is unlikely to be meaningful due to the large variation in iron chelation agents and routes of administration which do not allow for a clear comparison.
• Added safety endpoint to characterize the incidence of graft-vs-host disease (GVHD) to ensure that any occurrence of GVHD is adequately assessed amongst the AEs that are currently collected as part of this study.
• Added minimum enrollment for subjects without an IVS-I-110 mutation to ensure heterogenous representation of β0/β0 subjects reflective of the general genotypic distribution. |
||
19 Jun 2018 |
Amendment version 2.0:
Part 2: • Modified the time period for AE collection to be in relation to each subject’s time of neutrophil engraftment rather than to a specified Day post drug product infusion because subjects have differing amounts of time until neutrophil engraftment. Added time period “from informed consent/assent through Month 24 Visit” to ensure adequate assessment of AEs during the study. |
||
05 Apr 2019 |
Amendment version 3.0:
• Included changes from country-specific protocol Version 2.1.
• Clarified that transfusion requirements, use of iron removal therapies, and weighted average nadir Hb measurements will be annualized so that they can be fairly compared across time periods.
• Modified select secondary efficacy endpoints: Adjusted secondary endpoints for total Hb levels to unsupported total Hb levels to reduce the contribution of transfused pRBCs to total Hb assessments. Added new secondary endpoint of “Time from last iron chelation use to last follow-up”, allowing assessment of iron chelation use independent of dose information. Re-categorized quality of life (QoL) parameters as secondary endpoints instead of exploratory efficacy endpoints, as QoL are clinically meaningful parameters for assessing additional effects of treatment. Separated the “Length of in-patient hospital stay from initiation of conditioning to discharge” endpoint from the other health resource utilization endpoints and added it as an individual endpoint. This parameter was not intended for comparison with the pre-enrollment period.
• Prohibited the use of hydroxyurea during the study, and included luspatercept (a potential new drug on the market) as an additional example of a potentially disease-modifying therapy.
• Added recommendation to not use anti-retroviral medicines before mobilization and after drug product infusion, as they could theoretically interfere with the efficacy of the drug product.
• Corrected the SOE to add assessment of immunological parameters at end-of-study visit Month 24.
• Integration site analyses were updated to include qPCR to improve precision. |
||
16 Aug 2019 |
Amendment version 4.0:
• Sample size number has been increased from approximately 15 to approximately 18 subjects (with at least 2 additional subjects with a β0/β0 genotype) to reflect the number of subjects that have or are intended to be treated.
• To account for the increase in sample size, the 70% success criterion has been updated from 11 out of 15 subjects to 13 out of 18 subjects, and the lower 1-sided confidence bound has been updated from 44.9% to 46.5%. |
||
18 Oct 2020 |
Amendment version 5.0:
• Replaced the former primary endpoint of TR with TI. TI is a more meaningful clinical outcome than TR, and is to be used for regulatory decision making as discussed with regulatory authories.
• Moved TR into the secondary endpoints.
• To account for the new primary endpoint of TI, the success criterion, sample size estimation, and statistical analyses for the primary and secondary endpoints were updated.
• Updated the assessment of clonal predominance, which will now be assessed based on the frequency of clones with lentiviral vector (LVV) insertions rather than the frequency of individual LVV integration site (IS). Clonal contribution as determined by IS-specific qPCR normalized against human genomic genes is the most suitable current method available to accurately determine the relative predominance of each given clone independent of how many unique IS may be present within that clone.
• Designated clonal predominance as an exploratory safety endpoint and the remaining safety endpoints as secondary endpoints.
• Added text to provide guidelines around study procedures impacted by the force of nature events and analysis of assessments impacted by the COVID-19 pandemic.
• Updated clinical laboratory tests to allow for further investigator when additional follow-up may be required (e.g., unexpected blood test results).
• Clarified that SAEs that start between completion of the parent study and enrollment in long-term follow-up Study LTF-303 will be recorded in the HGB-212 SAE report form.
• Added text to extend the time period for follow-up of newborns after regulatory correspondence. |
||
10 Jun 2021 |
Amendment version 6.0:
• Updated the criteria for which a clinical work-up following ISA is recommended, updated the clinical work-up procedure to include a follow-up ISA, and updated the process to be used upon detection of clonal predominance or malignancy. These updates allowed for more stringent monitoring for malignancies or potential malignancies following treatment with beti-cel.
• Specified that bone marrow samples may be archived and that genetic testing may be performed if clinically indicated.
• Provided considerations for vaccines as concomitant medications per guidance from regulatory agency.
• Removed the statement that a subject may be withdrawn from the study if they have undetectable VCN in peripheral blood cells for 2 consecutive measurements at least 1 month apart. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
