Trial Outcomes & Findings for GRASPA (Erythrocytes Encapsulating L-asparaginase) in Patients With Relapse of Acute Lymphoblastic Leukemia (NCT NCT01518517)

Last Updated: 2022-02-02

Results Overview

Co-primary efficacy endpoint: duration in days of asparaginase activity \>100 U/L in whole blood during the induction treatment phase: last available date/time of activity \>100 UI/L before activity drops below 100 U/L - date/time of first activity \>100 UI/L. Asparaginase activity is compared for GRASPA versus native ASNase to demonstrate the non-inferiority of GRASPA.

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

85 participants

Primary outcome timeframe

Induction treatment period (i.e. 28 days)

Results posted on

2022-02-02

Participant Flow

Participant milestones

Participant milestones
Measure	GRASPA (Non Allergic Population) Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: * for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) * for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	Reference L-asparaginase (Non Allergic Population) For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL). •for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks). NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity) •for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy	GRASPA (Allergic Population) Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: * for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) * for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
Overall Study STARTED	29	30	26
Overall Study COMPLETED	1	3	0
Overall Study NOT COMPLETED	28	27	26

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

GRASPA (Erythrocytes Encapsulating L-asparaginase) in Patients With Relapse of Acute Lymphoblastic Leukemia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	GRASPA (Non Allergic Population) n=29 Participants Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: * for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) * for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	Reference L-asparaginase (Non Allergic Population n=30 Participants For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL). •for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks). NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity) •for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy	GRASPA (Allergic Population) n=26 Participants Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: * for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) * for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	Total n=85 Participants Total of all reporting groups
Age, Categorical <=18 years	23 Participants n=5 Participants	23 Participants n=7 Participants	15 Participants n=5 Participants	61 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	6 Participants n=5 Participants	7 Participants n=7 Participants	11 Participants n=5 Participants	24 Participants n=4 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Sex: Female, Male Female	11 Participants n=5 Participants	10 Participants n=7 Participants	8 Participants n=5 Participants	29 Participants n=4 Participants
Sex: Female, Male Male	18 Participants n=5 Participants	20 Participants n=7 Participants	18 Participants n=5 Participants	56 Participants n=4 Participants

PRIMARY outcome

Timeframe: Induction treatment period (i.e. 28 days)

Population: Only non allergic population evaluated for efficacy (i.e. 2 randomized arms). Only patient receiving treatment are considered.

Outcome measures

Outcome measures
Measure	GRASPA Non Allergic n=26 Participants Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: * for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) * for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	Reference L-asparaginase n=28 Participants For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL). •for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks). NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity) •for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy	GRASPA (Allergic Population) Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: * for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) * for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
Duration of Asparaginase Activity >100 U/L During Induction	18.9 days Interval 16.7 to 21.0	8.5 days Interval 6.0 to 11.1	—

PRIMARY outcome

Timeframe: Induction treatment period (i.e. 28 days)

Population: Only patient receiving treatment are considered.

Co-primary safety endpoint: allergic reaction regardless of grade during induction phase. Only those reactions that were reported in relation to the treatment to which the patient was randomised were counted.

Outcome measures

Outcome measures
Measure	GRASPA Non Allergic n=26 Participants Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: * for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) * for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	Reference L-asparaginase n=28 Participants For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL). •for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks). NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity) •for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy	GRASPA (Allergic Population) n=26 Participants Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: * for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) * for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
Allergic Reaction During Induction Phase	0 reactions	13 reactions	3 reactions

SECONDARY outcome

Timeframe: Induction treatment period (i.e. 28 days)

CR is defined as, no physical evidence of leukemia, normal CBC, cytologic remission: normally regenerating bone marrow, with \<5% leukemic blasts and the absence of detectable CNS or extramedullary disease, evaluated with physical examination and CSF findings, at the end of induction

Outcome measures

Outcome measures
Measure	GRASPA Non Allergic n=25 Participants Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: * for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) * for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	Reference L-asparaginase n=28 Participants For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL). •for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks). NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity) •for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy	GRASPA (Allergic Population) n=25 Participants Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: * for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) * for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
Complete Remission (CR)	19 Participants	13 Participants	15 Participants

SECONDARY outcome

Timeframe: Overall trial period to 36 months

Population: Entries given below are number of patients dying in each group

OS is defined as the time from randomisation or date of inclusion (allergic arm) until death due to any cause. Patients who did not die were censored at 36 months of follow-up or the date of the patient's last visit, whichever was earlier.

Outcome measures

Outcome measures
Measure	GRASPA Non Allergic n=26 Participants Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: * for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) * for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	Reference L-asparaginase n=28 Participants For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL). •for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks). NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity) •for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy	GRASPA (Allergic Population) n=26 Participants Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: * for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) * for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
Overall Survival (OS)	9 Participants	12 Participants	14 Participants

SECONDARY outcome

Timeframe: Overall trial period to 36 months

Population: Entries below are the numbers of patients with events in each treatment group

EFS is defined as the time from randomisation until the first documented sign of disease relapse or death due to any cause. In line with CHMP guidance (CHMP, 2016), patients who did not achieve CR at the end of the induction period were considered to have had an event at time 0. For the patients enrolled in the GRASPA allergic arm, EFS is defined from the date of inclusion in the study. Patients who achieved CR at the end of induction and who did not have a documented relapse or death due to any cause were censored at 36 months of follow-up or the date of the patient's last visit, whichever was earlier.

Outcome measures

Outcome measures
Measure	GRASPA Non Allergic n=26 Participants Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: * for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) * for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	Reference L-asparaginase n=28 Participants For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL). •for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks). NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity) •for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy	GRASPA (Allergic Population) n=26 Participants Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: * for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) * for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
Event Free Survival	15 Participants	17 Participants	19 Participants

Adverse Events

GRASPA (Non Allergic Population)

Serious events: 23 serious events

Other events: 26 other events

Deaths: 9 deaths

Reference L-asparaginase (Non Allergic Population)

Serious events: 26 serious events

Other events: 28 other events

Deaths: 12 deaths

GRASPA (Allergic Population)

Serious events: 23 serious events

Other events: 26 other events

Deaths: 14 deaths

Serious adverse events

Other adverse events

Additional Information

Anne-Sophie Clermont

Erytech Pharma

Phone: +33 4 78 78 15 70

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	GRASPA (Non Allergic Population) n=26 participants at risk Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: * for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) * for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	Reference L-asparaginase (Non Allergic Population) n=28 participants at risk For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL). •for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks). NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity) •for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy	GRASPA (Allergic Population) n=26 participants at risk Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: * for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) * for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Leukaemia recurrent	30.8% 8/26 • Number of events 9 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	32.1% 9/28 • Number of events 9 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	26.9% 7/26 • Number of events 8 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Immune system disorders drug hypersensitivity	11.5% 3/26 • Number of events 3 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	25.0% 7/28 • Number of events 7 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	11.5% 3/26 • Number of events 3 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Respiratory, thoracic and mediastinal disorders Mucosal inflammation	11.5% 3/26 • Number of events 3 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	14.3% 4/28 • Number of events 4 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	19.2% 5/26 • Number of events 5 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Respiratory, thoracic and mediastinal disorders lung disorder	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	7.1% 2/28 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Blood and lymphatic system disorders Febrile bone marrow aplasia	42.3% 11/26 • Number of events 23 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	25.0% 7/28 • Number of events 10 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	19.2% 5/26 • Number of events 7 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/28 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	11.5% 3/26 • Number of events 3 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Blood and lymphatic system disorders Febrile neutropenia	15.4% 4/26 • Number of events 4 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	17.9% 5/28 • Number of events 9 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	15.4% 4/26 • Number of events 7 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Nervous system disorders Cerebral haemorrhage	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/28 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	3.8% 1/26 • Number of events 1 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
General disorders Mucosal inflammation	57.7% 15/26 • Number of events 15 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	28.6% 8/28 • Number of events 8 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	23.1% 6/26 • Number of events 6 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Gastrointestinal disorders Pancreatitis	3.8% 1/26 • Number of events 1 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	10.7% 3/28 • Number of events 3 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	3.8% 1/26 • Number of events 1 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Gastrointestinal disorders Intestinal ischaemia	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	3.6% 1/28 • Number of events 1 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Renal and urinary disorders Renal failure	3.8% 1/26 • Number of events 1 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	3.6% 1/28 • Number of events 1 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Infections and infestations Sepsis	15.4% 4/26 • Number of events 4 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	7.1% 2/28 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Infections and infestations Anal Abscess	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	7.1% 2/28 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Infections and infestations Bacteraemia	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/28 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	7.7% 2/26 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Infections and infestations Septic shock	11.5% 3/26 • Number of events 3 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	3.6% 1/28 • Number of events 1 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	3.8% 1/26 • Number of events 1 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Infections and infestations Staphylococcal sepsis	11.5% 3/26 • Number of events 3 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	3.6% 1/28 • Number of events 1 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Infections and infestations Fusarium infection	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/28 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	3.8% 1/26 • Number of events 1 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Infections and infestations Human herpesvirus 6 infection	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/28 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	3.8% 1/26 • Number of events 1 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.

Other adverse events
Measure	GRASPA (Non Allergic Population) n=26 participants at risk Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: * for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) * for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	Reference L-asparaginase (Non Allergic Population) n=28 participants at risk For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL). •for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks). NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity) •for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy	GRASPA (Allergic Population) n=26 participants at risk Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: * for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) * for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
Vascular disorders Haematoma	7.7% 2/26 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/28 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Immune system disorders Drug hypersensitivity	26.9% 7/26 • Number of events 8 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	64.3% 18/28 • Number of events 21 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	65.4% 17/26 • Number of events 21 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Immune system disorders Graft versus host disease	7.7% 2/26 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	7.1% 2/28 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
General disorders Pyrexia	7.7% 2/26 • Number of events 3 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/28 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	15.4% 4/26 • Number of events 4 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
General disorders Asthenia	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/28 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	7.7% 2/26 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Psychiatric disorders Depression	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	7.1% 2/28 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	3.8% 1/26 • Number of events 1 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Injury, poisoning and procedural complications Allergic transfusion reaction	7.7% 2/26 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	7.1% 2/28 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	7.7% 2/26 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Investigations Transaminases increased	61.5% 16/26 • Number of events 40 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	57.1% 16/28 • Number of events 33 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	57.7% 15/26 • Number of events 21 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Investigations Hypokalaemia	50.0% 13/26 • Number of events 13 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	39.3% 11/28 • Number of events 12 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	34.6% 9/26 • Number of events 12 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Investigations Antithrombin III decreased	15.4% 4/26 • Number of events 7 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	71.4% 20/28 • Number of events 44 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	34.6% 9/26 • Number of events 11 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Investigations Gamma-glutamyltransferase increased	30.8% 8/26 • Number of events 20 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	50.0% 14/28 • Number of events 15 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	26.9% 7/26 • Number of events 16 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Investigations Blood albumin decreased	19.2% 5/26 • Number of events 5 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	39.3% 11/28 • Number of events 15 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	23.1% 6/26 • Number of events 7 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Investigations Hyponatraemia	23.1% 6/26 • Number of events 6 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	35.7% 10/28 • Number of events 19 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	26.9% 7/26 • Number of events 8 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Investigations blood bilirubin increased	15.4% 4/26 • Number of events 6 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	32.1% 9/28 • Number of events 11 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	26.9% 7/26 • Number of events 8 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Investigations Hyperglycaemia	19.2% 5/26 • Number of events 6 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	25.0% 7/28 • Number of events 12 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	23.1% 6/26 • Number of events 12 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Investigations Activated partial thromboplastin time prolonged	3.8% 1/26 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	14.3% 4/28 • Number of events 7 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	19.2% 5/26 • Number of events 5 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Investigations Hypocalcaemia	11.5% 3/26 • Number of events 3 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	14.3% 4/28 • Number of events 4 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	3.8% 1/26 • Number of events 3 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Investigations Blood triglycerides increased	7.7% 2/26 • Number of events 4 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	10.7% 3/28 • Number of events 4 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	11.5% 3/26 • Number of events 3 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Investigations Prothrombin level decreased	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	10.7% 3/28 • Number of events 5 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Investigations Blood lactate dehydrogenase increased	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	7.1% 2/28 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	3.8% 1/26 • Number of events 1 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Investigations Blood potassium increased	11.5% 3/26 • Number of events 3 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	7.1% 2/28 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Investigations C-reactive protein increased	7.7% 2/26 • Number of events 3 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/28 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Blood and lymphatic system disorders Leukopenia	96.2% 25/26 • Number of events 76 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	96.4% 27/28 • Number of events 81 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	100.0% 26/26 • Number of events 74 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Blood and lymphatic system disorders Thrombocytopenia	92.3% 24/26 • Number of events 69 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	92.9% 26/28 • Number of events 71 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	84.6% 22/26 • Number of events 71 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Blood and lymphatic system disorders Neutropenia	92.3% 24/26 • Number of events 89 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	89.3% 25/28 • Number of events 93 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	96.2% 25/26 • Number of events 81 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Blood and lymphatic system disorders Lymphopenia	80.8% 21/26 • Number of events 43 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	82.1% 23/28 • Number of events 43 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	76.9% 20/26 • Number of events 49 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Blood and lymphatic system disorders Febrile bone marrow aplasia	19.2% 5/26 • Number of events 17 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	25.0% 7/28 • Number of events 17 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	30.8% 8/26 • Number of events 13 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Blood and lymphatic system disorders Hypofibrinogenaemia	34.6% 9/26 • Number of events 11 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	67.9% 19/28 • Number of events 37 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	42.3% 11/26 • Number of events 12 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Blood and lymphatic system disorders Febrile neutropenia	3.8% 1/26 • Number of events 4 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	17.9% 5/28 • Number of events 9 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	11.5% 3/26 • Number of events 6 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Blood and lymphatic system disorders Anaemia	26.9% 7/26 • Number of events 9 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	32.1% 9/28 • Number of events 14 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	23.1% 6/26 • Number of events 6 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Blood and lymphatic system disorders Bone marrow failure	7.7% 2/26 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	10.7% 3/28 • Number of events 4 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	3.8% 1/26 • Number of events 1 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Blood and lymphatic system disorders Blood phosphorus decreased	15.4% 4/26 • Number of events 5 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	10.7% 3/28 • Number of events 3 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	11.5% 3/26 • Number of events 3 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Gastrointestinal disorders Pancreatitis	3.8% 1/26 • Number of events 1 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	7.1% 2/28 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Gastrointestinal disorders Abdominal pain	3.8% 1/26 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	7.1% 2/28 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	7.7% 2/26 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Gastrointestinal disorders Diarrhoea	11.5% 3/26 • Number of events 3 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	7.1% 2/28 • Number of events 3 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	7.7% 2/26 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	7.1% 2/28 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Gastrointestinal disorders Vomiting	15.4% 4/26 • Number of events 4 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	3.6% 1/28 • Number of events 1 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	3.8% 1/26 • Number of events 1 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Hepatobiliary disorders Hepatotoxicity	7.7% 2/26 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	21.4% 6/28 • Number of events 12 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	30.8% 8/26 • Number of events 9 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Hepatobiliary disorders Cholestasis	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/28 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	7.7% 2/26 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.
Renal and urinary disorders renal failure acute	0.00% 0/26 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	0.00% 0/28 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.	7.7% 2/26 • Number of events 2 • AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months) Only patient receiving treatment are considered as safety population.