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Clinical Trial Results:
A randomized, open-label, multicenter, two arm, phase II study to evaluate treatment compliance, efficacy and safety of an improved deferasirox formulation (granules) in pediatric patients with iron overload

Summary
EudraCT number	2013-004739-55
Trial protocol	BE BG FR HU DK IT
Global end of trial date	15 Jan 2024

Results information
Results version number	v1
This version publication date	25 Jul 2024
First version publication date	25 Jul 2024
Other versions	v2

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

CICL670F2202

ISRCTN number

-

US NCT number

NCT02435212

WHO universal trial number (UTN)

-

Sponsor organisation name

Novartis Pharmaceuticals

Sponsor organisation address

Novartis Campus, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com

Is trial part of an agreed paediatric investigation plan (PIP)

No

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

15 Jan 2024

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

15 Jan 2024

Was the trial ended prematurely?

No

Main objective of the trial

• To evaluate both formulations on subject compliance, using stick pack/tablet count over 24-weeks of treatment in ICT naive subjects during Core phase. • To evaluate the change from baseline in serum ferritin after 24-weeks of treatment for both formulations in ICT naive subjects during the Core phase.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

21 Oct 2015

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

No

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 8

Country: Number of subjects enrolled

Bulgaria: 13

Country: Number of subjects enrolled

Malaysia: 18

Country: Number of subjects enrolled

United States: 17

Country: Number of subjects enrolled

Russian Federation: 6

Country: Number of subjects enrolled

Philippines: 12

Country: Number of subjects enrolled

Thailand: 40

Country: Number of subjects enrolled

Türkiye: 18

Country: Number of subjects enrolled

Oman: 27

Country: Number of subjects enrolled

Italy: 13

Country: Number of subjects enrolled

Lebanon: 23

Country: Number of subjects enrolled

France: 9

Country: Number of subjects enrolled

Hungary: 1

Country: Number of subjects enrolled

Panama: 2

Country: Number of subjects enrolled

Tunisia: 5

Country: Number of subjects enrolled

Egypt: 6

Country: Number of subjects enrolled

India: 6

Worldwide total number of subjects

224

EEA total number of subjects

44

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

195

Adolescents (12-17 years)

29

Adults (18-64 years)

0

From 65 to 84 years

0

85 years and over

0

Subject disposition

Top of page

Recruitment details

-

Screening details

After enrollment, participants previously treated with iron chelation therapy (ICT) underwent a 5-day chelation washout period prior to the commencement of the 48-week treatment (Core phase).

Period 1 title

Core Phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

DFX DT

Arm description

Participants received deferasirox (DFX) dispersible tablets (DT) orally once daily based on body weight for 48 weeks in the Core phase. The starting dose was 20mg/kg/day which was then adjusted based on tolerability, safety and efficacy considerations. After the Core phase, participants could enter the Optional Extension phase and cross over to DFX granules administered orally once daily in the form of stick packs for up to 5 years. Participants entering the Optional Extension phase received the equivalent strength-adjusted DFX granules dose corresponding to the last DT dose in the Core phase taking dose adjustment guidelines into account.

Arm type

Experimental

Investigational medicinal product name

Deferasirox dispersible tablet

Investigational medicinal product code

Other name

Pharmaceutical forms

Dispersible tablet

Routes of administration

Oral use

Dosage and administration details

Deferasirox DT orally once daily based on body weight for 48 weeks in the Core phase. The starting dose was 20mg/kg/day which was then adjusted based on tolerability, safety and efficacy considerations.

DFX Granule

Arm description

Participants received deferasirox (DFX) granules orally once daily based on body weight in the form of stick packs for 48 weeks in the Core phase. The starting dose was 14 mg/kg/day which was then adjusted based on tolerability, safety and efficacy considerations. After the Core phase, participants could enter the Optional Extension phase and continued receiving DFX granules at the same dose as was given at the end of the Core phase taking dose adjustment guidelines into account for up to 5 years.

Arm type

Experimental

Investigational medicinal product name

Deferasirox granule

Investigational medicinal product code

Other name

Pharmaceutical forms

Granules

Routes of administration

Oral use

Dosage and administration details

Deferasirox granules orally once daily based on body weight in the form of stick packs for 48 weeks in the Core phase. The starting dose was 14 mg/kg/day which was then adjusted based on tolerability, safety and efficacy considerations.

Number of subjects in period 1	DFX DT	DFX Granule
Started	112	112
Completed	87	99
Not completed	25	13
Consent withdrawn by subject	3	-
Physician decision	3	-
Recovery	1	-
Adverse event	8	5
Lost to follow-up	-	1
Withdrawal by parent/guardian	9	4
Protocol deviation	1	2
Lack of efficacy	-	1

Period 2 title

Optional Extension Phase

Is this the baseline period?

No

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

DFX DT

Arm description

Participants received deferasirox (DFX) dispersible tablets (DT) orally once daily based on body weight for 48 weeks in the Core phase. The starting dose was 20mg/kg/day which was then adjusted based on tolerability, safety and efficacy considerations. After the Core phase, participants could enter the Optional Extension phase and cross over to DFX granules administered orally once daily in the form of stick packs for up to 5 years. Participants entering the Optional Extension phase received the equivalent strength-adjusted DFX granules dose corresponding to the last DT dose in the Core phase taking dose adjustment guidelines into account.

Arm type

Experimental

Investigational medicinal product name

Deferasirox granule

Investigational medicinal product code

Other name

Pharmaceutical forms

Granules

Routes of administration

Oral use

Dosage and administration details

On the optional extension phase, DFX granules were administered orally once daily in the form of stick packs for up to 5 years. The dose received was the equivalent strength-adjusted DFX granules dose corresponding to the last DT dose in the Core phase taking dose adjustment guidelines into account.

DFX Granule

Arm description

Participants received deferasirox (DFX) granules orally once daily based on body weight in the form of stick packs for 48 weeks in the Core phase. The starting dose was 14 mg/kg/day which was then adjusted based on tolerability, safety and efficacy considerations. After the Core phase, participants could enter the Optional Extension phase and continued receiving DFX granules at the same dose as was given at the end of the Core phase taking dose adjustment guidelines into account for up to 5 years.

Arm type

Experimental

Investigational medicinal product name

Deferasirox granule

Investigational medicinal product code

Other name

Pharmaceutical forms

Granules

Routes of administration

Oral use

Dosage and administration details

On the optional extension phase, DFX granules were continued administered at the same dose as was given at the end of the Core phase taking dose adjustment guidelines into account for up to 5 years.

Number of subjects in period 2 ^[1]	DFX DT	DFX Granule
Started	69	77
Completed	42	46
Not completed	27	31
Adverse event, serious fatal	1	-
Physician decision	6	8
Consent withdrawn by subject	2	2
Recovery	1	1
Adverse event, non-fatal	3	9
Technical problems	2	-
Withdrawal by parent/guardian	10	7
Lack of efficacy	2	3
Protocol deviation	-	1

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: The extension phase was optional for patients who completed the core phase.

Baseline characteristics

Top of page

Reporting group title

DFX DT

Reporting group description

Participants received deferasirox (DFX) dispersible tablets (DT) orally once daily based on body weight for 48 weeks in the Core phase. The starting dose was 20mg/kg/day which was then adjusted based on tolerability, safety and efficacy considerations. After the Core phase, participants could enter the Optional Extension phase and cross over to DFX granules administered orally once daily in the form of stick packs for up to 5 years. Participants entering the Optional Extension phase received the equivalent strength-adjusted DFX granules dose corresponding to the last DT dose in the Core phase taking dose adjustment guidelines into account.

Reporting group title

DFX Granule

Reporting group description

Participants received deferasirox (DFX) granules orally once daily based on body weight in the form of stick packs for 48 weeks in the Core phase. The starting dose was 14 mg/kg/day which was then adjusted based on tolerability, safety and efficacy considerations. After the Core phase, participants could enter the Optional Extension phase and continued receiving DFX granules at the same dose as was given at the end of the Core phase taking dose adjustment guidelines into account for up to 5 years.

Reporting group values	DFX DT	DFX Granule	Total
Number of subjects	112	112	224
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	99	96	195
Adolescents (12-17 years)	13	16	29
Adults (18-64 years)	0	0	0
From 65-84 years	0	0	0
85 years and over	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	5.8 ( 3.89 )	5.9 ( 3.94 )	-
Sex/Gender, Customized
Units: participants
Female	54	56	110
Male	58	56	114
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	7	7	14
Not Hispanic or Latino	104	105	209
Unknown or Not Reported	1	0	1
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0
Asian	38	44	82
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	11	8	19
White	57	52	109
More than one race	0	0	0
Unknown or Not Reported	6	8	14

End points

Top of page

Reporting group title

DFX DT

Reporting group description

Participants received deferasirox (DFX) dispersible tablets (DT) orally once daily based on body weight for 48 weeks in the Core phase. The starting dose was 20mg/kg/day which was then adjusted based on tolerability, safety and efficacy considerations. After the Core phase, participants could enter the Optional Extension phase and cross over to DFX granules administered orally once daily in the form of stick packs for up to 5 years. Participants entering the Optional Extension phase received the equivalent strength-adjusted DFX granules dose corresponding to the last DT dose in the Core phase taking dose adjustment guidelines into account.

Reporting group title

DFX Granule

Reporting group description

Participants received deferasirox (DFX) granules orally once daily based on body weight in the form of stick packs for 48 weeks in the Core phase. The starting dose was 14 mg/kg/day which was then adjusted based on tolerability, safety and efficacy considerations. After the Core phase, participants could enter the Optional Extension phase and continued receiving DFX granules at the same dose as was given at the end of the Core phase taking dose adjustment guidelines into account for up to 5 years.

Reporting group title

DFX DT

Reporting group description

Participants received deferasirox (DFX) dispersible tablets (DT) orally once daily based on body weight for 48 weeks in the Core phase. The starting dose was 20mg/kg/day which was then adjusted based on tolerability, safety and efficacy considerations. After the Core phase, participants could enter the Optional Extension phase and cross over to DFX granules administered orally once daily in the form of stick packs for up to 5 years. Participants entering the Optional Extension phase received the equivalent strength-adjusted DFX granules dose corresponding to the last DT dose in the Core phase taking dose adjustment guidelines into account.

Reporting group title

DFX Granule

Reporting group description

Participants received deferasirox (DFX) granules orally once daily based on body weight in the form of stick packs for 48 weeks in the Core phase. The starting dose was 14 mg/kg/day which was then adjusted based on tolerability, safety and efficacy considerations. After the Core phase, participants could enter the Optional Extension phase and continued receiving DFX granules at the same dose as was given at the end of the Core phase taking dose adjustment guidelines into account for up to 5 years.

Subject analysis set title

DFX DT - Core phase

Subject analysis set type

Full analysis

Subject analysis set description

Participants received deferasirox (DFX) dispersible tablets (DT) orally once daily based on body weight for 48 weeks in the Core phase. The starting dose was 20mg/kg/day which was then adjusted based on tolerability, safety and efficacy considerations.

Subject analysis set title

DFX Granule - Core phase

Subject analysis set type

Full analysis

Subject analysis set description

Participants received deferasirox (DFX) granules orally once daily based on body weight in the form of stick packs for 48 weeks in the Core phase. The starting dose was 14 mg/kg/day which was then adjusted based on tolerability, safety and efficacy considerations.

Subject analysis set title

DFX DT Cross-over Granule - Optional Extension Phase

Subject analysis set type

Full analysis

Subject analysis set description

After the Core phase, participants could enter the Optional Extension phase and cross over to DFX granules administered orally once daily in the form of stick packs for up to 5 years. Participants entering the Optional Extension phase received the equivalent strength-adjusted DFX granules dose corresponding to the last DT dose in the Core phase taking dose adjustment guidelines into account.

Subject analysis set title

DFX Granules - Core and Optional Extension Phase

Subject analysis set type

Full analysis

Subject analysis set description

Participants received deferasirox (DFX) granules orally once daily based on body weight in the form of stick packs for 48 weeks in the Core phase. The starting dose was 14 mg/kg/day which was then adjusted based on tolerability, safety and efficacy considerations. After the Core phase, participants could enter the Optional Extension phase and continued receiving DFX granules at the same dose as was given at the end of the Core phase taking dose adjustment guidelines into account for up to 5 years.

Primary: Percentage of overall compliance using stick pack or tablet counts in iron chelation therapy (ICT)-naïve participants during the Core phase

Top of page

End point title

Percentage of overall compliance using stick pack or tablet counts in iron chelation therapy (ICT)-naïve participants during the Core phase

End point description

Compliance was calculated as the ratio of total count consumed to total count prescribed of deferasirox granule stick packs or dispersible tablets, where total count consumed was derived from cumulative dispensed, returned and lost/wasted counts over 24 weeks of treatment and total count prescribed was derived from cumulative prescribed count over 24 weeks of treatment.

End point type

Primary

End point timeframe

24 weeks

End point values	DFX DT	DFX Granule
Number of subjects analysed	54	54
Units: percentage of compliance
arithmetic mean (confidence interval 95%)	89.45 (85.29 to 93.61)	91.78 (87.81 to 95.75)

Overall compliance

Comparison groups

DFX DT v DFX Granule

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3598

Method

ANCOVA

Parameter type

Least squares mean

Point estimate

2.58

Confidence interval

level

95%

sides

2-sided

lower limit

-2.99

upper limit

8.15

Variability estimate

Standard error of the mean

Dispersion value

2.803

Primary: Change from Baseline in serum ferritin (SF) for both study drug formulations in ICT naïve participants during the Core phase

Top of page

End point title

Change from Baseline in serum ferritin (SF) for both study drug formulations in ICT naïve participants during the Core phase

End point description

The analysis included the comparison of means between the two treatment arms of change from baseline after 24 weeks of treatment in serum ferritin in pediatric ICT naïve participants with iron overload. The endpoint was assessed at Week 25 visit. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.

End point type

Primary

End point timeframe

From Baseline to Week 25

End point values	DFX DT	DFX Granule
Number of subjects analysed	54	54
Units: μg/L
arithmetic mean (confidence interval 95%)
Baseline (n=54,54)	2063.7 (1807.17 to 2320.15)	1955.5 (1712.57 to 2198.49)
Week 25 (n=38,44)	2216.3 (1929.59 to 2502.93)	2228.4 (2011.69 to 2445.18)
Change from Baseline to Week 25 (n=38,44)	250.5 (-84.63 to 585.58)	340.0 (115.48 to 564.59)

Serum Ferritin

Comparison groups

DFX DT v DFX Granule

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2546

Method

ANCOVA

Parameter type

Least squares mean

Point estimate

176.36

Confidence interval

level

95%

sides

2-sided

lower limit

-129

upper limit

481.72

Variability estimate

Standard error of the mean

Dispersion value

153.933

Secondary: Percentage of overall compliance using stick pack or tablet counts in ICT-naïve participants during the Core phase

Top of page

End point title

Percentage of overall compliance using stick pack or tablet counts in ICT-naïve participants during the Core phase

End point description

Compliance was calculated as the ratio of total count consumed to total count prescribed of deferasirox granule stick packs or dispersible tablets over 48 weeks of treatment.

End point type

Secondary

End point timeframe

48 weeks

End point values	DFX DT	DFX Granule
Number of subjects analysed	54	54
Units: percentage of compliance
arithmetic mean (confidence interval 95%)	91.57 (87.65 to 95.49)	94.80 (91.48 to 98.13)

No statistical analyses for this end point

Secondary: Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in ICT naïve Participants During the Core Phase

Top of page

End point title

Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in ICT naïve Participants During the Core Phase

End point description

The analysis included the comparison of means between the two treatment arms of change from baseline after 48 weeks of treatment in serum ferritin in pediatric ICT naïve participants with iron overload.

End point type

Secondary

End point timeframe

From Baseline to 48 weeks

End point values	DFX DT	DFX Granule
Number of subjects analysed	54	54
Units: μg/L
arithmetic mean (confidence interval 95%)	305.8 (4.28 to 607.24)	317.0 (69.10 to 564.88)

No statistical analyses for this end point

Secondary: Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in pre-treated Participants During the Core Phase

Top of page

End point title

Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in pre-treated Participants During the Core Phase

End point description

The analysis included the comparison of means between the two treatment arms of change from baseline after 24 weeks and after 48 weeks of treatment in serum ferritin in pre-treated participants. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.

End point type

Secondary

End point timeframe

From Baseline to 24 weeks and 48 weeks

End point values	DFX DT	DFX Granule
Number of subjects analysed	58	58
Units: μg/L
arithmetic mean (confidence interval 95%)
Change from Baseline to Week 25 (n=48,52)	59.0 (-210.88 to 328.79)	150.3 (-59.43 to 360.01)
Change from Baseline to Week 48 (n=52,50)	207.7 (-94.29 to 509.68)	215.7 (-50.47 to 481.95)

No statistical analyses for this end point

Secondary: Change Over-time in Domain Score of Modified Satisfaction with Iron Chelation Therapy (mSICT) using Patient Reported Outcomes (PRO) Questionnaires

Top of page

End point title

Change Over-time in Domain Score of Modified Satisfaction with Iron Chelation Therapy (mSICT) using Patient Reported Outcomes (PRO) Questionnaires

End point description

Participants aged between 10 years and less than 18 years at enrollment completed PRO questionnaires by themselves. The mSICT questionnaire for PRO consisted of 3 domains: adherence, satisfaction/preference, and concerns. The adherence domain had a minimum score of 6 and maximum score of 30; a lower score for adherence indicates better adherence. Satisfaction/preference domain had a minimum score of 2 and maximum score of 10; a lower score for satisfaction/preference indicates better satisfaction/preference. Concerns domain had a minimum score of 3 and maximum score of 15; a higher score for concerns indicate fewer concerns. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.

End point type

Secondary

End point timeframe

At Week 2, Week 3, Week 25 and Week 48

End point values	DFX DT	DFX Granule
Number of subjects analysed	16	17
Units: score on a scale
arithmetic mean (standard deviation)
Adherence (Week 2) (n=13,15)	9.5 ( 2.30 )	7.6 ( 1.99 )
Adherence (Week 3) (n=16,17)	10.9 ( 4.95 )	6.6 ( 0.79 )
Adherence (Week 25) (n=13,11)	11.9 ( 3.93 )	9.2 ( 3.31 )
Adherence (Week 48) (n=13,15)	12.9 ( 4.17 )	8.4 ( 2.29 )
Satisfaction/preference (Week 2) (n=13,15)	5.2 ( 2.09 )	2.9 ( 1.36 )
Satisfaction/preference (Week 3) (n=16,17)	4.0 ( 1.32 )	3.1 ( 1.22 )
Satisfaction/preference (Week 25) (n=13,11)	5.5 ( 2.37 )	3.0 ( 1.10 )
Satisfaction/preference (Week 48) (n=13,15)	4.8 ( 2.24 )	3.1 ( 0.92 )
Concerns (Week 2) (n=13,15)	13.1 ( 2.18 )	14.5 ( 1.06 )
Concerns (Week 3) (n=16,17)	13.4 ( 2.10 )	14.4 ( 0.80 )
Concerns (Week 25) (n=13,11)	11.5 ( 3.13 )	14.5 ( 1.21 )
Concerns (Week 48) (n=13,15)	12.8 ( 2.20 )	13.5 ( 2.75 )

No statistical analyses for this end point

Secondary: Change Over-time in Domain Score of Modified Satisfaction with Iron Chelation Therapy (mSICT) using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's perspective)

Top of page

End point title

Change Over-time in Domain Score of Modified Satisfaction with Iron Chelation Therapy (mSICT) using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's perspective)

End point description

The ObsRO questionnaires for participants aged between 2 years and less than 10 years were designed as observations made by caregivers such as the parent or legal guardian. The caregivers continued completing the ObsRO questionnaires even after the participant turned 10 years for consistency in responses. The mSICT questionnaire consisted of 2 domains: adherence and concerns per caregiver's perspective. The adherence domain had a minimum score of 5 and a maximum score of 25; a lower score for adherence indicates better adherence. The concerns domain had a minimum score of 1 and a maximum score of 5; a higher score for concerns indicates fewer concerns. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.

End point type

Secondary

End point timeframe

At Week 2, Week 3, Week 25 and Week 48

End point values	DFX DT	DFX Granule
Number of subjects analysed	73	74
Units: score on a scale
arithmetic mean (standard deviation)
Adherence (Week 2) (n=68,64)	7.7 ( 2.84 )	5.8 ( 1.32 )
Adherence (Week 3) (n=73,74)	7.8 ( 2.64 )	5.8 ( 1.43 )
Adherence (Week 25) (n=61,53)	7.1 ( 2.35 )	6.5 ( 1.69 )
Adherence (Week 48) (n=60,54)	7.5 ( 2.53 )	6.8 ( 2.57 )
Concerns (Week 2) (n=68,64)	3.9 ( 1.32 )	4.5 ( 0.94 )
Concerns (Week 3) (n=73,74)	4.1 ( 1.31 )	4.7 ( 0.71 )
Concerns (Week 25) (n=61,53)	4.3 ( 1.00 )	4.5 ( 0.89 )
Concerns (Week 48) (n=60,54)	4.0 ( 1.24 )	4.6 ( 0.77 )

No statistical analyses for this end point

Secondary: Change Over-time in Domain Score of Modified Satisfaction with Iron Chelation Therapy (mSICT) using Observer Reported Outcomes (ObsRO) Questionnaire (Child's perspective)

Top of page

End point title

Change Over-time in Domain Score of Modified Satisfaction with Iron Chelation Therapy (mSICT) using Observer Reported Outcomes (ObsRO) Questionnaire (Child's perspective)

End point description

The ObsRO questionnaires for participants aged between 2 years and less than 10 years were designed as observations made by caregivers such as the parent or legal guardian. The caregivers continued completing the ObsRO questionnaires even after the participant turned 10 years for consistency in responses. The mSICT questionnaire is presented for 2 domains: adherence and concerns per child's perspective. The adherence domain had a minimum score of 6 and a maximum score of 30; a lower score for adherence indicates better adherence. The concerns domain had a minimum score of 2 and a maximum score of 10; a higher score for concerns indicates fewer concerns. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.

End point type

Secondary

End point timeframe

At Week 2, Week 3, Week 25 and Week 48

End point values	DFX DT	DFX Granule
Number of subjects analysed	73	74
Units: score on a scale
arithmetic mean (standard deviation)
Adherence (Week 2) (n=68,64)	12.1 ( 4.57 )	8.2 ( 2.28 )
Adherence (Week 3) (n=73,74)	11.7 ( 3.78 )	8.2 ( 2.64 )
Adherence (Week 25) (n=61,53)	11.1 ( 3.82 )	9.1 ( 2.64 )
Adherence (Week 48) (n=60,54)	11.3 ( 3.99 )	9.1 ( 3.00 )
Concerns (Week 2) (n=68,64)	8.5 ( 2.29 )	9.2 ( 1.66 )
Concerns (Week 3) (n=73,74)	8.7 ( 2.00 )	8.8 ( 2.04 )
Concerns (Week 25) (n=61,53)	8.6 ( 1.94 )	8.7 ( 1.85 )
Concerns (Week 48) (n=60,54)	8.8 ( 1.75 )	9.0 ( 1.82 )

No statistical analyses for this end point

Secondary: Change Over-time in Domain Score of Palatability using Patient Reported Outcomes (PRO) Questionnaires

Top of page

End point title

Change Over-time in Domain Score of Palatability using Patient Reported Outcomes (PRO) Questionnaires

End point description

The palatability questionnaire was used to measure: taste, aftertaste, whether medication was taken and how the participant perceived the amount of medication taken. This questionnaire had a minimum score of 0 and maximum score of 11; a higher score means better palatability. Participants aged between 10 years and less than 18 years at enrollment completed the PRO questionnaire by themselves. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.

End point type

Secondary

End point timeframe

At Week 2, Week 3, Week 25 and Week 48

End point values	DFX DT	DFX Granule
Number of subjects analysed	16	17
Units: score on a scale
arithmetic mean (standard deviation)
Week 2 (n=13,15)	8.8 ( 3.32 )	10.3 ( 1.91 )
Week 3 (n=16,17)	9.6 ( 2.83 )	10.9 ( 0.24 )
Week 25 (n=13,11)	9.2 ( 2.70 )	10.4 ( 1.80 )
Week 48 (n=13,14)	9.4 ( 3.07 )	11.0 ( 0.00 )

No statistical analyses for this end point

Secondary: Change Over-time in Domain Score of Palatability using Observer Reported Outcomes (ObsRO) Questionnaire

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End point title

Change Over-time in Domain Score of Palatability using Observer Reported Outcomes (ObsRO) Questionnaire

End point description

The palatability questionnaire was used to measure: taste, aftertaste, whether medication was taken and how the participant perceived the amount of medication taken. This questionnaire had a minimum score of 0 and maximum score of 11; a higher score means better palatability. The ObsRO questionnaires for participants aged between 2 years and less than 10 years were designed as observations made by caregivers such as the parent or legal guardian. The caregivers continued completing the ObsRO questionnaires even after the participant turned 10 years for consistency in responses. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.

End point type

Secondary

End point timeframe

At Week 2, Week 3, Week 25 and Week 48

End point values	DFX DT	DFX Granule
Number of subjects analysed	72	72
Units: score on a scale
arithmetic mean (standard deviation)
Week 2 (n=68,62)	8.9 ( 3.13 )	10.9 ( 0.90 )
Week 3 (n=72,72)	9.4 ( 2.88 )	10.8 ( 0.79 )
Week 25 (n=61,52)	9.3 ( 2.83 )	10.6 ( 1.73 )
Week 48 (n=60,53)	9.0 ( 3.11 )	10.9 ( 0.96 )

No statistical analyses for this end point

Secondary: Change over time in weekly dose violation rate using Compliance Patient Reported Outcomes (PRO) Questionnaire

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End point title

Change over time in weekly dose violation rate using Compliance Patient Reported Outcomes (PRO) Questionnaire

End point description

The compliance questionnaire consisted of 2 items: 1. To assess if the medication was taken (yes/no) and 2. To record of the time when the medication was taken (with a not applicable option for participants who did not take their medication). Daily diary records were used to calculate the rate of dose violation in each study arm (doses missed completely or not taken before 12 PM). The dose violation rate was calculated as: [Number of dose violations / Drug exposure (days)] *100. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.

End point type

Secondary

End point timeframe

At Week 1, Week 13, Week 25, Week 37 and Week 48

End point values	DFX DT	DFX Granule
Number of subjects analysed	16	16
Units: percentage of days with dose violations
arithmetic mean (standard deviation)
Week 1 (n=16,16)	26.86 ( 37.966 )	26.79 ( 38.992 )
Week 13 (n=15,12)	12.78 ( 31.000 )	23.41 ( 35.906 )
Week 25 (n=12,9)	13.19 ( 29.614 )	25.93 ( 42.583 )
Week 37 (n=9,9)	18.89 ( 32.745 )	30.16 ( 41.921 )
Week 48 (n=7,6)	2.86 ( 7.559 )	52.38 ( 52.424 )

No statistical analyses for this end point

Secondary: Change over time in weekly dose violation rate using Compliance Observer Reported Outcomes (ObsRO) Questionnaire

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End point title

Change over time in weekly dose violation rate using Compliance Observer Reported Outcomes (ObsRO) Questionnaire

End point description

The compliance questionnaire consisted of 2 items: 1. To assess if the medication was taken (yes/no) and 2. To record the time when the medication was taken (with a not applicable option for participants who did not take their medication). Daily diary records were used to calculate the rate of dose violation in each treatment arm (doses missed completely or not taken before 12 PM). The ObsRO questionnaires for participants aged between 2 years and less than 10 years were designed as observations made by caregivers such as the parent or legal guardian. The caregivers continued completing the ObsRO questionnaires even after the participant turned 10 years for consistency in responses. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.

End point type

Secondary

End point timeframe

At Week 1, Week 13, Week 25, Week 37 and Week 48

End point values	DFX DT	DFX Granule
Number of subjects analysed	62	60
Units: score on a scale
arithmetic mean (standard deviation)
Week 1 (n=62,60)	18.80 ( 29.912 )	27.79 ( 37.577 )
Week 13 (n=60,57)	10.38 ( 27.374 )	18.65 ( 35.513 )
Week 25 (n=48,53)	7.79 ( 23.025 )	13.72 ( 31.813 )
Week 37 (n=54,53)	13.86 ( 31.769 )	20.01 ( 37.632 )
Week 48 (n=36,34)	13.56 ( 32.211 )	14.50 ( 31.123 )

No statistical analyses for this end point

Secondary: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) during the Core Phase

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End point title

Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) during the Core Phase

End point description

An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study.

End point type

Secondary

End point timeframe

From Baseline to 48 weeks

End point values	DFX DT - Core phase	DFX Granule - Core phase
Number of subjects analysed	111	110
Units: participants
All AEs	108	100
All SAEs	23	27

No statistical analyses for this end point

Secondary: Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance

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End point title

Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance

End point description

Pre-dose pharmacokinetic (PK) data from participants in the Pharmacokinetic Analysis Set 1 (PAS-1) were analyzed to assess variability of individual participant’s compliance. A linear mixed effect power model to pre-dose samples which fulfill compliance criteria in terms of steady state (4 consecutive same doses prior to the PK sample drawn), time-windows (PK sample drawn 20 to 28 hours after previous dose) and without any vomiting episodes within the 4 hours prior to the PK sample were fitted. The model considered dose, treatment group, stratification factors and potential other factors, such as body weight as covariates. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.

End point type

Secondary

End point timeframe

At Weeks 1, 3, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, and 45

End point values	DFX DT	DFX Granule
Number of subjects analysed	106	105
Units: μmol/L
geometric mean (geometric coefficient of variation)
Week 1 (n=95,93)	2.93 ( 369.5 )	1.40 ( 235.4 )
Week 3 (n=59,73)	14.2 ( 137.0 )	11.8 ( 117.1 )
Week 5 (n=69,73)	14.4 ( 115.7 )	11.7 ( 127.5 )
Week 9 (n=68,74)	20.1 ( 115.8 )	12.1 ( 97.1 )
Week 13 (n=63,66)	19.7 ( 124.2 )	13.5 ( 107.5 )
Week 17 (n=62,56)	18.4 ( 109.4 )	13.1 ( 135.3 )
Week 21 (n=64,64)	19.6 ( 120.4 )	13.4 ( 163.6 )
Week 25 (n=60,62)	17.1 ( 147.2 )	15.9 ( 108.6 )
Week 29 (n=63,65)	23.8 ( 111.3 )	13.2 ( 156.6 )
Week 33 (n=65,69)	21.4 ( 184.0 )	14.1 ( 175.6 )
Week 37 (n=62,72)	20.8 ( 137.1 )	14.6 ( 135.3 )
Week 41 (n=66,71)	21.8 ( 131.6 )	15.5 ( 134.7 )
Week 45 (n=63,71)	28.3 ( 141.2 )	19.0 ( 117.0 )

No statistical analyses for this end point

Secondary: Concentrations of Deferasirox Between 2 and 4 Hours Post-dose at Weeks 5 and 9

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End point title

Concentrations of Deferasirox Between 2 and 4 Hours Post-dose at Weeks 5 and 9

End point description

Post-dose pharmacokinetic (PK) data from participants in the Pharmacokinetic Analysis Set 1 (PAS-1) were analyzed along with Pre-dose PK data. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.

End point type

Secondary

End point timeframe

At Week 5 and Week 9

End point values	DFX DT	DFX Granule
Number of subjects analysed	106	105
Units: μmol/L
geometric mean (geometric coefficient of variation)
Week 5 (3 hour post-dose) (n=66,70)	65.2 ( 80.5 )	53.2 ( 86.2 )
Week 9 (3 hour post-dose) (n=62,61)	70.4 ( 77.0 )	59.8 ( 61.7 )

No statistical analyses for this end point

Secondary: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Entire Granule Period

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End point title

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Entire Granule Period

End point description

An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation after participant providing written informed consent for participation in the study. In the DFX Granules arm, AEs are reported since the initial randomization to the arm in the core phase and continuing in the extension phase. In the DFX cross-over arm, AEs are reported for participants since the participant crossed-over from dispersible tablet to granules in the extension phase only.

End point type

Secondary

End point timeframe

From Baseline to 305 weeks

End point values	DFX DT Cross-over Granule - Optional Extension Phase	DFX Granules - Core and Optional Extension Phase
Number of subjects analysed	69	110
Units: participants
AEs	64	106
Suspected AEs	48	73
SAEs	22	38
Suspected SAEs	4	7

No statistical analyses for this end point

Secondary: Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period

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End point title

Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period

End point description

An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation after participant providing written informed consent for participation in the study. In the DFX Granules arm, AEs are reported since the initial randomization to the arm in the core phase and continuing in the extension phase. In the DFX cross-over arm, AEs are reported for participants since the participant crossed-over from dispersible tablet to granules in the extension phase only. AESI included active monitoring for renal toxicity; including renal failure, hepatic toxicity; including hepatic failure, and gastrointestinal hemorrhage

End point type

Secondary

End point timeframe

From Baseline to 305 weeks

End point values	DFX DT Cross-over Granule - Optional Extension Phase	DFX Granules - Core and Optional Extension Phase
Number of subjects analysed	69	110
Units: participants
Any AESI	52	79
Gastrointestinal hemorrhages	3	4
Hearing loss	5	5
Lens opacities, Retinal changes and Optic neuritis	0	2
Liver disorders - Hepatic failure	1	0
Liver disorders - Increased liver transaminases	16	46
Peripheral blood cytopenias	5	7
Renal disorders - Acute renal failure	1	0
Renal disorders - Increased serum creatinine	4	8
Renal disorders -Proteinuria	40	49
Renal disorders - Renal tubular disorders	4	0
Severe Cutaneous Adverse Reactions (SCARs)	0	1

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From initial randomization up to 48 weeks (Core phase) and Up to 5 years from entering the extension phase (Optional Extension phase)

Adverse event reporting additional description

The Safety Set consisted of all participants who received at least 1 dose of granule formulation during the core or extension phase. The participants in extension phase received granules regardless of which arm they were initially randomized. Three participants did not receive the study drug and hence were excluded from the safety set.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.1

Reporting group title

DFX DT Cross-over Granule - Optional Extension Phase

Reporting group description

After the Core phase, participants could enter the Optional Extension phase and cross over to DFX granules administered orally once daily in the form of stick packs for up to 5 years. Participants entering the Optional Extension phase received the equivalent strength-adjusted DFX granules dose corresponding to the last DT dose in the Core phase taking dose adjustment guidelines into account.

Reporting group title

DFX Granules - Optional Extension Phase

Reporting group description

After the Core phase, participants could enter the Optional Extension phase and continued receiving DFX granules at the same dose as was given at the end of the Core phase taking dose adjustment guidelines into account for up to 5 years.

Reporting group title

DFX Granule- Core Phase

Reporting group description

Participants received deferasirox (DFX) granules orally once daily based on body weight in the form of stick packs for 48 weeks in the Core phase. The starting dose was 14 mg/kg/day which was then adjusted based on tolerability, safety and efficacy considerations.

Reporting group title

DFX DT- Core Phase

Reporting group description

Participants received deferasirox (DFX) dispersible tablets (DT) orally once daily based on body weight for 48 weeks in the Core phase. The starting dose was 20mg/kg/day which was then adjusted based on tolerability, safety and efficacy considerations.

Serious adverse events	DFX DT Cross-over Granule - Optional Extension Phase	DFX Granules - Optional Extension Phase	DFX Granule- Core Phase	DFX DT- Core Phase
Total subjects affected by serious adverse events
subjects affected / exposed	22 / 69 (31.88%)	20 / 77 (25.97%)	27 / 110 (24.55%)	23 / 111 (20.72%)
number of deaths (all causes)	1	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Vascular disorders
Circulatory collapse
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 69 (1.45%)	2 / 77 (2.60%)	4 / 110 (3.64%)	4 / 111 (3.60%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Tonsillar hypertrophy
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	0 / 110 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obstructive sleep apnoea syndrome
subjects affected / exposed	0 / 69 (0.00%)	1 / 77 (1.30%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchial hyperreactivity
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	0 / 110 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute chest syndrome
subjects affected / exposed	1 / 69 (1.45%)	2 / 77 (2.60%)	1 / 110 (0.91%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Urine protein/creatinine ratio increased
subjects affected / exposed	0 / 69 (0.00%)	1 / 77 (1.30%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	2 / 69 (2.90%)	0 / 77 (0.00%)	0 / 110 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 11	0 / 0	0 / 0	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	1 / 110 (0.91%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ligament sprain
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile nonhaemolytic transfusion reaction
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	1 / 110 (0.91%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Craniofacial fracture
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lip injury
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	1 / 110 (0.91%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Overdose
subjects affected / exposed	1 / 69 (1.45%)	1 / 77 (1.30%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transfusion reaction
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	1 / 110 (0.91%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Tension headache
subjects affected / exposed	0 / 69 (0.00%)	1 / 77 (1.30%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Hypersplenism
subjects affected / exposed	0 / 69 (0.00%)	1 / 77 (1.30%)	0 / 110 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	1 / 110 (0.91%)	2 / 111 (1.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 69 (0.00%)	1 / 77 (1.30%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sickle cell anaemia with crisis
subjects affected / exposed	0 / 69 (0.00%)	2 / 77 (2.60%)	3 / 110 (2.73%)	5 / 111 (4.50%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 5	0 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenitis
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	1 / 110 (0.91%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	0 / 110 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 69 (0.00%)	1 / 77 (1.30%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Pancreatitis acute
subjects affected / exposed	0 / 69 (0.00%)	1 / 77 (1.30%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stress ulcer
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	1 / 110 (0.91%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	2 / 110 (1.82%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malpositioned teeth
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	0 / 110 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 69 (0.00%)	1 / 77 (1.30%)	0 / 110 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Food poisoning
subjects affected / exposed	0 / 69 (0.00%)	1 / 77 (1.30%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 69 (0.00%)	1 / 77 (1.30%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Jaundice cholestatic
subjects affected / exposed	0 / 69 (0.00%)	1 / 77 (1.30%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertransaminasaemia
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	0 / 110 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis acute
subjects affected / exposed	0 / 69 (0.00%)	1 / 77 (1.30%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 69 (0.00%)	3 / 77 (3.90%)	0 / 110 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 69 (0.00%)	1 / 77 (1.30%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis acute
subjects affected / exposed	0 / 69 (0.00%)	1 / 77 (1.30%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	0 / 69 (0.00%)	1 / 77 (1.30%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Urticaria
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug reaction with eosinophilia and systemic symptoms
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	1 / 110 (0.91%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Fanconi syndrome acquired
subjects affected / exposed	3 / 69 (4.35%)	0 / 77 (0.00%)	0 / 110 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	3 / 3	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	1 / 110 (0.91%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Amoebiasis
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	0 / 110 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ascariasis
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	0 / 110 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	0 / 69 (0.00%)	1 / 77 (1.30%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dengue fever
subjects affected / exposed	1 / 69 (1.45%)	1 / 77 (1.30%)	2 / 110 (1.82%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 69 (0.00%)	1 / 77 (1.30%)	0 / 110 (0.00%)	3 / 111 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	2 / 110 (1.82%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	1 / 110 (0.91%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis viral
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dengue haemorrhagic fever
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	4 / 69 (5.80%)	4 / 77 (5.19%)	2 / 110 (1.82%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 4	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	0 / 110 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis salmonella
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	1 / 110 (0.91%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	2 / 111 (1.80%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nasopharyngitis
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	0 / 110 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media acute
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	1 / 110 (0.91%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Parotid abscess
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	1 / 110 (0.91%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Periorbital cellulitis
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	2 / 69 (2.90%)	1 / 77 (1.30%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngotonsillitis
subjects affected / exposed	0 / 69 (0.00%)	1 / 77 (1.30%)	1 / 110 (0.91%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	1 / 110 (0.91%)	3 / 111 (2.70%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	2 / 69 (2.90%)	1 / 77 (1.30%)	0 / 110 (0.00%)	2 / 111 (1.80%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Systemic viral infection
subjects affected / exposed	0 / 69 (0.00%)	1 / 77 (1.30%)	1 / 110 (0.91%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	2 / 69 (2.90%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinobronchitis
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Shigella infection
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	0 / 110 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Scarlet fever
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia respiratory syncytial viral
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	1 / 110 (0.91%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	1 / 110 (0.91%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	2 / 69 (2.90%)	2 / 77 (2.60%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	1 / 110 (0.91%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	2 / 111 (1.80%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Varicella
subjects affected / exposed	0 / 69 (0.00%)	1 / 77 (1.30%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	1 / 110 (0.91%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Lactase deficiency
subjects affected / exposed	0 / 69 (0.00%)	0 / 77 (0.00%)	1 / 110 (0.91%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 69 (0.00%)	2 / 77 (2.60%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	1 / 69 (1.45%)	0 / 77 (0.00%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	2 / 69 (2.90%)	2 / 77 (2.60%)	0 / 110 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	DFX DT Cross-over Granule - Optional Extension Phase	DFX Granules - Optional Extension Phase	DFX Granule- Core Phase	DFX DT- Core Phase
Total subjects affected by non serious adverse events
subjects affected / exposed	63 / 69 (91.30%)	63 / 77 (81.82%)	97 / 110 (88.18%)	104 / 111 (93.69%)
Investigations
Blood bilirubin increased
subjects affected / exposed	4 / 69 (5.80%)	5 / 77 (6.49%)	3 / 110 (2.73%)	4 / 111 (3.60%)
occurrences all number	5	7	4	7
Blood creatinine increased
subjects affected / exposed	3 / 69 (4.35%)	6 / 77 (7.79%)	0 / 110 (0.00%)	3 / 111 (2.70%)
occurrences all number	9	10	0	3
Transaminases increased
subjects affected / exposed	2 / 69 (2.90%)	8 / 77 (10.39%)	9 / 110 (8.18%)	7 / 111 (6.31%)
occurrences all number	2	18	15	10
Urine protein/creatinine ratio increased
subjects affected / exposed	36 / 69 (52.17%)	28 / 77 (36.36%)	27 / 110 (24.55%)	39 / 111 (35.14%)
occurrences all number	103	92	48	69
Alanine aminotransferase increased
subjects affected / exposed	11 / 69 (15.94%)	11 / 77 (14.29%)	20 / 110 (18.18%)	15 / 111 (13.51%)
occurrences all number	13	24	29	26
Bilirubin conjugated increased
subjects affected / exposed	2 / 69 (2.90%)	3 / 77 (3.90%)	12 / 110 (10.91%)	16 / 111 (14.41%)
occurrences all number	3	3	29	35
Aspartate aminotransferase increased
subjects affected / exposed	8 / 69 (11.59%)	7 / 77 (9.09%)	12 / 110 (10.91%)	11 / 111 (9.91%)
occurrences all number	8	16	13	19
Nervous system disorders
Headache
subjects affected / exposed	5 / 69 (7.25%)	2 / 77 (2.60%)	9 / 110 (8.18%)	8 / 111 (7.21%)
occurrences all number	7	2	9	10
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	15 / 69 (21.74%)	16 / 77 (20.78%)	26 / 110 (23.64%)	24 / 111 (21.62%)
occurrences all number	20	21	35	39
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	3 / 69 (4.35%)	4 / 77 (5.19%)	4 / 110 (3.64%)	4 / 111 (3.60%)
occurrences all number	4	5	5	4
Abdominal pain
subjects affected / exposed	4 / 69 (5.80%)	0 / 77 (0.00%)	12 / 110 (10.91%)	4 / 111 (3.60%)
occurrences all number	5	0	16	6
Constipation
subjects affected / exposed	4 / 69 (5.80%)	0 / 77 (0.00%)	2 / 110 (1.82%)	5 / 111 (4.50%)
occurrences all number	4	0	2	6
Dental caries
subjects affected / exposed	3 / 69 (4.35%)	2 / 77 (2.60%)	5 / 110 (4.55%)	7 / 111 (6.31%)
occurrences all number	4	3	5	7
Diarrhoea
subjects affected / exposed	7 / 69 (10.14%)	6 / 77 (7.79%)	9 / 110 (8.18%)	14 / 111 (12.61%)
occurrences all number	10	7	15	15
Gastritis
subjects affected / exposed	4 / 69 (5.80%)	4 / 77 (5.19%)	1 / 110 (0.91%)	0 / 111 (0.00%)
occurrences all number	4	5	1	0
Vomiting
subjects affected / exposed	9 / 69 (13.04%)	4 / 77 (5.19%)	9 / 110 (8.18%)	15 / 111 (13.51%)
occurrences all number	13	5	14	20
Nausea
subjects affected / exposed	3 / 69 (4.35%)	1 / 77 (1.30%)	4 / 110 (3.64%)	8 / 111 (7.21%)
occurrences all number	3	1	4	9
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	14 / 69 (20.29%)	9 / 77 (11.69%)	15 / 110 (13.64%)	12 / 111 (10.81%)
occurrences all number	18	18	17	14
Rhinorrhoea
subjects affected / exposed	4 / 69 (5.80%)	6 / 77 (7.79%)	7 / 110 (6.36%)	4 / 111 (3.60%)
occurrences all number	4	11	7	4
Rhinitis allergic
subjects affected / exposed	3 / 69 (4.35%)	5 / 77 (6.49%)	5 / 110 (4.55%)	0 / 111 (0.00%)
occurrences all number	4	5	6	0
Oropharyngeal pain
subjects affected / exposed	3 / 69 (4.35%)	2 / 77 (2.60%)	8 / 110 (7.27%)	1 / 111 (0.90%)
occurrences all number	3	2	9	1
Epistaxis
subjects affected / exposed	4 / 69 (5.80%)	0 / 77 (0.00%)	3 / 110 (2.73%)	1 / 111 (0.90%)
occurrences all number	6	0	3	1
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	2 / 69 (2.90%)	4 / 77 (5.19%)	6 / 110 (5.45%)	7 / 111 (6.31%)
occurrences all number	2	4	6	8
Renal and urinary disorders
Proteinuria
subjects affected / exposed	4 / 69 (5.80%)	9 / 77 (11.69%)	9 / 110 (8.18%)	8 / 111 (7.21%)
occurrences all number	19	62	16	16
Infections and infestations
Gastroenteritis
subjects affected / exposed	5 / 69 (7.25%)	6 / 77 (7.79%)	5 / 110 (4.55%)	8 / 111 (7.21%)
occurrences all number	8	9	5	10
Rhinitis
subjects affected / exposed	3 / 69 (4.35%)	1 / 77 (1.30%)	9 / 110 (8.18%)	3 / 111 (2.70%)
occurrences all number	10	1	12	3
Pharyngitis
subjects affected / exposed	12 / 69 (17.39%)	7 / 77 (9.09%)	11 / 110 (10.00%)	3 / 111 (2.70%)
occurrences all number	16	9	12	4
Nasopharyngitis
subjects affected / exposed	14 / 69 (20.29%)	11 / 77 (14.29%)	11 / 110 (10.00%)	12 / 111 (10.81%)
occurrences all number	36	24	14	13
Influenza
subjects affected / exposed	2 / 69 (2.90%)	7 / 77 (9.09%)	5 / 110 (4.55%)	4 / 111 (3.60%)
occurrences all number	2	7	5	6
COVID-19
subjects affected / exposed	8 / 69 (11.59%)	9 / 77 (11.69%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences all number	9	9	0	0
Bronchitis
subjects affected / exposed	4 / 69 (5.80%)	3 / 77 (3.90%)	3 / 110 (2.73%)	4 / 111 (3.60%)
occurrences all number	5	3	5	5
Systemic viral infection
subjects affected / exposed	1 / 69 (1.45%)	4 / 77 (5.19%)	0 / 110 (0.00%)	0 / 111 (0.00%)
occurrences all number	1	4	0	0
Tonsillitis
subjects affected / exposed	5 / 69 (7.25%)	3 / 77 (3.90%)	7 / 110 (6.36%)	2 / 111 (1.80%)
occurrences all number	7	3	8	2
Upper respiratory tract infection
subjects affected / exposed	23 / 69 (33.33%)	24 / 77 (31.17%)	31 / 110 (28.18%)	34 / 111 (30.63%)
occurrences all number	58	44	42	51
Urinary tract infection
subjects affected / exposed	6 / 69 (8.70%)	6 / 77 (7.79%)	3 / 110 (2.73%)	2 / 111 (1.80%)
occurrences all number	8	18	3	2

More information

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Were there any global substantial amendments to the protocol? Yes

01 Dec 2015

The main changes of this amendment was: 1. Expand the study population by revising the inclusion criteria; 2. Modify the secondary objectives; 3. In order to optimize the patient safety and the toxicity monitoring, eligibility criteria and the management guidelines for cardiac and hepatic toxicity have been revised; 4. modified dose modification rules for hepatic toxicity management guidelines; 5. Clarification to the concomitant medications and contraception; 6. Statistical methods and data analysis section has been updated.

15 Jun 2016

The purpose of this amendment was: 1. To allow the sites in Egypt to use a local laboratory instead of central laboratory for the analysis of safety required in this trial and to exempt patients’ enrolled in Egypt from the collection of PK samples. This exemption is granted to Egypt due to national restriction on export of any biological samples out of Egypt. 2. To clarify the inclusion criteria #2 for France concerning children aged from 2 to 6 years old as per Exjade prescribing information.

24 Aug 2016

The purpose of this amendment was: 1. To add an optional extension phase to the existing study. 2. To sharpen the clarification of the eligibility criteria related to renal criteria in order to promote better Investigator understanding, leading to better adherence and improved renal safety. 3. To provide the investigators with further clarified dose modification guidance for renal monitoring with regards to creatinine clearance, increased serum creatinine and proteinuria. Clear guidance on how to reinitiate treatment after required dose interruption has also been included in order to improve patient safety.

15 Jun 2017

The purpose of this amendment was to include an interim analysis, allow for paper PRO completion, and clarify various points to improve site understanding and consistency in implementation of the protocol.

06 Dec 2017

The purpose of this amendment was to modify the assessment timepoint for the primary analysis (currently change from baseline for serum ferritin and compliance after 48 weeks of treatment), and to reduce the sample size for the chelation naive patients, following recent interaction with Health Authorities. The eligibility criteria for the extension phase have been modified.

24 Jun 2021

The main purpose of this amendment was to introduce the requirement for central collection and assessment of photographs from ocular examinations (lens photographs and wide angle fundus photographs) collected during the study by a Novartis designated imaging Contract Research Organization (CRO). This change is in response to a Health Authority request to submit CALYPSO ophthalmic data (for up to 2 years of follow up) to support the ocular safety evaluation of deferasirox.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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