Efficacy/Safety Study of Deferiprone Compared to Deferasirox in Paediatric Patients

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ClinicalTrials.gov Identifier: NCT01825512

Recruitment Status : Completed

First Posted : April 5, 2013

Results First Posted : April 8, 2021

Last Update Posted : May 4, 2021

View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborator:

European Commission

Information provided by (Responsible Party):

Consorzio per Valutazioni Biologiche e Farmacologiche

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	Chronic Iron Overload
Interventions	Drug: Deferiprone Drug: Deferasirox
Enrollment	435

Participant Flow

Recruitment Details
Pre-assignment Details	Informed consent was collected for 435 patients that were enrolled in the study, however 42 of them were excluded from the study for the following reasons: 17 did not meet inclusion criteria, 5 withdrew the consent and 20 were lost to follow-up.


Arm/Group Title	Deferiprone	Deferasirox
Arm/Group Description	75-100 mg/kg/day seven days per wee...	20 to 40 mg/kg/day seven days per w...
Arm/Group Description	75-100 mg/kg/day seven days per week Deferiprone: Deferiprone 80 mg/mL oral solution	20 to 40 mg/kg/day seven days per week Deferasirox: Deferasirox is used at the following dosage strengths: 125 mg, 250 mg and 500 mg
Period Title: Baseline
Started	194	199
Completed	193	197
Not Completed	1	2
Period Title: Treatment
Started	193	197
Completed	140	170
Not Completed	53	27

Baseline Characteristics

Arm/Group Title		Deferiprone	Deferasirox	Total
Arm/Group Description		75-100 mg/kg/day seven days per wee...	20 to 40 mg/kg/day seven days per w...	Total of all reporting groups
Arm/Group Description		75-100 mg/kg/day seven days per week Deferiprone: Deferiprone 80 mg/mL oral solution	20 to 40 mg/kg/day seven days per week Deferasirox: Deferasirox is used at the following dosage strengths: 125 mg, 250 mg and 500 mg	Total of all reporting groups
Overall Number of Baseline Participants		193	197	390
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Customized Measure Type: Number Unit of measure: Participants
<6 years	Number Analyzed	193 participants	197 participants	390 participants
<6 years		59	58	117
> or equal to 6 years and <10 years	Number Analyzed	193 participants	197 participants	390 participants
> or equal to 6 years and <10 years		47	47	94
> or equal to 10 years	Number Analyzed	193 participants	197 participants	390 participants
> or equal to 10 years		87	92	179
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	193 participants	197 participants	390 participants
	Female	80 41.5%	93 47.2%	173 44.4%
	Male	113 58.5%	104 52.8%	217 55.6%
Race/Ethnicity, Customized Measure Type: Number Unit of measure: Participants
Europe	Number Analyzed	193 participants	197 participants	390 participants
Europe		56	56	112
North Africa	Number Analyzed	193 participants	197 participants	390 participants
North Africa		121	122	243
Rest of Africa	Number Analyzed	193 participants	197 participants	390 participants
Rest of Africa		6	5	11
Asia	Number Analyzed	193 participants	197 participants	390 participants
Asia		0	1	1
North America	Number Analyzed	193 participants	197 participants	390 participants
North America		0	0	0
Latin America	Number Analyzed	193 participants	197 participants	390 participants
Latin America		0	0	0
Other	Number Analyzed	193 participants	197 participants	390 participants
Other		5	6	11
Missing	Number Analyzed	193 participants	197 participants	390 participants
Missing		5	7	12
Region of Enrollment Measure Type: Number Unit of measure: Participants
United Kingdom	Number Analyzed	193 participants	197 participants	390 participants
United Kingdom		11	12	23
Italy	Number Analyzed	193 participants	197 participants	390 participants
Italy		30	28	58
Tunisia	Number Analyzed	193 participants	197 participants	390 participants
Tunisia		28	28	56
Egypt	Number Analyzed	193 participants	197 participants	390 participants
Egypt		96	99	197
Albania	Number Analyzed	193 participants	197 participants	390 participants
Albania		19	20	39
Greece	Number Analyzed	193 participants	197 participants	390 participants
Greece		5	6	11
Cyprus	Number Analyzed	193 participants	197 participants	390 participants
Cyprus		4	4	8
Ferritin level ^[1] Mean (Standard Deviation) Unit of measure: Ng/ml
	Number Analyzed	163 participants	173 participants	336 participants
		2756 (2175)	2989 (2409)	2876 (2298)
		[1] Measure Analysis Population Description: The difference is due to missing data at baseline

Outcome Measures

1.Primary Outcome


Title	Percentage of Successfully Chelated Patients
Description	Percentage of successfully chelated patients is assessed by serum ferr...
Description	Percentage of successfully chelated patients is assessed by serum ferritin levels (in all patients) and cardiac MRI T2* (in patients above 10 years of age able to perform an MRI scan without sedation)
Time Frame	at baseline and after 12 months

Outcome Measure Data

Analysis Population Description

Per-protocol population 1 (PP1): number of patients for whom the primary composite efficacy endpoint data were available at baseline and after 1 year of treatment (271 subjects)


Arm/Group Title	Deferiprone	Deferasirox
Arm/Group Description:	75-100 mg/kg/day seven days per wee...	20 to 40 mg/kg/day seven days per w...
Arm/Group Description:	75-100 mg/kg/day seven days per week Deferiprone: Deferiprone 80 mg/mL oral solution	20 to 40 mg/kg/day seven days per week Deferasirox: Deferasirox is used at the following dosage strengths: 125 mg, 250 mg and 500 mg
Overall Number of Participants Analyzed	125	146
Measure Type: Count of Participants Unit of Measure: Participants
	69 55.2%	80 54.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Deferiprone, Deferasirox
	Comments	[Not Specified]
	Type of Statistical Test	Non-Inferiority
	Comments	Deferiprone was declared non inferior to Deferasirox if the lower limit of the 95% confidence interval for the difference in the proportion of successful chelation in the two groups is above -12.5%.

Method of Estimation	Estimation Parameter	Treatment success rate
	Estimated Value	-12.5
	Confidence Interval	(1-Sided) 95% -12.5
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Liver MRI
Description	Change in liver iron concentration (measured using liver MRI), assesse...
Description	Change in liver iron concentration (measured using liver MRI), assessed as difference between value at 12 months minus value at baseline.
Time Frame	at baseline and after 12 months

Outcome Measure Data

Analysis Population Description

Per-protocol population 3 (PP3): number of patients for whom liver iron concentration were available at baseline and after 1 year of treatment (106 subjects)


Arm/Group Title	Deferiprone	Deferasirox
Arm/Group Description:	75-100 mg/kg/day seven days per wee...	20 to 40 mg/kg/day seven days per w...
Arm/Group Description:	75-100 mg/kg/day seven days per week Deferiprone: Deferiprone 80 mg/mL oral solution	20 to 40 mg/kg/day seven days per week Deferasirox: Deferasirox is used at the following dosage strengths: 125 mg, 250 mg and 500 mg
Overall Number of Participants Analyzed	46	60
Mean (Standard Error) Unit of Measure: mg/g
	-0.848 (0.887)	-2.975 (0.776)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Deferiprone, Deferasirox
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	GLM model

Statistical Test of Hypothesis	P-Value	0.074
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.128
	Confidence Interval	(2-Sided) 95% -0.213 to 4.468
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.18
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Cardiac MRI T2*
Description	Change in cardiac iron concentration (measured using cardiac MRI T2*),...
Description	Change in cardiac iron concentration (measured using cardiac MRI T2), assessed as difference between value at 12 months minus value at baseline. MRI T2 is a non-invasive method based on gradient echo (GRE) sequences, where T2* represents the spin-spin relaxation times, measured in milliseconds. The faster the curve decreases (ie, the smaller T2), the greater amount of iron is in the tissue. Treatment success was assessed as follows: if baseline cardiac T2 was less than 20 ms, an increase of 10% or more after 1 year of treatment was defined as treatment success; if baseline cardiac T2* was more than 20 ms, any increase or a decrease of less than 10% after 1 year of treatment was defined as treatment success.
Time Frame	at baseline and after 12 months

Outcome Measure Data

Analysis Population Description

Per-protocol population 3 (PP3): number of patients for whom cardiac T2* concentration were available at baseline and after 1 year of treatment (108 subjects)


Arm/Group Title	Deferiprone	Deferasirox
Arm/Group Description:	75-100 mg/kg/day seven days per wee...	20 to 40 mg/kg/day seven days per w...
Arm/Group Description:	75-100 mg/kg/day seven days per week Deferiprone: Deferiprone 80 mg/mL oral solution	20 to 40 mg/kg/day seven days per week Deferasirox: Deferasirox is used at the following dosage strengths: 125 mg, 250 mg and 500 mg
Overall Number of Participants Analyzed	49	59
Mean (Standard Error) Unit of Measure: milliseconds (ms)
	0.488 (1.284)	1.121 (1.169)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Deferiprone, Deferasirox
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	GLM Analysis

Statistical Test of Hypothesis	P-Value	0.717
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.633
	Confidence Interval	(2-Sided) 95% -4.085 to 2.819
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.741
	Estimation Comments	[Not Specified]

4.Secondary Outcome


Title	Ferritin Level
Description	Change in serum ferritin level, assessed as difference between value a...
Description	Change in serum ferritin level, assessed as difference between value at 12 months minus value at baseline.
Time Frame	at baseline and after 12 months

Outcome Measure Data

Analysis Population Description

Per-protocol population 2 (PP2): number of patients for whom the per-protocol centralised serum ferritin concentration data were available at baseline and after 1 year of treatment (303 subjects, this population was larger than PP1 because PP2 included patients who did not have cardiac T2* data)


Arm/Group Title	Deferiprone	Deferasirox
Arm/Group Description:	75-100 mg/kg/day seven days per wee...	20 to 40 mg/kg/day seven days per w...
Arm/Group Description:	75-100 mg/kg/day seven days per week Deferiprone: Deferiprone 80 mg/mL oral solution	20 to 40 mg/kg/day seven days per week Deferasirox: Deferasirox is used at the following dosage strengths: 125 mg, 250 mg and 500 mg
Overall Number of Participants Analyzed	137	166
Mean (Standard Error) Unit of Measure: ng/mL
	-397.583 (121.794)	-398.184 (110.619)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Deferiprone, Deferasirox
	Comments	[Not Specified]
	Type of Statistical Test	Non-Inferiority
	Comments	Non inferiority of Deferiprone to Deferasirox is tested considering a non-inferiority margin of 400 ng/mL.

Statistical Test of Hypothesis	P-Value	0.997
	Comments	[Not Specified]
	Method	GLM
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.601
	Confidence Interval	(2-Sided) 95% -323.580 to 324.781
	Parameter Dispersion	Type: Standard Error of the Mean Value: 164.734
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	through study completion, an average of 1 year for subject
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Deferiprone		Deferasirox
Arm/Group Description	75-100 mg/kg/day seven days per wee...		20 to 40 mg/kg/day seven days per w...
Arm/Group Description	75-100 mg/kg/day seven days per week Deferiprone: Deferiprone 80 mg/mL oral solution		20 to 40 mg/kg/day seven days per week Deferasirox: Deferasirox is used at the following dosage strengths: 125 mg, 250 mg and 500 mg
All-Cause Mortality
	Deferiprone		Deferasirox
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/193 (0.00%)		0/197 (0.00%)
Serious Adverse Events Serious Adverse Events
	Deferiprone		Deferasirox
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/193 (6.74%)		14/197 (7.11%)
Blood and lymphatic system disorders
agranulocytosis ^† 3 [1]	3/193 (1.55%)	3	0/197 (0.00%)	0
neutropenia ^† 4 [2]	2/193 (1.04%)	2	0/197 (0.00%)	0
sickle cell anaemia with crisis subjects affected/exposed ^† 5 [3]	0/193 (0.00%)	0	2/197 (1.02%)	2
Gastrointestinal disorders
diarrhoea ^† 10 [4]	0/193 (0.00%)	0	1/197 (0.51%)	1
General disorders
pyrexia ^† 7 [5]	1/193 (0.52%)	1	1/197 (0.51%)	1
chest pain ^† 8 [6]	0/193 (0.00%)	0	2/197 (1.02%)	2
gait disturbance ^† 9 [7]	0/193 (0.00%)	0	1/197 (0.51%)	1
Hepatobiliary disorders
hypertransaminasaemia ^† 11 [8]	2/193 (1.04%)	2	1/197 (0.51%)	1
Infections and infestations
gastroenteritis ^† 14 [9]	0/193 (0.00%)	0	1/197 (0.51%)	1
meningitis meningococcal ^{† 15 [10]}	0/193 (0.00%)	0	1/197 (0.51%)	1
herpangina ^{† 16 [11]}	0/193 (0.00%)	0	1/197 (0.51%)	1
pneumonia ^{† 17 [12]}	2/193 (1.04%)	2	1/197 (0.51%)	1
subcutaneous abscess ^{† 18 [13]}	0/193 (0.00%)	0	1/197 (0.51%)	1
urinary tract infection ^{† 19 [14]}	1/193 (0.52%)	1	1/197 (0.51%)	1
herpes virus infection ^{† 20 [15]}	0/193 (0.00%)	0	1/197 (0.51%)	1
impetigo ^{† 21 [16]}	0/193 (0.00%)	0	1/197 (0.51%)	1
upper respiratory tract infection ^{† 22 [17]}	0/193 (0.00%)	0	1/197 (0.51%)	1
Injury, poisoning and procedural complications
testicular injury ^† 1 [18]	1/193 (0.52%)	1	0/197 (0.00%)	0
Musculoskeletal and connective tissue disorders
pain in extremity ^{† 13 [19]}	0/193 (0.00%)	0	1/197 (0.51%)	1
Nervous system disorders
seizure ^† 6 [20]	1/193 (0.52%)	1	0/197 (0.00%)	0
Renal and urinary disorders
acute kidney injury ^{† 12 [21]}	0/193 (0.00%)	0	2/197 (1.02%)	2
Surgical and medical procedures
splenectomy ^† 2 [22]	1/193 (0.52%)	1	0/197 (0.00%)	0
1 Term from vocabulary, testicular injury 2 Term from vocabulary, splenectomy 3 Term from vocabulary, agranulocytosis 4 Term from vocabulary, neutropenia 5 Term from vocabulary, sickle cell anaemia 6 Term from vocabulary, seizure 7 Term from vocabulary, pyrexia 8 Term from vocabulary, chest pain 9 Term from vocabulary, gait disturbance 10 Term from vocabulary, diarrhoea 11 Term from vocabulary, hypertransaminasaemi 12 Term from vocabulary, acute kidney injury 13 Term from vocabulary, pain in extremity 14 Term from vocabulary, gastroenteritis 15 Term from vocabulary, meningitis meningoco 16 Term from vocabulary, herpangina 17 Term from vocabulary, pneumonia 18 Term from vocabulary, subcutaneous abscess 19 Term from vocabulary, urinary tract infect 20 Term from vocabulary, herpes virus infecti 21 Term from vocabulary, impetigo 22 Term from vocabulary, upper respiratory tr † Indicates events were collected by systematic assessment [1] agranulocytosis [2] neutropenia [3] sickle cell anaemia with crisis subjects affected/exposed [4] diarrhoea [5] pyrexia [6] chest pain [7] gait disturbance [8] hypertransaminasaemia [9] gastroenteritis [10] meningitis meningococcal [11] herpangina [12] pneumonia [13] subcutaneous abscess [14] urinary tract infection [15] herpes virus infection [16] impetigo [17] upper respiratory tract infection [18] testicular injury [19] pain in extremity [20] seizure [21] acute kidney injury [22] splenectomy
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	4%
	Deferiprone		Deferasirox
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	152/193 (78.76%)		89/197 (45.18%)
Blood and lymphatic system disorders
neutropenia ^†	18/193 (9.33%)	26	11/197 (5.58%)	15
General disorders
pyrexia ^†	28/193 (14.51%)	40	32/197 (16.24%)	56
abdominal pain ^†	20/193 (10.36%)	24	8/197 (4.06%)	9
vomiting ^†	33/193 (17.10%)	42	8/197 (4.06%)	10
Infections and infestations
pharyngitis ^†	15/193 (7.77%)	18	9/197 (4.57%)	11
Musculoskeletal and connective tissue disorders
arthralgia ^†	23/193 (11.92%)	28	5/197 (2.54%)	5
Respiratory, thoracic and mediastinal disorders
cough ^† 1 [1]	15/193 (7.77%)	21	16/197 (8.12%)	25
1 Term from vocabulary, cough † Indicates events were collected by systematic assessment [1] cough

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Donato Bonifazi
Organization:	Consorzio per Valutazioni Biologiche e Farmacologiche
Phone:	+393936698076
EMail:	ceo@cvbf.net

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Giannuzzi V, Felisi M, Bonifazi D, Devlieger H, Papanikolaou G, Ragab L, Fattoum S, Tempesta B, Reggiardo G, Ceci A. Ethical and procedural issues for applying researcher-driven multi-national paediatric clinical trials in and outside the European Union: the challenging experience of the DEEP project. BMC Med Ethics. 2021 Apr 29;22(1):49. doi: 10.1186/s12910-021-00618-2.

Maggio A, Kattamis A, Felisi M, Reggiardo G, El-Beshlawy A, Bejaoui M, Sherief L, Christou S, Cosmi C, Della Pasqua O, Del Vecchio GC, Filosa A, Cuccia L, Hassab H, Kreka M, Origa R, Putti MC, Spino M, Telfer P, Tempesta B, Vitrano A, Tsang YC, Zaka A, Tricta F, Bonifazi D, Ceci A. Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial. Lancet Haematol. 2020 Jun;7(6):e469-e478. doi: 10.1016/S2352-3026(20)30100-9.

Layout table for additonal information

Responsible Party:	Consorzio per Valutazioni Biologiche e Farmacologiche
ClinicalTrials.gov Identifier:	NCT01825512
Other Study ID Numbers:	DEEP-2
First Submitted:	April 3, 2013
First Posted:	April 5, 2013
Results First Submitted:	January 27, 2021
Results First Posted:	April 8, 2021
Last Update Posted:	May 4, 2021

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