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

• Sponsor: Consorzio per Valutazioni Biologiche e Farmacologiche (Other)
• Overall Status: Completed
• CT.gov ID: NCT01825512
• Collaborator: European Commission (Other)
• Enrollment: 435
• Locations: 22
• Arms: 2
• Actual Duration (Months): 42.2
• Patients Per Site: 19.8
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Multicentre, randomised, open label, non-inferiority active-controlled trial to evaluate efficacy and safety of a 12-months treatment with deferiprone (DFP) at dose of 75-100 mg/kg/day versus deferasirox (DFX) at dose of 20-40 mg/kg/day in paediatric patients (1 month < 18 years old) affected by hereditary haemoglobinopathies and requiring frequent transfusions and chelation.

Condition or Disease	Intervention/Treatment	Phase
Chronic Iron Overload	Drug: Deferiprone; Drug: Deferasirox	Phase 3

Detailed Description

Haemoglobinopathies are a group of inherited disorders characterized by structural variations of the haemoglobin molecule. Most of the patients affected require for survival chronic red blood cells transfusions to overcome ineffective erythropoiesis. Unfortunately, all chronically transfused patients become clinically iron overloaded as there is no physiological mechanism for the removal of iron from the body. The pathologic changes and clinical manifestations associated to chronic iron overload are common among all transfusional iron-overload patients, albeit best documented in patients with beta-thalassemia major. The recommended treatment consists in regular blood transfusions combined with chelating therapy to remove the harmful iron accumulation in the body.

Currently, in the clinical practice particularly in children and adolescents, the criteria leading to the choice of the chelating agent include also the adherence to therapy, thus favouring the use of oral chelators (Ceci A et al., 2011) DFP (Deferiprone) was the first oral chelator authorised in Europe in 1999 as second line treatment for the treatment of iron overload in patients with thalassaemia major when DFO (Deferoxamine) is contraindicated or inadequate. However, despite a wide experience of DFP with iron overloaded (specifically thalassaemic )patients, limited data are available for younger children. For this reason the need for additional data in younger children is expressively included in the 2009 PDCO (Paediatric Committee) Priority List.

The purpose of this study is to assess the non-inferiority of DFP compared to DFX (deferasirox)in paediatric patients affected by hereditary haemoglobinopathies requiring chronic transfusions and chelation. Non inferiority will be established in terms of percentage of patients successfully chelated, as assessed by serum ferritin levels (in all patients) and cardiac MRI T2* (in patients above 10 years of age able to have an MRI scan without sedation).

Study Design

• Study Type: Interventional
• Actual Enrollment: 435 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Multicentre, Randomised, Open Label, Non-inferiority Trial to Evaluate the Efficacy and Safety of Deferiprone Compared to Deferasirox in Patients Aged From 1 Month to Less Than 18 Years Affected by Transfusion Dependent Haemoglobinopathies
• Actual Study Start Date: Mar 17, 2014
• Actual Primary Completion Date: Sep 21, 2017
• Actual Study Completion Date: Sep 21, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Deferiprone 75-100 mg/kg/day seven days per week	Drug: Deferiprone; Deferiprone 80 mg/mL oral solution; Other Names: DFP
Active Comparator: Deferasirox 20 to 40 mg/kg/day seven days per week	Drug: Deferasirox; Deferasirox is used at the following dosage strengths: 125 mg, 250 mg and 500 mg; Other Names: DFX ATC Code:V03AC03

Outcome Measures

Primary Outcome Measures

1. Percentage of Successfully Chelated Patients [at baseline and after 12 months]

   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)

Secondary Outcome Measures

1. Liver MRI [at baseline and after 12 months]

   Change in liver iron concentration (measured using liver MRI), assessed as difference between value at 12 months minus value at baseline.

2. Cardiac MRI T2* [at baseline and after 12 months]

   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.

3. Ferritin Level [at baseline and after 12 months]

   Change in serum ferritin level, assessed as difference between value at 12 months minus value at baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Month to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients of both genders aged from 1 month up to less than 18 years at the time of enrolment

• Patients affected by any hereditary haemoglobinopathy requiring chronic transfusion therapy and chelation, including but not limited to thalassemia syndromes and sickle cell disease

• Patients on current treatment with deferoxamine (DFO) or DFX or DFP in a chronic transfusion program receiving at least 150 mL/kg/year of packed red blood cells (corresponding approximately to 12 transfusions);

• For patients naïve to chelation treatment: patients that have received at least 150 mL/kg of packed red blood cells (corresponding to approximately 12 transfusions) in a chronic transfusion program and with serum ferritin levels ≥ 800 ng/mL;

• Until availability of results from the PK Study (Study DEEP-1, EudraCT n. 2012-000658-67) for patients aged from 1 month to less than 6 years: known intolerance or contraindication to DFO;

• Written informed consent and patient's informed assent, relating to his/her comprehension abilities and level of maturity

Exclusion Criteria:

• Patients with intolerance or known contraindication to either DFP or DFX

• Patients receiving DFX at a dose > 40 mg/kg/day or DFP at a dose > 100 mg/kg/day at screening

• Platelet count <100.000/mm3 during the run-in phase

• Absolute neutrophils count <1.500/mm3 during the run-in phase

• Hb levels lower than 8g/dL during the run-in phase

• Evidence of abnormal liver function

• Iron overload from causes other than transfusional haemosiderosis

• Severe heart dysfunction secondary to iron overload

• Serum creatinine level > ULN (Upper Limit of Normal) for age during the run-in phase

• History of significant medical or psychiatric disorder

• The patient has received another investigational drug within 30 days prior to this clinical trial

• Fever and other signs/symptoms of infection in the 10 days before baseline assessment

• Concomitant use of trivalent cation-dependent medicinal products such as aluminium-based antacids

• Positive test for β-HCG (Human chorionic gonadotropin) and lactating female patients

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital 'Ihsan Çabej'	Lushnjë		Albania
2	Qendra Spitalore Universitare "Nene Tereza" Tirane	Tirana		Albania
3	Department of Medical and Public health Services of the Ministry of Health	Nicosia		Cyprus
4	Alexandria University Hospital - Faculty of Medicine	Alexandria		Egypt
5	Cairo University Faculty of Medicine	Cairo		Egypt
6	Zagazig University Hospitals	Zagazig		Egypt
7	National And Kapodistrian University of Athens	Athens		Greece
8	Centro di Thalassemia, Ospedale Civile di Lentini	Lentini	SR	Italy
9	Università di Bari - Facoltà di Medicina	Bari		Italy
10	ASL Cagliari Ospedale Regionale per le Microcitemie	Cagliari		Italy
11	Azienda Ospedaliera di Rilievo Nazionale e di Alta Specializzazione Garibaldi	Catania		Italy
12	Presidio Ospedaliero "Annunziata", Centro di Studi della Microcitemia	Cosenza		Italy
13	A.O.Universitaria Meyer	Firenze		Italy
14	Clinica Pediatrica Policlinico di Modena	Modena		Italy
15	Azienda Ospedaliera di Rilievo Nazionale "Antonio Cardarelli"	Napoli		Italy
16	Azienda Ospedaliera di Padova	Padova		Italy
17	Ospedali Riuniti Villa Sofia - Cervello	Palermo		Italy
18	U.O.C. Ematologia - Emoglobinopatie, Ospedale G. Di Cristina	Palermo		Italy
19	Clinica Pediatrica Università - ASL 1 D.H per Talassemia	Sassari		Italy
20	Centre National de Greffe de Moelle Osseuse Tunis	Tunis		Tunisia
21	Barts Health NHS Trust	London		United Kingdom
22	Queen's Hospital	Romford		United Kingdom

Sponsors and Collaborators

• Consorzio per Valutazioni Biologiche e Farmacologiche
• European Commission

Investigators

• Study Director: Donato Bonifazi, Dr, Consorzio per Valutazioni Biologiche e Farmacologiche
• Principal Investigator: Aurelio Maggio, MD, Ospedali Riuniti Villa Sofia-Cervello

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 10, 2015

More Information

Publications

None provided.

• Responsible Party: Consorzio per Valutazioni Biologiche e Farmacologiche
• ClinicalTrials.gov Identifier: NCT01825512
• Other Study ID Numbers: DEEP-2
• First Posted: Apr 5, 2013
• Last Update Posted: May 4, 2021
• Last Verified: Oct 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Consorzio per Valutazioni Biologiche e Farmacologiche: chronic iron overload; hereditary haemoglobinopathy; beta thalassaemia major; chelating agents; deferiprone; deferasirox; children; paediatrics
• Additional relevant MeSH terms: Hemoglobinopathies; Iron Overload; Deferasirox; Deferiprone

Study Results

Participant Flow

Pre-assignment Detail	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 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: Baseline
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 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 Participants	193	197	390
Age, Customized (participants) [Number]
<6 years	59 30.6%	58 29.4%	117 30%
> or equal to 6 years and <10 years	47 24.4%	47 23.9%	94 24.1%
> or equal to 10 years	87 45.1%	92 46.7%	179 45.9%
Sex: Female, Male (Count of Participants)
Female	80 41.5%	93 47.2%	173 44.4%
Male	113 58.5%	104 52.8%	217 55.6%
Race/Ethnicity, Customized (participants) [Number]
Europe	56 29%	56 28.4%	112 28.7%
North Africa	121 62.7%	122 61.9%	243 62.3%
Rest of Africa	6 3.1%	5 2.5%	11 2.8%
Asia	0 0%	1 0.5%	1 0.3%
North America	0 0%	0 0%	0 0%
Latin America	0 0%	0 0%	0 0%
Other	5 2.6%	6 3%	11 2.8%
Missing	5 2.6%	7 3.6%	12 3.1%
Region of Enrollment (participants) [Number]
United Kingdom	11 5.7%	12 6.1%	23 5.9%
Italy	30 15.5%	28 14.2%	58 14.9%
Tunisia	28 14.5%	28 14.2%	56 14.4%
Egypt	96 49.7%	99 50.3%	197 50.5%
Albania	19 9.8%	20 10.2%	39 10%
Greece	5 2.6%	6 3%	11 2.8%
Cyprus	4 2.1%	4 2%	8 2.1%
Ferritin level (ng/ml) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ng/ml]	2756 (2175)	2989 (2409)	2876 (2298)

Outcome Measures

1. Primary Outcome

Title	Percentage of Successfully Chelated Patients
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 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
Measure Participants	125	146
Count of Participants [Participants]	69 35.8%	80 40.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Deferiprone, Deferasirox
	Comments
	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%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment success rate
	Estimated Value	-12.5
	Confidence Interval	(1-Sided) 95%; -12.5 to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Liver MRI
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 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
Measure Participants	46	60
Mean (Standard Error) [mg/g]	-0.848 (0.887)	-2.975 (0.776)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Deferiprone, Deferasirox
	Comments
	Type of Statistical Test	Other
	Comments	GLM model
Statistical Test of Hypothesis	p-Value	0.074
	Comments
	Method	ANCOVA
	Comments
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

3. Secondary Outcome

Title	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 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
Measure Participants	49	59
Mean (Standard Error) [milliseconds (ms)]	0.488 (1.284)	1.121 (1.169)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Deferiprone, Deferasirox
	Comments
	Type of Statistical Test	Other
	Comments	GLM Analysis
Statistical Test of Hypothesis	p-Value	0.717
	Comments
	Method	ANCOVA
	Comments
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

4. Secondary Outcome

Title	Ferritin Level
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 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
Measure Participants	137	166
Mean (Standard Error) [ng/mL]	-397.583 (121.794)	-398.184 (110.619)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Deferiprone, Deferasirox
	Comments
	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
	Method	GLM
	Comments
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

Adverse Events

Time Frame	through study completion, an average of 1 year for subject
Arm/Group Title	Deferiprone		Deferasirox
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	0/193 (0%)		0/197 (0%)
Serious Adverse Events
	Deferiprone		Deferasirox
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/193 (6.7%)		14/197 (7.1%)
Blood and lymphatic system disorders
agranulocytosis	3/193 (1.6%)	3	0/197 (0%)	0
neutropenia	2/193 (1%)	2	0/197 (0%)	0
sickle cell anaemia with crisis subjects affected/exposed	0/193 (0%)	0	2/197 (1%)	2
Gastrointestinal disorders
diarrhoea	0/193 (0%)	0	1/197 (0.5%)	1
General disorders
pyrexia	1/193 (0.5%)	1	1/197 (0.5%)	1
chest pain	0/193 (0%)	0	2/197 (1%)	2
gait disturbance	0/193 (0%)	0	1/197 (0.5%)	1
Hepatobiliary disorders
hypertransaminasaemia	2/193 (1%)	2	1/197 (0.5%)	1
Infections and infestations
gastroenteritis	0/193 (0%)	0	1/197 (0.5%)	1
meningitis meningococcal	0/193 (0%)	0	1/197 (0.5%)	1
herpangina	0/193 (0%)	0	1/197 (0.5%)	1
pneumonia	2/193 (1%)	2	1/197 (0.5%)	1
subcutaneous abscess	0/193 (0%)	0	1/197 (0.5%)	1
urinary tract infection	1/193 (0.5%)	1	1/197 (0.5%)	1
herpes virus infection	0/193 (0%)	0	1/197 (0.5%)	1
impetigo	0/193 (0%)	0	1/197 (0.5%)	1
upper respiratory tract infection	0/193 (0%)	0	1/197 (0.5%)	1
Injury, poisoning and procedural complications
testicular injury	1/193 (0.5%)	1	0/197 (0%)	0
Musculoskeletal and connective tissue disorders
pain in extremity	0/193 (0%)	0	1/197 (0.5%)	1
Nervous system disorders
seizure	1/193 (0.5%)	1	0/197 (0%)	0
Renal and urinary disorders
acute kidney injury	0/193 (0%)	0	2/197 (1%)	2
Surgical and medical procedures
splenectomy	1/193 (0.5%)	1	0/197 (0%)	0
Other (Not Including Serious) Adverse Events
	Deferiprone		Deferasirox
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	152/193 (78.8%)		89/197 (45.2%)
Blood and lymphatic system disorders
neutropenia	18/193 (9.3%)	26	11/197 (5.6%)	15
General disorders
pyrexia	28/193 (14.5%)	40	32/197 (16.2%)	56
abdominal pain	20/193 (10.4%)	24	8/197 (4.1%)	9
vomiting	33/193 (17.1%)	42	8/197 (4.1%)	10
Infections and infestations
pharyngitis	15/193 (7.8%)	18	9/197 (4.6%)	11
Musculoskeletal and connective tissue disorders
arthralgia	23/193 (11.9%)	28	5/197 (2.5%)	5
Respiratory, thoracic and mediastinal disorders
cough	15/193 (7.8%)	21	16/197 (8.1%)	25

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.