Methods

Study design: single‐centre RCT

Study grouping: parallel group
Study duration: treatment duration 12 months; follow‐up: not stated

Participants

Baseline characteristics

DFP, DFO

• Total # of participants: 12 randomised; 8 analysed

• Age mean (SD): 16.6 (4.8) years, range 9 to 23 years

• Sex: not reported

• Ethnicity: not reported

• Thalassaemia genotype N (%): 100% β‐thalassaemia

• Baseline ferritin levels (ng/mL) mean (SD): 4453 (2858)

• Previous iron chelation: not reported

• Duration of any iron chelation: not reported

• LIC (mg/g) mean (SD): 27.0 (13.4)

• Splenectomy n (%): not reported

• QoL (mean (SD)): not reported

• Hb, g/L mean (SD): 89 (5)

DFP

• Total # of participants: 12

• Age mean (SD): 15.9 (4.2) years

• Sex: not reported

• Ethnicity: not reported

• Thalassaemia genotype N (%): 100% β‐thalassaemia

• Baseline ferritin levels (ng/mL): 4070 (3223)

• Previous iron chelation: not reported

• Duration of any iron chelation: not reported

• LIC (mg/g): 30.7 (10.6)

• Splenectomy n (%): not reported

• QoL (mean (SD)): not reported

• Hb, g/L mean (SD): 89 (5), range 9 to 23 years

Inclusion criteria: iron‐overloaded people with thalassaemia at least 4 years old

Exclusion criteria: lack of compliance, known toxicity or intolerance preventing therapy with DFO and DFP, neutropenia (neutrophils < 1.5×10⁹/L), thrombocytopenia (platelets < 100×10⁹/L), renal, hepatic or decompensated heart failure, active viral illness being treated with interferon‐α/ribavirin, repeated Yersinia infections, HIV–positivity, pregnancy or nursing, and patients of reproductive age not taking adequate contraceptive precautions

Interventions

Treatment arm: DFO (50 mg/kg/day subcutaneously twice weekly (mean (SD) dose: 43.8 (2.8) mg/kg)) combined with DFP (75 mg/kg/day, daily (mean (SD) dose: 78.2 (1.4) mg/kg/day))
Comparator arm: DFP (75 mg/kg/day, daily (mean (SD) dose: 78.2 (2.6) mg/kg/day))

Outcomes

Adherence: compliance was assessed by drug accounting at each visit (by counting the returned empty blisters of DFP and used vials of DFO) as well as by a trial‐specific questionnaire completed by the participants and/or their legal representative/guardian at quarterly intervals.

The same questionnaire also served for the assessment of tolerance to treatment and QoL

Trial‐reported outcomes

1. Changes in LIC and SF (primary outcome)
2. Total iron excretion
3. Urinary iron excretion
4. Iron balance
5. Cardiac function (Echo)
6. Toxicity
7. Assessment of tolerance to treatment and QoL

Identification

Source of funding: none stated although the drugs were supplied by Lipomed AG, Switzerland

Notes

All participants had prior exposure to DFO (dose, schedule and duration were not reported) and all had a washout period of 2 weeks with no iron chelation before initiating trial treatment
Sample‐size calculation not reported

Country: Turkey

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"The randomization sequence was generated by the Department of Mathematical Statistics at the University of Berne, Switzerland according to local policy". Following central registration of a subject by the investigator, the trial co‐ordinator assigned the intervention according to the randomisation sequence

Allocation concealment (selection bias)

High risk

The trial report states that the intervention was assigned according to the randomisation sequence “without concealing the sequence prior to allocation”

Blinding of participants and personnel (performance bias)
All outcomes except mortality or other objective outcomes

High risk

The authors did not report any information as to whether participants, personnel were blinded to treatment allocation but one treatment subcutaneous and other oral so difficult to blind

Blinding of outcome assessment (detection bias)
All outcomes except mortality

Unclear risk

The authors did not report any information as to whether outcome assessors were blinded to treatment allocation

Incomplete outcome data (attrition bias)
All outcomes

High risk

There was an imbalance in missing data across the treatment arms. 4 participants from the comparator group (DFO) were not included in the outcome analysis: 2 withdrew consent due to refusal to take DFO; 1 died from arrhythmia induced congestive heart failure at start of trial; and 1 developed agranulocytosis at week 14

Selective reporting (reporting bias)

Low risk

All outcomes were reported

Other bias

Unclear risk

There is an imbalance in baseline LIC and Ferritin between groups

Methods

Study design: RCT

Study grouping: parallel group

Length of trial or follow‐up not stated. Not stated if open label; but no mention of blinding and DFO is infusion versus tablet

Participants

Baseline characteristics

DFP, DFO

• Total # of participants: 50

• Age: ≥ 8 years

• Sex: not reported

• Ethnicity: not reported

• Thalassaemia genotype N (%): 100% β‐thalassaemia

• Baseline ferritin levels (ng/mL): not reported

• Previous iron chelation: DFO

• Duration of any iron chelation: not reported

• LIC (mg/g): not reported

• Splenectomy n (%): not reported

• QoL (mean (SD)): not reported

• Hb, g/L: not reported

DFP

• Total # of participants: 50

• Age: ≥ 8 years

• Sex: not reported

• Ethnicity: not reported

• Thalassaemia genotype N (%): β‐thalassaemia

• Baseline ferritin levels (ng/mL): not reported

• Previous iron chelation: DFO

• Duration of any iron chelation: not reported

• Liver iron concentration LIC (mg/g): not reported

• Splenectomy n (%): not reported

• QoL (mean (SD)): not reported

• Hb, g/L: not reported

DFO

• Total # of participants: 50

• Age: greater or equal to 8 years

• Thalassaemia genotype N (%): 100% β‐thalassaemia

• Baseline ferritin levels (ng/mL): not reported

• Previous iron chelation: DFO

• Duration of any iron chelation: not reported

• LIC (mg/g): not reported

• Splenectomy n (%): not reported

• QoL (mean (SD)): not reported

• Hb, g/L: not reported

Inclusion criteria: 8 years, RBC transfusion every 3 to 4 weeks, on DFO prior to study as single therapy.

Exclusion criteria: not stated

Participants PRBCs /3 – 4 weeks to maintain Hb > 9 g/dL

Interventions

DFP, DFO

• Medication intervention: daily DFP, DFO twice‐weekly DFO (40 mg/kg/day); Deferipron e (75 mg/kg/day).

DFP

• Medication intervention: daily DFP Deferipron e (75 mg/kg/day).

DFO

• Medication intervention: DFO 5 days/week DFO (40 mg/kg/day)

Outcomes

Adherence to iron chelation therapy rates

Questionnaire on chelation therapy, reasons for non‐compliance, side effects, life activities, transfusion regimen

Trial‐reported outcomes

1. CBC monthly

2. SF levels

3. liver and kidney functions

4. blood glucose level

5. serum calcium and phosphorus/3 months and T3, T4,TSH, LH, FSH

6. echocardiography

7. bone density

8. auditory and visual examination twice

Identification

Sponsorship source: Zagazig University Hospital, Zagazig

Country: Egypt

Setting: University Hospital

Comments: Abstract Poster 124

Authors name: Sherif Badawy

Institution: Ann Robert H. Lurie Children’s Hospital of Chicago

Email: [email protected]

Address: Ann Robert H. Lurie Children’s Hospital of Chicago Northwestern University Feinberg School of Medicine225 East Chicago Avenue, Box 30, Chicago, Illinois 60611‐2605

Notes

Contacted author and study data not available at this time. Sample‐size calculation not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Judgement comment: no description of sequence generation

Allocation concealment (selection bias)

Unclear risk

Judgement comment: no description of allocation concealment

Blinding of participants and personnel (performance bias)
All outcomes except mortality or other objective outcomes

High risk

Judgement comment no description, but one drug is subcutaneous injection (DFO). Open label

Blinding of outcome assessment (detection bias)
All outcomes except mortality

Unclear risk

Judgement comment: no description of blinding of assessors

Incomplete outcome data (attrition bias)
All outcomes

High risk

Judgement comment: no data on number of participants who completed the study and how many in each group experienced complications. Lack of detail on number of compliant or non‐compliant participants

Selective reporting (reporting bias)

High risk

Judgement comment: not clear which groups and how many experienced adverse events. No data reported on SF or other outcomes

Other bias

Unclear risk

Judgement comment: results of the trial were not published in detail and no data available when authors were contacted

Methods

Study design: single‐centre RCT

Study grouping: parallel group

Study duration: 6 months

Participants

Baseline characteristics

Comprehensive medication management

• Total # of participants: 24

• Age (mean (SD)): 12 (2.7)

• Sex N (%): F: 15 (62.5); M: 9 (37.5)

• Ethnicity: not reported

• Thalassaemia genotype (%): β‐thalassaemia major 100%

• Baseline ferritin levels (ng/mL) (mean (SD)): 3949 (1864)

• Previous iron chelation: N/A

• Duration of any iron chelation: N/A

• LIC (mg/g): not stated

• Splenectomy n (%): 6 (25.9)

• QoL PedsQL median (IQR): 55.16 (43.42 ‐ 63.75)

• Hb, g/L: not stated

Standard care (as defined in the trial)

• Total # of participants: 24

• Age (mean (SD)): 13 (2.8)

• Sex N (%): F: 15 (62.5); M: 9 (37.5)

• Ethnicity: not reported

• Thalassaemia genotype (%: β‐thalassaemia major 100%

• Baseline ferritin levels (ng/mL) (mean (SD)): 3871 (1881)

• Previous iron chelation: N/A

• Duration of any iron chelation: N/A

• LIC (mg/g): not stated

• Splenectomy n (%): 9 (37.5)

• QoL PedsQL median (IQR): 49.12(38.13 ‐ 56.95)

• Hb, g/L: not stated

Inclusion criteria: transfusion‐dependent children with β‐thalassaemia major aged 8 to 18 years with SF level of more than 1000 µg/L

Exclusion criteria: people with cognitive impairment

Interventions

Comprehensive medication management

• interview with participants at each visit, drug‐related problems identified, care plan introduced / monitored to include dosage modification, education. Follow‐up compliance via regular phone calls

Standard care (as defined in the trial)

• all participants presented to the clinic regularly every 2 ‐ 4 weeks according to the need for receiving blood transfusion, blood samples were drawn for CBC assessment. Physical examination was done by physician including assessment of hepatomegaly, splenomegaly and any health‐related problems

Outcomes

Adherence to iron chelation therapy rates

"DRP identification: The clinical pharmacist analysed the collected data to detect whether any DRPs existed and allocated them to one of the seven categories as classified by Cipolle et al. [18]: unnecessary drug therapy, need for additional drug therapy, ineffective drug product, dosage too low, adverse drug reaction, dosage too high, non‐compliance"

Trial‐reported outcomes

1. SF levels were measured at baseline, 3 months and after 6 months

2. CBC with WBC differential was assessed at every visit, and SCr and ALT were measured routinely for all the participants every 3 months

3. Health‐related QoL was assessed at baseline and at the end of the trial (after 6 months) using PedsQL™ 4.0 Generic Core Scale questionnaire. PedsQL is a 23‐item multidimensional model with 4 domains for paediatric health‐related QoL measurement: physical functioning (8 items), emotional functioning (5 items), social functioning (5 items) and school functioning (5 items) (19).

Identification

Sponsorship source: not stated

Country: Egypt

Setting: Hematology clinic

Authors name: Lamia El Wakeel

Institution: Pediatric Hematology Clinic, Children’s Hospital, Ain Shams University,

Email: [email protected]

Address: Lamia El Wakeel, Pediatric Hematology Clinic, Children’s Hospital, AinShams University, 4, Street 292 New Maadi, Cairo, Egypt

Notes

Sample‐size calculation not reported.
Drug‐related outcomes do not have any comparable data reported. Only outcomes with comparable data reported are SF levels and health‐related QoL

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "The study was a prospective, randomized, controlled study. It was conducted on pediatric BTM patients admitted to the Pediatric Hematology Clinic," Stratified randomization was used considering the iron chelation therapy as the stratification factor

Judgement comment: no description of how randomisation was done or by whom

Allocation concealment (selection bias)

Unclear risk

The control group (n = 24) received standard medical care by a physician while the intervention group received standard medical care plus clinical pharmacist‐provided services.

Judgement comment: no description of how participants were allocated to the pharmacist intervention or standard care

Blinding of participants and personnel (performance bias)
All outcomes except mortality or other objective outcomes

High risk

Judgement comment: not possible to blind a pharmacist intervention versus no pharmacist intervention

Blinding of outcome assessment (detection bias)
All outcomes except mortality

High risk

Judgement comment: no indication that outcome assessors where different from pharmacists who implemented the intervention. Also most outcomes were reported only in the intervention group except for ferritin levels and health‐related QoL

Incomplete outcome data (attrition bias)
All outcomes

High risk

Judgement comment: all drug‐related outcomes were only reported in the intervention group including adherence ‐ no comparative data available. Multiple interventions in small number of participants

Selective reporting (reporting bias)

High risk

Judgement comment: drug‐related outcomes reported only in intervention group. No comparative data. The participants within the intervention arm seem to have complex and multiple changes. Difficult to tease out the actual intervention that effected a change

Other bias

Unclear risk

Judgement comment: small sample size and only report intervention group

Methods

Study design: RCT

Study grouping: parallel group

This trial was designed as a 5‐year, multicentre, randomised, open‐label trial with blinded data management and data analyses to evaluate whether the DFP treatment is superior to the DFO treatment

Follow‐up after trial. An additional 5 years of follow‐up after the end of the trial was planned to collect data on the survival, cause of death and chelation treatment of this cohort of participants. During this period, the participants were allowed to change their chelation treatment

Participants

Baseline characteristics

DFP

• Total # of participants: 47

• Age: mean (SD): 41.3 (14.8)

• Sex n (%): F: 24 (50)

• Ethnicity: not reported

• Thalassaemia genotype (%): thalassaemia Intermedia 100%

• Baseline ferritin levels (ng/mL) median (IQR): 1221 (743)

• Age at initiation of DFO years: mean (SD): 29.9 (16.8)

• LIC (mg/g/dw) median (IQR): 3800 (2800)

• Splenectomy n (%): 42 (89.3)

• QoL: mean (SD): not reported

• Hb, g/L mean (SD): 88 (10)

DFO

• Total # of participants: 41

• Age: mean (SD): 41.2 (14.3)

• Sex n (%): F: 23 (51.1)

• Ethnicity: not reported

• Thalassaemia genotype (%): thalassemia intermedia 100%

• Baseline ferritin levels (ng/mL) (median (IQR)): 1,122 (910)

• Age at initiation of DFO years: mean (SD): 29.6 (17.4)

• LIC (mg/g/dw) median (IQR): 3800 (4668)

• Splenectomy n (%): 35 (77.7)

• QoL: mean (SD): not reported

• Hb, g/L mean (SD): 89 (12)

Inclusion criteria: people with thalassaemia intermedia (based on clinical and molecular criteria), SF between 800 and 3000 µg/L, 13 years of age, consent from patient or parent or guardian (if 13 to 18)

Exclusion criteria: known intolerance to treatment, platelet count < 100 ×10⁹/L, white cell count of < 3 ×10⁹/L, severe liver damage, sepsis or heart failure (or both)

Pretreatment: none of the participants in the DFP group and 8 in the DFO group withdrew from the trial. 1 participant in the DFP group and 3 in the DFO group changed their chelation therapy (P value = 0.357)

If the participants were treated with a subcutaneous administration of DFO (30 ‐ 50 mg/kg per day, 8 – 12 hours for 5 days a week) before inclusion in the trial, a DFO washout was executed for 1 week before randomisation.The minimum number of participants required for each treatment group was calculated, assuming equal allocation under the hypothesis of equality between the 2 treatment groups at each point during the course.The recommended number of participants was 30.

One participant in the DFP group and 3 in the DFO group changed their chelation therapy

Interventions

DFP

• DFP (Apotex; Toronto, ON, Canada) administered at 75 mg/kg/day, divided into 3 oral daily doses for 7 days/week

DFO

• DFO (BiofuturaPharma, Omezia, Italy), administered by subcutaneous infusion (8 – 10 hours) at 50 mg/kg per day for 5 days/week

Treatment failure was defined as an increase in the SF level to greater than 1000 lg/L from baseline, confirmed by at least 2 consecutive determinations. Participants who failed were switched to the alternative treatment and followed until the end of the trial. The criteria for a dosage reduction to 50 mg/kg of DFP per day were arthralgia and nausea, and the criterion for a reduction to 30 mg/kg of DFO per day was a local reaction at the site of infusion. Both treatments were reduced if the ferritin levels for 2 consecutive determinations were less than 400 lg/L. The treatment was resumed when the ferritin levels were greater than 700 lg/L for at least 2 determinations

Outcomes

Adherence to iron chelation therapy rates

Compliance was assessed by counting the number of DFP pills in each returned bag and by assessing the number of infusions of DFO registered on the electronic pump

Trial‐reported outcomes
1. The primary endpoint was treatment effectiveness, evaluated as the mean change in the SF level over the 5‐year period. This type of evaluation strengthened the power of the test for the sample‐size calculation compared with the standard.

2. The secondary endpoints were safety and survival analysis after 5 years

Identification

Sponsorship source: contract grant sponsor: Franco and Piera Cutino Foundation

Country: Italy (17 centres)

Setting: haematology and thalassaemia clinical centres at institutions

Recruitment: January 2001 to January 2006

Trial registration: NCT00733811

Authors name: Aurelio Maggio

Institution: Unita Operativa Complessa Ematologia II,

Email: [email protected]

Address: U.O.C. Ematologia II, A.O.R. “Villa Sofia – V. Cervello”, Palermo, Italy

Notes

Sample‐size calculation reported for primary outcome

Notes: 9 participants changed from DFP therapy

5 to DFO

2 to none

1 to DFX

1 to
DFP‐DFO

6 participants changed from DFO therapy

4 to DFP
1 to DFX
1 to DFP‐DFO

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The randomization sequence was based on a computer‐ randomized list arranged in permuted blocks of 10 with a 1:1 ratio."

Allocation concealment (selection bias)

Low risk

To ensure for allocation concealment, treatments were assigned by telephone contact from the coordinating centre. The sequence was concealed until the interventions were assigned. Randomization was performed for each consecutive patient after verification of the exclusion criteria

Blinding of participants and personnel (performance bias)
All outcomes except mortality or other objective outcomes

High risk

Quote: "open‐label trial"

Judgement comment: 1 of 2 arms was desferal pump infusers, participants would know. Participants on DFO attended for weekly blood tests.

Blinding of outcome assessment (detection bias)
All outcomes except mortality

Low risk

Quote: "with blinded data management and data analysis"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No loss to follow‐up for 5‐year trial

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Unclear risk

Unclear how participant variation relating to SF levels may have had effect on results. Although all outcomes were reported for the 5 year trial in the 5 years of follow‐up only mortality was reported

Methods

Study design: single‐centre RCT

Study grouping: parallel group, follow‐up for 54 weeks

Participants

Baseline characteristics

DFP/DFO

• Total # of participants: 18

• Age (mean (SD): 11.0 (4.9)

• Sex: F: 10; M: 8

• Ethnicity: not reported

• Thalassaemia genotype N (%) : β‐thalassaemia major: 100%

• Baseline ferritin levels (ug/mL) (mean (SD) (range)): 2865 (983) (1500 – 4800)

• Previous iron chelation: not reported

• LIC (mg/g) mean (SD) (range): 17.1 (9.1) (4.9 ‐ 33.6) N = 16

• Splenectomy n (%): 11 (61)

• QoL mean (SD): not reported

• Hb, g/L (mean (SD) (range): 68 (5) (55 – 75)

DFP

• Total # of participants: N = 18

• Age (mean (SD) (range)): 10.8 (5.1) (5 ‐ 26)

• Sex: F: 6; M: 12

• Ethnicity: not reported

• Thalassaemia genotype N (%) : β‐thalassaemia major: 100%

• Baseline ferritin levels (ug/mL) (mean (SD) (range)): 2926 (1107) (1560 – 5000)

• Previous iron chelation: not reported

• LIC (mg/g) (mean (SD) (range)): 15.8 (7.1) (2.3 – 29.3) N = 17

• Splenectomy n (%): 9 (50)

• QoL mean (SD): not reported

• Hb, g/L mean (SD) (range): 69 (6) (58 – 80)

DFO

• Total # of participants: N = 20

• Age (mean (SD) (range)): 13.1 (5.9) (5.5 ‐ 24)

• Sex: F: 9; M: 11

• Ethnicity: not reported

• Sickle cell genotype N (%) ‐ not applicable:

• Thalassaemia genotype N (%): β‐thalassaemia major: 100%

• Baseline ferritin levels (ug/mL) (mean (SD)(range)): 2 838 (967) (1500 – 4300)

• Previous iron chelation: not reported

• LIC (mg/g) mean (SD) (range): 22.5 (10.1) (6.0 – 41.7) N = 15

• Splenectomy n (%): 10 (50)

• QoL mean (SD): not reported

• Hb, g/L mean (SD) (range): 69 (5) (60 – 80)

Inclusion criteria: males or females with thalassaemia major attending the Hematology Clinic at Cairo University Children Hospital; participants had to be iron overloaded with transfusion dependency and older than 4 years of age

Exclusion criteria: known to have DFP or DFO toxicity; neutrophil count less than 1.5×10⁹/L; platelet count less than 100×10⁹/L; renal or hepatic insufficiency; decompensated heart failure; without contraceptive precaution; pregnant or nursing

Interventions

DFP/DFO

• DFP + DFO (dose 60 ‐ 83 mg/kg/day and DFO 23 to 50 mg/kg per dose) DFP 7 days and DFO over 8 hours 2 days/week)

DFP

• DFP only (dose 60 to 83 mg/kg/day) 7 days per week

DFO

• DFO 23 to 50 mg kg/day monotherapy for 5 days/week

Outcomes

Adherence to iron chelation therapy rates

Compliance was assessed by performing a drug accounting at each patient visit by counting the returned empty blisters of DFP and used vials of DFO

Trial‐reported outcomes

1. Incidence of chelation therapy‐related SAEs (reported in AEs)

2. Iron overload defined by ferritin over 1000 µg/L and/or clinical symptoms and/or signs of iron overload and/or need for medically indicated additional or change in chelation therapy (mean ferritin levels extrapolated from graph ‐ no SD provided)

3. Other AEs related to iron chelation (in this trial participants with an event are reported. 1 person could experience more than 1 event)

4. LIC mg/g dry weight (change from baseline (extrapolated from graph Least squares means / lower and upper value))

Identification

Sponsorship source

Country: Egypt

Setting: Hematology Clinic at Cairo University Children Hospital, Egypt

Comments: 2 authors from Lipomed (DFP): C. Manz : C. Tarabishi Clinical Research Development, Lipomed AG, Arlesheim, Switzerland

Authors name: A. El‐Beshlawy

Institution: Faculty of Medicine, Cairo University,

Email: [email protected]

Address: Faculty of Medicine, Cairo University, 32 Falaky Street, Bab El‐Louk, Cairo, Egypt

Notes

Sample‐size calculation reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Judgement comment: no description of how randomisation was accomplished: The participants were randomly assigned into 1 of 3 treatment arms

Allocation concealment (selection bias)

Unclear risk

Judgement comment: no description of allocation concealment

Blinding of participants and personnel (performance bias)
All outcomes except mortality or other objective outcomes

High risk

No mention of blinding ‐ since DFO is an injection and DFP is oral likely participants and personnel not blinded

Blinding of outcome assessment (detection bias)
All outcomes except mortality

Unclear risk

Judgement comment: no blinding mentioned

Incomplete outcome data (attrition bias)
All outcomes

High risk

Judgement comment: a total of 10 participants dropped out of the trial as a result of several complications. Only 56 participants completed 54 weeks of treatment. Evaluation of LIC could not be done in another 8 participants. Reports on per protocol participants

Selective reporting (reporting bias)

High risk

Compliance not reported as number or percentage of participants compliant throughout trial: "Four patients, all treated with DFO‐based regimen, were excluded from the study due to lack of compliance. Compliance was otherwise excellent during the entire study. The majority of patients had no problems with the intake and swallowing of the DFP tablets. By contrast, 80% of patients in the combination arm and 76% of patients in the DFO monotherapy arm complained about difficulties in the parenteral use of DFO or problems to insert a needle", SF and LIC are partially reported in charts and no actual numbers are provided in the text. Also the focus on UIE over LIC and SF measures is misleading as DFP is known to have a higher UIE but this can be highly variable over multiple measurements. LIC is the gold standard and there was no difference in this outcome between groups.

Other bias

Unclear risk

There was a higher incidence of AEs in the combined group and the DFP group versus the DFO group

Methods

Study design: RCT in 2 treatment centres

Study grouping: parallel group

Study duration: 1 year

Participants

Baseline characteristics

Group A: DFP/DFO

• Total # of participants: 48

• Age: mean (SD): 15.25 (2.31)

• Sex: male n (%): 30 (62.5)

• Ethnicity: not reported

• Thalassaemia genotype N (%): Not stated all participants appear to have β‐thalassaemia major

• Baseline ferritin levels (ng/mL): mean (SD): 4379.07 (895.00); range 3632 ‐ 6210

• Duration of any iron chelation (years): mean (SD): 8.71 (2.7)

• LIC (mg/g): mean (SD): 12.69 (2.23); range: 12.69 ‐ 2.23

• Splenectomy n (%): 21 (43.7)

• QoL mean (SD): 63.09 (5.77)

• Hb, g/L mean (SD): 81.1 ( 3.3)

• Mean geometric cardiac T2*(ms): mean (SD): 16.32 (1.82); range: 14.9 – 18.2

Group B: DFP/DFX

• Total # of participants: 48

• Age: mean (SD): 14.05 (2.21)

• Sex: male n (%): 32 (66.6)

• Ethnicity: not reported

• Thalassaemia genotype N (%): not stated all participants appear to have β‐thalassaemia major

• Baseline ferritin levels (ng/mL) mean (SD): 4289.19 (866.21); range: 3451 ‐ 7122

• Duration of any iron chelation (years): mean (SD): 8.95 (2.8)

• LIC (mg/g): mean (SD): 12.52 (2.28); range: 9.82 ‐ 15.12

• Splenectomy n (%): 20 (41.6)

• QoL mean (SD): 63.38 (5.98)

• Hb, g/L mean (SD): 79 (3.8)

• Mean geometric cardiac T2*(ms): mean (SD):16.59 (1.85); range: 15.7 ‐ 18.9

Inclusion criteria: people with β‐thalassaemia major aged 10 – 18 years with severe iron overload defined as: ferritin > 2500 μg/L on maximum tolerated dose of a single iron chelator with up trend of ferritin over the last 12 months prior to the study. People with LIC more than 7 mg/g by MRI R2* and mean cardiac T2* less than 20 and more than 6 ms calculated as geometric mean without clinical symptoms of cardiac dysfunction (shortness of breath at rest or exertion, orthopnoea, exercise intolerance, lower extremity oedema, arrhythmias). Adequacy of prior chelation defined as taking 75% of the calculated dose/month on maximum tolerated dose with upward ferritin trend

Exclusion criteria: past history of agranulocytosis, clinically significant GI or renal disease, clinical cardiac disease, or with LVEF < 50% on baseline echocardiography; evidence of active hepatitis or serum transaminases > 3 times above ULN or renal impairment (serum creatinine > ULN) participation in a previous investigational drug study within the 30 days preceding screening, known allergy to DFX, DFP, and DFO.

Pre‐treatment: baseline difference in mean Hb (P 0.004)

Interventions

DFP/DFO

• DFP 75 mg/kg/day divided into 2 doses taken orally at 8 a.m. and 3 p.m. for 7 days (with 6 – 8 hours interval between the 2 doses) combined with DFO 40 mg/kg/day by subcutaneous infusion over 10 hours starting at 10 p.m. for 6 days/week

DFP/DFX

• DFP 75 mg/kg/day, divided into 2 doses taken orally at 8 a.m. and 3 p.m. combined with DFX30 mg/kg/day taken orally at 10 p.m. for 7 days/week

To achieve an acceptable treatment washout, chelation therapy was withdrawn for 2 weeks before randomisation, after verifying inclusion and exclusion criteria. The transfusion regimen aimed to maintain the participants pre‐transfusion Hb ≥80 g/L by receiving approximately 15 mL/kg packed RBCs every 3 – 4 weeks

Outcomes

Adherence to iron chelation therapy rates

Compliance was evaluated by counting of returned tablets for the oral chelators and of the vials for DFO. The percentage of actual dose that participant had taken in relation to the total prescribed dose was calculated

Trial‐reported outcomes

1. % change in SF (from baseline to the end of trial)

2. % change in LIC (from baseline to the end of trial)

3. % change in cardiac MRI (from baseline to the end of trial)

4. SAEs and AEs (safety assessment)

5. Compliance

6. Satisfaction

7. QoL

Identification

Sponsorship source: Ain Shams University

Country: Egypt and Oman

Setting: Thalassemia treatment centres (Ain Shams University, Egypt and Sultan Qaboos University Hospital, Oman)

Comments: Government Clinical Trial NCT01511848

Authors name: Amira Abdel Moneam Adly,

Institution: Department of Pediatrics, Ain Shams University, Cairo, Egypt

Email: [email protected]

Address: 6 A ElSheshini street, Shoubra, Soudia buildings, Cairo, Egypt

Notes

The chelation regimens in the last year prior to the trial were daily DFX (14 participants), daily DFP (29 participants), and DFP 4 days/week alternating with subcutaneous DFO 3 days/week (53 participants)

Sample‐size calculation reported
Author contacted for additional info on SF 36 mean (SD) 6 months and end of trial

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The randomisation sequence was based on a computer randomised list in permuted blocks of 10 with a 1 : 1 ratio, generated at both University of Ain Shams and Sultan Qaboos"

Allocation concealment (selection bias)

Low risk

Quote: "To ensure no allocation bias, treatment group was assigned by telephone contact from the coordinating center in Ain Shams"

Blinding of participants and personnel (performance bias)
All outcomes except mortality or other objective outcomes

High risk

Oral versus subcutaneous medication therefore participants would be aware which medication arm they had been randomised to

Blinding of outcome assessment (detection bias)
All outcomes except mortality

Low risk

Quote: "open‐label study with blinded data management and data analyses"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Judgement comment: treatment was started within the following 24 hr, and all the included participants continued till the end of study with no participants were lost follow‐up

Selective reporting (reporting bias)

Unclear risk

Judgement comment: provide only P values for patient satisfaction, satisfaction with ICT self‐reported satisfaction and all 'significantly' higher in group B; no actual end of trial data provided (mean (SD)). All outcomes are reported

Other bias

Unclear risk

Judgement comment: it is not clear how the investigators would have known that infections, GI disorders or skin disorders were not related to the drug therapies

Methods

Study Design: 2‐arm parallel RCT conducted in Italy and Greece
Number of centres: multicentre (3 centres)
Duration of treatment: 12 month
Follow‐up: not stated.

Participants

DFP/DFO

• Total # of participants: randomised 30, analysed 29 (withdrawn after 2 days on trial before taking DFP)

• Age (mean (SD): 19.8 (6.1) years

• Sex: F: 13; M: 16

• Ethnicity: not reported

• Thalassaemia genotype N (%) : β‐thalassaemia major: 100%

• Baseline ferritin levels (ug/mL) mean (SD): 2048 (685)

• Previous iron chelation: not reported

• LIC (mg/g) mean (SD) (range): 17.1 (9.1) (4.9 – 33.6) N = 16

• Splenectomy n (%): 11 (61)

• QoL mean (SD): not reported

• Hb, g/L mean (SD) (range): 68 (5) (55 – 75)

DFP/DFO

• Total # of participants: randomised 30, analysed 30

• Age (mean (SD)): 18.7 (4.8) years

• Sex: F: 18; M: 12

• Ethnicity: not reported

• Thalassaemia genotype N (%) : β‐thalassaemia major: 100%

• Baseline ferritin levels (ug/mL) (mean (SD): 2257 (748)

• Previous iron chelation: not reported

• LIC (mg/g) mean (SD) (range): 17.1 (9.1) (4.9 – 33.6) N = 16

• Splenectomy n (%): 11 (61)

• QoL mean (SD): not reported

• Hb, gL mean (SD) (range): 68 (5) (55 – 75)

Inclusion criteria: participants were 10 years or older with a diagnosis of thalassaemia major undergoing iron chelation therapy with subcutaneous DFO, with a SF value between 1000 ‐ 4000 μg/L over the previous year.

Exclusion criteria: not reported

Interventions

DFO: 20 ‐ 60 mg/kg/day subcutaneously on 5 ‐ 7 days a week (mean (SD) dose at baseline: 34.8 (8.9) mg/kg/day and at end of trial: 37.8 (8.9) mg/kg/day))

DFO/DFP: DFO 20 ‐ 60 mg/kg/day subcutaneously on 2 days a week (mean (SD) dose DFO for the 29 participants who completed the trial at baseline: 36.0 (5.8) mg/kg/day and at end of trial: 33.3 (6.64) mg/kg/day) with DFP 25 mg/kg/ body weight 3 x daily for 5 days a week)

Outcomes

Adherence see compliance below

Trial‐reported outcomes

1. SF change at 1 year
2. LIC (measured by SQUID) change at 1 year
3. ALT
4. FBC
5. Zinc levels
6. AEs
7. Participant compliance: compliance with DFP was assessed by pill counts, diary cards and an electronic cap that recorded the time and date of each opening of the tablet container. Compliance with DFO was assessed by diary cards, weekly physical examination of infusion sites, and by the Crono™ infusion pump that recorded the number of completed infusions
Primary outcome: not identified

Identification

Source of funding: Apotex Research Inc, Toronto, Canada. The last author of the study is an Apotex employee

Notes

The trial inferred that participants had previously received DFO treatment but no details as to dose, schedule or duration were reported
Sample‐size calculation not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

The authors did not report any information about how randomisation was undertaken

Allocation concealment (selection bias)

Unclear risk

The authors did not report any information about how treatment allocation was concealed

Blinding of participants and personnel (performance bias)
All outcomes except mortality or other objective outcomes

Unclear risk

The authors did not report any information as to whether participants, personnel or outcome assessors were blinded to treatment allocation

Blinding of outcome assessment (detection bias)
All outcomes except mortality

Unclear risk

The authors did not report any information as to whether outcome assessors were blinded to treatment allocation

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Although 1 participant in the treatment group was withdrawn due to intolerance to DFP, this is unlikely to effect the findings of the trial

Selective reporting (reporting bias)

Unclear risk

Compliance to DFP was pre‐specified as an outcome but was not measured or reported in the manuscript

Other bias

Low risk

The trial appears to be free of other sources of bias

Methods

Study design: single‐centre RCT

Study grouping: parallel group

Trial duration: September 2014 to September 2015

Participants

Baseline characteristics

DFX

• Total # of participants: 30

• Age mean (SD): 8.9 (2.2)

• Sex male/female: 9/21

• Thalassaemia genotype (%): β‐thalassaemia major: 100%

• Baseline ferritin levels (ng/mL) median (range): 3216 (2100 ‐ 5862)

• Previous iron chelation: 100%

• Duration of any iron chelation: not reported

• LIC (mg/g): not reported

• Splenectomy n (%): 4 (13.3)

• QoL mean (SD): not reported

• Hb, g/dL mean (SD): 85 (12)

DFO

• Total # of participants: 30

• Age mean (SD): 9.7 (1.9)

• Sex male/female: 10/20

• Thalassaemia genotype (%): β‐thalassaemia major: 100%

• Baseline ferritin levels (ng/mL) median (range): 2773 (1980 ‐ 4884)

• Previous iron chelation: 100%

• Duration of any iron chelation: not reported

• LIC (mg/g): not reported

• Splenectomy n (%): 17 (56.7)

• QoL mean (SD): not reported

• Hb, g/dL mean (SD): 7.9 (2.4)

Inclusion criteria: transfusion‐dependent β‐thalassaemia major, ages were ≥ 6 years, and they had SF levels greater than 1500 µg/L and were on irregular subcutaneous DFO chelation therapy

Exclusion criteria: serum creatinine above the upper age‐related normal range, significant proteinuria (urinary protein/creatinine ratio 1.0 in a non–first‐void urine sample at baseline), elevated ALT more than 3‐fold of the ULN, GI diseases, clinically relevant auditory and/or ocular toxicity related to iron chelation therapy, cardiac disease, and/or SAEs with DFO or DFX, and absolute heutrophilic count 1500/mm3 or platelet count 100,000/mm3

Pre‐treatment: significant difference between the 2 groups with participants having splenectomy 4 in DFX group compared to 17 in DFO group (P = 0.001), hepatitis C status 2 in DFX group compared to 11 in DFO group (P = 0.005) and baseline ALT baseline mean of 28.2 in the DFX group compared to 46.1 in the DFO group (P = 0.001)

Interventions

DFX

• DFX was administered orally as a single daily dose of 20 ‐ 40 mg/kg/day on an empty stomach after dissolution in water, apple juice, or orange juice to assure adequate bioavailability. Starting dose of DFX was individualized based on the frequency of blood transfusions

DFO

• DFO was administered at 20 ‐ 50 mg/kg/day via subcutaneous infusion over 8 ‐ 10 hours, 5 days per week

7‐day washout phase

Outcomes

Adherence to iron chelation therapy rates

During the study, we kept records of all dosages administered, all study medications that were dispensed and returned, and intervals between visits to determine compliance with the treatment. The patients’ parents were instructed to contact the investigator if the patients were unable to take the study drug as prescribed

Trial‐reported outcomes

1. decrease in the SF level to < 1500 μg/L

2. Safety of the drugs that were used

Identification

Sponsorship source: not stated

Country: Egypt

Setting: out‐patient paediatric hematology clinic Al‐ Hussein University Hospital, Al‐Azhar University, Cairo, Egypt

Comments: no conflict of interest.

Authors name: Dr Omar Atef Tolba

Institution: Cairo University Children's Hospital

Email: [email protected]

Address: Dr Omar Atef Tolba, Cairo University Children's Hospital, Department of Pediatrics, Cairo University, Egypt. Tel: +201222101717, +20233025539, Fax: +20233025539

There is no conflict of interest declared

Notes

Sample‐size calculation not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "the patients were randomized in a 1:1 ratio based on permuted blocks to receive deferasirox (DFX) or deferoxamine (DFO) for one year."

Judgement comment: it is unclear risk as there is imbalance in the groups on several variables

Allocation concealment (selection bias)

Unclear risk

Judgement comment: allocation concealment not described and imbalance between groups

Blinding of participants and personnel (performance bias)
All outcomes except mortality or other objective outcomes

High risk

Judgement comment: oral tablet versus subcutaneous infusion ‐ unable to blind participants or personnel

Blinding of outcome assessment (detection bias)
All outcomes except mortality

High risk

Quote: "During the study, we kept records of all dosages administered, all study medications that were dispensed and returned, and intervals between visits to determine compliance with the treatment." Judgement Comment: Does not state if outcome assessors were blinded. Assessors would be aware the treatment participants were on.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "no discontinuation of drugs or drop‐out of follow‐up occurred."

Selective reporting (reporting bias)

High risk

Quote: "Post‐treatment levels of ALT and AST were significantly higher in the DFO group (p = 0.022, p = 0.020, respectively), both drugs have comparable safety profiles, as the adverse effects noted did not reach clinical significance or lead to discontinuation of treatment with either agent. In the light of the comparable efficacy and safety of both agents for the reduction of iron overload, as was reported in the monotherapy of patients with transfusion‐dependent thalassaemia (31, 32), the oral preparation merits convenience and therefore patient compliance and adherence to treatment regimen that needs to be taken on a long‐term basis."

"The oral DFX is recommended due to more convenience to assure adherence to treatment regimen."

Judgement comment: the data within this trial do not provide evidence that DFX assures adherence. Pre‐treatment ALT, AST were also higher in the DFO group ‐ and also reflects imbalance in randomisation. Most outcomes vaguely reported (i.e. compliance ‐ not percentages even though did a count and closely monitored). Also not clear if all drug‐related AEs reported (i.e. agranulocytosis). Further the evidence is uncertain from this trial that both drugs of comparable efficacy and safety

Other bias

Unclear risk

Small trial N = 60 and short‐term follow‐up. Sample‐size calculation not reported, and single‐centre trial

Methods

Study design: multicentre RCT

Study grouping: parallel group

Consecutive thalassaemia major participants (n = 275) were observed at the 25 SoSTE centres from September 30, 2000 to January 31, 2008

9 participants did not meet inclusion criteria and 53 patients declined to participate. The remaining 213 participants were included; 105 and 108 respectively, were randomly allocated to DFP–DFO sequential treatment or DFP alone (Fig 1). None of the participants were lost to follow‐up

Study duration: 5 year follow‐up

Participants

Baseline characteristics

DFP/DFO

• Total # of participants: 105

• Age: mean (SD): 23 (8.0)

• Sex: N (%): F: 55 (50.9)

• Thalassaemia genotype (%): thalassaemia major (100%)

• Baseline ferritin levels (ng/mL): mean (SD): 1727 (669)

• Previous iron chelation: N = 105

• Duration of any iron chelation: not stated

• LIC (mg/g): mean SD: 4.6 (2.8)

• Splenectomy: N (%): 17 (14.0)

• QoL mean (SD): not reported

• Hb, g/L: mean SD: 99 (10)

DFP

• Total # of participants: N = 108

• Age: mean SD: 23 (7.8)

• Sex: N (%): F: 66 (61.1)

• Thalassaemia genotype (%): thalassaemia major (100%)

• Baseline ferritin levels (ng/mL): mean (SD): 1868 (845)

• Previous iron chelation: N = 108

• Duration of any iron chelation: not stated

• LIC (mg/g): mean (SD): 4.0 (2.3)

• Splenectomy: N (%): 15 (12.7)

• QoL mean (SD): not reported

• Hb, g/L: mean (SD): 98 (10)

Inclusion criteria: thalassaemia major, SF between 800 and 3000 ug/L over 13 years of age

Exclusion criteria: known intolerance treatment, platelet count 100 x 109/l or leucocyte count 3.0 x 109/l, severe liver damage, heart failure

Interventions

DFP/DFO

• DFP 75 mg/kg, divided into 3 oral daily doses, for 4 days/week and DFO subcutaneous infusion (8–12 hours) at 50 mg/kg per day for the remaining 3 days/week

DFP

• DFP alone, at the same dosage (75 mg/kg divided into 3 oral daily doses), administered 7 days a week

Outcomes

Adherence

Compliance was assessed by counting the pills in each returned bag of DFP and by assessing the number of infusions of DFO registered on the electronic pump

Trial‐reported outcomes

1. Difference between multiple observations of SF concentrations during the 5‐year treatment. A correlation between LIC and SF levels has previously been shown in cohort of people with thalassaemia major treated with DFP (Olivieri et al, 1995).

2. Survival analysis

3. AEs

4. Costs

5. Multislice‐multiecho T2* MRI scan, available since June 2004, was used in a subgroup of participants to evaluate variations in the iron content of the heart and liver during the trial

Identification

Sponsorship source: Italian Society for the Study of Thalassaemia and Haemoglobinopathies (SoSTE)

Country: Italy

Setting: 25 SoSTE centres in Italy

Comments: NCT 00733811

Authors name: Aurelio Maggio

Institution: A.O.V. Cervello, U.O.C. di Ematologia

Email: [email protected]

Address: A.O.V. Cervello, U.O.C. di Ematologia II,Cervello’’, Palermo, Italy

Notes

Follow‐up was planned for 5 years; however, because of the beneficial effects, in terms of SF levels reduction in the sequential DFP–DFO group, observed after the interim analysis performed at 31 January 2008 the trial was stopped before the planned 5 years of treatment were completed for all participants years but mean (SD) duration of treatment was 2.5 (2.2) and 2.9 ( 2.1) years for DFP and sequential DFP–DFO groups, respectively

Sample‐size calculation reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The randomization sequence was based on a computer‐randomized list in permuted blocks of 10 with a 1:1 ratio,"

Judgement comment: the randomization sequence was based on a computer‐randomized list in permuted blocks of 10 with a 1:1 ratio. The sequence was concealed until interventions were assigned. Randomization was performed per each consecutive participant after verification of the exclusion criteria

Allocation concealment (selection bias)

Low risk

Quote: "To ensure allocation concealment, treatment was assigned by telephone contact from the coordinating centre"

Blinding of participants and personnel (performance bias)
All outcomes except mortality or other objective outcomes

High risk

Trial was open‐label

Blinding of outcome assessment (detection bias)
All outcomes except mortality

Low risk

Quote: "All outcome assessments were done under code by physicians blinded to the trial treatment."

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

The statistical analysis was based on the 'intention‐to‐treat' principle. None of the participants were lost to follow‐up. However, SF measurements were only complete for all participants in the first year of the trial and decrease substantially thereafter to n = 32 in the combined group and n = 26 in the DFP group

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Unclear risk

"Only 21 (35%) subjects in the DFP‐alone and 12 (24%) in the sequential DFP–DFO group withdrew definitely from the trial (Table V). The mean time for definitive withdrawal was 152 ± 103 (days) in DFP‐alone versus 112 ± 76 (days) in the sequential DFP–DFO group respectively." "The planned duration of treatment was 5 years. However, because of the beneficial effects, in terms of serum ferritin levels reduction in the sequential DFP–DFO group, observed after the interim analysis performed at January 31, 2008 the trial was stopped before the planned 5 years of treatment were completed for all patients. Therefore, the mean duration of treatment was 2.5 ± 2.2 and 2.9 ± 2.1 years for DFP and sequential DFP–DFO group respectively"

Judgement comment: withdrawal rate is high and the trial stopped early

Methods

2‐arm parallel RCT.
Number of centres: 1.
Trial dates: not stated.
Duration of treatment: 1 year.
Follow‐up: none.

Trial undertaken: Chronic Care Centre, Beirut, Lebanon.

Participants

Number randomised: 25 (treatment group: 14; comparator group: 11)
Number analysed: 25 (treatment group: 14; comparator group: 11)

β‐thalassaemia participants, severely iron overloaded and previously poorly chelated
Age range: 12 ‐ 40 years
Sex: treatment: 43% male, comparator: 64% male
Ethnicity: not stated

Interventions

DFO

• DFO by subcutaneous injection, 40 ‐ 50 mg/kg 8 ‐ 12 hours a day, 5 ‐ 7 days/week

DFP/DFO

• DFP 75 mg/kg/day orally in 3 divided doses, 7 days a week, DFO by subcutaneous injection, daily dose of 2 g over 8 ‐ 12 hours, 2 days a week

Outcomes

Adherence see compliance below

Trial‐reported outcomes

1. Mean serum iron concentration at baseline, 6 & 12 months (primary outcome)
2. Number RBC units during the trial
3. Iron excretion at 1 & 12 months
4. Hb level measured weekly for 3 months then monthly for 9 months
5. Liver function measured weekly for 3 months then monthly for 9 months
6. Renal function measured weekly for 3 months then monthly for 9 months
7. Side effects
8. Participant compliance: compliance was assessed by the number of vials of DFX or tablets of DFP used. Safety was determined by detailed clinical and laboratory examination. Participants were also asked to complete questionnaires about any side‐effects they experienced.

Identification

Source of funding: not stated.

Notes

Prior exposure to iron chelators: DFO, less than 4 times a week, dose and duration not reported.

Sample‐size calculation not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

The authors did not report any information about how randomisation was undertaken

Allocation concealment (selection bias)

Unclear risk

The authors did not report any information about how treatment allocation was concealed

Blinding of participants and personnel (performance bias)
All outcomes except mortality or other objective outcomes

Unclear risk

The authors did not report any information as to whether participants, personnel were blinded to treatment allocation

Blinding of outcome assessment (detection bias)
All outcomes except mortality

Unclear risk

The authors did not report any information as to whether outcome assessors were blinded to treatment allocation

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All randomised participants were included in the analysis for all outcomes: there were no missing outcome data

Selective reporting (reporting bias)

High risk

Data for 2 pre‐specified outcomes were not reported in the paper: iron excretion at 1 and 12 months and renal function. Both are important clinical markers of the efficacy of iron chelation therapy

Other bias

Low risk

The trial appears to be free of other sources of bias

Methods

2‐arm parallel RCT
Number of centres: 2
Trial dates: November 1993 ‐ September 1995
Duration of treatment: analysis undertaken after 24 months (mean (SD) duration 33 (1.0) months, range 24 ‐ 43 months)
Follow‐up: none

Trial undertaken: Hospital Centres in Toronto and Montreal, Canada. These data are from the Toronto participants only

Participants

Baseline characteristics

Number randomised: 64 (DFO: 32; DFP: 32)
Number analysed: 37 (DFO: 18; DFP: 19). The trial reports details for why 6 and 7 participants respectively were not included in the analysis. The remaining participants had not completed 24 months treatment at the time of analysis for this trial report

DFP (L1)

• Age: not reported

• Sex: F: 11; M: 14

• Thalassaemia genotype (%): thalassaemia major: 100%

• Baseline ferritin levels (ng/mL) mean (SD): 2194 (1251)

• Previous iron chelation: not reported

• Duration of any iron chelation (duration of treatment in this trial ‐ mean (SD) months): 11.0 (4.2) range 2 ‐ 15

• LIC (mg/g): 9.56 (4.77) Range 2.7 ‐ 21.7

• Splenectomy n (%): not reported

• QoL mean (SD): not reported

• Hb, g/L: not reported

DFO

• Age: not reported

• Sex: F: 11 M: 14

• Thalassaemia genotype (%): thalassaemia major: 100%

• Baseline ferritin levels (ng/mL) mean (SD): 2089 (048)

• Previous iron chelation: Not reported

• Duration of any iron chelation (duration of treatment in this trial ‐ mean (SD) months): 11.63 (3.26), range 2 ‐ 15 months

• LIC (mg/g): 7.43 (3.59), range 2.4 ‐ 15.7

• Splenectomy n (%): not reported

• QoL mean (SD): not reported

• Hb, g/L: not reported

Inclusion criteria: diagnosed with homozygous β‐thalassaemia, 10 years of age or older, willing to participate in the trial

Exclusion criteria:

• refùsal to participate in the screening

• previously treated with DFP

• serious adverse reactions to DFO

• failed to attend 20% of the visits in the first 3 months of the trial

• receiving other investigational drugs

• past history of malignancy

• medical, psychological or psychiatric risk

• therapy with an investigational drug would be unwise

• were pregnant or breast feeding

• not using a reliable birth control method

Pre‐treatment:

• stratified into high (7 mg Fe/g dry weight liver tissue) and low iron‐overloaded (7 mg Fe/g dw) according to their hepatic iron concentration as assessed either by liver biopsy or a SQUID (or both)

• 8 participants have been withdrawn from the study due to AEs (2), family reasons (1), psychiatric disorder (1), chronic neutropenia prior to starting on DFP (2), bone marrow transplantation (1) and non compliance with the trial protocol (1)

• 25 participants on DFP and 26 participants on DFO have been used in the present analysis.

• Author goes on to report that results of n = 5 in DFO were not evaluated as there was no compliance data. A further n = 5 participants on DFP and n = 2 were excluded for the analysis of the correlation between compliance + successful outcome (as measured by LIC) as there were 6 months of data available. Therefore, for the main outcome the actual N = 39 (n = 20 in DFP and n = 19 in DFO

Interventions

DFP (L1)

• DFP 75 mg/kg/day in 3 divided doses

DFO

• DFO 50 mg/kg/night, 4 ‐ 7 night/week

Outcomes

Adherence see adherence below

Trial‐reported outcomes

1. Change in LIC (measured by SQUID or biopsy) between 12 months prior to randomisation & 24 months duration on trial treatment

2. Adherence to iron chelation therapy rates defined as per cent of doses administered (number of doses of the iron chelator taken, out of number prescribed), measured for a minimum of 3 months

Identification

Sponsorship source: no sponsorship stated

Country: Canada

Setting: Transfusion Clinic

Authors name: Nancy Olivieri

Institution: University of Toronto

Source of funding: not stated

Notes

Prior exposure to iron chelators: not reported
Abstract publication. Some data from Pope 1995 thesis included for baseline characteristics

Sample‐size calculation not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Quote: "After stratification patients by LIC (>7mg Fe/g; < 7mg Fe/g) 'patients were assigned by a research pharmacist who did not know the patients"

Allocation concealment (selection bias)

Unclear risk

The authors did not report any information about how treatment allocation was concealed

Blinding of participants and personnel (performance bias)
All outcomes except mortality or other objective outcomes

High risk

1 treatment a pump and 1 treatment a tablet, participants and researchers would not be blinded to treatment

Blinding of outcome assessment (detection bias)
All outcomes except mortality

Unclear risk

The authors did not report any information as to whether outcome assessors were blinded to treatment allocation

Incomplete outcome data (attrition bias)
All outcomes

High risk

The trial analysed data from 58% of randomised participants. Of the 42% randomised participants who were not available for outcome analysis:
• 22% randomised participants had not completed the required 24 months treatment at the time of analysis for this trial report;
• 16% DFP‐treated participants and 5% DFO treated participants were withdrawn due to treatment induced side effects

This missing data may inappropriately affect the statistical findings of the trial

Selective reporting (reporting bias)

Low risk

All outcomes pre‐specified were reported in the manuscript

Other bias

Unclear risk

The trial was reported in an abstract, thus there are few data available to make an assessment of whether the trial was free of other bias. Trial stopped early by manufacturer

Methods

2‐arm parallel RCT
Number of centres: 4
Trial dates: December 2002 ‐ March 2005
Duration of treatment: 1 year
Follow‐up: outcome data recorded for duration of treatment

Trial undertaken: 4 participating centres in Italy and Greece

Participants

Number randomised: 61 DFO: 32; DFP: 29
Number analysed: variable across outcomes. Minimum and maximum numbers analysed were: treatment group: 30 ‐ 32; comparator group: 27 ‐ 29. Trial reported details as to why data from 1 participant in the treatment group and 2 in the comparator group were withdrawn from treatment

Transfusion‐dependent homozygous participants with β‐thalassaemia major
Age: mean (SD) treatment group: 26.2 (4.7) years; mean (SD) comparator group: 25.1 (5.8) years
Sex: treatment group: 50% male; comparator group: 52% male
Ethnicity: Greek/Italian: treatment group: 18/14; comparator group: 16/13

Interventions

DFO

• DFO by subcutaneous injection, 50 mg/kg for 5 or more days a week

DFP

• DFP initial dose 75 mg/kg/day increasing to 100 mg/kg/day. Mean actual dose: 92 mg/kg/day

Outcomes

Adherence rates: DFP compliance was measured using the Medication Event Monitoring System device (Aardex, Zug, Switzerland) and calculated as the percent of openings with an interval longer than 4 hours recorded, divided by number of doses prescribed. DFO compliance was calculated as the percentage of completed infusions, as determined by the Crono pumps, divided by the number of infusions prescribed.

Trial‐reported outcomes

1. Change over 1 year in myocardial T2* (primary outcome)
2. Cardiac volumes and function
3. LIC
4. SF
5. ANC
6. AEs
7. ALT
8. Serum zinc levels
9. Serum creatinine levels

Identification

Trial sponsor: Apotex (manufacturer of DFP)

Notes

Prior exposure to iron chelators: DFO at a mean (SD) dose of 39 (8) mg/kg/day for 5 ‐ 7 days/week

Sample‐size calculation reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

The authors did not report any information about how randomisation was undertaken

Allocation concealment (selection bias)

Unclear risk

The authors did not report any information about whether treatment allocation was concealed

Blinding of participants and personnel (performance bias)
All outcomes except mortality or other objective outcomes

High risk

Open label one treatment subcutaneous and the other oral so not possible to mask treatments

Blinding of outcome assessment (detection bias)
All outcomes except mortality

Low risk

The primary outcome was independently measured in a different country (UK) to where the trial took place and the findings were not communicated back to the clinicians during the course of the trial

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants were included in the analysis of the outcomes SF and AEs
Data from 1 participant in the treatment (DFO) group were not included in the analysis of the cardiac outcomes (primary outcome) and last observation carried forward method was used to accommodate the missing data from 3 other participants (1 treatment group and 2 from the comparator group) in the cardiac outcomes (primary outcome)
2 participants in each treatment group did not have a LIC assessment at 12 months and the data from these participants were missing from the analysis

Selective reporting (reporting bias)

High risk

The following pre‐specified outcomes were not reported in the manuscript: ANC; ALT; serum zinc levels; and serum creatinine levels

Other bias

High risk

There are several imbalances in baseline characteristics between the 2 interventions including a major imbalance in SF measures with the DFO group having much higher levels as well as a greater proportion of participants with severe iron overload (above 2500 µg/L)

Methods

Study design: RCT

Study grouping: parallel group

CORDELIA was a prospective, multinational, randomised, open‐label, parallel‐group, phase 2 trial. A total of 81.2% of participants (n = 160) completed 1 year of treatment

Participants

"Overall, 925 patients were screened and 197 randomized. The majority of patients screened were β‐thalassemia major patients (902/925; 99.1%). Other patients who were screened and for whom underlying anaemia was captured had low/intermediate 1 myelodysplastic syndrome (n = 4), Diamond–Blackfan anaemia, β‐thalassemia intermedia, congenital dyserythropoietic anaemia, and paroxysmal nocturnal haemoglobinuria (all n = 1). Only β‐thalassemia major patients fulfilled the inclusion criteria and were enrolled in the study. A total of 81.2% of patients (n = 160) completed 1 year of treatment"

Baseline characteristics

DFX (Exjade)

• Total # of participants: 98

• Age mean (SD): 19.9 (6.5)

• Sex (M:F ratio n): 58:40

• Thalassaemia genotype (%): thalassaemia major: 100%

• Previous iron chelation: DFO: 41 (42.7); DFP: 9 (9.4); DFO + DFP: 21 (21.9); DFX: 18.1(8.8); Unknown or irregular: 7(7.3)

• Duration of any iron chelation mean (SD) years: 14.0 (7.0)

• LIC (mg Fe/g dw): < 7: 11 (12.1); 7 to < 15: 14 (15.4); ≥15: 66 (72.5)

• Splenectomy n (%): not reported

• QoL (mean (SD)): not reported

• Median SF (range), ng/mL (per protocol population): 5062 (613 ‐ 15331)

DFO (Desferal)

• Total # of participants: 99

• Age mean (SD): 19.7 (6.3)

• Sex (M:F ratio n): 57:42

• Thalassaemia genotype (%): thalassaemia major: 100%

• Previous iron chelation: DFO: 39 (42.9); DFP: 5 (5.5); DFO + DFP: 21 9 (23.1); DFX: 23 (25.3); Unknown or irregular: 3 (3.3)

• Duration of any iron chelation mean (SD) years: 14.3 (7.2)

• LIC (mg Fe/g dw): 7: 8 (9.9); 7 to 15: 14 (17.3); ≥15: 59 (72.8)

• Splenectomy n (%): not reported

• QoL (mean (SD)): not reported

• Median SF (range), ng/mL (per protocol population): 4684 (677 ‐ 13342)

Inclusion criteria: people with β‐thalassemia major, Diamond–Blackfan anaemia, low/intermediate myelodysplastic syndromes, or sideroblastic anaemia, aged ≥ 10 years with myocardial T2* 6 ‐ 20 ms, LVEF ≥ 56%, R2 MRI LIC ≥ 3 mg Fe/g dw, lifetime history of ≥ 50 units RBC transfusions, and receiving ≥10 unit/year of RBC transfusions

Exclusion criteria: participants with serum creatinine above the ULN or significant proteinuria (urinary protein/creatinine ratio ≥1.0 mg/mg in a non–first‐void urine sample at baseline; people with ALT 5 x the ULN only if their LIC was 10 mg Fe/g dw; considerable impaired GI function or GI disease; history of clinically relevant ocular and/or auditory toxicity related to iron chelation; therapy, and history of HIV seropositivity or malignancy within the past 5 years; clinical symptoms of cardiac dysfunction (shortness of breath at rest or exertion, orthopnoea, exercise intolerance, lower‐extremity edema, arrhythmias)

Interventions

DFX (Exjade)

• Once‐daily DFX starting dose was 20 mg/kg per day for 2 weeks, followed by 30 mg/kg per day for 1 week, and then continued with 40 mg/kg per day

DFO (Desferal)

• An intensified dosing regimen of DFO was administered at 50 to 60 mg/kg per day via subcutaneous infusion over 8 ‐ 12 hours, 5 ‐ 7 days a week, in accordance with Thalassaemia International Federation Guidelines

Mean actual dose over 1‐year treatment was 36.7 6 4.2 mg/kg per day DFX (range, 19.7‐ 43.3 mg/kg per day). Mean actual dose of DFO was 41.5 6 8.7 (13.2 ‐ 60.2) mg/kg per day, when normalized to a 7‐day regimen

Outcomes

Adherence to iron chelation therapy rates: not stated how adherence was measured

Trial‐reported outcomes

1. Ratio of Gmean myocardial T2* after 1 year of treatment with DFX divided by the ratio of Gmean for DFO
2. Change in LVEF after 1 year of treatment, assessed by absolute change from baseline CMR

3. Absolute change from baseline in LIC after 1‐year treatment

4. Absolute change from baseline in SF after 1‐year treatment

Identification

Sponsorship source: Novartis Pharma AG

Country: multinational, 11 countries

Setting: 22 centres across 11 countries

Comments: the authors thank Debbi Gorman of Mudskipper Business Ltd for medical editorial assistance. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals

Authors name: Dudley J. Pennell

Institution: National Institute for Health, Research Cardiovascular Biomedical Research Unit

Email: [email protected]

Address: National Institute for Health Research Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK

Notes

Novartis Pharmaceuticals Corporation (East Hanover, NJ, USA) co‐ordinated the design and execution of this trial and contributed to the analysis and interpretation of the trial data. Novartis Pharmaceuticals Corporation also collaborated with the external authors to assist in the development and approval of the manuscript for publication

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "22 centers across 11 countries. Following a 35‐day screening phase, patients were randomized in a 1:1 ratio" Randomisation was based on permuted blocks; stratification by centre was not conducted

Allocation concealment (selection bias)

Unclear risk

Judgement comment: no description of allocation concealment except that randomisation was based on permuted blocks

Blinding of participants and personnel (performance bias)
All outcomes except mortality or other objective outcomes

High risk

Judgement comment: open‐label trial ‐ subcutaneous pump versus oral tablet ‐ difficult to blind

Blinding of outcome assessment (detection bias)
All outcomes except mortality

Low risk

Quote: "Core laboratories were blinded to treatment allocation.In order to eliminate potential unrecognized biases, the core clinical trial team was blinded to the treatment assignment prior to the database lock for the primary analysis."

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Judgement comment: 21 withdrawn DFO arm 16 in DFX (78 to 82 completed trial) Efficacy outcomes reported in per protocol and safety in the participants who received the trial drug

Selective reporting (reporting bias)

Unclear risk

Investigator‐reported AEs, regardless of causality, were reported in 65 (67.7%) DFX participants and 69 (75.8%) DFO participants (supplemental Table 2). AEs suspected to be related to trial drug occurred in 35.4% of DFX participants and 30.8% of DFO participants

Judgement comments: It is unclear if investigator‐reported AEs and those suspected to be related to trial drug include the same AEs. Also, they only report the end of trial LIC value for the DFX group

Other bias

Low risk

The trial appears to be free of other sources of bias

Methods

Study design: multicentre RCT conducted in several countries

Study grouping: parallel group

Study duration: 24 weeks

Participants

Baseline characteristics

DFX film‐coated tablet

• Total # of participants: N = 87

• Age: 34.6 (19.97)

• Sex: F: 41

• Thalassaemia genotype N (%): thalassaemia major: 70 (80.5)

• Previous iron chelation: 79 (90.8)

• Median SF (range), ng/mL: 2983 (939 – 8250)

• Splenectomy n (%): not reported

• QoL mean (SD): not reported

• Hb, g/L: not reported

DFX dispersible tablet

• Total # of participants: N = 86

• Age: 35.1 (18.60)

• Sex: F: 47

• Thalassaemia genotype N (%): thalassaemia major: 70 (81.4)

• Baseline ferritin levels (ng/mL) mean (SD): 2089 (048)

• Previous iron chelation: 77 (89.5)

• Median SF (range), ng/mL: 2485 (915 – 8250)

• Splenectomy n (%): not reported

• QoL mean (SD): not reported

• Hb, g/L: not reported

Inclusion criteria:

• Males and females aged ≥ 10 years

• Transfusion‐dependent thalassaemia and iron overload, requiring DFX dispersible tablet at doses of ≥ 30 mg/kg/day as per the investigator's decision or participants with very low, low or intermediate (int) risk myelodysplastic syndrome and iron overload, requiring DFX dispersible tablet at doses of ≥ 20 mg/kg/day as per the investigator's decision

• History of transfusion of at least 20 PRBC units and anticipated to be transfused with at least 8 units of PRBCs annually during the study

• SF > 1000 ng/mL, measured at screening Visit 1 and screening Visit 2 (the mean value will be used for eligibility criteria).

Exclusion criteria:

• Creatinine clearance below the contraindication limit in the locally approved prescribing information. Creatinine clearance will be estimated from serum creatinine at screening Visit 1 and screening Visit 2 and the mean value will be used for eligibility criteria

• Serum creatinine > 1.5 x ULN at screening measured at screening Visit 1 and screening Visit 2 (the mean value will be used for eligibility criteria)

• ALT (SGPT) > 5 x ULN, unless LIC confirmed as >10 mg Fe/dw within 6 months prior to screening visit 1. Significant proteinuria as indicated by a urinary protein/creatinine ratio > 0.5 mg/mg in a non‐first void urine sample at screening Visit 1 or screening Visit 2

• Participants with significant impaired GI function or GI disease that may significantly alter the absorption of oral DFX (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome, or small bowel resection)

• Liver disease with severity of Child‐Pugh Class B or C

Interventions

DFX film‐coated tablets

• DFX film‐coated provided as 90 mg, 180 mg and 360 mg film‐coated tablets for oral use

DFX dispersible tablet

• DFX dispersible tablet provided as 125 mg, 250 mg and 500 mg dispersible tablets for oral use

Outcomes

Adherence to iron chelation therapy rates

Compliance with medication as assessed by relative consumed tablet count

Trial‐reported outcomes

1. Overall safety of both DFX formulations, measured by frequency and severity of AEs and changes in laboratory values from baseline to 24 weeks.

2. Evaluation of both formulations on selected GI AEs (diarrhoea, constipation, nausea, vomiting, and abdominal pain) during treatment

3. Estimation of treatment compliance

4. Evaluation of both formulations on participant satisfaction, palatability, and GI symptoms using PROs

5. Evaluation of the pharmacokinetics of both formulations

6. Reported % compliant with upper and lower percentages

Identification

Sponsorship source: Novartis Pharmaceuticals

Country: USA

Comments: NCT02125877

Authors name: Ali Taher

Institution: American University of Beirut Medical Center

Email: [email protected]

Address: Haematology and Oncology, Department of Internal Medicine, Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon

Notes

Sample‐size calculation not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomization was stratified by underlying disease and previous chelation treatment."

No clear description of randomisation or if participants were randomised centrally

Allocation concealment (selection bias)

High risk

Quote: "Post‐ hoc analyses identified that 23 patients on FCT (26%) were started on a dose that was higher than recommended in the protocol compared with 8 patients (9.3%) on DT (not recognized or reported by the investigators as dosing error)."

Judgement comment: the trial was open label and most participants had been on 1 or the other of the trial drugs prior to the trial ‐ doses may have corresponded to prior dosing since there was no description of allocation concealment

Blinding of participants and personnel (performance bias)
All outcomes except mortality or other objective outcomes

High risk

Judgement comment: open‐label

Blinding of outcome assessment (detection bias)
All outcomes except mortality

High risk

No description of how outcome assessment was performed ‐ centrally or blinded open‐label trial

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Quote: "Overall, all patients were satisfied with their medicine during the study period; satisfaction scores were higher with deferasirox FCT compared with DT at all visits."

Judgement comment: no data provided on number of participants or scores just general statements

Selective reporting (reporting bias)

High risk

Quote: "patients discontinued treatment because of AEs (n = 10), protocol deviation (n = 5), withdrawal of consent (n = 3), patient guardian decision (n = 2), and other reasons (administrative problems, death, and physician’s decision, n = 1 each)."

Judgement comment: investigators do not report all outcomes by treatment assignment, and AEs and SAEs are reported as suspected relationship to trial drug and occurring in > or equal to 10%

Other bias

Unclear risk

"The absolute reduction in median serum ferritin (range) in patients receiving FCT was –350 (–4440–3572) ng/mL and in those receiving DT was –85.5 (–2146–8250) ng/mL); these correspond to a relative change of –14.0% with FCT and –4.1% with DT."

Judgement comment: some of difference in change could be accounted for more participants starting on a higher dose of film‐coated tablet

Methods

2‐arm parallel RCT
Number of centres: multicentre (12 centres)
Duration of treatment: 12 months
Follow‐up: not stated

Trial undertaken: thalassaemia out‐patient clinics in Sardinia

Participants

Number randomised: 65 (treatment group: 33; comparator group: 32)
Number analysed: not reported

Number completing treatment: 60 (treatment group: 32; comparator group: 28). The reason for the withdrawal was not fully reported by the trial authors

Participants aged 18 years or older with a diagnosis of β‐thalassaemia, currently maintained on subcutaneous DFO and with a myocardial T2* between 8 ‐ 20 ms
Age: treatment group: mean (SD) 28.7 (5.3) years; comparator group: mean (SD) 28.8 (4.2) years Age range for both arms was 18 ‐ 42 years
Sex: treatment group: 39% male; comparator group: 44% male
Ethnicity: not stated

Interventions

DFO

• DFO 40 ‐ 50 mg/kg subcutaneously for 5 days a week (DFO actual dose: 43.4 mg/kg for 5 days) with an oral placebo (no further details reported)

DFO/DFP

• DFO 40 ‐ 50 mg/kg subcutaneously for 5 days a week (DFO actual dose: 34.9 mg/kg for 5 days) with DFP 75 mg/kg daily for 7 days a week

Outcomes

Adherence see compliance below

Trial‐reported outcomes

1. Change over 1 year in myocardial T2* (primary outcome)
2. Change in liver T2* at 12 months
3. SF
4. Left ventricular volume & function
5. Brachial artery reactivity as a marker of heart failure
6. Participant compliance with chelation treatments: DFO compliance was calculated as the percentage of completed infusions, as determined by the Crono pumps, divided by the number of infusions prescribed. DFP/placebo compliance was measured through pill counting at the bi‐monthly visits
7. AEs
8. BNP test

Identification

Source of funding: CORDA, Royal Brompton & Harefield Hospitals Charitable funds, Cooley’s Anemia Foundation, Apotex, UK Thalassaemia Society, University College London Special trustees Chairty

Notes

Prior exposure to iron chelation: DFO mean (SD) dose 36.4 (11.1) mg/kg per day for 5.5 day/week (equivalent to 40.5 mg/kg for 5 day/week). Participants were excluded if they had previously received DFP

Sample‐size calculation reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

The authors did not report any information about how randomisation was undertaken

Allocation concealment (selection bias)

High risk

Trial reports that the participants and clinicians were aware of how treatment was to be allocated

Blinding of participants and personnel (performance bias)
All outcomes except mortality or other objective outcomes

Unclear risk

The authors did not report any information as to whether participants or personnel were blinded to treatment allocation

Blinding of outcome assessment (detection bias)
All outcomes except mortality

Unclear risk

The authors did not report any information as to whether outcome assessors were blinded to treatment allocation

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

As the trial does not report the number of participants included in each outcome assessment. The trial reports the number completing treatment and the reasons why 3 participants in the treatment group (1 adverse event & 2 participant requests) and 4 participants in the comparator group (3 adverse events & 1 participant request) were withdrawn from the trial

Selective reporting (reporting bias)

Low risk

All outcomes pre‐specified were reported in the manuscript

Other bias

Low risk

The trial appears to be free of other sources of bias

Methods

Study design: RCT

Study grouping: parallel group

The study duration was 52 weeks. Participants were recruited by investigators at 44 sites in the USA, France, Italy, UK and Canada

Participants

Baseline characteristics

DFX

• Total # of participants: 132

• Age: 15 range 3 ‐ 54

• Sex (female %): 60.6

• Sickle cell genotype N (%): 100

• Baseline ferritin levels (ng/mL) median (min ‐ max): 3460 (1082 ‐ 1201)

• Previous iron chelation %: 62.9

• Splenectomy n (%): not reported

• QoL mean (SD): not reported

DFO

• Total # of participants: 63

• Age: 16. Range 3 ‐ 51

• Sex (female %): 55.6

• Sickle cell genotype N (%): 100

• Baseline ferritin levels (ng/mL) median (min ‐ max): 2834 (1015 ‐ 15578)

• Previous iron chelation %: 60.3

• Splenectomy n (%): not reported

• QoL (mean (SD)): not reported

Age group (% DFX, DFO)
< 6 years: 3.0, 4.8
6 to < 12 years: 22.7, 23.8
12 to <16 years: 25.0, 20.6
16 to < 50 years: 47.7, 49.2
50 to < 65 years: 1.5, 1.6

Inclusion criteria:

• People with SCD ≥ to 2 years of age and with iron overload from repeated blood transfusions

• People receiving regular blood transfusions or those sporadically transfused who received at least 20 units of packed RBCs or equivalent were eligible

• Prior chelation therapy was permitted but was not mandatory

• The serum ferritin level for entry into the screening period of this study was ≥ 1000 µg/L

Exclusion criteria

• People were excluded if they had a serum creatinine above the ULN

• Significant proteinuria (as indicated by a urinary protein:creatinine ratio of ≥ 0.5 confirmed at 2 visits)

• Active hepatitis B or C

• Second and third atrioventricular block, QT interval prolongation, or therapy with digoxin or similar medications

• Treatment with beta blockers or angiotensin‐converting enzyme inhibitors was permitted. Those with chelation therapy‐associated ocular toxicity were excluded

Interventions

DFX

• The initial 24 participants enrolled were randomised to receive DFX 10 mg/kg, all subsequent participants randomised to DFX were dosed at 10 – 30 mg/kg according to baseline LIC. DFX was given once daily each morning as a dispersed solution in water, half‐an‐hour before breakfast. The dose of DFX was reduced by 1 dose level and not re‐escalated for participants 15 years and older if serum creatinine increased 33% above baseline on two consecutive occasions. For children less than 15 years of age, the dose was only decreased if these values were also above the age‐appropriate ULN. DFX was interrupted for moderate or severe skin rash and re‐instituted at half the initial dose, and dose re‐escalation was permitted

DFO

• DFO was administered as a slow subcutaneous infusion over 8 – 12 hours using electronic Microject Chrono infusion pumps on 5 – 7 days a week. In order to facilitate the comparison of different schedules, all DFO doses reported were normalised to administration for 5 days/week (i.e. 50 mg/kg administered 7 days/week would be reported as 70 mg/kg)

Outcomes

Adherence to iron chelation therapy rates

Compliance. For DFX, compliance was assessed by counting the number of tablets returned in bottles at each visit. For DFO, the numbers of vials returned at each visit were counted

Trial‐reported outcomes

1. Safety assessments

2. Laboratory assessments were performed at least monthly and included complete blood counts with differential counts. Biochemistry testing included electrolytes, glucose, liver function tests, gamma‐glutaryl‐transferase, lactate dehydrogenase, cholesterol, triglycerides, uric acid, total protein, C‐reactive protein, copper and zinc levels. Iron parameters included total iron, transferrin, transferrin saturation and ferritin. Urinary testing performed on random collections included determination of creatinine, total protein and albumin

3. Physical examinations, ECGs, audiometry and ophthalmological tests were performed at baseline, 12, 24, 36 and 52 weeks. In participants less than 16 years of age, additional assessments included growth velocity and pubertal stage

4. Efficacy assessments. LIC was determined by SQUID biospectrometry at baseline, 24 and 52 weeks. The 24‐week assessment was performed primarily for safety purposes, and the change in LIC was calculated between baseline and 52 weeks. SF was assessed monthly during the trial and the change was determined using the baseline and final ferritin level

Identification

Sponsorship source: Novartis Pharmaceuticals

Country: international (Canada, France, Italy, UK and USA)

Setting: medical centre outpatient

Authors name: Elliott Vichinsky

Institution: Children’s Hospital and Research Center at Oakland,

Email: [email protected]

Address: Children’s Hospital and Research Center at Oakland, 747 52nd Street, Oakland, CA 94609, USA

Novartis Pharmaceuticals Corporation (East Hanover, NJ, USA) co‐ordinated the design and execution of this trial and contributed to the analysis and interpretation of the trial data. Novartis Pharmaceuticals Corporation also collaborated with the external authors to assist in the development and approval of the manuscript for publication

Notes

Sample‐size calculation reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The randomisation was performed using an interactive voice response system"

Allocation concealment (selection bias)

Unclear risk

Quote: "stratified according to the following age groups: 2 to < 6 years, 6 to < 12 years, 12 to < 16 years and 16 years and older. The randomisation sequence included permuted block groups of six patients for each of the three age strata."

Judgement comment: some of the age groups had few participants and unclear if allocation would remain concealed with permuted block groups of 6 participants

Blinding of participants and personnel (performance bias)
All outcomes except mortality or other objective outcomes

High risk

Judgement comment: no mention of blinding, but DFO is delivered by infusion pumps and DFX is a solution in water, so blinding not feasible

Blinding of outcome assessment (detection bias)
All outcomes except mortality

High risk

Judgement comment: no description of blinding: Novartis Pharmaceuticals Corporation (East Hanover, NJ, USA) co‐ordinated the design and execution of this trial and contributed to the analysis and interpretation of the trial data. The data were analysed under supervision of the trial statistician and were reviewed by the investigators

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All outcomes reported. 8 participants did not complete and were not included. 6 DFX arm withdraw consent, one in DFO arm. 3 DFO non compliant, 2 DFX and 1 DFO lost to follow‐up

Selective reporting (reporting bias)

Unclear risk

Quote: "Adverse events, irrespective of the relationship to study medication, which occurred in more than 10% of patients receiving either treatment, are shown in Table III. As arbitrarily defined by an increased frequency of at least 5% indicating a potential relationship to drug administration."

Judgement comment: do not report the total number of AEs in all participants, as well there was a substantial number of participants experience SAEs and there is no list of the type except for pain crisis: The number of participants receiving DFX and DFO that reported SAEs was similar (46.2% and 42.9% respectively) and the most common SAE in both groups was sickle cell anaemia with crisis (33.3% and 31.7% respectively). Also table of AEs report % and no totals so impossible to determine total number of participants with an AE

Other bias

Unclear risk

Quote: "The reasons for withdrawal of consent were not included in the database."

Quote: "The initial 24 patients enrolled were randomised to receive deferasirox 10 mg/kg or deferoxamine at recommended doses of 20–60 mg/kg based on initial LIC. Subsequently, additional safety information became available for deferasirox suggesting a need to modify the starting dose (Cappellini et al, 2006). Therefore, following the enrolment of the first 24 patients, the study was amended so that all subsequent patients randomised to deferasirox were dosed at 10–30 mg/kg according to baseline LIC"

Judgement comment: it is important to understand reasons for withdrawals and also the nature of the missing safety information which may have implications for dosing and effects of the dosing amendment