Although, phase 3 of clinical trial in evaluation of efficacy and safety of Exjade® had been preformed in other populations (14
), this study on the Osveral® the Iranian brand of deferasirox has been designed to rule out the effects from differences due to variations in genetic; diet; complexity in absorption, metabolism and the pharmacokinetic characteristics of oral medications; and even cultures and beliefs regarding the imported or domestic products on clinical outcomes. In addition due to some published data about the diversity in efficacy and safety of some other drugs in Iranian thalassemic patients, there was a desire to evaluate efficacy and safety of this new generic drug Osveral® in Iranian patients (11
). On the other hand opponents of conducting a clinical study referred to this fact that there is no need to do clinical trial in chemical non biologic generic drugs after physical, chemical and bioequivalence comparison tests with the main drug (21
). Finally this study, which was first proposed by Management Center for Transplantation and Special Disease of Health deputy of Iran Ministry of Health, was conducted by members of the Iranian Pediatric Hematology and Oncology Society in 2008 and ended on May 2010.
Among all enrolled patients, 407 had the complete and acceptable data. Lack of laboratory data at the time of enrollment and/or during the study; disregarding treatment protocol; and short treatment period of less than one year of using their medicine were among the main reasons for patients to drop out from the study.
In comparison to another multi centric non comparative single arm study on 237 thalassemic patients in the Middle East region, our study is further extended (15
). Efficacy of Iron chelating agents were evaluated in many studies by measurement of dry liver iron concentration (LIC) and it was considered as a standard method for assessment of efficacy (14
On the other hand, significant correlations between changes in serum ferritin and liver iron concentration (LIC) have been identified across various underlying anemia (14
). In addition the measurement of serum ferritin is convenient and inexpensive, and serial measurements provide a relatively robust marker of iron burden. Accordingly current guidelines for assessment of iron burden and monitoring the efficacy of chelation therapy recommend the use of serum ferritin (23
Therefore due to limitations in LIC measurement in different centers and non compliance of patients and parents especially for liver biopsy in children, in the present study serum ferritin level instead of LIC measurement was purposed as an indicator of body iron burden.
It seems that using end of study difference in serum ferritin level as an indicator of efficacy is more suitable for long term studies because of less significant influence of frequent changes in serum ferritin level in various clinical patterns such as infections, inflammations, and liver dysfunction (14
). In this study MRC-SF during one year as main index and primary endpoint of efficacy show a significant decline in SF. However, considering the increasing MRC-SF trend in the lasted 4 months, although statistically non-significant, the study seems should be extended longer for a better evaluation of efficacy.
In ESCALATOR study the reduction of serum ferritin at the end of study toward base line ferritin in children (−166 ng/ml) was not as high as in adults (−846 ng/ml); and this difference was statistically significant. This significant difference was explained by higher iron overload due to huge blood transfusion in children in comparison to adults (15
). Discrepancy between results of this study and ESCALATOR study in the case of age groups may be due to the effect of chronic iron overload on liver in adults who lose the sensitivity of their serum ferritin level as an indicator of iron burden. EPIC study showed a median absolute reduction of serum ferritin of −163 ng/ml and −5.1% relative decline at the end of study but there was no comparison among different age groups (16
Negative iron balance was not encountered in many clinical trials with 20 mg/kg and less, (14
) but in several investigations especially in phase III clinical trails-due lack of enough data available about the drug- the initial dosage (≤20 mg/kg) was administered which might finally affect the efficacy of iron chelating therapy (14
). For example in ESCALATOR study with initial median ferritin of 3326 ng/ml, the starting dose was 20 mg/kg in all patients and the increase of dosage after 26 weeks was detected in 78% of patients (15
). However in this study the starting dose and dosage adjustment was based on iron load (serum ferritin and/or LIC), iron intake, and the amount of transfusion. Therefore, the dosage increased and decreased in 44.7% and 4.7%, of patients under study respectively.
Frequencies of causes for discontinuation of treatment in this study compared with other studies are included in . Although there was no definite description in other studies, unsatisfactory therapeutic effect (leads to drug discontinuation) are defined in our study as increase of serum ferritin more than 30% of baseline in more than 3 months despite dosage adjustment. Non compliance such as consent withdrawal and follow up discontinuation was mostly due to worriness about reported complications of deferasirox as a new medication which lead them to discontinue Osveral® even with presentation of first symptoms of any adverse effect.
Frequency of drug discontinuation in other studies.
Despite 153 reported adverse effects which led to drug discontinuation in EPIC study, there was no frequency reports about the type of AEs (16
). However in the present study among 13 patients whose AEs led to treatment termination the most prevalent complications by sequence are as below: proteinuria, 4 patients (31%); increase in serum liver transaminases more than 5 folds of normal,4 patients (31%); severe rash, 2 patients (15.5%);creatinine increase, blurred vision and diarrhea, each one in 1 patient (7.7%).
In other important trials the prevalence of AEs were 76 and 85 percent, however when those complications defined according to judgment of physicians, the frequencies were between 44–50 percent (15
In their studies, adverse effects without any investigation concerning the causes were reported in 152 patients (37.2%).
The most prevalent complications in this study were transient increase of serum creatinine and more than 5 folds of normal increase in serum liver transaminases. Skin rashes and proteinuria were less prevalent and the gastro-intestinal complications were rare.
The low rate of skin rashes and gastro-intestinal complications in comparison with other studies () could be considered as mild complications which were not sensed by patients and not reported by the physician. For instance from 6 patients reported with rash, 2 cases discontinued the drug despite proper management. This can also explain the diversity in overall rate of complications reported in this study (37.2%) in comparison with other studies (76–85%). Mildness of majority of skin rashes and gastro-intestinal complications of Exjade® are reported in official documents (30
Frequency of complications in other studies.
Diversity in statistics about transient increase of creatinine comes from different definitions about this index. In some studies the increase of creatinine level in two consecutive measures; was not only more than 33% of baseline, but also more than age specific limit especially in children; were considered as creatinine rise (26
). On the other hand, other studies rely on definition of creatinine rise more than 33% of baseline or both of the definitions (14
). With the first definition there were 58 cases (14.2%) with rising creatinine in our study, 55 of them were children and 3 were adults. On the other hand, this difference may be related to physician judgment in allocating complications to deferasirox in some studies. For example in ESCALATOR study, despite creatinine rise in 73 patients (31%) above 33% baseline and 6 patients (2.5%) above age specific limits, the complications which were allocated to drug by investigator, were reported just in 9 patients (3.8%) and there was not any drug interruption due to complication despite one case of renal failure (15
In this study increase in serum liver transaminases (both ALT and AST) more than 5 folds of normal limits was considered as liver dysfunction, while other studies relied on more than10 folds of normal limits of ALT. Therefore, it seems that the prevalence of liver dysfunction in this study was less than other studies. Absence of complications such as hearing disorders, cataract, and cytopenia which were reported in other studies may be due to short duration of this study (1 year) compared with other studies.
In conclusion, the results of the Iranian generic oral iron chelating agent (Osveral®) both in iron chelating efficacy and safety was acceptable. But despite extended sample size in comparison to other studies, for more detailed results it is proposed that the study to be conducted for a more extended period of time with more patients. It seems that the patients satisfaction in different age groups would be the most required variable in future studies. Also it is advisable to include other methods of iron overload assessment liver tissue iron concentration and R2MRI in studies. Finally extension of ongoing generic medications in thalassemic patients emphasizes the importance of multi center clinical studies in Iran.