A multicentre, multi-national, double-blind, randomised, active-controlled, parallel-group clinical study to assess the safety and efficacy of PDA10 (Epoetin-Alfa) vs. Eprex® in patients with anaemia of chronic renal failure

Anaemic ESKD patients on chronic HD between 18 to below 75 years were screened as prospective subjects. Written informed consent in line with Korean and Malaysian Good Clinical Practice was obtained prior to any study procedures.

Taking into account a 20% drop-out rate, a sample size of 316 subjects was planned to achieve sufficient power determining bioequivalence. Inclusion criteria were ESKD undergoing chronic HD for at least 3 months, through a functioning native arterio-venous fistula, at or within 5% of their dry weight during baseline period and on ESA treatment prior to screening. For female patients, those of childbearing age with negative pregnancy tests and on contraception or, post-menopausal were included. Patients needed to fulfil certain stability criteria in dosage of ESA; Hb, serum ferritin and transferrin saturation (TSAT) levels and frequency of HD per week prior to randomisation.

Other than the general mandatory exclusion criteria, patients with hyperkalaemia, epilepsy, malnutrition, current diagnosis of anaemia due to other causes and history of pure red cell aplasia were excluded. Patients with dialysis catheters or synthetic grafts were also excluded because of higher infection risk among this group of patients. Those with uncontrolled hypertension (pre-dialysis diastolic blood pressure of > 110 mmHg), severe hyperparathyroidism (i.e. parathyroid hormone levels > 150 pmol/l) or those who needed blood transfusions, within 12 weeks prior to randomisation were also excluded.

The study was divided into three phases (Fig. 1). The titration phase assessed the patients’ disease stability and established their baseline characteristics. In certain cases, this was prolonged up to 20 weeks. This included an observation (baseline) period during the last 4 weeks.

Patients already on Eprex® with a Hb level of < 10 g/dl during the screening period or those treated with other ESA for at least 12 weeks prior, had to participate in the titration phase. Those on Eprex® treatment for ≥12 weeks with a Hb level of 10–12 g/dl prior to titration phase and adequate HD thrice weekly with a documented urea reduction ratio > 65% or delivered Kt/V ≥ 1.2 required participation only in the 4-week baseline period. To be eligible for randomisation and entry into the following phase, all patients had to be on a stable intravenous (IV) Eprex® dose, had a stable Hb level between 10 and 12 g/dl and serum ferritin and/or TSAT levels of ≥100 ng/ml and ≥ 20% respectively, during the baseline period. A stable IV Eprex® dose was defined as not > 25% change in weekly dose and no clinically relevant change of HD regime during the baseline period. Titration of IV Eprex® dose (up- or down-titration of 25% of starting dose or, withholding of dose) was done 4-weekly based on the latest 2-weekly Hb levels. More frequent changes were made only when the value or rate of Hb change was outside the pre-set safety parameters of Hb < 10 g/dl or ≥ 12 g/dl or, increase of Hb by < 0.3 g/dl or > 1.0 g/dl every 2 weeks. All patients were also treated with iron therapy based on individual iron levels during this phase. A guideline for intravenous iron therapy is detailed in study protocol (Additional file 1).

The titration phase was followed by a 28-week double-blind treatment phase (maintenance phase) which included an evaluation period at the last 4 weeks. Eligible patients were randomised to receive one of the two study regimens (PDA10 or Eprex®) in a 1:1 ratio IV. During this phase, efficacy and safety were evaluated with Hb, haematocrit and IV Eprex® dose monitored 2-weekly and dose adjustments made, if required, every 4-weekly based on a pre-set scheme similar to the titration phase. A guideline for erythropoietin stimulating agent injections is detailed in study protocol (Additional file 1).

Subjects who completed the study at week 28 were offered a continuation of PDA10 treatment by entering a 24-week open-label extension phase for long-term safety and tolerability evaluation which is beyond the scope of this article.

PDA10 or Eprex® was supplied in pre-filled syringes (PFS) that had the same external appearance and functionality. During the titration phase all patients were administered Eprex® for the first 12 weeks. Those who met all randomisation criteria were randomised and treated with either the investigational product (PDA10 2000 IU/0.5 ml) or reference product (Eprex® 2000 IU/0.5 ml) for 28 weeks in a double-blind fashion.

Both treatments were administered as an IV bolus 1–3 times a week. The maximum dosage in the titration and maintenance phases could not exceed 300 IU/kg/dose. Only the investigational and reference treatments were allowed except during treatment of adverse events (AEs) and administration of other medications at the discretion of the principal investigators.

Of the total 565 patients screened between October 2013 till June 2016, 298 were eligible for randomisation of which two patients, one from each group, were not treated (one at patient’s request in the PDA10 group and the other lost to follow-up in the Eprex® group). The PDA10 group had 150 subjects whilst the Eprex® group had 146 subjects who were eventually treated. Maintenance phase was completed by 143 patients in the PDA10 and 127 in the Eprex® groups. A total of 7 (2 due to AEs) and 19 (11 due to AEs) patients were withdrawn during the maintenance phase from the PDA10 and Eprex® groups, respectively. Of the 296 patients randomised and started on the study medications, 290 (147 and 143 from the PDA10 and Eprex® groups, respectively) were included in the FAS. Excluding those who had been withdrawn and had major protocol deviations from the FAS, total 256 subjects (136 in PDA10 group, 120 in Eprex® group) were included in the PPS (Fig. 2). Total number analysed for safety was 296.

Demographic data and baseline characteristics of the PPS are presented by treatment group in Table 1.

The two treatment arms were similar in demographics and baseline characteristics. The mean age was 52.64 years (standard deviation [SD] 12.71) and majority were males (62.89%). Up to 75.8% of study subjects were from Malaysia and 24.2%, from Korea. Mean duration of renal anaemia was 61.23 months.

There were no statistically significant differences between treatment groups in the proportion of patients with a past medical history and those with concurrent diseases. The most common concurrent disease by preferred term (PT) was ESKD (100%) followed by renal anaemia (96.06%) and hypertension (91.80%). All patients in both groups had history of taking anti-anaemic preparations whilst 96.09% were also on vitamins. The inter-group difference in the proportion of patients with concomitant medications was also not significant.

The mean change in Hb level between the baseline and evaluation periods in the PPS is presented in Table 2. Both the PPS and FAS had no significant difference in baseline Hb levels. The results in the FAS showed a similar trend to those in the PPS i.e. the least square mean (± standard error) for the mean absolute change in Hb level during the evaluation period compared to the baseline period was − 0.283 (± 0.084) g/dl and − 0.275 (± 0.085) g/dl in the PDA10 and Eprex® groups, respectively. Both sets had significant difference in mean Hb change between treatment groups showing therapeutic equivalence (two one sided test result, p < 0.0001).

The weekly dose/kg body weight during the baseline and evaluation periods and the change in weekly dose during the evaluation period from the baseline period in the PPS are presented in Table 3. In the FAS analysis, the least square mean (± standard error) for the mean absolute change in the weekly dose/kg body weight was 7.77 (± 4.21) IU/kg/week and − 7.31 (± 4.25) IU/kg/week in the PDA10 group and Eprex® groups, respectively. The results in the PPS and FAS showed therapeutic equivalence between the test and reference drugs (two one-sided test result, p < 0.0001).

The haematocrit levels during the baseline and evaluation periods and their changes are presented in Fig. 3. The mean (± SD) change at the evaluation period compared to the baseline was − 0.71% (± 2.944) in the PDA10 group (p = 0.552) and 0.007% (± 3.498) in the Eprex® group (p = 0.608) with no statistical significance between both groups (p = 0.445). The FAS showed trends similar to those of the PPS.

One hundred and eleven (81.62%) and 108 (90.0%) patients in the PDA10 and Eprex® groups, respectively had a Hb level out of the target range (10–12 g/dl) during the maintenance phase and the difference in the proportion between the treatments in both PPS and FAS was not statistically significant (p = 0.057). In the PPS, 85 (62.50%) and 61 (50.83%) of patients in the PDA10 and Eprex® groups, respectively were within target range during the evaluation period with no difference between both groups (p = 0.0600). However, the proportion of patients within the target range showed statistical difference between the treatments in the FAS (p = 0.036). As shown in Fig. 4, the mean Hb concentrations and ESA dosage were stable throughout the treatment period in both treatment arms.

None of the patients assessed at baseline were positive for immunogenicity. At week 28, anti-epoetin antibodies were not observed in both treatment groups. The immunogenicity test results of both treatment groups were comparable.

A total of 296 patients (150 and 146 in the PDA10 and Eprex® groups, respectively) who met the definition of the safety set were included (Table 4).

The mean duration of the study drug administration by treatment group was 187.3 days and 176.3 days in the PDA10 and Eprex® groups. There was no difference in extent of exposure between both groups.

There was no difference in the number of subjects experiencing TEAE in both groups. The most common infection related TEAE was respiratory tract infections in 14.00 and 16.44% followed by gastrointestinal infections in 4.00 and 2.74% of patients in the PDA-10 and Eprex® groups, respectively. This was statistically not significant. The most common adverse drug reactions (ADRs) was “Hypertension” in 0.67% (PDA10 group) and 1.37% (Eprex® group). Other than one patient each reporting “blood pressure inadequately controlled” and “rash” in the PDA10 group, there were no other ADRs reported. In this study, all clinically significant abnormal laboratory findings were reported as AEs and were found to be unrelated to the study products. There were also no deaths or serious AEs reported in both groups that were related to the study products.