APO-EPO-02

APOTEX Inc.

150 Signet Drive, Toronto, Canada, M9L 1T9

Apotex Clinical Operations, APOTEX Inc., clinicalqa@apotex.com

Apotex Clinical Operations, APOTEX Inc., clinicalqa@apotex.com

APOTEX Inc.

150 Signet Drive, Toronto, Canada, M9L 1T9

Clincal Operations, APOTEX Inc., clinicalqa@apotex.com

Clincal Operations, APOTEX Inc., clinicalqa@apotex.com

No

No

No

Final

27 Sep 2019

Yes

18 Sep 2017

Yes

18 Sep 2017

No

To assess the therapeutic equivalence of Apotex’s epoetin alfa (APO-EPO) versus US registered epoetin alfa (Procrit®) for correction of the hemoglobin (Hb) concentration in patients with anemia of chronic kidney disease (CKD) stage 5 maintained on stable hemodialysis (CKD stage 5D).

The study was conducted in accordance with the protocol, principles of Good Clinical Practice (GCP), Declaration of Helsinki and amendments, and applicable local regulations. Independent oversight of study was provided by Data and Safety Monitoring Board, which assessed the accumulating safety data from the study (10 meetings were conducted during study course). All subjects were fully informed of all aspects of clinical study, including its experimental nature, its purpose, the procedures involved, the expected duration, the potential risk and benefits, any discomfort it may entail as well as possibility to discontinue at any time in the local language. Collected protected health information obtained during the study was processed in compliance with the Personal Data Protection laws and legislations governing personal data protection in all countries.

01 Oct 2012

No

Yes

Poland: 18

Romania: 19

Slovakia: 8

Bulgaria: 162

Czechia: 10

Greece: 52

Georgia: 39

Lebanon: 4

Serbia: 93

Tunisia: 39

Ukraine: 89

533

269

0

0

0

0

0

0

392

140

1

Correction phase

Randomised - controlled

The assessor(s) – investigators participating in the patient assessments were blinded to the treatment allocation throughout the study. The allocated treatment was disclosed only to the unblinded study staff, who was responsible for the receipt, accountability, preparation, and administration of the study treatment. The unblinded staff did not communicate to the assessor(s) the medication allocation.

Yes

recombinant human epoetin alfa

APO-EPO

Solution for injection in vial

Subcutaneous use

Provided as single-dose preservative-free vials containing 2,000, 3,000, 4,000 or 10,000 units of epoetin alfa per milliliter in citrate-buffered formulation. The starting dose will be 25 IU/kg, administered s.c., t.i.w (i.e. a total dose of 75 IU/kg per week) and will be titrated individually in order to achieve stable Hb concentrations of 10.0-11.0 g/dl.

recombinant human epoetin alfa

Procrit

Solution for injection in vial

Subcutaneous use

Provided as a single-dose, preservative-free vial. Each 1 ml of solution contains 2,000, 3,000, 4,000,or 10,000 units of epoetin alfa. The starting dose will be 25 IU/kg, administered s.c., t.i.w (i.e. a total dose of 75 IU/kg per week) and will be titrated individually in order to achieve stable Hb concentrations of 10.0-11.0 g/dl.

Maintenance phase

Randomised - controlled

The assessor(s) – investigators participating in the patient assessments were blinded to the treatment allocation throughout the study. The allocated treatment was disclosed only to the unblinded study staff, who was responsible for the receipt, accountability, preparation, and administration of the study treatment. The unblinded staff did not communicate to the assessor(s) the medication allocation.

Yes

recombinant human epoetin alfa

APO-EPO

Solution for injection in vial

Subcutaneous use

Provided as single-dose preservative-free vials containing 2,000, 3,000, 4,000 or 10,000 units of epoetin alfa per milliliter in citrate-buffered formulation. The starting dose will be 25 IU/kg, administered s.c., t.i.w (i.e. a total dose of 75 IU/kg per week) and will be titrated individually in order to achieve stable Hb concentrations of 10.0-11.0 g/dl.

recombinant human epoetin alfa

Procrit

Solution for injection in vial

Subcutaneous use

Provided as single-dose preservative-free vials. Each 1 ml of solution contains 2,000, 3,000, 4,000 or 10,000 units of epoetin alfa. The starting dose will be 25 IU/kg, administered s.c., t.i.w (i.e. a total dose of 75 IU/kg per week) and will be titrated individually in order to achieve stable Hb concentrations of 10.0-11.0 g/dl.

APO-EPO

Procrit

Intention-to-Treat

The ITT analysis set comprised of all randomized subjects who received at least one dose of study drug and who provided at least one post-baseline Hb measurement. The ITT analysis set was analyzed as randomized, except for the primary endpoint, which was analyzed both “as randomized” and “as treated”.

Modified Intention-to-Treat

As both co-primary endpoints were based on Evaluation Phase data only, the mITT analysis set included those subjects who started this phase and had available measurements for at least one of the 2 co-primary endpoints in the Evaluation Phase (measured between Week 21-24). The mITT analysis set was analyzed both “as randomized” and “as treated”.

Per protocol

The PP analysis set comprised of all subjects from the mITT analysis set who had no major PDs that affected the interpretation of the primary and co-primary endpoints had completed at least 2 weeks in the Evaluation Phase, and whose mean Hb level during the Evaluation Phase was maintained in the prescribed interval of 10-11 g/dL. Major PDs and their impact on primary and co-primary endpoints were defined in the Protocol Deviation Handling Plan and were assessed during the Blinded Data Review Meeting.

APO-EPO

Procrit

APO-EPO

Procrit

Intention-to-Treat

The ITT analysis set comprised of all randomized subjects who received at least one dose of study drug and who provided at least one post-baseline Hb measurement. The ITT analysis set was analyzed as randomized, except for the primary endpoint, which was analyzed both “as randomized” and “as treated”.

Modified Intention-to-Treat

As both co-primary endpoints were based on Evaluation Phase data only, the mITT analysis set included those subjects who started this phase and had available measurements for at least one of the 2 co-primary endpoints in the Evaluation Phase (measured between Week 21-24). The mITT analysis set was analyzed both “as randomized” and “as treated”.

Per protocol

The PP analysis set comprised of all subjects from the mITT analysis set who had no major PDs that affected the interpretation of the primary and co-primary endpoints had completed at least 2 weeks in the Evaluation Phase, and whose mean Hb level during the Evaluation Phase was maintained in the prescribed interval of 10-11 g/dL. Major PDs and their impact on primary and co-primary endpoints were defined in the Protocol Deviation Handling Plan and were assessed during the Blinded Data Review Meeting.

Mean weekly dose of epoetin per kilogram of body weight necessary to maintain hemoglobin within 10.0-11.0 g/dL level during the last 4 weeks of the correction phase

Primary

Last 4 weeks of correction phase (Week 21-24)

95% CI for the mean treatment difference (APO-EPO - Procrit) was calculated within a mixed model framework accounting for treatment arm, week, and residual renal function at screening

Procrit v APO-EPO

489

Pre-specified

-0.01

2-sided

Mean hemoglobin concentration during the last 4 weeks of the correction phase

Primary

Last 4 weeks of correction phase (Week 21-24)

95% CI for the mean treatment difference (APO-EPO - Procrit) was calculated within a mixed model framework accounting for treatment arm, week, and residual renal function at screening

APO-EPO v Procrit

489

Pre-specified

0.05

2-sided

Number and proportion of subjects with treatment success, i.e. Hb concentration between 10.0 - 11.0 g/dL for 2 consecutive weeks without any blood transfusion within the preceding 3 months.

Secondary

Correction phase, at each two consecutive weeks (Week 23-24 is presented).

Percent difference between arms (APO-EPO – Procrit) and the Miettinen-Nurminen confidence limits for differences between success rates were calculated.

Procrit v APO-EPO

475

Pre-specified

-0.6

2-sided

Proportion of subjects needing blood transfusions during the treatment period.

Secondary

Treatment period

APO-EPO v Procrit

527

Pre-specified

-0.8

2-sided

Number and proportion of subjects with the maintenance success (maintenance of mean Hb concentration of 10.0-11.0 g/dL for at least 4 consecutive weeks in the Maintenance Phase) without any blood transfusion within the preceding 3 months.

Secondary

4 consecutive weeks in the Maintenance phase (Week 44-48 is presented)

Proportion of subjects with maintenance success.

Procrit v APO-EPO

443

Pre-specified

3.9

2-sided

Number and proportion of subjects with Hb values outside the target range (<10.0 g/dL) (in the Correction and Maintenance Phases, by visit);

Secondary

In the correction and maintenance phase, by visit (week 24 and week 48 are presented)

Proportion of subjects with hemoglobin result outside the target range (<10 g/dL) at the end of the correction phase (week 24).

APO-EPO v Procrit

485

Pre-specified

-1.1

2-sided

Proportion of subjects with hemoglobin result outside the target range (<10 g/dL) at the end of the maintenance phase (week 48).

APO-EPO v Procrit

448

Pre-specified

-4.3

2-sided

Number and proportion of subjects with Hb values outside the target range (>11.0 g/dL) (in the Correction and Maintenance Phases, by visit);

Secondary

In the correction and maintenance phase, by visit (week 24 and week 48 are presented)

Proportion of subjects with hemoglobin result outside the target range (>11 g/dL) at the end of the correction phase (week 24).

APO-EPO v Procrit

485

Pre-specified

3.9

2-sided

Proportion of subjects with hemoglobin result outside the target range (>11 g/dL) at the end of the maintenance phase (week 48).

APO-EPO v Procrit

448

Pre-specified

1.3

2-sided

Number and proportion of subjects with hematocrit measurements > 30%.

Secondary

In the correction and maintenance phase, by visit (week 24 and week 48 are presented)

Proportion of subjects with hemotocrit >30% at the end of the correction phase (week 24).

APO-EPO v Procrit

485

Pre-specified

7.1

2-sided

Proportion of subjects with hemotocrit >30% at the end of the maintenance phase (week 48).

APO-EPO v Procrit

448

Pre-specified

5.9

2-sided

Number and proportion of subjects with TSAT < 20% or ferritin < 100 ng/mL and requiring i.v. supplementation of iron.

Secondary

In the correction and maintenance phase, by visit (week 24 and week 48 are presented)

Proportion of subjects at the end of the correction phase (week 24).

APO-EPO v Procrit

484

Pre-specified

-2.6

2-sided

Proportion of subjects with hemoglobin result outside the target range (<10 g/dL) at the end of the maintenance phase (week 48).

APO-EPO v Procrit

444

Pre-specified

-4

2-sided

Supportive analysis of the co-primary endpoint in the per protocol analysis set. Mean weekly dose of epoetin per kilogram of body weight necessary to maintain hemoglobin within 10.0-11.0 g/dL level during the last 4 weeks of the correction phase.

Other pre-specified

Last 4 weeks of correction phase (Week 21-24)

95% CI for the mean treatment difference (APO-EPO - Procrit) was calculated within a mixed model framework accounting for treatment arm, week, and residual renal function at screening

APO-EPO v Procrit

223

Pre-specified

7.89

2-sided

Other pre-specified

Last 4 weeks of correction phase (Week 21-24)

95% CI for the mean treatment difference (APO-EPO - Procrit) was calculated within a mixed model framework accounting for treatment arm, week, and residual renal function at screening.

APO-EPO v Procrit

223

Pre-specified

-0.03

2-sided

Mean weekly dose of epoetin per kilogram of body weight necessary to maintain hemoglobin within 10.0-11.0 g/dL level during the last 4 weeks of the correction phase. Multiple imputation was performed for all subjects with missing data in the ITT analysis set.

Other pre-specified

Last 4 weeks of correction phase (Week 21-24)

Supporting analysis for the co-primary endpoint on the ITT analysis set after multiple imputation.

APO-EPO v Procrit

530

Pre-specified

1.64

2-sided

95% CI for the mean treatment difference (APO-EPO - Procrit) was calculated within a mixed model framework accounting for treatment arm, week, and residual renal function at screening. Multiple imputation was performed for all subjects with missing data in the ITT analysis set.

Other pre-specified

Last 4 weeks of correction phase (Week 21-24)

Supporting analysis for the co-primary endpoint on the ITT analysis set after multiple imputation.

APO-EPO v Procrit

530

Pre-specified

0.03

2-sided

95% CI for the mean treatment difference (APO-EPO - Procrit) was calculated within a mixed model framework accounting for treatment arm, week, and residual renal function at screening.

Other pre-specified

Last 4 weeks of correction phase (Week 21-24)

Sensitivity analysis.

APO-EPO v Procrit

489

Pre-specified

-0.06

2-sided

95% CI for the mean treatment difference (APO-EPO - Procrit) was calculated within a mixed model framework accounting for treatment arm, week, and residual renal function at screening.

Other pre-specified

Last 4 weeks of correction phase (Week 21-24)

Sensitivity analysis.

Procrit v APO-EPO

489

Pre-specified

0.05

2-sided

From the first study drug administration until the last study visit.

15.1

APO-EPO

Procrit