Trial Outcomes & Findings for Study to Evaluate the Efficacy and Safety of HX575 Hexal AG vs ERYPO® for the Treatment of Anemia in Hemodialysis Patients (NCT NCT00666835)

Last Updated: 2023-07-03

Results Overview

Primary endpoint was the mean absolute change in Hb level between the screening/baseline and the evaluation period. A two-sided 95 % confidence interval for the difference in mean change (mean of evaluation period - mean of screening/baseline period) in Hb between epoetin alfa HX575 Hexal AG and ERYPO® Janssen-Cilag was computed. The difference was estimated from an analysis of a co-variance model including factors treatment, center, mean baseline Hb (\<11.5 and ≥11.5 g/dL) as factors and change of the mean weekly dose from screening/baseline to the evaluation period (of HX575 epoetin alfa Hexal AG or ERYPO® Janssen-Cilag) as a covariate. HX575 Hexal AG was considered at least as good as ERYPO® Janssen-Cilag if the 95 % confidence interval of the difference in mean changes in Hb levels between HX575 Hexal AG and ERYPO® Janssen-Cilag lied entirely within the interval \[-0.5 g/dL; 0.5 g/dL\]. Primary Endpoint was analyzed based on intent-to-treat (ITT) population.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

478 participants

Primary outcome timeframe

28 weeks

Results posted on

2023-07-03

Participant Flow

A total of 568 patients were screened. 479 were eligible for inclusion and were randomized. 478 patients were started on treatment with either epoetin alfa HX575 Hexal AG or ERYPO®, Janssen-Cilag. As the randomization followed a 2:1 scheme, 314 patients received HX575 Hexal AG and 164 patients received ERYPO®.

The first part of the study was designed as a double-blind, randomized, multicenter, parallel-group equivalence study and consisted of two phases: Phase I (dose adjustment and maintenance of Hb level; until week 24) followed by Phase II (evaluation period: four week evaluation period to determine the primary efficacy endpoint; weeks 25 until 28).

Participant milestones

Participant milestones
Measure	HX575 Epoetin Alfa Hexal AG Eligible patients were switched from the comparator to epoetin alfa HX575 Hexal AG in ratio 2:1. Treatment was done intravenously (solution for injection i.v.) in pre-filled syringes for 24 weeks. The maximum weekly dose was 300 UI/kg body weight (given 1 to 3 times) to maintain hemoglobin levels between 10-13 g/dL. Baseline HB value after 24 weeks was required for efficacy analysis at week 28.	ERYPO®, Janssen-Cilag Eligible patients were randomized and continued to be treated intravenously with ERYPO®, Janssen-Cilag in pre-filled syringes (solution for injection i.v.) for 24 weeks. The maximum weekly dose was 300 UI/kg body weight (given 1 to 3 times) to maintain hemoglobin levels between 10-13 g/dL. Baseline HB value after 24 weeks was required for efficacy analysis at week 28.
Overall Study STARTED	314	164
Overall Study COMPLETED	261	142
Overall Study NOT COMPLETED	53	22

Reasons for withdrawal

Reasons for withdrawal
Measure	HX575 Epoetin Alfa Hexal AG Eligible patients were switched from the comparator to epoetin alfa HX575 Hexal AG in ratio 2:1. Treatment was done intravenously (solution for injection i.v.) in pre-filled syringes for 24 weeks. The maximum weekly dose was 300 UI/kg body weight (given 1 to 3 times) to maintain hemoglobin levels between 10-13 g/dL. Baseline HB value after 24 weeks was required for efficacy analysis at week 28.	ERYPO®, Janssen-Cilag Eligible patients were randomized and continued to be treated intravenously with ERYPO®, Janssen-Cilag in pre-filled syringes (solution for injection i.v.) for 24 weeks. The maximum weekly dose was 300 UI/kg body weight (given 1 to 3 times) to maintain hemoglobin levels between 10-13 g/dL. Baseline HB value after 24 weeks was required for efficacy analysis at week 28.
Overall Study Withdrawal by Subject	5	2
Overall Study Lack of Efficacy	0	1
Overall Study Incl./excl. not fulfilled	7	2
Overall Study Adverse Event	7	6
Overall Study Protocol Violation	2	0
Overall Study Death	15	4
Overall Study Kidney Transplantation (NTX)	10	2
Overall Study Hemoglobulin concentration	4	3
Overall Study Planned operation	2	0
Overall Study Physician Decision	1	2

Baseline Characteristics

Study to Evaluate the Efficacy and Safety of HX575 Hexal AG vs ERYPO® for the Treatment of Anemia in Hemodialysis Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	HX575 Epoetin Alfa Hexal AG n=314 Participants Eligible patients were switched from the comparator to HX575 epoetin alfa Hexal AG in ratio 2:1. Treatment was done intravenously (solution for injection i.v.) in pre-filled syringes for 24 weeks. The maximum weekly dose was 300 UI/kg body weight (given 1 to 3 times) to maintain hemoglobin levels between 10-13 g/dL. Baseline HB value after 24 weeks was required for efficacy analysis at week 28.	ERYPO®, Janssen-Cilag n=164 Participants Eligible patients were randomized and continued to be treated with ERYPO® Janssen-Cilag intravenously in pre-filled syringes (solution for injection i.v.) for 24 weeks. The maximum weekly dose was 300 UI/kg body weight (given 1 to 3 times) to maintain hemoglobin levels between 10-13 g/dL. Baseline HB value after 24 weeks was required for efficacy analysis at week 28.	Total n=478 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	145 Participants n=5 Participants	84 Participants n=7 Participants	229 Participants n=5 Participants
Age, Categorical >=65 years	169 Participants n=5 Participants	80 Participants n=7 Participants	249 Participants n=5 Participants
Age, Continuous	62.3 years STANDARD_DEVIATION 14.4 • n=5 Participants	62.6 years STANDARD_DEVIATION 13.8 • n=7 Participants	62.4 years STANDARD_DEVIATION 14.2 • n=5 Participants
Sex: Female, Male Female	138 Participants n=5 Participants	98 Participants n=7 Participants	236 Participants n=5 Participants
Sex: Female, Male Male	176 Participants n=5 Participants	66 Participants n=7 Participants	242 Participants n=5 Participants
Region of Enrollment Austria	70 participants n=5 Participants	37 participants n=7 Participants	107 participants n=5 Participants
Region of Enrollment Germany	244 participants n=5 Participants	127 participants n=7 Participants	371 participants n=5 Participants
Body weight	76.3 kg STANDARD_DEVIATION 15.5 • n=5 Participants	76.0 kg STANDARD_DEVIATION 17.7 • n=7 Participants	76.2 kg STANDARD_DEVIATION 16.2 • n=5 Participants

PRIMARY outcome

Timeframe: 28 weeks

Population: Primary Endpoint was analyzed based on ITT population: all treated patients with a post baseline hemoglobin value.

Outcome measures

Outcome measures
Measure	HX575 Epoetin Alfa Hexal AG n=207 Participants Eligible patients were switched from the comparator to HX575 epoetin alfa Hexal AG in ratio 2:1. Treatment was done intravenously (solution for injection i.v.) in pre-filled syringes for 24 weeks. The maximum weekly dose was 300 UI/kg body weight (given 1 to 3 times) to maintain hemoglobin levels between 10-13 g/dL. Baseline HB value after 24 weeks was required for efficacy analysis at week 28.	ERYPO®, Janssen-Cilag n=118 Participants Eligible patients were randomized and continued to be treated with ERYPO®, Janssen-Cilag in pre-filled syringes intravenously (solution for injection i.v.) for 24 weeks. The maximum weekly dose was 300 UI/kg body weight (given 1 to 3 times) to maintain hemoglobin levels between 10-13 g/dL. Baseline HB value after 24 weeks was required for efficacy analysis at week 28.
To Compare the Efficacy of HX575 Hexal AG and ERYPO® Janssen-Cilag.	0.147 g/dL Standard Error 0.092	0.063 g/dL Standard Error 0.117

SECONDARY outcome

Timeframe: 28 weeks

Population: Intent-to-treat population (ITT): all randomized patients who received at least one dose of the study medication and for whom at least one post-baseline value of the primary endpoint Hb was available. A prerequisite to be included in the ITT population was that they were treated for four weeks with Hb values available during this period.

The mean absolute change in Hb levels between the screening/baseline period and the evaluation period was analyzed for the intent-to-treat (ITT) population in the same way as the primary efficacy endpoint. A two-sided 95 % confidence interval for the difference in mean change (mean of evaluation period - mean of screening/baseline period) in Hb between HX575 epoetin alfa Hexal AG and ERYPO® Janssen-Cilag was computed. The difference was estimated from an analysis of a co-variance model including factors treatment, center, mean baseline Hb (\<11.5 and ≥11.5 g/dL) as factors and change of the mean weekly dose from screening/baseline to the evaluation period (of HX575 epoetin alfa Hexal AG or ERYPO® Janssen-Cilag) as a covariate. HX575 Hexal AG was considered at least as good as ERYPO® Janssen-Cilag if the 95 % confidence interval of the difference in mean changes in Hb levels between HX575 Hexal AG and ERYPO® Janssen-Cilag lied entirely within the interval \[-0.5 g/dL; 0.5 g/dL\].

Outcome measures

Outcome measures
Measure	HX575 Epoetin Alfa Hexal AG n=304 Participants Eligible patients were switched from the comparator to HX575 epoetin alfa Hexal AG in ratio 2:1. Treatment was done intravenously (solution for injection i.v.) in pre-filled syringes for 24 weeks. The maximum weekly dose was 300 UI/kg body weight (given 1 to 3 times) to maintain hemoglobin levels between 10-13 g/dL. Baseline HB value after 24 weeks was required for efficacy analysis at week 28.	ERYPO®, Janssen-Cilag n=161 Participants Eligible patients were randomized and continued to be treated with ERYPO®, Janssen-Cilag in pre-filled syringes intravenously (solution for injection i.v.) for 24 weeks. The maximum weekly dose was 300 UI/kg body weight (given 1 to 3 times) to maintain hemoglobin levels between 10-13 g/dL. Baseline HB value after 24 weeks was required for efficacy analysis at week 28.
Mean Absolute Change in Hemoglobin Level From the Screening/Baseline Period to the Evaluation Period - ITT Population	0.003 g/dL Standard Error 0.079	-0.187 g/dL Standard Error 0.105

Adverse Events

HX575 Epoetin Alfa Hexal AG

Serious events: 112 serious events

Other events: 283 other events

Deaths: 19 deaths

ERYPO®, Janssen-Cilag

Serious events: 57 serious events

Other events: 154 other events

Deaths: 5 deaths

Serious adverse events

Other adverse events

Additional Information

Biopharmaceutical Clinical Development, Strategic Planning

Sandoz

Phone: 0049 80244760

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	HX575 Epoetin Alfa Hexal AG n=314 participants at risk Eligible patients were switched from the comparator to HX575 epoetin alfa Hexal AG in ratio 2:1 to be intravenously (solution for injection i.v.) treated with HX575 in pre-filled syringes for 24 weeks. The maximum weekly dose was 300 UI/kg body weight (given 1 to 3 times) to maintain hemoglobin levels between 10-13 g/dL. Baseline HB value after 24 weeks was required for efficacy analysis at week 28.	ERYPO®, Janssen-Cilag n=164 participants at risk Eligible patients were randomized and continued to be treated with ERYPO®, Janssen-Cilag in pre-filled syringes intravenously (solution for injection i.v.) for 24 weeks. The maximum weekly dose was 300 UI/kg body weight (given 1 to 3 times) to maintain hemoglobin levels between 10-13 g/dL. Baseline HB value after 24 weeks was required for efficacy analysis at week 28.
Infections and infestations Nasopharyngitis	17.5% 55/314 • Number of events 73 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.	21.3% 35/164 • Number of events 41 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.
Infections and infestations Bronchitis	8.9% 28/314 • Number of events 34 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.	11.6% 19/164 • Number of events 20 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.
Injury, poisoning and procedural complications Haemodialysis-induced symptom	15.6% 49/314 • Number of events 224 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.	14.0% 23/164 • Number of events 100 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.
Injury, poisoning and procedural complications Procedural hypotension	14.0% 44/314 • Number of events 137 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.	14.0% 23/164 • Number of events 60 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.
Injury, poisoning and procedural complications Procedural hypertension	5.1% 16/314 • Number of events 76 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.	6.1% 10/164 • Number of events 39 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.
Injury, poisoning and procedural complications Arteriovenous fistula site complication	5.7% 18/314 • Number of events 20 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.	4.3% 7/164 • Number of events 8 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.
Gastrointestinal disorders Diarrhoea	20.1% 63/314 • Number of events 85 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.	13.4% 22/164 • Number of events 23 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.
Gastrointestinal disorders Vomiting	8.6% 27/314 • Number of events 36 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.	11.0% 18/164 • Number of events 21 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.
Gastrointestinal disorders Nausea	9.6% 30/314 • Number of events 43 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.	8.5% 14/164 • Number of events 20 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.
Musculoskeletal and connective tissue disorders Muscle spasms	24.5% 77/314 • Number of events 276 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.	23.2% 38/164 • Number of events 86 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.
Musculoskeletal and connective tissue disorders Back pain	5.1% 16/314 • Number of events 19 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.	6.7% 11/164 • Number of events 16 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.
Musculoskeletal and connective tissue disorders Shoulder pain	5.1% 16/314 • Number of events 17 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.	6.7% 11/164 • Number of events 14 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.
Vascular disorders Hypotension	15.3% 48/314 • Number of events 142 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.	12.2% 20/164 • Number of events 26 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.
Vascular disorders Hypertension	9.2% 29/314 • Number of events 62 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.	5.5% 9/164 • Number of events 17 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.
Nervous system disorders Headache	9.2% 29/314 • Number of events 53 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.	7.9% 13/164 • Number of events 20 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.
Respiratory, thoracic and mediastinal disorders Dyspnoea	5.7% 18/314 • Number of events 23 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.	8.5% 14/164 • Number of events 25 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.
Skin and subcutaneous tissue disorders Pruritus	5.4% 17/314 • Number of events 20 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.	7.3% 12/164 • Number of events 12 • Recording of AEs included periods before first application and until the end of application of study medication. Occurrence of AEs was recorded from time when patient had given his/her informed consent until the final visit of the main study period (visit 28). By definition, AEs starting in the period after first application until the end of the main period were considered to be 'treatment-emergent' AEs. Analysis based on safety population: patients received at least 1 dose of treatment.