Trial to Evaluate the Efficacy and Safety of a New Full Length Recombinant Human FVIII for Hemophilia A (Leopold I)

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Bayer

ClinicalTrials.gov Identifier:

NCT01029340

First received: December 8, 2009

Last updated: October 14, 2016

Last verified: October 2016

History of Changes

Results First Received: May 27, 2013

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Open Label; Primary Purpose: Treatment
Conditions:	Blood Coagulation Disorders Hemophilia A
Interventions:	Biological: Recombinant Factor VIII (BAY81-8973) Biological: Recombinant Factor VIII (Kogenate FS, BAY14-2222)

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants were recruited from specialized hemophilia treatment centers.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
14 participants were enrolled in each of Arms 1 and 2 in Part A. Of these, 11 participants continued into each of Arms 3 and 4 in Part B. Arm 3 enrolled 20 and Arm 4 enrolled 21 additional participants who had not participated in Part A. Arm 5 enrolled 5 participants specifically for surgery in Part C who had not participated in Parts A or B.

Reporting Groups

	Description
Arm 1: Recombinant Factor VIII (BAY81-8973) Then Kogenate FS	Part A - Arm 1: Participants first received one single intravenous (IV) injection of BAY81-8973 50 IU/kg, then 1 single IV injection of Kogenate FS (BAY14-2222) 50 IU/kg with a wash-out period of at least 2-3 days in between
Arm 2: Kogenate FS Then Recombinant Factor VIII (BAY81-8973)	Part A - Arm 2: Participants first received one single intravenous (IV) injection of Kogenate FS (BAY14-2222) 50 IU/kg, then 1 single IV injection of BAY81-8973 50 IU/kg with a wash-out period of at least 2-3 days in between
Arm 3: Recombinant Factor VIII by CS/EP Then by CS/ADJ	Part B - Arm 3: Participants received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by Chromogenic Substrate Assay Potency Per European Pharmacopeia (CS/EP) for 6 months and then crossed over to study drug measured by Chromogenic Substrate Assay/Adjusted (CS/ADJ) to Label Potency for 6 months
Arm 4: Recombinant Factor VIII by CS/ADJ Then by CS/EP	Part B - Arm 4:. Participants received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by Chromogenic Substrate Assay/Adjusted (CS/ADJ) to Label Potency for 6 months and then crossed over to study drug measured by Chromogenic Substrate Assay Per European Pharmacopeia (CS/EP) for 6 months
Arm 5: Recombinant Factor VIII by CS/EP	Part C - Arm 5: Participants received a loading dose of approximately 50 IU/kg of BAY81-8973 before the first surgical incision followed by further treatment with BAY81-8973 according to surgical requirements for up to 3 weeks
Arm 6: Recombinant Factor VIII (BAY81-8973) Part B + Extension	Participants received IV injections of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by Chromogenic Substrate Assay Potency Per European Pharmacopeia (CS/EP) for 6 months and CS/ADJ for 6 months sequence according to randomization and up to 12 months (CS/EP) during extension

Participant Flow for 7 periods

Period 1: Part A Treatment Period

	Arm 1: Recombinant Factor VIII (BAY81-8973) Then Kogenate FS	Arm 2: Kogenate FS Then Recombinant Factor VIII (BAY81-8973)
STARTED	14	14
Participants Received Treatment	14	14
Safety Population	13 ^[1]	14
COMPLETED	14	14
NOT COMPLETED	0	0

^[1]	One excluded because receiving Kogenate FS twice.

Period 2: Part A Follow up Period

	Arm 1: Recombinant Factor VIII (BAY81-8973) Then Kogenate FS	Arm 2: Kogenate FS Then Recombinant Factor VIII (BAY81-8973)
STARTED	14	14
COMPLETED	14	14
NOT COMPLETED	0	0

Period 3: Part B Treatment Period

	Arm 3: Recombinant Factor VIII by CS/EP Then by CS/ADJ	Arm 4: Recombinant Factor VIII by CS/ADJ Then by CS/EP
STARTED	31 ^[1]	32 ^[2]
Participants Received Treatment	30	32
COMPLETED	29	32
NOT COMPLETED	2	0
Withdrawal by Subject	1	0
Protocol Violation	1	0

^[1]	Enrolled 4 participants from Arm 1 and 7 participants from Arm 2
^[2]	Enrolled 7 participants from Arm 1 and 4 participants from Arm 2

Period 4: Part B Follow up Period

	Arm 3: Recombinant Factor VIII by CS/EP Then by CS/ADJ	Arm 4: Recombinant Factor VIII by CS/ADJ Then by CS/EP
STARTED	29	32
COMPLETED	29	32
NOT COMPLETED	0	0

Period 5: Extension Period

	Arm 1: Recombinant Factor VIII (BAY81-8973) Then Kogenate FS	Arm 2: Kogenate FS Then Recombinant Factor VIII (BAY81-8973)	Arm 3: Recombinant Factor VIII by CS/EP Then by CS/ADJ	Arm 4: Recombinant Factor VIII by CS/ADJ Then by CS/EP	Arm 5: Recombinant Factor VIII by CS/EP	Arm 6: Recombinant Factor VIII (BAY81-8973) Part B + Extension
STARTED	0	0	0	0	0	55
COMPLETED	0	0	0	0	0	43
NOT COMPLETED	0	0	0	0	0	12
Adverse Event	0	0	0	0	0	1
starting another study	0	0	0	0	0	8
non-compliance	0	0	0	0	0	1
Withdrawal by Subject	0	0	0	0	0	1
Physician Decision	0	0	0	0	0	1

Period 6: Part C Treatment Period

	Arm 1: Recombinant Factor VIII (BAY81-8973) Then Kogenate FS	Arm 2: Kogenate FS Then Recombinant Factor VIII (BAY81-8973)	Arm 3: Recombinant Factor VIII by CS/EP Then by CS/ADJ	Arm 4: Recombinant Factor VIII by CS/ADJ Then by CS/EP	Arm 5: Recombinant Factor VIII by CS/EP	Arm 6: Recombinant Factor VIII (BAY81-8973) Part B + Extension
STARTED	0	0	0	0	5	0
Participants Received Treatment	0	0	0	0	5	0
COMPLETED	0	0	0	0	5	0
NOT COMPLETED	0	0	0	0	0	0

Period 7: Part C Follow up Period

	Arm 1: Recombinant Factor VIII (BAY81-8973) Then Kogenate FS	Arm 2: Kogenate FS Then Recombinant Factor VIII (BAY81-8973)	Arm 3: Recombinant Factor VIII by CS/EP Then by CS/ADJ	Arm 4: Recombinant Factor VIII by CS/ADJ Then by CS/EP	Arm 5: Recombinant Factor VIII by CS/EP	Arm 6: Recombinant Factor VIII (BAY81-8973) Part B + Extension
STARTED	0	0	0	0	5	0
COMPLETED	0	0	0	0	5	0
NOT COMPLETED	0	0	0	0	0	0

Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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Reporting Groups

	Description
Arm 1: Recombinant Factor VIII (BAY81-8973) Then Kogenate FS	Part A - Arm 1: Participants first received one single intravenous (IV) injection of BAY81-8973 50 IU/kg, then 1 single IV injection of Kogenate FS (BAY14-2222) 50 IU/kg with a wash-out period of at least 2-3 days in between
Arm 2: Kogenate FS Then Recombinant Factor VIII (BAY81-8973)	Part A - Arm 2: Participants first received one single intravenous (IV) injection of Kogenate FS (BAY14-2222) 50 IU/kg, then 1 single IV injection of BAY81-8973 50 IU/kg with a wash-out period of at least 2-3 days in between
Arm 3: Recombinant Factor VIII by CS/EP Then by CS/ADJ	Part B - Arm 3: Participants received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by Chromogenic Substrate Assay Potency Per European Pharmacopeia for 6 months and then crossed over to study drug measured by Chromogenic Substrate Assay/Adjusted to Label Potency for 6 months
Arm 4: Recombinant Factor VIII by CS/ADJ Then by CS/EP	Part B - Arm 4:. Participants received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by Chromogenic Substrate Assay/Adjusted to Label Potency for 6 months and then crossed over to study drug measured by Chromogenic Substrate Assay Per European Pharmacopeia for 6 months
Arm 5: Recombinant Factor VIII (BAY81-8973) by CS/EP - Part C	Participants received a loading dose of approximately 50 IU/kg of BAY81-8973 before the first surgical incision, followed by further treatment with BAY81-8973 according to surgical requirements for up to 3 weeks
Total	Total of all reporting groups

Baseline Measures

Arm 1: Recombinant Factor VIII (BAY81-8973) Then Kogenate FS

Arm 2: Kogenate FS Then Recombinant Factor VIII (BAY81-8973)

Arm 3: Recombinant Factor VIII by CS/EP Then by CS/ADJ

Arm 4: Recombinant Factor VIII by CS/ADJ Then by CS/EP

Arm 5: Recombinant Factor VIII (BAY81-8973) by CS/EP - Part C

Total

Overall Participants Analyzed
[Units: Participants]

Age, Customized ^{[1] [2] [3]}
[Units: Participants]

Part A < 18 years

NA ^[2]

NA ^[3]

Part A =/> 18 years

NA ^[2]

NA ^[3]

Part B < 18 years

NA ^[2]

NA ^[3]

Part B =/> 18 years

NA ^[2]

NA ^[3]

Part C < 18 years

NA ^[2]

NA ^[3]

Part C =/> 18 years

NA ^[2]

NA ^[3]

^[1]	Part A based on pharmacokinetic (PK) analysis set; Parts B and C based on safety analysis set
^[2]	Data is not available because participants did not participate in this phase.
^[3]	Total not calculated because data are not available (NA) in one or more arms.

Gender, Customized ^{[1] [2] [3]}
[Units: Participants]

Part A - Female

NA ^[2]

NA ^[3]

Part A - Male

NA ^[2]

NA ^[3]

Part B - Female

NA ^[2]

NA ^[3]

Part B - Male

NA ^[2]

NA ^[3]

Part C - Female

NA ^[2]

NA ^[3]

Part C - Male

NA ^[2]

NA ^[3]

^[1]	Part A based on PK analysis set; Parts B and C based on safety analysis set
^[2]	Data is not available because participants did not participate in this phase.
^[3]	Total not calculated because data are not available (NA) in one or more arms.

Most recent treatment before enrolment in the study ^{[1] [2] [3]}
[Units: Participants]

On-demand

NA ^[2]

NA ^[3]

Prophylaxis

NA ^[2]

NA ^[3]

^[1]	Parts A, B and C all based on safety analysis set
^[2]	Data is not available because participants did not participate in this phase.
^[3]	Total not calculated because data are not available (NA) in one or more arms.

Outcome Measures

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1. Primary:

Part A - Area Under the Drug Concentration-time Curve (AUC) [ Time Frame: Samples taken at pre-injection, and at 0.25, 0.5, 1, 3, 6, 8, 24, 30 and 48 hours post injection. AUC calculated from time of injection to infinity. ]

Show Outcome Measure 1

2. Primary:

Part A - Half-life (t 1/2) [ Time Frame: Samples taken at pre-injection, and at 0.25, 0.5, 1, 3, 6, 8, 24, 30 and 48 hours post injection. ]

Show Outcome Measure 2

3. Primary:

Part B - Annualized Number of Total Bleeds [ Time Frame: 12 months after randomization ]

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4. Secondary:

Part B - The in Vivo Recovery Values of Human Factor VIII (FVIII) [ Time Frame: 15-30 minutes after the injection ]

Show Outcome Measure 4

5. Secondary:

Part B - Annualized Number of Bleeds in Each 6-month Potency Assignment Period [ Time Frame: 6 months on each potency ]

Show Outcome Measure 5

6. Secondary:

Part B - Control of Bleeding as Measured by the Number of Injections Required to Treat a Bleed [ Time Frame: 6 months on each potency ]

Show Outcome Measure 6

7. Secondary:

Part B - Changes From Baseline at 12 Months in Quality of Life (QoL) as Measured by Transformed Total Score of Haemo-QoL Questionnaire [ Time Frame: Baseline and 12 months ]

Show Outcome Measure 7

8. Secondary:

Part B - Changes From Baseline at 12 Months in Utility Index as Measured by EQ–5D Questionaire [ Time Frame: Baseline and 12 months ]

Show Outcome Measure 8

9. Secondary:

Part A - Number of Participants With Inhibitory Antibody Formation [ Time Frame: Up to 6 weeks after first injection of study drug ]

Show Outcome Measure 9

10. Secondary:

Part B - Number of Participants With Incidence of Inhibitory Antibody Formation [ Time Frame: Up to 12 months after drug administration ]

Show Outcome Measure 10

11. Secondary:

Part C - Number of Participants With Incidence of Inhibitory Antibody Formation [ Time Frame: before and 3 weeks after surgery ]

Show Outcome Measure 11

12. Secondary:

Part A - Number of Participants With Incidence of Antibody Formation to Heat-shock Protein (HSP-70) [ Time Frame: Up to 6 weeks after drug administration ]

Show Outcome Measure 12

13. Secondary:

Part B - Number of Participants With Incidence of Antibody Formation to Heat-shock Protein (HSP-70) [ Time Frame: Up to 12 months after drug administration ]

Show Outcome Measure 13

14. Secondary:

Part C - Number of Participants With Incidence of Antibody Formation to Heat-shock Protein (HSP-70) [ Time Frame: before and 3 weeks after surgery ]

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15. Secondary:

Part A - Number of Participants With Incidence of Antibody Formation to Host Cell Proteins (HCP) [ Time Frame: Up to 4 weeks after drug administration ]

Show Outcome Measure 15

16. Secondary:

Part B - Number of Participants With Incidence of Antibody Formation to Host Cell Proteins (HCP) [ Time Frame: Up to 12 months after drug administration ]

Show Outcome Measure 16

17. Secondary:

Part C - Number of Participants With Incidence of Antibody Formation to Host Cell Proteins (HCP) [ Time Frame: before and 3 weeks after surgery ]

Show Outcome Measure 17

18. Secondary:

Part B - Number of Participants With Assessment of the Hemostasis During Major Surgery [ Time Frame: An average of 1 month after start of treatment ]

Show Outcome Measure 18

19. Secondary:

Part C - Number of Participants With Assessment of the Hemostasis During Major Surgery [ Time Frame: at the time of surgery ]

Show Outcome Measure 19

Serious Adverse Events

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Other Adverse Events

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Time Frame	From the date of signing informed consent through study completion, i.e. 21 Dec 2009 to 14 Mar 2013
Additional Description	The objective of Part C was efficacy assessment of surgery hemostasis, not safety assessment. It was allowed to include the same patient for several surgeries and for each surgery the patient was assigned a new patient number. Due to this approach, one patient with 3 surgeries was analyzed as 3 different patients, therefore the number at risk is 7.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Recombinant Factor VIII (BAY81-8973) - Part A	Participants received one single intravenous (IV) injection of BAY81-8973 50 IU/kg
Kogenate FS (BAY14-2222) - Part A	Participants received one single intravenous (IV) injection of Kogenate FS (BAY14-2222) 50 IU/kg
Recombinant Factor VIII (BAY81-8973) Part B and Extension	Participants received IV injections of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by Chromogenic Substrate Assay Potency Per European Pharmacopeia (CS/EP) for 6 months and CS/ADJ for 6 months sequence according to randomization and up to 12 months (CS/EP) during extension
Recombinant Factor VIII (BAY81-8973) by CS/EP - Part C	Participants in Part C received a loading dose of approximately 50 IU/kg of BAY81-8973 (nearest whole vial amount) for less than 15 minutes before the first surgical incision. Then they received further treatment with BAY81-8973 according to surgical requirements up to 3 weeks.

Other Adverse Events

	Recombinant Factor VIII (BAY81-8973) - Part A	Kogenate FS (BAY14-2222) - Part A	Recombinant Factor VIII (BAY81-8973) Part B and Extension	Recombinant Factor VIII (BAY81-8973) by CS/EP - Part C
Total, Other (not including serious) Adverse Events
# participants affected / at risk	0/27 (0.00%)	1/28 (3.57%)	43/62 (69.35%)	5/7 (71.43%)
Blood and lymphatic system disorders
Anaemia ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	0/62 (0.00%)	1/7 (14.29%)
Thymus disorder ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	0/62 (0.00%)	1/7 (14.29%)
Gastrointestinal disorders
Dental caries ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	4/62 (6.45%)	0/7 (0.00%)
Diarrhoea ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	4/62 (6.45%)	2/7 (28.57%)
Dyspepsia ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	1/62 (1.61%)	1/7 (14.29%)
Nausea ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	4/62 (6.45%)	1/7 (14.29%)
Vomiting ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	4/62 (6.45%)	0/7 (0.00%)
General disorders
Chest pain ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	4/62 (6.45%)	0/7 (0.00%)
Pyrexia ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	1/62 (1.61%)	2/7 (28.57%)
Infections and infestations
Influenza ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	6/62 (9.68%)	0/7 (0.00%)
Nasopharyngitis ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	14/62 (22.58%)	0/7 (0.00%)
Pharyngitis ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	5/62 (8.06%)	0/7 (0.00%)
Upper respiratory tract infection ^* 1
# participants affected / at risk	0/27 (0.00%)	1/28 (3.57%)	8/62 (12.90%)	0/7 (0.00%)
Device related infection ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	0/62 (0.00%)	1/7 (14.29%)
Musculoskeletal and connective tissue disorders
Arthralgia ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	6/62 (9.68%)	0/7 (0.00%)
Back pain ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	4/62 (6.45%)	0/7 (0.00%)
Renal and urinary disorders
Anuria ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	0/62 (0.00%)	1/7 (14.29%)
Respiratory, thoracic and mediastinal disorders
Cough ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	5/62 (8.06%)	0/7 (0.00%)
Pleural effusion ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	0/62 (0.00%)	1/7 (14.29%)
Pulmonary artery dilatation ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	0/62 (0.00%)	1/7 (14.29%)
Skin and subcutaneous tissue disorders
Dermatitis contact ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	0/62 (0.00%)	1/7 (14.29%)
Vascular disorders
Hypertension ^* 1
# participants affected / at risk	0/27 (0.00%)	0/28 (0.00%)	5/62 (8.06%)	0/7 (0.00%)

*	Events were collected by non-systematic assessment
1	Term from vocabulary, MedDRA (15.1)

Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.

Results Point of Contact:

Name/Title: Therapeutic Area Head
Organization: BAYER
e-mail: clinical-trial-contact@bayerhealthcare.com

Publications of Results:

Kitchen S, Katterle Y, Beckmann H, Maas Enriquez M. Chromogenic assay for BAY 81-8973 potency assignment has no impact on clinical outcome or monitoring in patient samples. J Thromb Haemost. 2016 Jun;14(6):1192-9. doi: 10.1111/jth.13322. Epub 2016 May 3.

Oldenburg J, Windyga J, Hampton K, Lalezari S, Tseneklidou-Stoeter D, Beckmann H, Maas Enriquez M. Safety and efficacy of BAY 81-8973 for surgery in previously treated patients with haemophilia A: results of the LEOPOLD clinical trial programme. Haemophilia. 2016 May;22(3):349-53. doi: 10.1111/hae.12839. Epub 2016 Mar 1.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Saxena K, Lalezari S, Oldenburg J, Tseneklidou-Stoeter D, Beckmann H, Yoon M, Maas Enriquez M. Efficacy and safety of BAY 81-8973, a full-length recombinant factor VIII: results from the LEOPOLD I trial. Haemophilia. 2016 Sep;22(5):706-12. doi: 10.1111/hae.12952. Epub 2016 Jun 24.

Responsible Party:	Bayer
ClinicalTrials.gov Identifier:	NCT01029340 History of Changes
Other Study ID Numbers:	12954 2009-012149-43 ( EudraCT Number )
Study First Received:	December 8, 2009
Results First Received:	May 27, 2013
Last Updated:	October 14, 2016

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