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Clinical Trial Results:
A Post Approval Commitment study to evaluate the efficacy, safety, and pharmacokinetics of KOVALTRY in Chinese children, adolescents/adults with severe hemophilia A.

Summary
EudraCT number	2021-003537-11
Trial protocol	Outside EU/EEA
Global end of trial date	15 Mar 2024

Results information
Results version number	v1(current)
This version publication date	22 Sep 2024
First version publication date	22 Sep 2024
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

BAY81-8973/19855

ISRCTN number

US NCT number

NCT04565236

WHO universal trial number (UTN)

Sponsor organisation name

Bayer AG

Sponsor organisation address

Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368

Public contact

Therapeutic Area Head, Bayer AG, +49 30 300139003, clinical-trials-contact@bayer.com

Scientific contact

Therapeutic Area Head, Bayer AG, +49 30 300139003, clinical-trials-contact@bayer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

15 Mar 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

15 Mar 2024

Was the trial ended prematurely?

Main objective of the trial

Part A: To evaluate the efficacy of prophylaxis treatment with KOVALTRY in Chinese children (<12 years) and adolescents/adults (≥12 years) with severe hemophilia A. Part B: To assess the efficacy of KOVALTRY within 48 hours of previous prophylaxis infusion in previously untreated/minimally treated Chinese children (<6 years of age) with severe hemophilia A.

Protection of trial subjects

The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects (or their legally authorized representative according to local legislation). Participating subjects (or their legally authorized representative according to local legislation) signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.

Background therapy

Evidence for comparator

Actual start date of recruitment

22 Sep 2020

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

China: 45

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The Part A of study was conducted in multicenter in China between 22 SEP 2020 and 04 JAN 2022. The Part B of study was conducted in multicenter in China between 07 SEP 2021 and 15 MAR 2024.

Screening details

A total of 44 subjects were enrolled in Part A of the study. Of these, 2 subjects did not pass screening and 42 subjects participated in Part A. A total of 3 participants were enrolled in Part B of the study, and all of them passed screening.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part A: PTPs <12 years

Arm description

Previously treated severe hemophilia A patients (PTPs) aged below 12 years received KOVALTRY prophylaxis and treatment.

Arm type

Experimental

Investigational medicinal product name

Recombinant Factor VIII (KOVALTRY, BAY81-8973)

Investigational medicinal product code

BAY81-8973

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

25 to 50 IU of KOVALTRY per kg body weight (rounded to the nearest vial size) twice weekly, three times weekly, or every other day according to individual requirements

Part A: PTPs ≥12 years

Arm description

Previously treated severe hemophilia A patients (PTPs) aged 12 to 65 years received KOVALTRY for prophylaxis and treatment.

Arm type

Experimental

Investigational medicinal product name

Recombinant Factor VIII (KOVALTRY, BAY81-8973)

Investigational medicinal product code

BAY81-8973

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

12 years: 25 to 50 IU of KOVALTRY per kg body weight (rounded to the nearest vial size) twice weekly, three times weekly, or every other day according to individual requirements; >12 years: 20 to 40 IU of KOVALTRY per kg of body weight (rounded to the nearest vial size) two or three times per week according to individual requirements

Part B: PUPs <6 years

Arm description

Previously untreated severe hemophilia A patients (PUPs) aged below 6 years of age received KOVALTRY for prophylaxis and treatment.

Arm type

Experimental

Investigational medicinal product name

Recombinant Factor VIII (KOVALTRY, BAY81-8973)

Investigational medicinal product code

BAY81-8973

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

15 to 50 IU (minimum 250 IU) of KOVALTRY per kg body weight (rounded to the nearest vial size) at least 1 day per week. Alternatively, prophylaxis could be started directly with a once-a-week schedule minimum dose of 250 IU for PUPs/MTPs of any weight.

Part B: MTPs <6 years

Arm description

Minimally treated severe hemophilia A patients (MTPs) aged below 6 years received KOVALTRY for prophylaxis and treatment.

Arm type

Experimental

Investigational medicinal product name

Recombinant Factor VIII (KOVALTRY, BAY81-8973)

Investigational medicinal product code

BAY81-8973

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Number of subjects in period 1	Part A: PTPs <12 years	Part A: PTPs ≥12 years	Part B: PUPs <6 years	Part B: MTPs <6 years
Started	30	12	2	1
Completed	30	12	1	1
Not completed	0	0	1	0
Patient/Guardian Decision	-	-	1	-

Baseline characteristics

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Reporting group title

Part A: PTPs <12 years

Reporting group description

Previously treated severe hemophilia A patients (PTPs) aged below 12 years received KOVALTRY prophylaxis and treatment.

Reporting group title

Part A: PTPs ≥12 years

Reporting group description

Previously treated severe hemophilia A patients (PTPs) aged 12 to 65 years received KOVALTRY for prophylaxis and treatment.

Reporting group title

Part B: PUPs <6 years

Reporting group description

Previously untreated severe hemophilia A patients (PUPs) aged below 6 years of age received KOVALTRY for prophylaxis and treatment.

Reporting group title

Part B: MTPs <6 years

Reporting group description

Minimally treated severe hemophilia A patients (MTPs) aged below 6 years received KOVALTRY for prophylaxis and treatment.

Reporting group values	Part A: PTPs <12 years	Part A: PTPs ≥12 years	Part B: PUPs <6 years	Part B: MTPs <6 years	Total
Number of subjects	30	12	2	1	45
Age categorical
Units: Subjects
Infants and toddlers (28 days-23 months)	0	0	1	0	1
Children (2-11 years)	30	0	1	1	32
Adolescents (12-17 years)	0	5	0	0	5
Adults (18-64 years)	0	7	0	0	7
Sex: Female, Male
Units: participants
Female	0	0	0	0	0
Male	30	12	2	1	45
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0
Asian	30	12	2	1	45
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	0	0	0	0	0
White	0	0	0	0	0
More than one race	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0

End points

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Reporting group title

Part A: PTPs <12 years

Reporting group description

Previously treated severe hemophilia A patients (PTPs) aged below 12 years received KOVALTRY prophylaxis and treatment.

Reporting group title

Part A: PTPs ≥12 years

Reporting group description

Previously treated severe hemophilia A patients (PTPs) aged 12 to 65 years received KOVALTRY for prophylaxis and treatment.

Reporting group title

Part B: PUPs <6 years

Reporting group description

Previously untreated severe hemophilia A patients (PUPs) aged below 6 years of age received KOVALTRY for prophylaxis and treatment.

Reporting group title

Part B: MTPs <6 years

Reporting group description

Minimally treated severe hemophilia A patients (MTPs) aged below 6 years received KOVALTRY for prophylaxis and treatment.

Subject analysis set title

Modified Intent-To-Treat (mITT) population

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All study subjects who had infusion/bleeding data from the electronic patient diary (EPD) and/or case report form (CRF).

Subject analysis set title

Safety analysis set (SAF)

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects enrolled into the study and received at least 1 dose of study drug.

Subject analysis set title

Pharmacokinetic analysis set (PKS)

Subject analysis set type

Sub-group analysis

Subject analysis set description

All subjects with evaluable PK data

Primary: Annualized bleeding rate (ABR) of all bleeding episodes during prophylaxis treatment in Part A

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End point title

Annualized bleeding rate (ABR) of all bleeding episodes during prophylaxis treatment in Part A ^[1] ^[2]

End point description

Annualized number (mean +/- standard deviation) of all bleeding episodes that occurred during the prophylaxis treatment period is reported for previously treated patients (PTPs). All bleeding episodes: sum of spontaneous bleeds and trauma bleeds exclude bleeding due to surgery.

End point type

Primary

End point timeframe

Up to 6 months

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the nature of this trial, only descriptive statistics were performed. Neither confirmatory nor exploratory inferential statistical analyses were pre-specified. Thus those analyses were not performed.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: "ABR of all bleeding episodes during prophylaxis treatment in Part B" is reported as a separate endpoint.

End point values	Part A: PTPs <12 years	Part A: PTPs ≥12 years
Number of subjects analysed	30 ^[3]	12 ^[4]
Units: Bleed per year
arithmetic mean (standard deviation)	3.38 ( 4.17 )	1.86 ( 2.54 )

Notes
[3] - mITT
[4] - mITT

No statistical analyses for this end point

Primary: Annualized bleeding rate (ABR) of all bleeding episodes within 48 hours of previous prophylaxis infusion in Part B

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End point title

Annualized bleeding rate (ABR) of all bleeding episodes within 48 hours of previous prophylaxis infusion in Part B ^[5] ^[6]

End point description

Annualized number (mean +/- standard deviation) of all bleeding episodes that occurred within 48 hours of previous prophylaxis infusion is reported for previously untreated/minimally treated patients (PUPs/MTPs). All bleeding episodes: sum of spontaneous bleeds and trauma bleeds exclude bleeding due to surgery.

End point type

Primary

End point timeframe

Up to 48 hours post-infusion during 6 months

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the nature of this trial, only descriptive statistics were performed. Neither confirmatory nor exploratory inferential statistical analyses were pre-specified. Thus those analyses were not performed.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: "ABR of all bleeding episodes within 48 hours of previous prophylaxis infusion in Part A" is reported as a separate endpoint.

End point values	Part B: PUPs <6 years	Part B: MTPs <6 years
Number of subjects analysed	2 ^[7]	1 ^[8]
Units: Bleed per year
arithmetic mean (standard deviation)	0.00 ( 0.00 )	0.00 ( 0.00 )

Notes
[7] - mITT
[8] - mITT

No statistical analyses for this end point

Secondary: Annualized bleeding rate (ABR) of all bleeding episodes within 48 hours of previous prophylaxis infusion in Part A

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End point title

Annualized bleeding rate (ABR) of all bleeding episodes within 48 hours of previous prophylaxis infusion in Part A ^[9]

End point description

Annualized number (mean +/- standard deviation) of all bleeding episodes that occurred within 48 hours of previous prophylaxis infusion is reported for previously treated patients (PTPs). All bleeding episodes: sum of spontaneous bleeds and trauma bleeds exclude bleeding due to surgery.

End point type

Secondary

End point timeframe

Up to 48 hours post-infusion during 6 months

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: "ABR of all bleeding episodes within 48 hours of previous prophylaxis infusion in Part B" is reported as a separate endpoint.

End point values	Part A: PTPs <12 years	Part A: PTPs ≥12 years
Number of subjects analysed	30 ^[10]	12 ^[11]
Units: Bleed per year
arithmetic mean (standard deviation)	2.26 ( 3.10 )	1.36 ( 2.19 )

Notes
[10] - mITT
[11] - mITT

No statistical analyses for this end point

Secondary: Annualized bleeding rate (ABR) of all bleeding episodes during prophylaxis treatment in Part B

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End point title

Annualized bleeding rate (ABR) of all bleeding episodes during prophylaxis treatment in Part B ^[12]

End point description

Annualized number (mean +/- standard deviation) of all bleeding episodes that occurred during the prophylaxis treatment period is reported for previously untreated/minimally treated patients (PUPs/MTPs). All bleeding episodes: sum of spontaneous bleeds and trauma bleeds exclude bleeding due to surgery.

End point type

Secondary

End point timeframe

Up to 51 exposure days

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: "ABR of all bleeding episodes during prophylaxis treatment in Part A" is reported as a separate endpoint.

End point values	Part B: PUPs <6 years	Part B: MTPs <6 years
Number of subjects analysed	2 ^[13]	1 ^[14]
Units: Bleed per year
arithmetic mean (standard deviation)	1.13 ( 1.60 )	2.05 ( 0 )

Notes
[13] - mITT
[14] - mITT

No statistical analyses for this end point

Secondary: Number of infusions per bleeding episode

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End point title

Number of infusions per bleeding episode

End point description

The mean value of number of infusions for the treatment of one bleed to achieve hemostasis is reported.

End point type

Secondary

End point timeframe

Part A: up to 6 months; Part B: up to 51 exposure days

End point values	Part A: PTPs <12 years	Part A: PTPs ≥12 years	Part B: PUPs <6 years	Part B: MTPs <6 years
Number of subjects analysed	17 ^[15]	5 ^[16]	1 ^[17]	1 ^[18]
Units: Infusion
arithmetic mean (standard deviation)	1.78 ( 2.28 )	1.45 ( 1.29 )	14.00 ( 0.00 )	1.00 ( 0.00 )

Notes
[15] - Subjects in mITT with any bleed
[16] - Subjects in mITT with any bleed
[17] - Subjects in mITT with any bleed
[18] - Subjects in mITT with any bleed

No statistical analyses for this end point

Secondary: Number of bleeds per physician’s assessment of adequacy of hemostasis in minor surgery

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End point title

Number of bleeds per physician’s assessment of adequacy of hemostasis in minor surgery

End point description

For subjects who underwent minor surgeries during the study, investigators were ask to assess the adequacy of hemostasis during the surgeries as excellent, good, moderate or poor. Number of surgeries per assessment is reported.

End point type

Secondary

End point timeframe

Part A: up to 6 months; Part B: up to 51 exposure days

End point values	Part A: PTPs <12 years	Part A: PTPs ≥12 years	Part B: PUPs <6 years	Part B: MTPs <6 years
Number of subjects analysed	2 ^[19]	1 ^[20]	0 ^[21]	0 ^[22]
Units: Surgery
number (not applicable)
Total minor surgeries	2	2
Surgeries with EXCELLENT adequacy of hemostasis	2	2

Notes
[19] - Subjects in mITT with minor surgeries
[20] - Subject in mITT with minor surgeries
[21] - No subject with minor surgery
[22] - No subject with minor surgery

No statistical analyses for this end point

Secondary: FVIII in-vivo recovery in Part A

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End point title

FVIII in-vivo recovery in Part A ^[23]

End point description

End point type

Secondary

End point timeframe

At baseline, Month 2 and final visit

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: "FVIII in-vivo recovery in Part B" is reported as a separate endpoint.

End point values	Part A: PTPs <12 years	Part A: PTPs ≥12 years
Number of subjects analysed	30 ^[24]	12 ^[25]
Units: IU/dL per IU/kg
arithmetic mean (standard deviation)
Baseline	1.82 ( 0.26 )	2.03 ( 0.46 )
Month 2	1.86 ( 0.32 )	2.12 ( 0.42 )
Final visit	1.85 ( 0.33 )	2.06 ( 0.37 )

Notes
[24] - mITT, n=28 at baseline, =30 at Month 2 and final visit
[25] - mITT

No statistical analyses for this end point

Secondary: FVIII in-vivo recovery in Part B

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End point title

FVIII in-vivo recovery in Part B ^[26]

End point description

Incremental recovery of Factor VIII (FVIII) was determined by collecting blood samples pre-infusion and 15-30 minutes after the end of the infusion. Mean recovery values at different time points are reported. "99999" denotes that value could not be calculated because value of FVIII was not measured or because of missing values.

End point type

Secondary

End point timeframe

At baseline, Visit 6 (ED 20), unscheduled visit and final visit

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: "FVIII in-vivo recovery in Part A" is reported as a separate endpoint.

End point values	Part B: PUPs <6 years	Part B: MTPs <6 years
Number of subjects analysed	1 ^[27]	1 ^[28]
Units: IU/dL per IU/kg
arithmetic mean (standard deviation)
Baseline (Unscheduled visit for PUP)	1.90 ( 0.00 )	1.86 ( 0.00 )
Visit 6 (ED 20)	0.91 ( 0.00 )	1.22 ( 0.00 )
Final visit	1.55 ( 0.00 )	99999 ( 99999 )

Notes
[27] - Subject in mITT with calculable recovery value at any time points
[28] - mITT

No statistical analyses for this end point

Secondary: Factor VIII inhibitor development by the Nijmegen Bethesda assay

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End point title

Factor VIII inhibitor development by the Nijmegen Bethesda assay

End point description

Number of subjects who developed a positive Factor VIII (FVIII) inhibitor level (≥0.6 Bethesda unit [BU/mL]) during the study is reported.

End point type

Secondary

End point timeframe

Part A: up to 6 months; Part B: up to 51 exposure days

End point values	Part A: PTPs <12 years	Part A: PTPs ≥12 years	Part B: PUPs <6 years	Part B: MTPs <6 years
Number of subjects analysed	30 ^[29]	12 ^[30]	2 ^[31]	1 ^[32]
Units: Subject	0	0	0	0

Notes
[29] - SAF
[30] - SAF
[31] - SAF
[32] - SAF

No statistical analyses for this end point

Secondary: Number of participants with treatment-emergent adverse events

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End point title

Number of participants with treatment-emergent adverse events

End point description

An adverse event (AE) was any untoward medical occurrence in a subject, associated with the use of study intervention, whether or not considered related to the study intervention. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly/birth defect; another medical important serious event as judged by the investigator. AEs or SAEs were considered to be treatment emergent (TEAEs or TESAEs) if they started after the first KOVALTRY infusion and up to 3 days after the last dose.

End point type

Secondary

End point timeframe

Part A: up to 6 months; Part B: up to 51 exposure days

End point values	Part A: PTPs <12 years	Part A: PTPs ≥12 years	Part B: PUPs <6 years	Part B: MTPs <6 years
Number of subjects analysed	30 ^[33]	12 ^[34]	2 ^[35]	1 ^[36]
Units: Subject
Any TEAE	13	3	1	1
Maximum intensity for any TEAE - Mild	10	3	1	1
Maximum intensity for any TEAE - Moderate	2	0	0	0
Maximum intensity for any TEAE - Severe	1	0	0	0
Any study drug-related TEAE	1	0	0	0
Any TESAE	2	0	0	0
TEAE with outcome death	0	0	0	0

Notes
[33] - SAF
[34] - SAF
[35] - SAF
[36] - SAF

No statistical analyses for this end point

Secondary: Maximum observed concentration of FVIII in plasma (Cmax) in Part A

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End point title

Maximum observed concentration of FVIII in plasma (Cmax) in Part A ^[37]

End point description

For the assessment, subjects were administered a dose of 50 IU/kg KOVALTRY. Subjects must have no signs or symptoms of an acute bleeding episode. For subjects below 12 years, the evaluation was only performed once at baseline. For adolescents/adult participants 12 years or older, the evaluation was performed twice at baseline and at final visit. "99999" denotes that value was not calculated as no evaluation was performed.

End point type

Secondary

End point timeframe

Pre-infusion and up to 30 minutes post-infusion

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: PK analysis was only planned for Part A.

End point values	Part A: PTPs <12 years	Part A: PTPs ≥12 years
Number of subjects analysed	12 ^[38]	12 ^[39]
Units: IU/dL
geometric mean (geometric coefficient of variation)
Baseline	95.20 ( 15.24 )	114.64 ( 15.77 )
Final Visit/ Early Termination	99999 ( 99999 )	115.95 ( 17.47 )

Notes
[38] - PKS
[39] - PKS

No statistical analyses for this end point

Secondary: Area under the plasma concentration of FVIII versus time curve from zero to infinity (AUC) in Part A

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End point title

Area under the plasma concentration of FVIII versus time curve from zero to infinity (AUC) in Part A ^[40]

End point description

End point type

Secondary

End point timeframe

Pre-infusion and up to 24 hours post-infusion in subjects < 12 years or up to 48 hours post-infusion in subjects ≥ 12 years

Notes
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: PK analysis was only planned for Part A.

End point values	Part A: PTPs <12 years	Part A: PTPs ≥12 years
Number of subjects analysed	12 ^[41]	12 ^[42]
Units: h*IU/dL
geometric mean (geometric coefficient of variation)
Baseline	1292.97 ( 22.87 )	1519.38 ( 32.38 )
Final Visit/ Early Termination	99999 ( 99999 )	1559.29 ( 26.16 )

Notes
[41] - PKS
[42] - PKS

No statistical analyses for this end point

Secondary: Half-life (t1/2) of FVIII in plasma in Part A

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End point title

Half-life (t1/2) of FVIII in plasma in Part A ^[43]

End point description

End point type

Secondary

End point timeframe

Pre-infusion and up to 24 hours post-infusion in subjects < 12 years or up to 48 hours post-infusion in subjects ≥ 12 years

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: PK analysis was only planned for Part A.

End point values	Part A: PTPs <12 years	Part A: PTPs ≥12 years
Number of subjects analysed	12 ^[44]	12 ^[45]
Units: Hour
geometric mean (geometric coefficient of variation)
Baseline	10.3655 ( 21.22 )	11.8605 ( 19.25 )
Final Visit/ Early Termination	99999 ( 99999 )	11.2630 ( 17.29 )

Notes
[44] - PKS
[45] - PKS

No statistical analyses for this end point

Other pre-specified: Number of subjects without bleeding episode

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End point title

Number of subjects without bleeding episode

End point description

Number of subjects who did not experience any bleed during the prophylaxis treatment period or within 48 hours of previous prophylaxis infusion is reported.

End point type

Other pre-specified

End point timeframe

Part A: up to 6 months; Part B: up to 51 exposure days

End point values	Part A: PTPs <12 years	Part A: PTPs ≥12 years	Part B: PUPs <6 years	Part B: MTPs <6 years
Number of subjects analysed	30 ^[46]	12 ^[47]	2 ^[48]	1 ^[49]
Units: Subject
During prophylaxis treatment	13	7	1	0
Within 48 hours	16	8	2	1

Notes
[46] - mITT
[47] - mITT
[48] - mITT
[49] - mITT

No statistical analyses for this end point

Other pre-specified: Number of bleeds per assessment of response to treatment of bleeds

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End point title

Number of bleeds per assessment of response to treatment of bleeds

End point description

Subjects or caregivers were asked to assess the response to treatment of bleeds as excellent, good, moderate or poor. Number of bleeds per assessment is reported.

End point type

Other pre-specified

End point timeframe

Part A: up to 6 months; Part B: up to 51 exposure days

End point values	Part A: PTPs <12 years	Part A: PTPs ≥12 years	Part B: PUPs <6 years	Part B: MTPs <6 years
Number of subjects analysed	30 ^[50]	12 ^[51]	2 ^[52]	1 ^[53]
Units: Bleed
Total bleeds	51	11	1	1
Bleeds without response assessment to treatment	7	1	0	0
Bleeds with EXCELLENT response to treatment	4	5	0	0
Bleeds with GOOD response to treatment	25	2	0	1
Bleeds with MODERATE response to treatment	14	3	1	0
Bleeds with POOR response to treatment	1	0	0	0

Notes
[50] - mITT
[51] - mITT
[52] - mITT
[53] - mITT

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the first infusion and not later than three days after the last infusion in Part A or Part B. Adverse event reporting for the deaths (all causes) considers all deaths that occurred at any time during the study before the last contact.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

26.1

Reporting group title

Part A: PTPs <12 years

Reporting group description

Previously treated severe hemophilia A patients (PTPs) aged below 12 years received KOVALTRY prophylaxis and treatment

Reporting group title

Part A: PTPs >=12 years

Reporting group description

Previously treated severe hemophilia A patients (PTPs) aged 12 to 65 years received KOVALTRY for prophylaxis and treatment

Reporting group title

Part B: PUPs <6 years

Reporting group description

Previously untreated severe hemophilia A patients (PUPs) aged below 6 years of age received KOVALTRY for prophylaxis

Reporting group title

Part B: MTPs <6 years

Reporting group description

Minimally treated severe hemophilia A patients (MTPs) aged below 6 years received KOVALTRY for prophylaxis

Serious adverse events	Part A: PTPs <12 years	Part A: PTPs >=12 years	Part B: PUPs <6 years	Part B: MTPs <6 years
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 30 (6.67%)	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Nervous system disorders
Epilepsy
alternative assessment type: Systematic
subjects affected / exposed	1 / 30 (3.33%)	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Haemarthrosis
alternative assessment type: Systematic
subjects affected / exposed	1 / 30 (3.33%)	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Part A: PTPs <12 years	Part A: PTPs >=12 years	Part B: PUPs <6 years	Part B: MTPs <6 years
Total subjects affected by non serious adverse events
subjects affected / exposed	8 / 30 (26.67%)	3 / 12 (25.00%)	1 / 2 (50.00%)	1 / 1 (100.00%)
Vascular disorders
Hypertension
alternative assessment type: Systematic
subjects affected / exposed	0 / 30 (0.00%)	1 / 12 (8.33%)	0 / 2 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0
Gastrointestinal disorders
Diarrhoea
alternative assessment type: Systematic
subjects affected / exposed	0 / 30 (0.00%)	0 / 12 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0
Duodenal ulcer
alternative assessment type: Systematic
subjects affected / exposed	0 / 30 (0.00%)	1 / 12 (8.33%)	0 / 2 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Cough
alternative assessment type: Systematic
subjects affected / exposed	0 / 30 (0.00%)	0 / 12 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0
Rhinorrhoea
alternative assessment type: Systematic
subjects affected / exposed	0 / 30 (0.00%)	0 / 12 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0
Infections and infestations
Tonsillitis
alternative assessment type: Systematic
subjects affected / exposed	4 / 30 (13.33%)	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)
occurrences all number	4	0	0	0
Upper respiratory tract infection
alternative assessment type: Systematic
subjects affected / exposed	5 / 30 (16.67%)	1 / 12 (8.33%)	0 / 2 (0.00%)	0 / 1 (0.00%)
occurrences all number	10	1	0	0
Respiratory tract infection
alternative assessment type: Systematic
subjects affected / exposed	0 / 30 (0.00%)	0 / 12 (0.00%)	0 / 2 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	1
COVID-19
alternative assessment type: Systematic
subjects affected / exposed	0 / 30 (0.00%)	0 / 12 (0.00%)	0 / 2 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	1

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Were there any global substantial amendments to the protocol? Yes

22 Oct 2020

Amendment 1 specified the following modifications: - Addition of previously untreated patients (PUPs) and minimally treated patients (MTPs) to the study such that the study had 2 parts (Part A for previously treated patients and Part B for PUPs/MTPs) to fulfill post approval commitment received from the China Center for Drug Evaluation (CDE) and China National Medical Products Administration (NMPA). - Addition of a new section to describe optional immune tolerance induction (ITI) therapy to provide management options to participants who developed high titer FVIII inhibitor. - Change in the CRF location of documentation of AEs from Medical History section to AE Report Form to correct reporting process for AEs.

12 May 2023

Amendment 2 specified the following modifications, but no subject had been enrolled under this protocol amendment: - Changed all the assays planned in central lab to local lab for Part B. - Removed the Combined Screening and Baseline (PUPs only) in Part B. - Removed FVIII trough level assessment from Visit 2 in Part B. - The chromogenic assay was changed to one-stage clotting assay in all plasma concentrations of FVIII measurement for Part B.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Occurrence of "±” in relation with coefficient of variation is auto-generated by the database. Results of ABR of treated/target joint bleeding episodes and FVIII usage are not reported as they are other pre-defined endpoints per protocol.

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Clinical trials

Clinical Trial Results: A Post Approval Commitment study to evaluate the efficacy, safety, and pharmacokinetics of KOVALTRY in Chinese children, adolescents/adults with severe hemophilia A.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Annualized bleeding rate (ABR) of all bleeding episodes during prophylaxis treatment in Part A

Primary: Annualized bleeding rate (ABR) of all bleeding episodes during prophylaxis treatment in Part A

Primary: Annualized bleeding rate (ABR) of all bleeding episodes within 48 hours of previous prophylaxis infusion in Part B

Primary: Annualized bleeding rate (ABR) of all bleeding episodes within 48 hours of previous prophylaxis infusion in Part B

Secondary: Annualized bleeding rate (ABR) of all bleeding episodes within 48 hours of previous prophylaxis infusion in Part A

Secondary: Annualized bleeding rate (ABR) of all bleeding episodes within 48 hours of previous prophylaxis infusion in Part A

Secondary: Annualized bleeding rate (ABR) of all bleeding episodes during prophylaxis treatment in Part B

Secondary: Annualized bleeding rate (ABR) of all bleeding episodes during prophylaxis treatment in Part B

Secondary: Number of infusions per bleeding episode

Secondary: Number of infusions per bleeding episode

Secondary: Number of bleeds per physician’s assessment of adequacy of hemostasis in minor surgery

Secondary: Number of bleeds per physician’s assessment of adequacy of hemostasis in minor surgery

Secondary: FVIII in-vivo recovery in Part A

Secondary: FVIII in-vivo recovery in Part A

Secondary: FVIII in-vivo recovery in Part B

Secondary: FVIII in-vivo recovery in Part B

Secondary: Factor VIII inhibitor development by the Nijmegen Bethesda assay

Secondary: Factor VIII inhibitor development by the Nijmegen Bethesda assay

Secondary: Number of participants with treatment-emergent adverse events

Secondary: Number of participants with treatment-emergent adverse events

Secondary: Maximum observed concentration of FVIII in plasma (Cmax) in Part A

Secondary: Maximum observed concentration of FVIII in plasma (Cmax) in Part A

Secondary: Area under the plasma concentration of FVIII versus time curve from zero to infinity (AUC) in Part A

Secondary: Area under the plasma concentration of FVIII versus time curve from zero to infinity (AUC) in Part A

Secondary: Half-life (t1/2) of FVIII in plasma in Part A

Secondary: Half-life (t1/2) of FVIII in plasma in Part A

Other pre-specified: Number of subjects without bleeding episode

Other pre-specified: Number of subjects without bleeding episode

Other pre-specified: Number of bleeds per assessment of response to treatment of bleeds

Other pre-specified: Number of bleeds per assessment of response to treatment of bleeds

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Post Approval Commitment study to evaluate the efficacy, safety, and pharmacokinetics of KOVALTRY in Chinese children, adolescents/adults with severe hemophilia A.