BAX 855 PK-guided Dosing

Hemophilia A Clinical Trial

— PROPEL  

Official title:

Phase 3, Prospective, Randomized, Multi-center Clinical Study Comparing the Safety and Efficacy of BAX 855 Following PK-guided Prophylaxis Targeting Two Different FVIII Trough Levels in Subjects With Severe Hemophilia A

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02585960
• Other study ID #: 261303
• Secondary ID: 2014-005477-37
• Status: Completed
• Phase: Phase 3
• Start date: November 23, 2015
• Est. completion date: August 5, 2018

Study information

• Verified date: May 2021
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

1. To compare the efficacy and safety of pharmacokinetic (PK)-guided treatment with BAX 855 targeting FVIII trough levels of 1-3% and approximately 10% (8-12%)

2. To further characterize pharmacokinetic (PK) and pharmacodynamic (PD) parameters of BAX 855

Recruitment information / eligibility

• Status: Completed
• Enrollment: 135
• Est. completion date: August 5, 2018
• Est. primary completion date: August 5, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 65 Years

Eligibility

INCLUSION CRITERIA:

• Participants transitioning from another BAX 855 study who meet ALL of the following criteria are eligible for this study:

1. Participant has completed the end of study visit of a BAX 855 study or is transitioning from the ongoing Baxalta Continuation Study 261302.

2. Participant is either receiving on-demand treatment or prophylactic treatment with BAX 855 and had an Annual Bleed Rate (ABR) of = 2 documented and treated during the past 12 months.

3. Participant is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ count = 200 cells/mm^3, as confirmed by central laboratory.

4. Participant is willing and able to comply with the requirements of the protocol.

• Newly recruited participants (ie not transitioning from another BAX 855 study) including BAX855 naïve participants who meet ALL of the following criteria are eligible for this study:

1. Participant has severe hemophilia A (FVIII clotting activity < 1%) as confirmed by central laboratory OR by historically documented FVIII clotting activity performed by a certified clinical laboratory, optionally supported by a FVIII gene mutation consistent with severe hemophilia A

2. Participant has been previously treated with plasma-derived FVIII concentrates or recombinant FVIII for = 150 documented exposure days (EDs)

3. Participant is either receiving on-demand treatment or prophylactic treatment and had an annual bleeding rate of = 2 documented and treated during the past 12 months.

4. Participant has a Karnofsky performance score of = 60 at screening

5. Participant is HIV-; or HIV+ with stable disease and CD4+ count = 200 cells/mm^3, as confirmed by central laboratory at screening

6. Participant is hepatitis C virus negative (HCV-) by antibody (if positive, additional PCR testing will be performed), as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis

7. If female of childbearing potential, participant presents with a negative urine pregnancy test and agrees to employ adequate birth control measures for the duration of the study

8. Participant is willing and able to comply with the requirements of the protocol.

EXCLUSION CRITERIA:

• Participants transitioning from another BAX 855 study who meet ANY of the following criteria are not eligible for this study:

1. Participant has developed a confirmed inhibitory antibody to FVIII with a titer of = 0.6 BU using the Nijmegen modification of the Bethesda assay as determined at the central laboratory during the course of the previous BAX 855 study.

2. Participant has been diagnosed with an acquired hemostatic defect other than hemophilia A.

3. The participant's weight is < 35 kg or > 100 kg.

4. Participant's platelet count is < 100,000/mL.

5. Participant has an abnormal renal function (serum creatinine > 1.5 times the upper limit of normal).

6. Participant has active hepatic disease with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels = 5 times the upper limit of normal.

7. Participant is scheduled to receive a systemic immunomodulating drug (e.g. corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day, or a-interferon) other than anti-retroviral chemotherapy during the study.

8. Participant has a clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect participant's safety or compliance.

9. Participant is planning to take part in any other clinical study during the course of the study.

10. Participant is a member of the team conducting this study or is in a dependent relationship with one of the study team members. Dependent relationships include close relatives (ie, children, partner/spouse, siblings, parents) as well as employees of the investigator or site personnel conducting the study.

Newly recruited participants (ie not transitioning from another BAX 855 study) who meet ANY of the following criteria are not eligible for this study:

1. Participant has detectable FVIII inhibitory antibodies (= 0.6 BU using the Nijmegen modification of the Bethesda assay) as confirmed by central laboratory at screening.

2. Participant has a history of confirmed FVIII inhibitors with a titer = 0.6 Bethesda Units (BU) (as determined by the Nijmegen modification of the Bethesda assay or the assay employed with the respective cut-off in the local laboratory) at any time prior to screening.

3. Participant has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (eg, qualitative platelet defect or von Willebrand's disease).

4. The participant's weight is < 35 kg or > 100 kg.

5. Participant's platelet count is < 100,000/mL.

6. Participant has known hypersensitivity towards mouse or hamster proteins, PEG or Tween 80.

7. Participant has severe chronic hepatic dysfunction [eg, = 5 times upper limit of normal alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), as confirmed by central laboratory at screening, or a documented INR > 1.5].

8. Participant has severe renal impairment (serum creatinine > 1.5 times the upper limit of normal).

9. Participant has current or recent (< 30 days) use of other pegylated drugs prior to study participation or is scheduled to use such drugs during study participation.

10. Participant is scheduled to receive during the course of the study, a systemic immunomodulating drug (e.g. corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day, or a-interferon) other than anti-retroviral chemotherapy.

11. Participant has participated in another clinical study involving an IP or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study.

12. Participant has a medical, psychiatric, or cognitive illness or recreational drug/alcohol use that, in the opinion of the investigator, would affect participant safety or compliance.

13. Participant is a member of the team conducting this study or is in a dependent relationship with one of the study team members. Dependent relationships include close relatives (ie, children, partner/spouse, siblings, parents) as well as employees of the investigator or site personnel conducting the study.

Related Conditions & MeSH terms

• Hemophilia A

Intervention

Biological:
• PEGylated Recombinant Factor VIII
Pharmacokinetic (PK) evaluation
• PEGylated Recombinant Factor VIII
Standard treatment
• PEGylated Recombinant Factor VIII
Intensified treatment

Locations

Country	Name	City	State
Australia	Royal Brisbane Women's Hospital	Herston	Queensland
Australia	The Perth Blood Institute	Nedlands	Western Australia
Austria	AKH - Medizinische Universität Wien	Vienna
Bulgaria	UMHAT "Sv. Georgi", EAD	Plovdiv
Bulgaria	UMHAT 'Tsaritsa Yoanna - ISUL', EAD	Sofia
Bulgaria	MHAT 'Sv. Marina', EAD, Clinic of Clinical Hematology	Varna
France	Hôpital Morvan	Brest Cedex	Finistere
France	CHU de Caen - Hôpital Côte de Nacre	Caen
France	CHU Nice- Service hematologie	Nice	Alpes Maritimes
France	CHU Rennes - Hopital Pontchaillou	Rennes cedex 09	Ille Et Vilaine
France	CHU Charles Nicolle	Rouen
Germany	Hamophiliezentrum/Gerinnungssprechstunde	Berlin
Germany	Inst. f. Experimentelle Hamatologie u. Transfusionsmedizin	Bonn	Nordrhein Westfalen
Germany	COAGULATION RESEARCH CENTRE GmbH	Duisburg	Nordrhein Westfalen
Germany	MVZ Labor Dr. Reising-Ackermann	Leipzig
Germany	HZRM Hamophilie Zentrum Rhein Main GmbH	Mörfelden-Walldorf	Hessen
Hong Kong	University of Hong Kong	Hong Kong
Hong Kong	Prince of Wales Hospital	Shatin
Hungary	Magyar Honvedseg EK	Budapest
Hungary	DE OEC Belgyógyászati Int	Debrecen
Hungary	PTE ÁOK	Pecs
Israel	Chaim Sheba Medical Center	Tel-Hashomer
Italy	UOC Ematologia, Azienda ULSS 8 Asolo, Regione Veneto	Castelfranco Veneto	Treviso
Italy	Presidio Osped. Ferrarotto	Catania
Italy	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milano
Italy	Fondazione Policlinico Universitario A. Gemelli	Roma
Italy	Umberto I Pol. di Roma-Università di Roma La Sapienza	Roma
Italy	AOU Citta della Salute e della Scienza - Presidio Molinette	Torino
Italy	ULSS n. 6 "Vicenza"	Vicenza
Malaysia	Hospital Ampang	Ampang	Kuala Lumpur
Malaysia	Hospital Queen Elizabeth	Kota Kinabalu	Sabah
Malaysia	Hospital Kuala Lumpur	Kuala Lumpur
Malaysia	Hospital Melaka	Melaka
Malaysia	Hospital Pulau Pinang	Pulau Pinang
Norway	Oslo Universitetssykehus HF	Oslo
Poland	Wojewodzki Szpital Specjalistyczny im. Mikolaja Kopernika, Klinika Hematologii	Lodz
Poland	Alvamed	Poznan
Poland	Instytut Hematologii Ii Transfuzjologii	Warszawa
Poland	SP Szpital Kliniczny Nr 1 we Wroclawiu	Wroclaw
Romania	Spitalul Clinic Judetean de Urgenta Brasov	Brasov
Romania	Institutul Oncologic ClNa.	Cluj Napoca
Singapore	KK Women's And Children's Hospital	Singapore
Singapore	National University Hospital	Singapore
Singapore	Singapore General Hospital- Parent	Singapore
Spain	Complejo Hospitalario Universitario A Coruña	A Coruña	La Coruña
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Regional Universitario de Malaga	Malaga	Málaga
Spain	Hospital Universitari Son Espases	Palma de Mallorca	Baleares
Sweden	Sahlgrenska Universitetssjukhuset	Gothenburg
Sweden	Karolinska Universitetssjukhuset	Stockholm
Switzerland	Universitätsspital Zürich	Zürich
Taiwan	China Medical University Hospital	Taichung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	Tri-Service General Hospital	Taipei
Turkey	Acibadem Hastanesi	Adana
Turkey	Akdeniz University	Antalya
Turkey	Istanbul University	Istanbul
Turkey	Ege University	Izmir
Ukraine	Kyiv CCH #9 Dept of Surgery City SPC of Diagnostics & Treatment of Patients with HP	Kyiv
Ukraine	NChSH Okhmatdyt of MoHU Center of Children Oncohematology and Bone Marrow Transplantation	Kyiv
Ukraine	SI Institute of Blood Pathology and Transfusion Medicine of NAMSU	Lviv
Ukraine	M.V. Sklifosovskyi Poltava RCH Dept of Gematology HSEIU Ukrainian Medical Stomatological Academy	Poltava
United Kingdom	Bristol Royal Hospital for Children	Bristol	Avon
United Kingdom	University Hospital of Wales	Cardiff	West Glamorgan
United Kingdom	Leicester Royal Infirmary	Leicester	Leicestershire
United Kingdom	Royal Free Hospital	London	Greater London
United Kingdom	Royal Manchester Children's Hospital	Manchester	Greater Manchester
United Kingdom	Churchill Hospital	Oxford	Oxfordshire
United Kingdom	Southampton General Hospital	Southampton	Hampshire
United States	Emory University-ECC	Atlanta	Georgia
United States	University of Colorado	Aurora	Colorado
United States	Boston Children's Hospital	Boston	Massachusetts
United States	University of Florida College of Medicine	Gainesville	Florida
United States	Gulf States Hemophilia Centre	Houston	Texas
United States	University of Kentucky Medical Center	Lexington	Kentucky
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	University of Louisville KCPCRU	Louisville	Kentucky
United States	Tulane University	New Orleans	Louisiana
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	University of Utah	Salt Lake City	Utah
United States	University of Washington	Seattle	Washington
United States	Arizona Hemophilia & Thrombosis Center, located within The University of Arizona Cancer Center	Tucson	Arizona

Sponsors (2)

Lead Sponsor	Collaborator
Baxalta now part of Shire	Baxalta Innovations GmbH, now part of Shire

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Bulgaria,  France,  Germany,  Hong Kong,  Hungary,  Israel,  Italy,  Malaysia,  Norway,  Poland,  Romania,  Singapore,  Spain,  Sweden,  Switzerland,  Taiwan,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With a Total Annualized Bleeding Rate (ABR) of Zero for Second Six Months	Annualized bleeding rate was determined by dividing the number of bleeds by observation period in years.	Day 183 to Day 364 (6 months)
Secondary	Total Annualized Bleeding Rate for Second Six Months	Annualized bleeding rate was determined by dividing the number of bleeds by observation period in years.	Day 183 to Day 364 (6 months)
Secondary	Annualized Spontaneous Bleeding Rate for Second Six Months	Annualized spontaneous bleeding rate was determined by dividing the number of spontaneous bleeds by observation period in years. A bleed was defined as spontaneous if it was not related to injury/trauma.	Day 183 to Day 364 (6 months)
Secondary	Annualized Traumatic Bleeding Rate for Second Six Months	Annualized traumatic bleeding rate was determined by dividing the number of traumatic bleeds by observation period in years. A bleed was defined as traumatic if it was related to injury/trauma.	Day 183 to Day 364 (6 months)
Secondary	Annualized Joint Bleeding Rate (AJBR) for Second Six Months	Annualized joint bleeding rate was determined by dividing the number of joint bleeds by observation period in years. An acute joint bleed include some or all of the following: 'aura', pain, swelling, warmth of the skin over the joint, decreased range of motion and difficulty in using the limb compared with baseline or loss of function.	Day 183 to Day 364 (6 months)
Secondary	Total Weight-adjusted Consumption of BAX 855	Total weight-adjusted consumption of BAX 855 were reported.	From start of study treatment up to 12 months (completion or termination)
Secondary	Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions	The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and possibly requires more than 1 infusion for complete resolution; Fair: Probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens.	8 hours after study drug administration
Secondary	Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution	The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and possibly requires more than 1 infusion for complete resolution; Fair: Probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens.	From start of study treatment up to bleed resolution (up to 12 months)
Secondary	Treatment of Bleeding Episodes: Number of BAX 855 Infusions Per Bleeding Episode Required Until Bleed Resolution	Infusions of BAX 855 that were required until bleed resolution were reported.	From start of study treatment up to 12 months (completion or termination)
Secondary	Change From Baseline in Hemophilia Joint Health Score (HJHS)- Total Score	HJHS was assessed based on the following components of the elbow, knee, and ankle joints: swelling, duration of swelling, muscle atrophy, crepitus on motion, flexion loss, extension loss, joint pain, and strength, together with an assessment of the global gait. The HJHS is a validated 11-item scoring tool based on radiologic and clinical evaluation, sensitive to detect early signs and minor changes. HJHS ranges from 0 to 124. Higher values in the HJHS represent worse situation for the participant.	Baseline, Month 12
Secondary	Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds	The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and possibly requires more than 1 infusion for complete resolution; Fair: Probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens. Hemostatic efficacy was evaluated intra-operatively (from start to end of the procedure), post-operatively (from the end of procedure up to 24 h post procedure), and perioperatively (from the start of procedure to participant discharge from hospital or 14 days after completion of procedure; whichever was first).	Day 0 through discharge or 14 days post-surgery
Secondary	Blood Loss Per Participant in Case of Surgery	The intraoperative blood loss was measured by determining the volume of blood and fluid removal through suction into the collection container (waste box and/or cell saver) and the estimated blood loss into swabs and towels during the procedure, per the anesthesiologist's record. Postoperatively, blood loss was determined by the drainage volume collected, which mainly consisted of drainage fluid via vacuum or gravity drain, as applicable. In cases where no drain was present, blood loss was determined by the surgeon's clinical judgment, as applicable or entered as "not available". Blood loss was evaluated intra-operatively (from start to end of the procedure), post-operatively (from the end of procedure up to 24 h post procedure), and perioperatively (from the start of procedure to participant discharge from hospital or 14 days after completion of procedure; whichever was first).	Day 0 through discharge or 14 days post-surgery
Secondary	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE was any unfavorable and unintended sign (an abnormal laboratory finding), symptom (rash, pain, discomfort, fever, dizziness, etc.), disease (peritonitis, bacteremia, etc.), or outcome of death temporally associated with the use of an investigational product (IP), whether or not considered causally related to the IP. A SAE was defined as an untoward medical occurrence that at any dose met one or more of the following criteria: outcome was fatal/results in death, life-threatening, required in-patient hospitalization or resulted in prolongation of an existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event that was not immediately life-threatening or resulted in death or required hospitalization but jeopardize the participant or required medical or surgical intervention to prevent any of the above outcomes.	From start of study treatment up to 12 months (completion or termination)
Secondary	Number of Participants With Clinically Significant Changes in Vital Signs Reported as Treatment Related Adverse Events	Vital signs included systolic and diastolic blood pressure, pulse rate, respiratory rate, body temperature.	From start of study treatment up to 12 months (completion or termination)
Secondary	Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters Reported as Treatment Related Adverse Events	Clinical laboratory assessments included clinical chemistry, hematology, lipid panel, genetics, T-cell, B-cell and NK cell (TBNK) and viral serology.	From start of study treatment up to 12 months (completion or termination)
Secondary	Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein	Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein were reported here.	From start of study treatment up to 12 months (completion or termination)
Secondary	Change From Baseline in Physical Component Scores (PCS) of the Short Form-36 (SF-36) Health Survey	Short Form (36) Health Survey (SF-36) is a 36-item validated, generic health related quality of life (HR QoL) instrument. PCS is a summary scale of the dimensions physical functioning, role physical, bodily pain, and general health. The component score is normalized to a standard population. Scores range from 0 to 100 with higher scores representing better health. There is no total overall score; scoring is done for both sub-scores and summary scores.	Baseline, Month 12 (completion or termination)
Secondary	Area Under the Plasma Concentration of BAX 855 From Zero to Infinity (AUC0-inf)	Area under the plasma concentration versus time curve from time 0 to infinity of BAX 855 were reported.	Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
Secondary	Incremental Recovery (IR) at Maximum Plasma Concentration (Cmax) of BAX 855	IR at Cmax of BAX 855 were reported.	Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
Secondary	Plasma Half-life (T1/2) of BAX 855	T1/2 of BAX 855 in plasma were reported.	Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
Secondary	Mean Residence Time (MRT) of BAX 855	MRT of BAX 855 were reported.	Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
Secondary	Maximum Plasma Concentration (Cmax) of BAX 855	Cmax of BAX 855 were reported.	Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
Secondary	Time to Maximum Concentration of BAX 855 in Plasma (Tmax)	Tmax of BAX 855 were reported.	Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
Secondary	Total Body Clearance (CL) of BAX 855	Total body clearance of BAX 855 from blood by the kidney were reported.	Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
Secondary	Volume of Distribution at Steady State (Vss)	Volume of distribution was defined as the theoretical volume in which the total amount of drug was uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steadystate.	Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
Secondary	Incremental Recovery (IR) Over Time	Incremental recovery was calculated by BAX 855 increment (IU/dL) / BAX 855 dose (IU/kg).	Baseline, Month 3, 6, 7.5, 9, 10.5, 12 (Completion or termination)