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NCT00243386

Prophylaxis Study of Recombinant Factor VIII Manufactured Protein-Free (rAHF-PFM) in Patients With Hemophilia A

Completed Phase 4 Results posted Last updated 19 May 2021
What this trial tests

Phase 4 trial testing Antihemophilic factor, recombinant, manufactured protein-free in Hemophilia A in 82 participants. Completed in 16 June 2010.

Timeline
4 January 2006
Primary endpoint
16 June 2010
16 June 2010

Quick facts

Lead sponsorBaxalta now part of Shire
PhasePhase 4
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment82
Start date4 January 2006
Primary completion16 June 2010
Estimated completion16 June 2010
Sites29 locations across Italy, Russia, Greece, Austria, United Kingdom, Hungary, Poland, Slovenia

Drugs / interventions tested

Conditions studied

Sponsor

Baxalta now part of Shire — full company profile →

Who can join

Adults 7 to 65, any sex, with Hemophilia A. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Mean Transformed Annualized Bleed Rate Estimates From Each of the 1-year Prophylaxis Regimens Primary · 12 months ±2 weeks

Participants were Randomized to Receive 1 of the 2 Following Prophylaxis Regimens (Study Part 2): 1. Standard prophylaxis (20-40 IU/kg (every 48 ±6 hour), exact regimen determined by investigator) 2. PK-driven prophylaxis (20-80 IU/kg (every 72 ±6 hour), exact regimen determined by sponsor) Annualized bleed rates were transformed using the square root of the number of bleeding episodes observed (X = bleeds/year), X' = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using the t-test.

GroupValue95% CI
PK-Driven Prophylaxis1.61± 1.10
Standard Prophylaxis1.46± 0.98
Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and Standard Prophylaxis Treatment Regimens Secondary · On-demand 6 months (± 2 weeks); followed by Prophylaxis 12 months (± 2 weeks)

Annualized bleed rates were transformed using the square root of the number of bleeding episodes observed (X bleeds/year), X' = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using the paired t-test. Mean Difference of Transformed Annualized Bleeding Rate (TABR) = (On-Demand Treatment TABR) - (Standard Prophylaxis Treatment TABR). Participants from the On-Demand portion of the study were subsequently randomized to either Standard Prophylaxis or PK-Driven Prophylaxis, (i.e the same participan

GroupValue95% CI
On-Demand Versus Standard Prophylaxis5.29± 1.46
Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and PK-Driven Prophylaxis Treatment Regimens Secondary · On-demand 6 months (± 2 weeks); followed by Prophylaxis 12 months (± 2 weeks)

Annualized bleed rates were transformed using the square root of the number of bleeding episodes observed (X bleeds/year), X' = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using the paired t-test. Mean Difference of Transformed Annualized Bleeding Rate (TABR) = (On-Demand Treatment TABR) - (PK-Driven Prophylaxis Treatment TABR) Participants from the On-Demand portion of the study were subsequently randomized to either Standard Prophylaxis or PK-Driven Prophylaxis, (i.e the same participan

GroupValue95% CI
On-Demand Versus PK-Driven Prophylaxis5.00± 1.85
Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and Any Prophylaxis Treatment Regimens Secondary · On-demand 6 months (± 2 weeks); Prophylaxis 12 months (± 2 weeks)

Annualized bleed rates were transformed using the square root of the number of bleeding episodes observed (X bleeds/year), X' = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using the paired t-test. Mean Difference of Transformed Annualized Bleeding Rate (TABR) = (On-Demand Treatment TABR) - (Any Prophylaxis Treatment TABR). Any Prophylaxis = Standard or PK-Driven Prophylaxis Participants from the On-Demand portion of the study were subsequently randomized to either Standard Prophylaxis or

GroupValue95% CI
On-Demand Versus Any Prophylaxis5.14± 1.66
Total Weight-Adjusted Dose of rAHF-PFM Used Per Year for Each Prophylaxis Arm Secondary · 12 months ±2 weeks

Participants were Randomized to Receive 1 of the 2 Following Prophylaxis Regimens (Part 2 of the study): 1. Standard prophylaxis- infusions every 48 ±6 hours, dosed at 20 to 40 IU/kg. 2. PK-driven prophylaxis- infusions every 72 ±6 hours dosed at 20 to 80 IU/kg.

GroupValue95% CI
PK-Driven Prophylaxis5197.83268.4 – 8273.5
Standard Prophylaxis5768.24728.0 – 6425.4
Bleeding Episodes Treated With 1 to ≥4 Infusions Secondary · Throughout the study period (4 years and 5 months)

The number of bleeding episodes treated with 1, 2, 3, or ≥4 infusions of rAHF-PFM to achieve adequate hemostasis

1 infusion (n = 62, 13, 22)
GroupValue95% CI
On-Demand Treatment1168
Standard Prophylaxis Treatment68
PK-Driven Prophylaxis90
2 infusions (n = 51, 6, 9)
GroupValue95% CI
On-Demand Treatment277
Standard Prophylaxis Treatment12
PK-Driven Prophylaxis37
3 infusions (n = 27, 2, 4)
GroupValue95% CI
On-Demand Treatment128
Standard Prophylaxis Treatment4
PK-Driven Prophylaxis5
4 or more infusions (n = 21, 5, 5)
GroupValue95% CI
On-Demand Treatment50
Standard Prophylaxis Treatment9
PK-Driven Prophylaxis7
Assessment of Hemostasis for Treatment of Bleeding Episodes Secondary · On-demand 6 months (± 2 weeks); Prophylaxis 12 months (± 2 weeks)

Number of rAHF-PFM-treated bleeding episodes with an assessment of hemostasis (4-point ordinal scale): Excellent: Full pain relief \& bleeding cessation within \~8 hrs of 1 infusion. Additional infusions may have been given to maintain hemostasis; Good: Definite pain relief and/or improvement in bleeding within \~8 hrs after infusion. Possibly requires \>1 infusion for complete resolution; Fair: Probable or slight relief of pain \& slight improvement in bleeding within \~8 hrs after infusion. Requires \>1 infusion for complete resolution; None: No improvement or condition worsens

Excellent
GroupValue95% CI
On-Demand Regimen547
Standard Prophylaxis39
PK-Driven Prophylaxis33
Good
GroupValue95% CI
On-Demand Regimen943
Standard Prophylaxis38
PK-Driven Prophylaxis75
Fair
GroupValue95% CI
On-Demand Regimen167
Standard Prophylaxis16
PK-Driven Prophylaxis11
None
GroupValue95% CI
On-Demand Regimen3
Standard Prophylaxis0
PK-Driven Prophylaxis20
Unknown
GroupValue95% CI
On-Demand Regimen13
Standard Prophylaxis0
PK-Driven Prophylaxis0
Total Area Under the Curve (AUC) Secondary · Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion

Total AUC estimated by AUC 0-48h plus an area extrapolated from the log-linear regression model

GroupValue95% CI
≥14 Years of Age1334.45± 454.33
<14 Years of Age1061.26± 452.87
Area Under the Curve Secondary · Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion

Area under the factor VIII (FVIII) plasma concentration versus time curve (AUC) from 0 to 48 hours estimated using the linear trapezoidal method

GroupValue95% CI
≥14 Years of Age1213.98± 323.96
<14 Years of Age966.68± 330.83
Maximum Plasma Concentration (C-max) Secondary · Within 1 hour post-infusion

Maximal Factor VIII Concentration After Infusion

GroupValue95% CI
≥14 Years of Age91.12± 20.15
<14 Years of Age74.47± 11.30
Adjusted Incremental Recovery (IR) Secondary · 30 minutes pre-infusion to 48 hours post-infusion

Change in factor VIII concentration from pre- to post-infusion at initial and termination study visits. Adjusted IR defined as: \[Cmax (IU/dL) - pre-infusion FVIII (IU/dL)\]/dose (IU/kg)

GroupValue95% CI
≥14 Years of Age1.81± 0.41
<14 Years of Age1.47± 0.27
Terminal Half-life Secondary · Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion

Computed from the regression slope in the terminal phase of the model. Terminal half life is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%.

GroupValue95% CI
≥14 Years of Age13.91± 5.07
<14 Years of Age14.66± 5.21

Adverse events — posted to ClinicalTrials.gov

Time frame: Throughout the study period (4 years and 5 months). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

On-Demand
Serious: 7/73 (10%)
Deaths:
Standard Prophylaxis
Serious: 2/32 (6%)
Deaths:
PK-Driven Prophylaxis
Serious: 3/34 (9%)
Deaths:
SAEs Outside of the 3 Treatment Arms
Serious: 1/1 (100%)
Deaths:

Serious adverse events (13 terms)

ReactionSystemOn-DemandStandard ProphylaxisPK-Driven ProphylaxisSAEs Outside of the 3 Trea…
ABDOMINAL PAINGastrointestinal disorders
NAUSEAGastrointestinal disorders
TOOTH ABSCESSInfections and infestations
JOINT DISLOCATIONInjury, poisoning and procedural complications
HAEMOPHILIC ARTHROPATHYMusculoskeletal and connective tissue disorders
SYNOVITISMusculoskeletal and connective tissue disorders
CALCULUS URINARYRenal and urinary disorders
HOSPITALIZATIONSurgical and medical procedures
PULPITIS DENTALInfections and infestations
SOMNAMBULISMPsychiatric disorders
FACTOR VIII INHIBITIONBlood and lymphatic system disorders
APPENDICITISInfections and infestations
PAIN IN EXTREMITYMusculoskeletal and connective tissue disorders
Other adverse events (7 terms — click to expand)

ReactionSystemOn-DemandStandard ProphylaxisPK-Driven ProphylaxisSAEs Outside of the 3 Trea…
NASOPHARYNGITISInfections and infestations
DIARRHOEAGastrointestinal disorders
UPPER RESPIRATORY TRACT INFECTIONInfections and infestations
HEADACHENervous system disorders
IRRITABLE BOWEL SYNDROMEGastrointestinal disorders
ARTHRALGIAMusculoskeletal and connective tissue disorders
COUGHRespiratory, thoracic and mediastinal disorders

Most-reported serious reactions: ABDOMINAL PAIN, NAUSEA, TOOTH ABSCESS, JOINT DISLOCATION, HAEMOPHILIC ARTHROPATHY, SYNOVITIS, CALCULUS URINARY, HOSPITALIZATION.

Data from ClinicalTrials.gov NCT00243386 adverse events section.

Sponsor's own description

The primary purpose of this randomized, two-arm parallel clinical study in 66 previously treated patients with severe or moderately severe hemophilia A is to compare the rate of bleeding episodes for standard prophylaxis (20-40 IU/kg every 48 ± 6 hours; actual dose determined by the investigator) with that of alternate prophylaxis (20-80 IU/kg every 72 + 6 hours; actual dose determined by Baxter utilizing an algorithm and the patient's pharmacokinetic data). The rates of bleeding episodes for the on-demand regimen and the prophylaxis regimens will also be compared for the cross-over portion of the study. Enrolled patients will be treated originally on demand for a period of 6 months and then they will be randomized into one of the prophylaxis arms. Prophylactic treatment will last for a period of 12 months +/- 2 weeks.

Publications & conference data

2 peer-reviewed publications reference this trial (live from Europe PMC):

  1. A randomized comparison of two prophylaxis regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia A management.
    Valentino LA, Mamonov V, Hellmann A, Quon DV, et al · · 2012 · cited 187× · PMID 22212248 · DOI 10.1111/j.1538-7836.2011.04611.x
  2. Cost-Effectiveness Analysis of Recombinant Factor VIII Fc-Fusion Protein (rFVIIIFc) for the Treatment of Severe Hemophilia A in Italy Incorporating Real-World Dosing and Joint Health Data.
    Bullement A, McMordie ST, Hatswell AJ, Li N, et al · · 2020 · cited 15× · PMID 31280415 · DOI 10.1007/s41669-019-0158-8

Verify or expand the search:

Other trials of Antihemophilic factor, recombinant, manufactured protein-free

Trials testing the same drug.

Other recruiting trials for Hemophilia A

Currently open trials in the same condition.

Other Baxalta now part of Shire trials

Trials by the same sponsor.

Verify against primary sources

Data sources for this page

Drug Landscape aggregates and links these public records for informational use only. Always verify against the primary source before clinical or regulatory decisions. Canonical URL: https://druglandscape.com/trial/NCT00243386.

Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing