Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02697370 |
| Other study ID # |
12/SC/0363 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
February 18, 2016 |
| Last updated |
February 21, 2018 |
| Start date |
April 2013 |
| Est. completion date |
May 2015 |
Study information
| Verified date |
February 2018 |
| Source |
Hampshire Hospitals NHS Foundation Trust |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Patients with severe Haemophilia A need prophylactic factor VIII to reduce their risk of
joint and soft tissue bleeds and to prevent or reduce joint damage. It is common practice to
give enough factor VIII to maintain the trough level above 1% of normal and this has been
supported in retrospective studies.
The amount of factor VIII required to maintain this trough level varies markedly between
patients because their factor VIII half lives are different. This study will assess the role
of regular pharmacokinetic (PK)monitoring and dose adjusted factor VIII to establish whether
this is a more cost effective way of giving treatment and whether it is feasible in routine
clinical practice. Patients will be treated for 6 months with their standard factor VIII
regimen and followed up to establish their bleed frequency. They will then receive
pharmacokinetic adjusted factor VIII to maintain a trough above 1.5% for a year and their
bleed rate compared to standard treatment. If they have increased break through bleeds their
factor VIII will be increased to maintain a trough of 3%.
Description:
Study procedures
Recruitment and Consent Patients with severe Haemophilia A who are taking any regular
prophylactic regimen with infusions of factor VIII at least 3 times a week and do not have a
target joint will be eligible. Initial approach will be made by the Principal Investigator at
the patients next scheduled review appointment.
Phase 1: Study enrolment Participants will be allocated a unique patient number upon
enrolment into the study.
The following will be recorded at study enrolment:
- Date of birth
- Height and weight
- Baseline factor VIII based on historical data from the patient record
- History of a factor VIII inhibitor
- Information on the number and site of haemarthroses and soft tissue bleeds and total
amount of factor VIII used in the preceding 12 months will be recorded, if known
- Quality of life assessment by Utility-EQ5D
- Joint assessment by Haemophilia Joint Health Score (HJHS)
An abbreviated (3 sample) pharmacokinetic study will be undertaken as follows:
There will be no wash out. The patient's routine prophylactic infusion will be given in the
morning and the exact time (hours and minutes) and dose recorded. Since there is no wash out
the date, exact time and dose of the previous 2 prophylactic doses (i.e. 3 infusions in
total) must be accurately known.
Blood samples will then be taken to measure
1. Factor VIII levels
2. Von Willebrand factor (VWF) antigen level
3. Von Willebrand factor propeptide
4. Von Willebrand factor: factor VIII binding
5. Coagulation screen
6. Inhibitor assay by Nijmegen modification of Bethesda assay & ELISA (only first afternoon
timepoint)
7. CRP (only first afternoon time point)
Samples for above tests will be collected that afternoon, the following morning and the
following afternoon. The samples can be taken at any convenient time but the exact time
(hours and minutes) must be recorded. Factor VIII levels will be measured. The patient's
weight (kg), amount and exact time of the last 3 factor VIII infusions, measured factor VIII
levels and exact times of when the samples were taken will be communicated to the centre in
Uppsala and the pharmacokinetic parameters established using a Bayesian procedure based on a
population model.
The following will be established or recorded from the notes if already known
1. Blood group
2. Factor VIII mutation
3. DNA testing other genes that may affect factor VIII clearance e.g. lipoprotein receptor
4. Factor VIII and Von Willebrand factor genetic sequence
Phase 2: Standard treatment for 6 months
The patients will remain on their routine prophylactic regimen as determined by their
clinician for a period of 6 months. The patient's current factor VIII product will be used
and the factor VIII product should not change throughout the study. Patients will be
instructed to give all prophylactic infusions in the morning (defined as before midday).
The following procedures will be undertaken:
Patients will keep a diary of:
a All factor VIII infusions. Information will be collected on the dose of factor VIII,
time(hours and minutes) of infusion and reason for infusion (prophylaxis or treatment of a
bleed).
b Bleeding events. Information will be collected on the type of bleed (haemarthrosis or soft
tissue), site (identified by specific joint or position), cause (atraumatic or traumatic with
precipitating event), symptoms or signs of swelling, pain or loss of function and time.
Every 2 weeks for the first 2 months and subsequently monthly a nurse or doctor will make
contact by telephone, email or text to confirm that the diary is being completed.
At 3 months a doctor will review the patient and the diary and make appropriate changes to
treatment. Patients will have open access to contact or attend the Haemophilia Centre as is
currently the case. The clinician will make appropriate changes to treatment.
Phase 3: Pharmacokinetic tailored treatment
At the end of phase 2, i.e. 6 months after the start of the study the patient will attend the
haemophilia centre for:
- Review of bleed chart diary and treatment
- QOL assessment (Utility-EQ5D)
- Joint assessment (HJHS)
- An abbreviated (3 sample) pharmacokinetic study will be undertaken as follows:
As before there will be no wash out. The patient's routine prophylactic infusion will be
given in the morning and the exact time and dose recorded. Also the date, exact time and dose
of the previous 2 prophylactic doses (i.e. 3 infusions in total) must be accurately known and
recorded.
Blood samples will then be collected to measure parameters as in Phase 1
The centre in Uppsala will use the pharmacokinetic data to calculate the dose of factor VIII
(to be infused on alternate days) required to maintain a predicted factor VIII ≥1.5 IU/dL at
all times, and inform the patient's centre of the dose to prescribe (this will be rounded up
to the nearest full 250 IU vial).
This regimen will be prescribed for 12 months i.e. months 7-18 of the study. The patient's
current factor VIII product will be used. Patients will be instructed to give all
prophylactic infusions in the morning (defined as before midday).
The patients will follow the same procedures and keep a diary as in Phase 1.
At 3, 6 and 9 months (+/- 2 weeks) of starting the pharmacokinetic tailored treatment phase
(i.e. at the end of 9, 12 and 15 months (+/- 2 weeks) from starting the study), a doctor will
review the patient and the diary and make appropriate changes to treatment according to the
Phase 3 dose escalation protocol. At each of these visits participants will have their weight
and factor VIII levels measured As before there will be no wash out. The patient's routine
prophylactic infusion will be given in the morning and the exact time and dose recorded. The
date, exact time and dose of the previous 2 prophylactic doses must also be accurately known
and recorded.
Blood samples will be collected that afternoon, the following morning and the following
afternoon and parameters measured as in Phase 1.
The Uppsala centre will calculate the pharmacokinetic parameters. Based on these results the
dose required by the patient will be reviewed and recommend the most appropriate dose to
maintain a trough level ≥ 1.5 IU/dL.
Dose escalation Phase 2
If a participant experiences more than one clinically significant bleed in a 4 month period
during phase 2 (clinician routine prescribing) treatment will be adjusted by the clinician
according to that clinician's routine practice. This could mean that the prophylactic dose
does not change.
Phase 3
If a participant experiences more than one clinically significant bleed in a 4 month period
during phase 3 (pharmacokinetic tailored dosing) a dose escalation will occur. The
participant will have their prophylaxis dose increased to sustain a trough factor VIII level
above 3 IU/dL i.e. the prophylactic dose will be doubled. If the participant has more than
one clinically significant bleed in a subsequent 4 month period they will be withdrawn from
the study and return to routine care.
This means that no more than 4 clinically significant bleeds, per participant, will be
permitted in phase 3 (1 year) of the study. This figure is based on the finding that 5% of
patients on full dose standard prophylaxis have more than 3 bleeds per year and that the
median number of bleeds in prospective prophylaxis studies in adult patients is between 0 and
3 per year.
Study end
After 18 months the patients will undergo:
- Weight measurement
- Diary review of bleeds, treatments and adverse events
- Quality of life assessment by Utility-EQ5D
- Joint assessment by HJHS
- Blood will be taken for parameters as in Phase 1
The patient will then exit the study.
Adverse Events
A clinical review will be held after each clinically significant bleed on phase 3 of the
study. If a participant experiences more than 4 bleeds during phase 3 of the study, this will
be classed as an adverse event and the participant will be withdrawn from the study. If more
than 5 participants have more than 1 spontaneous clinically significant bleed in a 4 month
period after the dose escalation to 3%, the study will be reviewed by the IDMC and if
confirmed all participants will be reverted back to standard care and the study terminated.
Pharmacokinetic analysis and dose recommendation
Calculation of pharmacokinetic parameters and the dose of factor VIII for prophylactic during
phase 3 will be performed at the Department of Pharmaceutical Biosciences, Uppsala
University, under the supervision of Professor Bjorkman using NonmemR software. The factor
VIII levels, time and dose of factor VIII infusions and patients' weight will be sent to
Uppsala. No other information will be sent. The dose recommendation will be sent to the
treating centre by secure email within 7 days. The local centre will use the same information
available to Uppsala and the TCIworksR software to calculate the patients' pharmacokinetics
and dose recommendations. The dose recommendation of Uppsala will be used if the local
recommendation is different.
Method for measurement of patient pharmacokinetics
The study patients' pharmacokinetic parameters will be estimated by a Bayesian procedure
based on a population model, according to methods already in use e.g. for aminoglycoside
antibiotics, digoxin or immunomodulating drugs. Pharmacokinetic parameter estimates will be
obtained from the 6 month results and then be updated when new data is obtained after 9, 12,
15 and 18 months. A complete population pharmacokinetic analysis will be performed after
collection of all data with the aim to investigate:
1. Intra-individual (inter-occasion) variance in pharmacokinetics in relationship to
inter-individual variance.
2. The relationship of pharmacokinetic variables with patient characteristics (as
determined at each study occasion), in particular VWF:Ag level, VWF:factor VIII binding,
VWF propeptide, blood group, inflammation (CRP), inhibitor titre and factor VIII
mutation.
Analysis
First; the primary and secondary endpoints will be compared between phase I and II i.e.
number of clinically significant bleeds, total bleeds, clotting factor consumption/kg,
quality of life, and joint status. These comparisons will be performed using paired T-tests
and non parametric tests.
Second; the performance of pharmacokinetic calculation methods will be assessed: predicted
FVIII levels will be compared to measured FVIII levels, and inter- as well as inter patient
variability of PK parameters will be assessed.
Third; the determinants of bleed rate will be addressed using multivariate regression with a
negative binomial model and joint bleeds as well as total bleeds as the outcome. Using this
approach, the independent effects of calculated weekly time below 1%, baseline arthropathy,
and physical activity will be assessed.
Fourth; the association of patient characteristics (age, weight, BMI, blood group, VWF level,
factor VIII mutation, VWF:FVIII binding, VWF polymorphisms, current or past history of factor
VIII inhibitor or inflammation) and PK parameters (AUC and half life) will be assessed using
multivariate regression techniques.
Finally, patient characteristics associated with treatment failure (e.g. lower than predicted
factor VIII levels, higher activity, non-reproducible pharmacokinetic results or lack of
adherence) will be assessed, using descriptive statistics and multivariate logistic
regression if possible.
The study will be deemed to have a positive outcome if:
1. Patients are treated with factor VIII doses calculated from individual pharmacokinetics
for 12 months in at least 80% of cases.
2. The median increase in clinically significant bleeds in the pharmacokinetic dosed arm
compared to routine practice is less than 2 in 80% of the patients
3. There is a statistically significant reduction in the average factor VIII usage in the
pharmacokinetic dosed period compared to the clinician dosed period.
