Hemophilia Clinical Trial
Official title:
Musculoskeletal Function in Hemophilia in Developing Countries
Hemophilia, which results from deficiency of factor VIII or IX, is a common hereditary
X-linked bleeding disorder affecting up to 10/100,000 population. About 60-70% of them have
severe disease (factor level <1%). This group is characterized by the occurrence of frequent
spontaneous bleeding into joints and soft tissues. If inadequately treated, it results in
progressive damage to joints and muscles leading to crippling deformities. Close clinical
observation of these patients over many years has shown that those with >1% levels have much
less bleeding compared to those with less than 1%. This observation has gained immense
clinical importance in planning therapy for these patients.
To prevent progressive joint damage, the missing factor needs to be replaced. Much has
evolved in this practice in the last 50 years. From administration of whole blood in the
beginning, to plasma and cryoprecipitate, to purified plasma-derived concentrates and
finally recombinant factor concentrates. The standard of therapy now is to replace factors
frequently enough to maintain >1% factor levels at all times (“prophylaxis”) or administer
immediately on premonition or earliest signs of bleeding (“on demand” therapy). This has
greatly enhanced the quality of life of people with hemophilia. However, the optimal
regimens of factor replacement remain to be defined. The definition of what is optimal
management of this chronic condition, currently incurable for the vast majority of patients,
varies significantly in different parts of the world, depending on practicality and social
expectations. Models have care have been developed in Western countries based on careful
documentation of outcome over many years. Such data is lacking from developing countries.
This multi-center study aims to systematically record the outcome of musculoskeletal
function in people with hemophilia in developing countries for the first time and provide
information that can help plan care for the 80% of all hemophiliacs in the world who live in
these countries. Currently there is no well documented model of care at the range of factor
replacement practiced in these countries nor is there any significant information on the
long-term outcome of musculo-skeletal function among these patients.
3.1 Musculoskeletal function in hemophilia - natural history
Severe hemophilia is characterized by recurrent bleeding into large joints and muscles
resulting in progressive damage and deformity by the time the patient reaches the end of the
second decade ultimately leading to severe functional disability in many of the affected
people. This fact has been well known for long. The orthopedic outcome of a person with
severe hemophilia was perhaps not very different in different parts of the world till the
1960s. However, in the last three decades, the ability of factor replacement therapy to
completely modify the clinical outcome of severe hemophilia has been recognized. Factor
replacement therapy itself has evolved much over this period and infusion of large
quantities of factor concentrates has transformed the outlook of this condition. A person
with hemophilia can now lead a nearly normal life without fear of frequent bleeding into
joints.
3.2 Factor replacement for preserving musculoskeletal functions - the current models
As late as the early 1960s, factor replacement in large quantities was difficult because
only fresh plasma could be used. With the discovery of cryoprecipitate in 1964, (1) larger
quantities could be infused. Further purification and lyophilization made home-therapy
possible. (2) It was soon obvious that early factor replacement could reduce joint damage
significantly. Two schools of practice evolved: on-demand therapy where factor concentrates
were infused at the earliest evidence of bleeding and prophylactic therapy aimed at
maintaining factor level above 1% at all times. Both approaches required very large
quantities of factor concentrates but could completely alter the expression of disease by
preventing recurrent bleeding into joints. (3,4) What has facilitated this approach is the
enhanced safety of plasma derived and recombinant factor concentrates. (5,6) Improved
methods of donor selection and the introduction of viral inactivation steps in the
manufacturing process have made these concentrates safer than ever before. (7)
The most convincing data on the effectiveness of prophylactic factor replacement in
hemophilia is from Sweden. As shown with carefully documented long-term data, perfect joint
architecture can be preserved with large quantities of factor concentrates ranging in doses
from 4,000-9,000 IU/kg annually. (3) More recently, similar data from the Netherlands has
shown that with much lower doses ranging from 1,400-2,500 IU/kg annually, joint damage can
be very significantly reduced. (13) Unfortunately, both these studies have not reported the
disability status of their patients in relationship to the extent of joint damage. In other
words, it is not clear from this data whether the person with a joint score showing mild
damage is necessarily worse functionally that someone with joint cores showing moderate
damage. However, there is often a very large difference among them in terms of the total
quantity of factor replacement therapy. In fact, clinical experience suggests that there is
often a poor correlation between joint scores and functional disability in the joint.
Optimal regimens for factor replacement therefore still remain to be defined. Two large
multi-center studies to evaluate regimens for prophylactic therapy are underway in Italy and
Canada.
3.3 Models for factor replacement in developing countries
While these models of replacement therapy are very effective in preventing arthropathy, they
have also made hemophilia one of the most expensive diseases to treat. (8) Therefore the
benefits of such an approach have been limited to those people with hemophilia who live in
developed countries. (9) For three quarters of people with hemophilia in the world who live
in developing countries, treatment of this nature remains a distant dream. Most of them
receive very little or no factor concentrates. Blood bank products continue to be used for
factor replacement therapy. (10) As efforts are made to improve their care, it is necessary
to develop more practical models for management of hemophilia in these countries.
3.4 Aim of factor replacement therapy
The predominant cause of morbidity in hemophilia is the damage resulting from repeated
bleeding into joints. It has therefore been the aim of therapy to establish a standard where
there is no evidence of damage to the joints, clinically and radiologically. (11) The
effectiveness of this approach in preserving joint integrity has been so good that it has
now become the standard for therapy in economically developed countries. Unfortunately, the
annual cost of such therapy at $50-100,000/person has been so high that it has been
difficult even for countries with developed economies to adopt it universally.
It is certainly desirable for all people with hemophilia all over the world to have the same
level of care. However, the reality is that it is simply not economically feasible. While
the per capita GDP of developed economies are above $20,000, that of developing economies is
in the range of $500-3,000. (12) Apart from this, attitude towards health care varies
considerably with many countries spending less than $10 per person annually. In such
situations, it is necessary to establish a different philosophy for factor replacement. The
aim shifts from maintaining perfect joint integrity to reasonable joint function that will
allow the person to remain functionally independent. Out of necessity and not out of choice,
people with hemophilia in developing countries and their physicians have to accept this
fact.
The situation with factor replacement for joint bleeding in developing countries is
variable. The limited data available suggest that the total quantity of factor concentrate
used varies from about 2-30,000 IU/person annually corresponding to about 25-500 iu/kg/year.
(14,15) Some of these centers that use factor concentrates in the intermediate range have
reported preservation of reasonable joint function and functional independence. However,
this is not backed by carefully documented data on orthopedic outcome. A systematic
evaluation of orthopedic outcome with the different replacement protocols will help develop
suitable models for treatment of hemophilia in these countries and will also assist health
care planners in determining the cost of care. In recent years, considerable efforts are
being made in many developing countries to get support from governments or insurance
agencies for hemophilia care but the absence of adequate data on outcome with protocols that
are practical in these situations makes it difficult to convince the authorities that even
lower doses can preserve long-term functional independence.
A unique aspect of this study will be the assessment of functional independence of people
with hemophilia and its correlation with joint scores. Unfortunately assessment of
functional independence measure in hemophilia has not been standardized. After much
discussion at the WFH Congress at Seville and the subsequent meeting of the SSC of the ISTH
with the prospective co-investigators and advisors, including Drs.Donna DiMichele, H.
Marijke van den Berg, Bruce Evatt and Carol Kasper, it was decided to apply a generic
instrument such as the WeeFIM® till a more hemophilia specific instrument becomes available.
This instrument is easy to administer and has been shown to have excellent consistency. (16)
Baseline factor levels and quantum of factor replacement may not be the only determinants of
musculo-skeletal outcome in hemophilia. Levels of other coagulation proteins, including
presence of prothrombotic markers, can also alter clinical outcome. Polymorphisms of various
modulators of the inflammatory response may play a role. Though it is not envisaged to study
these parameters in this study, it has been planned to collect blood samples with informed
consent for evaluating these some of these parameters in future, if possible.
Hypothesis While it is likely that there will be good correlation between joint scores and
functional independence at low joint scores, this correlation is unlikely to be linear or
even significant, with increasing joint scores.
This study aims to document the outcome of musculo-skeletal function in a large number of
children with severe hemophilia receiving varying levels of factor replacement therapy over
a long period of time with particular emphasis not only on joint scores but on the
functional independence status of these patients.
;
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