Clinical Trial Update

A number of important clinical trials are either underway or about to begin. Enrolling the relatively large number of patients required for each of these clinical trials is and will continue to be a challenge, Dr. Victor Blanchette, Director of the Thrombosis and Hemostasis Program at the Hospital for Sick Children, Toronto (Canada), says. The expense of the studies makes it imperative that investigators design them properly and use clinically relevant endpoints.

“All of these studies address key unanswered questions in hemophilia care,” Dr. Blanchette says, “so, it is very important that the international community support them.”

Study: International Immune Tolerance (ITI) Study

What is it?: The ITI study was initiated in 2002 to determine the ideal regimen for ITI in hemophilia patients with inhibitors. Once subjects had achieved a titre of less than 10 BU, they were put on either a high-dose therapy or a low-dose regimen (the Dutch protocol). They were given 33 months to achieve consensus pharmacokinetic parameters for ITI success and then followed for an additional year to determine the rate of relapse.

What did we learn?: Of the 67 subjects who completed the study, 70% achieved tolerance, 5% were partial successes, and 25% were failures, says Dr. Donna DiMichele, Professor of Pediatrics at Weill Cornell Medical College (U.S.A.). The efficacy rates were similar across both the high-dose and low-dose arms of the study. However, the study size did not give the study sufficient power to actually confirm equivalence, and it was not feasible to enrol enough patients to achieve it, which is one reason the study was terminated.

While findings showed roughly equal efficacy between high- and low-dose regimens, they also revealed that patients on low doses took twice as long to reach a negative Bethesda titre and 50% longer to achieve tolerance. Dr. Charles Hay, Director of the Manchester Haemophilia Comprehensive Care Centre (U.K.), reports there were 294 serious adverse events, 10% of which were judged to be study-related and 57% were catheter-related. There was no demonstrable difference in catheter-related infections between treatment arms.

However, there was significantly more inter-current bleeding in the low-dose arms, most of which occurred before a negative titre was achieved. There were 325 reports of hemarthrosis in the low-dose arm, but only 122 in the high-dose arm. Muscle bleeds were similarly more numerous in the low-dose arm. “The significant differences in early bleed rates suggest the protective effect of high-dose immune tolerance induction,” Dr. Hay says.

Study: The Canadian Hemophilia Primary Prophylaxis Study

What is it?: A single arm, dose-escalation study being coordinated by the Hospital for Sick Children in Toronto, Canada. Currently 56 patients between the ages of one and two and a half years are enrolled. Treatment begins with 50 units per kilogram per week. The dose is escalated to 30 units twice per week, then 25 units every other day if patients have more than three bleeds into a single joint, four bleeds into a combination of joints in any three-month period, or five or more bleeds into any target joint.

What have we learned?: The study has been underway for 13 years. Ten years in, the median total joint score was 2. Half the boys on this dose-escalation regimen had detectable osteochondral changes at a median age of 8.8 years. Nearly one-third (32%) of index joints with no history of bleeding showed signs of soft tissue change (synovial hypertrophy, hemosiderin deposition, etc.) at the same age.

There is clearly a difference between these findings and those of the Joint Outcome Study, which reported only 7% of subjects with osteochondral changes, Dr. Blanchette says. “The long-term significance of the findings remains unclear, but follow-up of the Canadian cohort is ongoing.”

Study: The European Initiative to Prevent Joint Damage in Haemophilia A Children with Inhibitors (ENJOIH)

What is it?: The ENJOIH study is a Phase II multinational, multi-centre, randomized study whose objective is to evaluate the efficacy and safety of a prophylactic regimen with rFVIIa in reducing the frequency of joint bleeds and the development of joint damage, measured by the Hemophilia Joint Health Score (HJHS). Its goal is to enrol 50 patients at sites in Europe and the United States. Half of those enrolled will receive on-demand treatment, and the remainder will receive prophylactic treatment.

Status: The study has been cleared to enrol patients in Europe and has been filed in North America.

Study: The Survey of Plasma Product Exposed Toddlers (SIPPET)

What is it?: The SIPPET study is an international, multicentre, prospective, controlled, randomized open-label clinical trial designed to determine whether the type of treatment product (i.e. plasma-derived VWF/FVIII-containing concentrates vs. recombinant FVIII concentrates) has an effect on the risk of inhibitor formation. Patients meeting the enrolment criteria will be randomized to be treated exclusively with a single FVIII product either plasma-derived or recombinant, and followed up until inhibitor development or until 50 exposure days (EDs) or 3 years from enrolment have elapsed, whichever comes first. The objective is to enrol 300 patients from 60 centres in 25 countries over a two-year period.

Status: This study is currently enrolling patients.

Study: The Rescue Immunotolerance Studies in ITI Naive and Experienced Patients (RESIST Studies)

What is it?: The RESIST studies are prospective multinational, multi-centre trials open to patients with severe hemophilia and high-level inhibitors. These studies will investigate immune tolerance induction (ITI) in both naive patients and experienced patients to determine (1) whether the addition of von Willebrand factor offers an advantage to achieving immune tolerance, and (2) whether treatment with a FVIII concentrate containing VWF given at a high dose daily for up to 33 months is able to induce immune tolerance after previous attempts with concentrates containing only FVIII have failed.

Status: This study is currently enrolling patients.

Last Updated September 2010