The proposed U34 Clinical Planning Grant Cooperative Agreement is designed in response to Program Announcement RFA-HL-12-023, to determine the feasibility of conducting a Phase III randomized controlled clinical trial, The VWD Minimize Study, comparing recombinant interleukin-11 (rhIL-11) with tranexamic acid (TA), the current recommended non-hormonal treatment, to reduce menorrhagia in women with type 1 von Willebrand disease (VWD). In this planning grant, we will establish the feasibility of conducting a Phase III (R01) trial. The original concept for this study was developed as one of four clinical trial concepts by six hemophilia treatment center (HTC) physicians, members of the NHLBI State of the Science (SoS) Hemophilia/von Willebrand Subcommittee, who are members of the Steering Committee for this study. A major goal for women with VWD is to reduce menorrhagia and associated morbidity and poor quality of life. Current treatments are limited by toxicities, and few randomized trials are available to guide treatment. Thus, safer, more effective drugs are needed. We hypothesize that rhIL-11, given by subcutaneous injection once daily, is superior to the current recommended non-hormonal agent, TA, given orally three times daily, in reducing menorrhagia, with similar toxicity and acceptability, and improved quality of life. The ultimate goal of this project is to identify and resolve barriers to the conduct of a future phase II randomized, controlled clinical trial to reduce menorrhagia in women with VWD. By this approach, we hope to prepare, refine, and optimize methods, forms, and operating procedures;and determine a sufficient number of participating sites and eligible subjects to assure the feasibility of conducting a Phase III randomized controlled trial to reduce menorrhagia in women with VWD, the specific aims of which are:
Aim 1. To establish an HTC infrastructure of 50+ HTC physicians to build consensus on trial design, subject recruitment and participation to assure a sufficient number of eligible subjects to conduct a future R01 20-week clinical randomized trial to compare rhIL-11 and TA to reduce menstrual bleeding in females 18-45 years with type 1 VWD. The HTC network will be operationalized by 1) conducting structured interviews with HTC physicians and women with type 1 VWD to determine acceptability of trial design and participation potential;2) collaborating with a Steering Committee and the U24 Clinical resource to optimize trial design, recruitment strategy, and prepare case report forms and a manual of operations; 3) developing and pilot testing a web-based data entry system;4) conducting exploratory meetings with HTC-affiliated gynecologists to determine potential for trial participation and subject recruitment;and 5) hiring a dedicated nurse coordinator to prepare IRB submission and contracts for HTCs.
Aim 2. To determine the feasibility of a phase III 20-week randomized, superiority, parallel arm clinical trial to compare subcutaneous rhIL-11 with oral TA in reducing menorrhagia in females 18-45 years old with type 1 VWD enrolled at HTC. This will be accomplished by 1) preparing an education module on subcutaneous injection technique for nurse training of women with VWD;2) setting up an independent adjudication committee for centralized review and monitoring of the primary efficacy outcome and other measures in study subjects;3) establishing safety stopping guidelines to assure safety of the intervention, to minimize fluid retention and hypokalemia;4) setting up a repository of blood samples linked to study subject data via web-based data entry;and 5) seeking advice of a community advisory board to provide feedback and promote communication to assure success of the future Phase III trial.
The purpose of this U34 grant proposal is to determine the feasibility of a randomized, superiority, parallel arm, clinical trial to determine whether recombinant interleukin-11 is more effective than tranexamic acid in reducing menorrhagia in women with von Willebrand disease (VWD), when taken the first 5 days in each of 4 menstrual cycles. To assess feasibility, we will conduct structured interviews with patients and physicians to determine acceptability and participation potential;work with U24 Resource to optimize trial design, set up a 50+ center network to promote enrollment, and coordinate and complete contracts and IRB submissions.