A Pilot Crossover Trial of Prophylactic Wilate Compared to Placebo for Heavy Menstrual Bleeding in Patients with VWD

Official title

A Multi-cEnter, Pilot, Crossover Trial of Prophylactic Wilate CoMpared to PlacebO for Heavy Menstrual Bleeding in Patients with Von WillEbRand Disease

Overview

The EMPOWER trial is a pilot multi-center, placebo-controlled (normal saline), double-blind (patient and outcome assessor), crossover, 2-year randomized trial in female outpatients with von Willebrand disease (VWD) and heavy menstrual bleeding to determine trial feasibility and viability, and to explore assay sensitivity of the proposed efficacy clinical outcomes for a definitive randomized controlled trial

Detailed description

The EMPOWER trial is a pilot multi-center, placebo-controlled (normal saline), double-blind (patient and outcome assessor), crossover, 2-year randomized trial in female outpatients with von Willebrand disease (VWD) and heavy menstrual bleeding to determine trial feasibility and viability, and explore assay sensitivity of the proposed efficacy clinical outcomes for a definitive randomized controlled trial.

For the first treatment period, patients will be randomized to receive either plasma derived von Willebrand factor:Factor VIII (pdVWF:FVIII) concentrate (plus standard of care) or placebo (plus standard of care) for VWD-associated heavy menstrual bleeding for 4 cycles, crossing over to the comparator treatment during the second treatment period. The first treatment period will be followed by a 1 cycle washout period when no study-based treatment will be delivered.

The main purpose of the pilot will be to evaluate viability and feasibility of the trial design, as well as to explore assay sensitivity to inform determination of the primary efficacy outcome for the definitive randomized trial which will evaluate the effect of prophylaxis with pdVWF:FVIII concentrate compared with placebo on HMB in women with VWD. A secondary objective is to conduct a preliminary assessment of the effect on clinical outcomes of 2-3 doses of prophylaxis with pdVWF:FVIII concentrate when provided on the first 4 days of menstruation compared with placebo.

Interventions

• Drug Lyophilized concentrate of human coagulation von Willebrand Factor and factor VIII
  Wilate® is a plasma-derived, highly purified concentrate administered through intravenous injection. Wilate® contains an average VWF ristocetin cofactor activity to FVIII activity at ratio of 1:1.
• Other Placebo
  Patients randomized to the placebo arm will receive intravenous normal saline at the same approximate volume and frequency of Wilate ®.

Primary outcome measures

• Blinding Index (BI) score at the end of cycle 4 of treatment period 1 and 2 [Time frame: 2 years]
• Proportion of participant drop-out at the end of treatment period 1 and 2 [Time frame: 2 years]
• Proportion of participants with completed for the candidate primary clinical efficacy outcomes at the end of treatment period 1 and 2 [Time frame: 2 years]
• Number of participants enrolled in 2 years (i.e. ability to enroll at least 10 participants in 2 years) [Time frame: 2 years]
• Proportion of participants with carryover effect for the candidate primary clinical efficacy outcomes from period 1 to period 2 [Time frame: 2 years]

Secondary outcome measures (12)

• Mean of the 3 highest daily Modified PBAC (mPBAC) scores within each individual participant cycle averaged across 4 individual participant cycles at the end of each treatment period [Time frame: At the end of 8 menstrual cycles (approximately 10 days)]
• The proportion of patients who use of rescue therapy at the end of each treatment period [Time frame: At the end of 8 menstrual cycles (approximately 10 days)]
• Mean of the mPBAC score within each individual participant cycle averaged across 4 individual participant cycles [Time frame: At the end of 8 menstrual cycles (approximately 10 days)]
• Median of the mPBAC score within each individual participant cycle used to derive the median across 4 individual participant cycles [Time frame: At the end of 8 menstrual cycles (approximately 10 days)]
• Number of days of oral tranexamic acid use [Time frame: At the end of 8 menstrual cycles (approximately 10 days)]
• Number of days of Wilate® treatment received [Time frame: At the end of 8 menstrual cycles (approximately 10 days)]
• Duration of menstruation (measured in days) [Time frame: At the end of 8 menstrual cycles (approximately 10 days)]
• Major bleed according to the International Society on Thrombosis and Haemostasis (ISTH) definition [Time frame: At the end of 8 menstrual cycles (approximately 10 days)]
• Clinically relevant non-major bleed [Time frame: At the end of 8 menstrual cycles (approximately 10 days)]
• Hemoglobin levels (g/L) [Time frame: At the end of 8 menstrual cycles (approximately 10 days)]
• Ferritin levels (mcg/L) [Time frame: At the end of 8 menstrual cycles (approximately 10 days)]
• Use of additional hormonal therapy for heavy menstrual bleeding [Time frame: At the end of 8 menstrual cycles (approximately 10 days)]

Eligibility criteria

Inclusion criteria

• Patient capable of providing informed consent;
• Female patients with HMB over the age of 18 years, for whom prophylactic treatment with Wilate® is deemed clinically appropriate according to the medical discretion (based on their expert opinion given consideration of the patient's bleeding history and responsiveness to treatment) of the treating hemostasis-focused physician practicing at a Hemophilia Treatment Center;
• Modified PBAC score > 100 at screening;
• Patients with a diagnosis of inherited von Willebrand disease (any type);
• Stable treatment for HMB and iron deficiency anemia for 3 cycles before entering the study and anticipated to remain unchanged for the duration of the study;
• Patients willing to have an infusion administered by a nurse over the course of the study period;
• Patients who agree to use only the feminine hygiene products supplied by the sponsor.

Exclusion criteria

• Diagnosed with any other known bleeding disorder;
• Pregnancy or plans to become pregnant within the duration of the study;
• Breastfeeding or plans to breastfeed within the duration of the study;
• Known hypersensitivity reactions to human plasma-derived products or any ingredient in the formulation;
• Known antibodies to VWF or FVIII;
• Severe liver disease;
• Anticipated initiation of the following: oral, transdermal, injectable, and vaginal ring hormonal contraceptives; GnRH analogues; or a hormonal intrauterine device (IUD) within the study period;
• Anticipated elective procedure that is expected to require intensive treatment with VWF or FVIII for >10 days during the study period;
• Patients with >2 risk factors for VTE (risk factors are determined at discretion of treating physician) or recent history of thrombosis (i.e. within the last year).
• Patient concurrently receiving desmopressin (desmopressin cannot be taken concurrently with Wilate®, except for in the context of escalation treatment for excessive bleeding).
• Anticipated initiation of any new therapies for the treatment of heavy menstrual bleeding 3 weeks prior to enrollment

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Triple blind

Primary purpose

Treatment

Study locations

Canada · 1 center

• St. Michael's Hospital — Toronto

Identifiers

NCT: NCT06205095 · 2.5

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗