To Assess the Efficacy and Safety of RVT-1401 in the Treatment of Warm Autoimmune Hemolytic Anemia (ASCEND-WAIHA).

Overview

This is a Phase 2 non-randomized, open-label study to investigate the efficacy, safety and tolerability of RVT-1401 in patients with Warm Autoimmune Hemolytic Anemia.

Full Title of Study: “A Phase 2, Multicenter, Non-Randomized, Open-Label Study of RVT-1401 for the Treatment of Patients With Warm Autoimmune Hemolytic Anemia”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Sequential Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: July 1, 2021

Detailed Description

This is a Phase 2, non-randomized, sequential, open-label study to investigate the safety, tolerability, PK, PD, and efficacy of RVT-1401 (680 mg/weekly and 340 mg/weekly) in patients with Warm Autoimmune Hemolytic Anemia that is worsening or refractory in spite of therapy with steroids and or immunosuppressants or worsening with steroid or immunosuppressant taper. Two cohorts of participants will be enrolled in a non-randomized sequential approach. Participants will be enrolled into Cohort 1 (680 mg/weekly) first followed by Cohort 2 (340 mg/weekly). Following the initial dose at the Baseline Visit (Week 1, Day 1), study visits will occur weekly throughout the treatment period. Following the final dose at Week 12, visits will occur weekly through Week 14 and then at Week 16 and Week 20. Safety, PK, PD, and clinical assessments will be collected throughout the study. Each participant will participate in the study for up to approximately 24 weeks: up to a 4-week screening period, a 12-week treatment period, and an 8-week follow up period.

Interventions

  • Drug: RVT-1401 680 mg/weekly
    • Non-randomized subjects will receive subcutaneous injection of 680 mg weekly for 12 weeks of RVT-1401
  • Drug: RVT-1401 340 mg/weekly
    • Non-randomized subjects will receive subcutaneous injection of 340 mg weekly for 12 weeks of RVT-1401

Arms, Groups and Cohorts

  • Experimental: Cohort 1
    • Dosing Regimen A – 680 mg weekly for 12 weeks via once weekly subcutaneous (SC) injections
  • Experimental: Cohort 2
    • Dosing Regimen B – 340 mg weekly for 12 weeks via once weekly subcutaneous (SC) injections

Clinical Trial Outcome Measures

Primary Measures

  • Proportion of responders with target Hb levels
    • Time Frame: Post-intervention at Week 13
    • To investigate the efficacy of RVT-1401 by analyzing the proportion of subjects with Hb level ≥10g/dL with at least a ≥2 g/dL increase from baseline without rescue therapy or blood transfusions in the previous two weeks
  • Assessment of safety and tolerability by analysis of adverse event (AE) data
    • Time Frame: Through study completion, approximately 20 weeks.
    • To investigate the safety of RVT-1401 by analyzing the number of participants with adverse events, as defined in Section 11.1 of the protocol.
  • Assessment of safety and tolerability by analysis of abnormal vital signs
    • Time Frame: Through study completion, approximately 20 weeks.
    • To investigate the safety of RVT-1401 by analyzing the number of participants with abnormal vital signs compared to baseline.
  • Assessment of safety and tolerability by analysis of abnormal clinical laboratory values.
    • Time Frame: Through study completion, approximately 20 weeks.
    • To investigate the safety of RVT-1401 by analyzing the number of participants with abnormal clinical laboratory values compared to baseline.
  • Assessment of safety and tolerability by analysis of abnormal ECG parameters.
    • Time Frame: Through study completion, approximately 20 weeks.
    • To investigate the safety of RVT-1401 by analyzing the number of participants with abnormal ECG ( PR, QRS, QT, and QTcF intervals) parameters compared to baseline.

Secondary Measures

  • Laboratory Assessments: Hematology – Hemoglobin (Hb)
    • Time Frame: Through study completion, approximately 20 weeks.
    • To measure the change from baseline in Hb levels as an assessment of safety and tolerability of RVT-1401
  • Laboratory Assessment: Time to Change in Hb
    • Time Frame: Through study completion, approximately 20 weeks.
    • To measure the time to response, defined as Hb level ≥10g/dL with at least a ≥2 g/dL increase from baseline without rescue therapy or blood transfusions in the previous two weeks.
  • Laboratory Assessment: Hematology – Hematocrit levels
    • Time Frame: Through study completion, approximately 20 weeks.
    • To measure the of change from baseline in hematocrit levels as an assessment of safety and tolerability of RVT-1401
  • Proportion of participants with normal Hb levels
    • Time Frame: Week 13
    • To measure the proportion of participants with Hb levels in the normal range at week 13 as an assessment of safety and tolerability of RVT-1401
  • Time to achieve normal Hb levels
    • Time Frame: From date of dosing until normal Hb levels achieved, assessed up to 20 weeks
    • To measure the time to achieving Hb levels in the normal range as an assessment of safety and tolerability of RVT-1401
  • Mean change in fatigue
    • Time Frame: Through study completion, approximately 20 weeks.
    • To measure the change from baseline in the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) score as an assessment of safety and tolerability of RVT-1401
  • Mean change in dyspnea
    • Time Frame: Through study completion, approximately 20 weeks.
    • To measure the change in Medical Research Council (MRC) breathlessness scale as an assessment of safety and tolerability of RVT-1401
  • Mean change in health-related quality of life scores
    • Time Frame: Through study completion, approximately 20 weeks.
    • To measure of the change from baseline in EQ-5D-3L score (a standardized instrument for measuring generic health status) as an assessment of safety and tolerability of RVT-1401
  • Laboratory Assessment: Mean change in serum levels of total Immunoglobulin G (IgG) & IgG subclasses (I-IV)
    • Time Frame: Through study completion, approximately 20 weeks.
    • To measure of change from baseline in levels of total IgG & IgG subclasses (I-IV) as an assessment of safety and tolerability of RVT-1401
  • Plasma PK Analysis: To examine concentration-time data following repeated doses of RVT-1401 in patients with WAIHA
    • Time Frame: Through study completion, approximately 20 weeks.
    • To measure the concentration of RVT-1401 pre-dose (Ctrough) as an assessment of the PK RVT-1401
  • Laboratory Assessment: Mean changes in LDH
    • Time Frame: Through study completion, approximately 20 weeks.
    • To measure the change from baseline in Lactate dehydrogenase (LDH) as an assessment of safety and tolerability of RVT-1401
  • Laboratory Assessment: Mean changes bilirubin
    • Time Frame: Through study completion, approximately 20 weeks.
    • To measure the change from baseline in bilirubin as an assessment of safety and tolerability of RVT-1401
  • Laboratory Assessment: Mean changes haptoglobin
    • Time Frame: Through study completion, approximately 20 weeks.
    • To measure the change from baseline in haptoglobin as an assessment of safety and tolerability of RVT-1401
  • Immunogenicity: Change in anti-RVT-1401 antibodies following repeated doses in patients with WAIHA
    • Time Frame: Through study completion, approximately 20 weeks.
    • To measure the Immunogenicity determined by change from pre-dose in anti-RVT-1401 antibodies

Participating in This Clinical Trial

Inclusion Criteria

1. Male or female ≥ 18 years of age. 2. Diagnosis of primary or secondary WAIHA as documented by a positive direct antiglobulin test (DAT) specific for anti-IgG alone or anti-IgG plus C3d. 3. Secondary WAIHA may only include Stage 0 chronic lymphocytic leukemia (CLL) in which separate treatment is not indicated, nor anticipated to require active management for the duration of the study. 4. Have failed or not tolerated at least one prior WAIHA treatment regimen as per local standards (e.g., steroids, rituximab, azathioprine, cyclophosphamide, cyclosporine, mycophenolate mofetil (MMF), danazol, or vincristine). Failure is defined as worsening or refractory disease despite steroids and or immunosuppressants. 5. Participants with splenectomy ≥3 months from Day 1 who are up to date on vaccinations (based on age and local guidance) are allowed. 6. At Screening and Baseline, subject's hemoglobin level must be <10 g/dL and the subject must have documented symptoms related to anemia (e.g., weakness, dizziness, fatigue, shortness of breath, chest pain). 7. Subject's concurrent treatment for WAIHA may consist only of steroids (stable dose for at least two weeks prior to Day 1), immunosuppressant therapy (azathioprine, MMF, or cyclosporine) that has been at a stable dose for at least four weeks prior to Day 1, or erythropoietin (stable dose for at least 6 weeks prior to Day 1). [Note: starting doses of WAIHA therapy must be maintained throughout the study except in the case of a rescue medication as per local standards for safety. Steroid taper down to 10 mg/day will be allowed for participants who achieve response for at least 2 weeks.] 8. A female participant is eligible to participate if she is of: 1. Non-childbearing potential defined as pre-menopausal females with a documented bilateral tubal ligation, bilateral oophorectomy (removal of the ovaries) or hysterectomy; hysteroscopic sterilization, or postmenopausal defined as 12 months of spontaneous amenorrhea. 2. Child-bearing potential and agrees to use one of the contraception methods listed in the protocol for an appropriate period of time (as determined by the product label or Principal Investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female participants must agree to use contraception until 90 days after the last dose of study treatment. 9. Male participants must agree to use one of the contraception methods listed in the protocol. This criterion must be followed from the time of the first dose of study treatment until 90 days after the last dose of study treatment. 10. Willing and capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. Other, more specific inclusion criteria are defined in the protocol. Exclusion Criteria:

1. Participants with other types of AIHA (e.g., cold antibody AIHA, cold agglutinin syndrome, mixed type AIHA, or paroxysmal cold hemoglobinuria). 2. Participants requiring more than 2 units of RBC per week in the 2 weeks prior to Screening and Baseline. 3. Use of rituximab, any monoclonal antibody for immunomodulation, or proteasome inhibitor, within the past 3 months prior to Screening. 4. Immunoglobulins given by SC, IV (IVIG), or intramuscular route, or plasmapheresis/plasma exchange (PE) within 60 days before Screening. 5. Total IgG level <6 g/L (at Screening). 6. Absolute neutrophil count <1000 cells/mm3(at Screening). Other, more specific exclusion criteria are defined in the protocol.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Immunovant Sciences GmbH
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Contact(s)
    • Sangeeta Sawhney, M.D., (917) 521-5022, sangeeta.sawhney@immunovant.com

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