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

Phase 2

Terminated

• Conditions: Warm Autoimmune Hemolytic Anemia
• Interventions: Drug: RVT-1401 680 mg/weekly; Drug: RVT-1401 340 mg/weekly

• Registration Number: NCT04253236
• Lead Sponsor: Immunovant Sciences GmbH

Brief Summary

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.

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.

Study Timeline

• Study First Submitted: 2020-01-21
• Study First Submitted QC: 2020-01-31
• Study First Posted: 2020-02-05
• Study Start: 2020-08-11
• Primary Completion: 2021-04-01
• Study Completion: 2021-04-01
• Disposition First Submitted: 2022-03-16
• Disposition First Submitted QC: 2022-03-16
• Disposition First Posted: 2022-03-18
• Status Verified: 2022-07
• Results First Submitted: 2022-07-01
• Results First Submitted QC: 2022-07-01
• Last Update Submitted: 2022-07-01
• Results First Posted: 2022-07-28
• Last Update Posted: 2022-07-28

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 5

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort 1	RVT-1401 680 mg/weekly	Dosing Regimen A - 680 mg weekly for 12 weeks via once weekly subcutaneous (SC) injections
Cohort 2	RVT-1401 340 mg/weekly	Dosing Regimen B - 340 mg weekly for 12 weeks via once weekly subcutaneous (SC) injections

Primary Outcome Measures

Name	Time	Method
Number of Responders at Week 13	Week 13	Responders were defined as the participants with level of hemoglobin (Hb) \>=10 grams per deciliter (g/dL) with at least a \>=2 g/dL increase from Baseline without rescue therapy or blood transfusions in the previous two weeks.
Number of Participants With Any Treatment-emergent Adverse Event (TEAE), Serious AE (SAE), Treatment-related Adverse Event (AE), and Death	Up to Week 20	AEs were defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Clinically significant changes determined by the Investigator such as vital signs, Electrocardiograms (ECGs), and clinical laboratory values were also reported as AEs. TEAEs were defined as AEs that either started on or after the date of the first dose of study drug. SAEs were defined as any untoward medical occurrence that, at any dose: resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity, was a congenital anomaly/birth defect, or was an important medical event that may have jeopardized the participant or may have required medical or surgical intervention to prevent one of the other outcomes listed in the definition.

Secondary Outcome Measures

Name	Time	Method
Time to Response	Up to Week 13	The time to response was defined as the amount of time to achieve response (Hb levels \>=10 g/dL with at least a \>=2 g/dL increase from Baseline without rescue therapy or blood transfusions in the previous 2 weeks).
Time to Achieving Hb Levels in the Normal Range	Up to Week 13	Time to achieving Hb levels in the normal range was assessed.
Number of Participants With Change in Functional Assessment of Chronic Illness Therapy-fatigue (FACIT-F) Score	Up to Week 13	The FACIT-F scale was a validated scale which measured the physical, emotional and social implications of fatigue, one of the key clinical manifestations of warm autoimmune hemolytic anemia. Scores ranged from 0-52, a higher score indicated a higher quality of life. A score of less than 30 indicated severe fatigue. The scale took approximately 5-10 minutes to complete.
Number of Participants With Change in Medical Research Council (MRC) Breathlessness Scale	Up to Week 13	The MRC Breathlessness scale is a questionnaire that consisted of 5 statements about perceived Breathlessness and the focus of the scale was to quantify the disability associated with breathlessness. Score ranged from Grade 0 (limited to no disability) to Grade 4 (severe disability); higher score indicated severe disability.
Number of Participants With Change in Euro Quality-5 Dimension-3 Level (EQ-5D-3L) Score	Up to Week 20	The EQ-5D-3L is a validated measurement of health-related quality of life. The scale consists of 2 components, the EQ-5D descriptive system and the EQ visual analogue scale (VAS). The descriptive system evaluates mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: 1=no problems, 2=some problems, and 3=extreme problems; a lower score indicated better quality of life. The EQ VAS records the participant's self-rated health on a vertical visual analogue scale where the endpoints are labelled 'Best imaginable health state' (100) and 'Worst imaginable health state' (0).
Concentration of RVT-1401 Pre-dose	Pre-dose, Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 13 post-dose	Blood samples were planned to be collected at indicated time points to measure the concentration of RVT-1401 pre-dose (Ctrough) as an assessment of the pharmacokinetic (PK) RVT-1401.
Number of Participants With Presence of Anti-RVT 1401 Antibodies	Pre-dose on Weeks 1, 3, 5, 8, 13 and Week 20	Blood samples were collected at indicated time points to determine presence of anti-RVT 1401 antibodies. Participants with presence of anti-RVT 1401 antibodies is reported
Number of Participants With Change in Levels of Total Immunoglobulin (Ig)G and IgG Subclasses (1-4)	Up to Week 20	Blood samples were collected at indicated time points for pharmacodynamic (PD) analysis of serum total IgG and IgG subclasses (1-4) concentrations. Participants with changes in levels of Total IgG and IgG Subclasses (1-4) is reported.

Trial Locations

Locations (21)

Hospital Universitario Quirónsalud Madrid; 🇪🇸 Barcelona, Spain

Seoul National University Bundang Hospital; 🇰🇷 Seongnam, Korea, Republic of

Meir Medical Center; 🇮🇱 Kfar Saba, Israel

Samsung Medical Center; 🇰🇷 Seoul, Korea, Republic of

Gachon University Gil Medical Center; 🇰🇷 Incheon, Korea, Republic of

Faculty of Medicine, Khon Kaen University, Srinagarind Hospital; 🇹🇭 Khon Kaen, Thailand

Faculty of Medicine, Chiang Mai University, Maharaj Nakorn Chiang Mai Hospital; 🇹🇭 Chiang Mai, Thailand

Faculty of Medicine, Prince of Songkla University,Songklanagarind Hospital; 🇹🇭 Hat Yai, Thailand

Ha'Emek Medical Center; 🇮🇱 Afula, Israel

Korea University Anam Hospital; 🇰🇷 Seoul, Korea, Republic of

Seoul National University Hospital - Department of Internal Medicine; 🇰🇷 Seoul, Korea, Republic of

Asan Medical Center; 🇰🇷 Seoul, Korea, Republic of

Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital; 🇹🇭 Bangkok, Thailand

Hospital Universitario Quirón; 🇪🇸 Madrid, Spain

Royal Cornwall Hospital; 🇬🇧 Truro, United Kingdom

Carmal MC; 🇮🇱 Haifa, Israel

Norton Cancer Institute; 🇺🇸 Louisville, Kentucky, United States

Massachusetts General Hospital Cancer Center - Hematology/Oncology; 🇺🇸 Boston, Massachusetts, United States

Leo W. Jenkins Cancer Center; 🇺🇸 Greenville, North Carolina, United States

University of Michigan - Internal Medicine Division of Hematology/Oncology; 🇺🇸 Ann Arbor, Michigan, United States

University of Iowa Hospitals & Clinics; 🇺🇸 Iowa City, Iowa, United States