|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Warm Autoimmune Hemolytic Anemia
|Medical condition in easily understood language
|Warm Autoimmune Hemolytic Anemia
|Diseases [C] - Immune System Diseases [C20]
|E.1.2 Medical condition or disease under investigation
|Autoimmune hemolytic anemia
|System Organ Class
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|To examine the effect of RVT-1401 on proportion of responders (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).
To assess the safety and tolerability of RVT-1401 in subjects with WAIHA
|Secondary objectives of the trial
|To examine the effect of RVT-1401 on change in Hb levels
To examine the effect of RVT-1401 on time to response
To examine the effect of RVT-1401 on change in hematocrit levels
To examine the effect of RVT-1401 on proportion of participants with Hb levels in the normal range
To examine the effect of RVT-1401 on time to achieving Hb levels in the normal range
To examine the effect of RVT-1401 on change in fatigue
To examine the effect of RVT-1401 on change in dyspnea
To examine the effect of RVT-1401 on change in health-related quality of life
To assess the change in serum levels of total IgG & IgG subclasses (I-IV)
To examine RVT-1401 PK following repeated doses in patients with WAIHA
To assess the changes in LDH, bilirubin,haptoglobin
To measure anti-RVT-1401 antibodies following repeated doses in patients with WAIHA
|Trial contains a sub-study
|Principal 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. Haptoglobin < lower limit of normal (LLN) and lactate dehydrogenase (LDH) >upper limit of normal (ULN).
7. 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).
8. Karnofsky Performance status ≥ 60.
9. 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.]
10. A female participant is eligible to participate if she is of:
a. 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 [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) in the post-menopausal range is confirmatory].
b. Child-bearing potential and agrees to use one of the contraception methods listed in Section 6.6.1 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.
11. Male participants must agree to use one of the contraception methods listed in Section 6.6.1. 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.
12. Willing and capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
|Principal 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).
7. Albumin level <3.5 g/dL at Screening.
8. Known advanced liver disease including any diagnosis of cirrhosis of any stage.
Non- alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis (NASH) is allowable if there has been a recent (within 6 months) normal ultrasound, CT, or MRI. If the ultrasound, CT, or MRI demonstrate fatty changes alone, the participant may be enrolled if s/he has a normal range fibroscan for liver fibrosis.
9. AST or ALT ≥1.5x ULN at Screening.
The participant may only be enrolled if s/he has a recent (within 6 months) normal ultrasound, CT, or MRI. If the ultrasound, CT, or MRI demonstrate fatty changes alone, the participant may be enrolled if s/he has a normal range fibroscan for liver fibrosis.
10. Participant has any laboratory abnormality (at screening) that, in the opinion of the investigator, is clinically significant, has not resolved at baseline, and could jeopardize or would compromise the participant's ability to participate in this study.
11. Medical history of primary immunodeficiency, T-cell or humoral, including common variable immunodeficiency.
12. Have an active infection, a recent serious infection (i.e., requiring injectable antimicrobial therapy or hospitalization) within the 8 weeks prior to Screening.
13. History of or known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or Mycobacterium tuberculosis:
- Participants must have negative test results for HBV surface antigen, HBV core antibody, HIV 1 and 2 antibodies, and a negative QuantiFERON-TB Gold test at Screening.
- Participants with an indeterminate QuantiFERON-TB Gold test result will be allowed one retest; if not negative on retesting, the participant will be excluded.
14. Infection with hepatitis C virus (HCV):
- Participants must have a negative test result for HCV antibody.
- Participants with a known history of HCV must have documented evidence of sustained virologic response that is consistent with cure of hepatitis C infection. This is defined as undetectable or unquantifiable HCV RNA at least 12 weeks after stopping HCV treatment (HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C; 2014-2018, AASLD and IDSA). This should be confirmed with a negative HCV RNA test at Screening.
15. Active malignancy or history of malignancy in the 3 years prior to screening (exclusive of non-melanoma skin cancer and cervical cancer in situ).
16. Participant has any medical condition (acute or chronic illness) or psychiatric condition that, in the opinion of the investigator, could jeopardize or would compromise the participant's ability to participate in this study.
17. Body Mass Index (BMI) at Screening ≥ 40 kg/m2.
18. Use of investigational drug within 60 days or 5 half-lives of the drug (whichever is longer) before Screening.
19. Participant has received a live vaccination within 2 weeks prior to the Baseline Visit; or intends to have a live vaccination during the course of the study or within 7 weeks following the final dose of study treatment.
20. History of sensitivity to any of the study treatments, or components thereof or a history of anaphylaxis (i.e., serious, life-threatening allergic reactions) that, in the opinion of the Investigator or Medical Monitor, contraindicates their participation.
21. Pregnant or lactating females as determined by positive serum or urine human chorionic gonadotropin test at screening or baseline.
22. QTcF interval >450 milliseconds for males and >470 milliseconds for females at Screening (a single repeat is allowed for eligibility determination). QTcF >480 msec in participants with Bundle Branch Block.
23. Diagnosis of concomitant idiopathic thrombocytopenia purpura (ITP)/ Evans syndrome with platelet count <100,000.
|E.5 End points
|Primary end point(s)
|Proportion of responders at week 13
Assessment of safety and tolerability by analysis of adverse event (AE) data and changes from baseline in vital signs, ECGs, and clinical laboratory values
|Timepoint(s) of evaluation of this end point
|Secondary end point(s)
|Change from baseline in Hb levels
Time to response
Change from baseline in hematocrit levels
Proportion of participants with Hb levels in the normal range at week 13
Time to achieving Hb levels in the normal range
Change from baseline in FACIT-F score
Change from baseline in Medical Research Council (MRC) breathlessness scale
Change from baseline in EQ-5D-3L score
Change from baseline in levels of total IgG & IgG subclasses (I-IV)
Concentration of RVT-1401 pre-dose (Ctrough)
Change from baseline in LDH, bilirubin, and haptoglobin
Immunogenicity determined by change from pre-dose in anti-RVT-1401 antibodies, and characterization of any anti-RVT-1401 to confirm neutralization potential.
|Timepoint(s) of evaluation of this end point
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Other scope of the trial description
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Dosing Regimen A -680 mg weekly for 12 weeks; Dosing Regimen B - 340 mg weekly for 12 weeks
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Korea, Republic of
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days