| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adults with Warm Autoimmune Hemolytic Anemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Autoimmune Hemolytic Anemia |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10002285 |
| E.1.2 | Term | Anemia hemolytic autoimmune (NOS) |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of M281 in patients with warm autoimmune hemolytic anemia (wAIHA). |
|
| E.2.2 | Secondary objectives of the trial |
to evaluate the:
- Impact of nipocalimab treatment on fatigue
- Effects of nipocalimab on normalization of hemolytic markers
- Impacts of nipocalimab on corticosteroid use
- Association between immunoglobulin G (IgG) reduction and Hgb/hemolysis parameters
- Effects of nipocalimab on normalization of hematologic and hemolytic parameters
- Effects of nipocalimab on time to, and the duration of, Hgb response
- Effects of nipocalimab on quality of life and clinical status |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria-Double blind period
1.Male or female≥8 years of age.
2.Diagnosed with active primary or secondary wAIHA, defined as having all of the following:
a.Hemoglobin concentration<9 g/dL or<10 g/dL if symptomatic or on corticosteroids/immunosuppressants AND
b.Signs of hemolysis, defined as: lactate dehydrogenase (LDH) levels above the upper limit of normal (ULN), or haptoglobin below the lower limit of normal, or indirect bilirubin above the ULN AND
c.Serological evidence of anti-erythrocyte antibodies associated with a DAT that is either positive for IgG only or is positive for IgG and C3d (fragment of the third component of complement) at screening.
3.Has been diagnosed with wAIHA for at least 3months, and currently receiving or has previously received
treatment for wAIHA (treatment naive patients not eligible)
4.If on corticosteroids,the dose must be stable for at least 14days prior to randomization.
5.If currently receiving immunosuppressants (ISPs),the patient must have been on the given ISP for≥6 months and must have been on a stable dose for≥3months prior to Screening. Allowed concomitant ISPs are azathioprine,mycophenolate mofetil/mycophenolic acid,methotrexate,cyclosporine,tacrolimus,danazol and cyclophosphamide.
6.Have a platelet count≥30×109/L.
7.Patients who have undergone splenectomy must be at least 3months post resection prior to screening and must be vaccinated as per the United States Center for Disease Control and Prevention(CDC)annual
Recommended Immunization Schedule for Adults Aged 19Years or Older, United States
8.Patients with other autoimmune disease (eg, systemic lupus erythematosus or rheumatoid arthritis) and lymphoproliferative disorders may be eligible if they are stable (no changes in concomitant disease-related
medications and severity of disease for at least 3months prior to screening). Patients with
lymphoproliferative disease must have a low grade, be stable and be unlikely to require chemotherapy or monoclonal antibody therapy during the double blind period of the study. Patients requiring change of treatment or new treatment (but not rescue therapy for wAIHA) during the DBP will be terminated from the study.
9.Have sufficient venous access to allow drug administration by IV infusion and blood sampling as per the protocol.
10.Women of childbearing potential, defined as women physiologically capable of becoming pregnant, must have a negative serum pregnancy test at screening and a negative urine pregnancy test at Baseline. Menopausal women must have an elevated serum folliclestimulating hormone(FSH)level at Screening; if the FSH is not elevated, they are considered to be of childbearing potential and must have a
negative serum pregnancy test at screening and a negative urine pregnancy test at Baseline to be eligible.
11.Women of childbearing potential(including menopausal women who do not have elevated FSH)must agree to remain totally abstinent(ie, refrain from sexual intercourse during the study)or to consistently use a reliable and highly effective method of contraception(eg, condom plus diaphragm, condom plus spermicide, diaphragm plus spermicide, or intrauterine device or oral/injectable/implanted hormonal contraceptive used in combination with an additional barrier method)during the study and for 30 days after the last study treatment.
12.Male patients must agree to remain totally abstinent(ie, refrain from sexual intercourse during the study) or to consistently use a reliable and highly effective method of contraception (eg, condom plus diaphragm, condom plus spermicide, diaphragm plus spermicide, or intrauterine device or oral/injectable/implanted hormonal contraceptive used in combination with an additional barrier method) to avoid pregnancy of the patient's partner(s) during the study and for 100days following the last study treatment, unless the patient provides documentation of a vasectomy at least 6months prior to Screening. Male patients must also abstain from sperm donation during the study and for 100 days following the last treatment.
13.Patients using herbal, traditional Chinese etc. supplements, or medical marijuana are eligible if accepted by the Investigator.
14.Are able to understand and voluntarily provide written informed consent to participate in the study and comply with all study procedures.
15. Vaccinations prior to screening (incl.COVID-19).
Inclusion Criteria-Open-Label Extension
1.Have completed the double blind period (through Week 24), or have required rescue therapy after Week 4 of the double-blind period, or failed to demonstrate an increase from baseline in Hgb of a least 1 g/dL at or after Week 16 of the double-blind period.
2.Are able to understand and voluntarily provide written informed consent to participate in the OLE period and comply with all study procedures.
Inclusion Criteria #6, #8, #10, #11, and #12 from the Double-blind Period (Protocol Section 4.2.1) also apply to enrollment in the OLE |
|
| E.4 | Principal exclusion criteria |
Exclusion Criteria - Double blind period
1.Are currently taking IgG Fc-related protein therapeutics
2.Have received a transfusion within 30 days prior to randomization.
3.Have any other associated cause of hereditary or acquired hemolytic anemia.
4.Have received rituximab within 3 months prior to screening.
5.Have received IVIG within 6 weeks prior to screening.
6.Have cold antibody AIHA, cold agglutinin syndrome, mixed type (ie, warm and cold) AIHA, or paroxysmal cold hemoglobinuria.
7.Have a severe infection (eg, pneumonia, biliary tract infection, diverticulitis, Clostridium difficile infection) that requires parenteral anti-infectives and/or hospitalization, and/or is assessed as serious/clinically significant by the Investigator, within 8 weeks prior to screening. Any patient with an infection requiring oral antiinfectives (eg, sinusitis, bronchitis, uncomplicated urinary tract infection) within 4 weeks prior to screening will be excluded.
8.Have a chronic infection (eg, bronchiectasis, chronic osteomyelitis, chronic pyelonephritis) or require chronic treatment with anti-infectives (eg, antibiotics, antivirals).
9.Have received a live vaccine within 3 months prior to screening, or have a known need to receive a live vaccine during the study or within at least 3 months after the last dose of study drug.
10.Have any confirmed or suspected clinical immunodeficiency syndrome not related to treatment of his/her wAIHA, or has a family history of congenital or hereditary immunodeficiency unless confirmed absent in the patient.
11.Have any of the following viral testing outcomes: A history of HIV infection or positive test result for HIV-1 and HIV-2 antibodies; A positive test for hepatitis B virus surface antigen (HBsAg). For patients with a negative test for HBsAg along with a positive test for anti-hepatitis B core antibodies and a positive or negative test for anti-HBs antibodies, hepatitis B viral DNA detection will be performed. Patients with a positive hepatitis B viral DNA detection will be excluded; A positive test for hepatitis C virus (HCV) antibodies along with a positive detection for HCV ribonucleic acid (RNA).
12.Are currently breastfeeding, pregnant, intend to become pregnant during the study, or are planning egg donation during the study or within 30 days after the last dose of study drug.
13.Have current alcohol/substance abuse/dependence, a history of alcohol/substance abuse/dependence within the 12 months prior to screening, or, in the Investigator's opinion, show evidence of ongoing
alcohol/substance abuse/dependence.
14.Are currently participating in another interventional clinical trial or have received any investigational drug within the past 3 months prior to screening.
15.Have had any major surgery within 3 months prior to screening or have plans for or have been scheduled for any elective surgery or major dental procedure during the study.
16.Have a history of a major organ transplant (eg, heart, lung, kidney, liver), or hematopoietic stem cell/marrow transplant.
17.Have a history of severe and/or uncontrolled hepatic, gastrointestinal, renal, pulmonary, cardiovascular, psychiatric, neurological, or musculoskeletal disorder, hypertension, or any other medical or uncontrolled autoimmune disorder that, in the opinion of the Investigator, might interfere with the patient's full participation in the study, or might jeopardize the safety of the patient or the validity of the study results.
18.Received treatment for non-lymphoid malignancy within 1 year prior to screening, with the exceptions of properly treated basal or squamous cell carcinoma of the skin or properly treated carcinoma in situ of the
cervix.
19.Have any other medical condition(s) likely to require treatment with oral or parenteral glucocorticosteroids (GCS), or have required oral or parenteral GCS (inhalational, intra-articular, topical, or ocular GCS are not exclusionary) in the 2 weeks prior to randomization, or other medical condition(s) likely to require treatment with any immunosuppressive agents (IA) not being used to treat wAIHA, or have required any IA for 6 months prior to Screening.
20.Have previously received nipocalimab.
21.Have a hypersensitivity to nipocalimab or any constituent of the study drug solution.
22.Have had a prior severe therapeutic drug reaction that included shock or severe hypersensitivity to inj. biologics.
Exclusion Criteria - Open Label Extension
1.Met any of the stopping criteria (see Sections 6.4.1 of the protocol) or discontinued study drug during the double-blind period due to treatment-related AE.
2.Currently have a serious or clinically significant infection (eg, pneumonia, biliary tract infection, diverticulitis, C. difficile infection) requiring parenteral anti-infectives and/or hospitalization.
The following exclusion criteria from the Double-blind Period (Protocol Section 4.2.2) also apply to enrollment in the OLE: Exlusion Criteria #8 and #21. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is durable response in improvement of
Hgb, defined as the attainment of the following at 3 consecutive visits,
where at least the first is at or before Week 16, without the need of
rescue therapy:
• Hgb concentration ≥10 g/dL AND
• An increase from baseline in Hgb ≥2 g/dL
The first of the three consecutive visits must be at or before week 16 in
order to qualify for success in the primary efficacy endpoint. For
example, if a patient attained the above criteria at weeks 18, 20, and 22
and not before, this patient would not be considered a success. If the
patient attained the criteria at weeks 16, 18, and 20, the patient would
be considered a success.
In case 1 of the 3 consecutive Hgb observations is missing and the other
2 met the above criteria, the next non-missing Hgb observation must
also meet the criteria in order for the patient to qualify as a success in
the primary efficacy endpoint. No more than 1 missing observations is
allowed. For example, if a patient met the criteria at weeks 14, 16, and
20, and with a missing value at week 18, this patient would be
considered a success in the primary efficacy endpoint. If the patient met
the criteria at weeks 14, 18, and 22, but with missing data at weeks 16
and 20, the patient would not be considered a success.
Patients who took rescue therapy before reaching the criteria will be
treated as having failed the primary efficacy outcome.
If a patient has missing Hgb at both screening and baseline but is
randomized by mistake, the patient will be excluded from the ITT
analysis. This situation is unlikely to happen because the IVRS system
requires screening Hgb for randomization to occur. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The first of the three consecutive visits must be at or before week 16 in
order to qualify for success in the primary efficacy endpoint. In case 1 of
the 3 consecutive Hgb observations is missing and the other 2 met the
above criteria, the next non-missing Hgb observation must also meet the
criteria in order for the patient to qualify as a success in the primary
efficacy endpoint. No more than 1 missing observations is allowed. For
example, if a patient met the criteria at weeks 14, 16, and 20, and with a
missing value at week 18, this patient would be considered a success in
the primary efficacy endpoint. If the patient met the criteria at weeks
14, 18, and 22, but with missing data at weeks 16 and 20, the patient
would not be considered a success. |
|
| E.5.2 | Secondary end point(s) |
Key secondary endpoints:
-Change in the level of patient fatigue. Change from baseline in the total score from the FACIT-Fatigue Scale at the time of durable response or the end of the double-blind period.
-Simultaneous attainment of normal LDH (below the ULN), AND
haptoglobin (above the LLN), AND indirect bilirubin levels (below the ULN) at a minimum of 3 consecutive visits after baseline.
-Percent reduction from baseline in daily dose of prednisone or equivalent at week 24 among patients on prednisone or equivalent at baseline.
Other Secondary Endpoints:
-Association between IgG reduction and Hgb/hemolysis parameters: Hgb range at steady state (estimated using a model-based longitudinal analysis of Hgb/hemolysis parameters in relationship to IgG level and
dose regimen)
-Normalization of hematologic and hemolytic parameters: Hgb concentration, reticulocyte count, and hemolytic markers, and change from baseline in these parameters through Week 16 of the double-blind period Hgb concentration, reticulocyte count, and hemolytic markers, and change from baseline throughout the study
-Normalization of hemolytic markers
1. Attainment of a 2 g/dL Hgb increase from baseline AND normal LDH, and haptoglobin, and indirect bilirubin levels at any time during the study
2. Attainment of a 2 g/dL Hgb increase from baseline AND normal LDH and, haptoglobin, and indirect bilirubin levels at 3 consecutive visits
-Time to and duration of Hgb response
1.Time to response defined as the first time point at which the durable response criteria for the primary efficacy endpoint is met
2.Duration from the first time point at which the durable Hgb response criteria for the primary efficacy endpoint is met until the time point at which it is no longer met
-Change in the level of patient fatigue:
1.Change from baseline in the total score from the FACIT-Fatigue Scale at the time of durable response;
2.Change from baseline in the total score and item scores from the FACIT-Fatigue Scale during the double-blind period and the open-label extension (OLE)
-Changes in quality of life parameters based on EQ-5D-5L, SF-36, PGIS, PGIC, and FACIT-Fatigue Scale |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The first of the three consecutive visits must be at or before week 16 in
order to qualify for success in the primary efficacy endpoint. In case 1 of
the 3 consecutive Hgb observations is missing and the other 2 met the
above criteria, the next non-missing Hgb observation must also meet the
criteria in order for the patient to qualify as a success in the primary
efficacy endpoint. No more than 1 missing observations is allowed. For
example, if a patient met the criteria at weeks 14, 16, and 20, and with a
missing value at week 18, this patient would be considered a success in
the primary efficacy endpoint. If the patient met the criteria at weeks
14, 18, and 22, but with missing data at weeks 16 and 20, the patient
would not be considered a success. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability and Immunogenicity |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Israel |
| Ukraine |
| United States |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
| Czechia |
| Greece |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
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 |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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