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 M281 on the ability to decrease oral corticosteroids association between IgG reduction and Hgb/hemolysis parameters
- Effects of M281 on normalization of hemoglobin (Hgb) level
- Effects of M281 on normalization of hemolytic markers
-Effects of M281 on the ability to achieve a durable increase in, and stability of, Hgb level
-Impact of M281 treatment on fatigue |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion Criteria -
1. Male or female ≥18 years of age.
2. Diagnosed with active primary or secondary wAIHA, defined as having
all of the following:
a.Hemoglobin level <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 total bilirubin above the ULN AND
c.Serological evidence of anti-erythrocyte antibodies associated with a
positive DAT that is either positive for IgG only or is positive for IgG and
C3d (fragment of the third component of complement) at time of
diagnosis.
3.Has been diagnosed with wAIHA for at least 3 months, has received
standard of care treatment for wAIHA but is not currently under
adequate control
4.If on corticosteroids, are on a dose that has been stable for at least 14
days prior to randomization.
5.If currently receiving immunosuppressants, has been on a stable dose
for 30 days prior to Screening. Allowed concomitant
immunosuppressants are azathioprine, mycophenolate
mofetil/mycophenolic acid, cyclosporine, cyclophosphamide.
6.Have a platelet count ≥30 × 109/L.
7.Have screening serum albumin and serum calcium concentrations
within the normal range.
8.Have screening total serum IgG of at least 600 mg/dL.
9.Have a screening creatine kinase (CK) value <2 × ULN.
10.Have a negative QuantiFERON®-TB Gold test.
11.Patients who have undergone splenectomy must be at least 3 months
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 19 Years or
Older, United States
12.Patients with 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 3 months). Patients with
lymphoproliferative disease must have a low grade, be stable and be, in
the opinion of the Investigator, unlikely to require chemotherapy or
monoclonal antibody therapy during the study. Patients requiring change
of treatment or new treatment (but not rescue therapy) during the study
will be terminated from the study
13.Have sufficient venous access to allow drug administration by IV
infusion and blood sampling as per the protocol.
14.Women of childbearing potential (WOCBP), 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.
15.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.
Note: For the Czech Republic only, condom plus diaphragm, condom plus spermicide,
and diaphragm plus spermicide are not considered highly effective methods of
contraception.
16.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 100 days following the
last study treatment, unless the patient provides documentation of a
vasectomy at least 6 months prior to Screening. Male patients must also
abstain from sperm donation during the study and for 100 days following
the last treatment.
17.Are able to understand and voluntarily provide written informed
consent to participate in the study and comply with all study procedures. |
|
E.4 | Principal exclusion criteria |
Exclusion Criteria -
1.Have received a transfusion within 30 days prior to randomization.
2.Have any other associated cause of hereditary or acquired hemolytic
anemia.
3.Have received rituximab within 6 months prior to randomization.
Note: Patients who received rituximab within 3 months but have
evidence of worsening hemolysis (defined as LDH levels above ULN or
haptoglobin levels below the lower limit of the normal range (LLN) or
total bilirubin levels above the ULN) may be included in the study.
4. Has received IVIG within 6 weeks prior to randomization on Day 1. The patient may be
re-screened after the exclusionary period of 6 weeks has passed.
5.Have cold antibody AIHA, cold agglutinin syndrome, mixed type (ie,
warm and cold) AIHA, or paroxysmal cold hemoglobinuria.
6.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. The patient may be re-screened after the 8 week exclusionary
period has passed. Any patient with an infection requiring oral antiinfectives
(eg, sinusitis, bronchitis, uncomplicated urinary tract
infection) within 4 weeks prior to screening will be excluded, but may be
subsequently re-screened after the 4 week exclusionary period has
passed.
7.Have a chronic infection (eg, bronchiectasis, chronic osteomyelitis,
chronic pyelonephritis) or require chronic treatment with anti-infectives
(eg, antibiotics, antivirals).
8.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. The patient may be re
screened after the 3 month exclusionary period has ended.
9. Has 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.
10.Have a known history of, or positive test result for human
immunodeficiency virus-1 (HIV 1) and HIV 2 antibodies, hepatitis B virus
(HBV core antigen), or hepatitis C virus (HCV).
Note: Patients with past HCV may be included in the study if they have a
documented negative HCV ribonucleic acid level in the serum at 12
weeks or longer after the completion of HCV therapy.
11.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.
12.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.
13.Are currently participating in another interventional clinical trial or
have received any investigational drug within the past 3 months.
14.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.
15.Have a history of a major organ transplant (eg, heart, lung, kidney,
liver), or hematopoietic stem cell/marrow transplant.
16.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.
17.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.
18.Have a hypersensitivity to M281 or any constituent of the study drug
solution.
19.Have had a prior severe therapeutic drug reaction that included shock
or severe hypersensitivity.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the attainment of the following at 3, where at least the first is
consecutive visits at or before Week 16 without the need of rescue
therapy:
• Hgb level ≥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 baseline and screening 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) |
The following are secondary efficacy outcome measures:
• Change in oral corticosteroid use
o Overall percentage of patients that achieved any reduction in the
daily dose of corticosteroids while maintaining Hgb response from
baseline to the end of the double-blind period
o Percent reduction in daily corticosteroid dose in each group between
baseline and the end of the double-blind period
• Association between IgG reduction and Hgb/hemolysis parameters
o 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 Hgb level
o Hgb level and change from baseline in Hgb level through Week 16
o Hgb level and change from baseline in Hgb level throughout the study
• Normalization of hemolytic markers
o Attainment of a 2 g/dL Hgb increase from baseline AND normal LDH
and haptoglobin levels at any time during the study
o Attainment of a 2 g/dL Hgb increase from baseline AND normal LDH
and haptoglobin levels at 3 consecutive visits
• Duration of response
o Duration from the first time point at which the criteria for the primary
efficacy endpoint is met until the time point at which it is no longer met
o Females: attainment and maintenance of a Hgb level of 11 g/dL
during the 24 week double-blind period; Males: attainment and
maintenance of a Hgb level of 12 g/dL during the 24 week double-blind
period
• Change in the level of patient fatigue
o Change from baseline in the total score from the FACIT-Fatigue Scale
at the end of the double-blind period.
Secondary endpoints will be summarized descriptively. Categorical
variables will be summarized by treatment group using frequencies and
percentages. Differences between each M281 group and placebo will be
summarized as differences in proportions. Baseline adjusted estimates
of the treatment effect of each M281 group versus placebo will also be
derived using logistic regression with treatment group and the
stratification factor (screening Hgb) as covariates. The influence of other
covariates may be explored. Percentage reduction in corticosteroid dose,
duration of efficacy response, Hgb level, and change from baseline in
total score from FACIT-Fatigue Scale will be summarized as continuous
variables by treatment group using descriptive statistics such as n,
mean, median, standard deviation, minimum, and maximum. Differences
between each M281 group and placebo will be summarized as
differences of means. Baseline adjusted estimates of the treatment
effect of each M281 group versus placebo will also be derived using
linear regression with treatment group and stratification factor
(screening Hgb) as covariates. Mixed models will be used to evaluate
Hgb levels longitudinally in relationship to IgG reductions and dose
regimens. The influence of other covariates may be explored. Where
appropriate, 95% CIs around point estimates will be presented.
Additional details on analysis of secondary endpoints will be described in
the SAP. |
|
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 | 2 |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
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 |
Czech Republic |
Denmark |
France |
Germany |
Greece |
Hungary |
Italy |
Netherlands |
Poland |
Spain |
United Kingdom |
United States |
|
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 | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |