| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Warm antibody autoimmune hemolytic anemia (wAIHA) | |
| E.1.1.1 | Medical condition in easily understood language | | Autoimmune hemolytic anemia (AIHA) is an acquired disorder manifested by autoantibody- mediated red blood cell (RBC) destruction. | |
| 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 | 20.0 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10003825 | | E.1.2 | Term | Autoimmune hemolytic anemia | | E.1.2 | System Organ Class | 100000004851 | |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | The primary objective of this study is to compare the proportion of warm antibody autoimmune hemolytic anemia (wAIHA) subjects who achieve a durable hemoglobin response between the fostamatinib and placebo groups. | |
| E.2.2 | Secondary objectives of the trial | The secondary objectives of this study are:
1.To compare the proportion of subjects with hemoglobin response on at least one visit between the fostamatinib and placebo groups.
2.To compare the proportion of subjects who achieve a change from Baseline in hemoglobin level of ≥ 2 g/dL between the fostamatinib and placebo groups.
3.To compare the change in hemoglobin value from Baseline to the End of Treatment between the fostamatinib and placebo groups.
4.To compare the proportion of subjects who use permitted rescue medications after Week 4 between the fostamatinib and placebo groups.
5.To compare the change from Baseline to Week 24 in Functional Assessment of Chronic Illness Therapy - Fatigue scale (FACIT-F).
•The safety objective is to assess the safety of fostamatinib in subjects with wAIHA.
•Additional efficacy and pharmacoeconomic objectives will compare the fostamatinib and placebo groups for the endpoints noted in Section 4.5.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1. Subject must be willing and able to give written informed consent by signing an IRB approved Informed Consent Form prior to undergoing any study-specific procedures.
2. Subject must have a diagnosis of primary or secondary wAIHA as documented by a positive direct antiglobulin test (DAT) specific for anti-IgG or anti-IgA. Eligibility may be based on a historical DAT obtained within 12 months of the screening visit from a local laboratory, provided that specific IgG or IgA positivity is documented; otherwise, this assay will be done at screening by a central laboratory.
3. Has failed or not tolerated at least one prior wAIHA treatment, e.g., steroids, rituximab, azathioprine, cyclophosphamide, cyclosporine, mycophenolate mofetil (MMF), danazol, vincristine, ESA or splenectomy (folate, iron or other supplements do not fulfill this criterion).
4. Has haptoglobin <LLN or total bilirubin >ULN or lactate dehydrogenase (LDH) >ULN.
5. At screening, subject’s hemoglobin level must be ≤9 g/dL
OR
If the hemoglobin value is >9 g/dL and <10 g/dL, subject must be on an allowed wAIHA treatment (see Allowed AIHA Therapy table) AND the subject must have documented symptoms related to anemia (e.g., weakness, dizziness, fatigue, shortness of breath, chest pain).
6. Male or female at least 18 years of age at screening.
7. Karnofsky performance status (KPS) ≥70.
8. Subject’s concurrent treatment for wAIHA may consist of no more than two of any of the following agents: azathioprine, steroids, ESAs, mycophenolate mofetil, dapsone or danazol at a stable dose, as defined in the Allowed AIHA Therapies table. Subject has not taken any disallowed therapies in the intervals defined by the protocol.
9. Female subjects must be either post-menopausal for at least 1 year or surgically sterile; or, if of childbearing potential, must not be pregnant or lactating and must agree to use a highly effective method of birth control throughout the duration of the trial and for 30 days following the last dose. Acceptable methods of birth control are defined as: hormonal contraception (pill, injection or implant) used consistently for at least 30 days prior to screening, an intrauterine device (IUD), or intrauterine hormone-releasing system (IUS), or true abstinence (i.e. abstinence is in line with the preferred and usual lifestyle of the subject).
10. In the investigator’s opinion, the subject has the ability to understand the nature of the study and any hazards of participation and to communicate satisfactorily with the investigator.
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| E.4 | Principal exclusion criteria | 1. Subject with other types of AIHA (e.g., cold antibody AIHA, cold agglutinin syndrome, mixed type AIHA, or paroxysmal cold hemoglobinuria).
2. Subject has AIHA secondary to autoimmune disease, including systemic lupus erythematosus (SLE), or lymphoid malignancy if the underlying disease is not stable or is not well-controlled on current therapy, per investigator medical judgment.
3. Subject has a history of or active, clinically significant, cardiovascular, respiratory, gastrointestinal, renal, hepatic, neurological, psychiatric, musculoskeletal, genitourinary, dermatological, or other disorder that, in the investigator’s opinion, could affect the conduct of the study or the absorption, metabolism or excretion of the study drug.
4. Subject has uncontrolled or poorly controlled hypertension, defined as systolic blood pressure ≥135 mmHg or diastolic blood pressure ≥85 mmHg, whether or not the subject is receiving anti-hypertensive treatment.
5. Subject has one or more of the following laboratory abnormalities at screening: neutrophil count of <1,000/µL or platelet count of <30,000/μL, unless due to Evans syndrome; transaminase levels (i.e., alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) >1.5 x ULN.
6. Has documented HIV infection or active hepatitis B or hepatitis C infection.
7. Subject is currently enrolled in an investigational drug or device study or has used an investigational drug or device within 30 days or 5 half-lives (whichever is longer) of Day 1.
8. In the judgment of the investigator, the subject may not be able to fully comply with study requirements.
9. Subject has been treated with fostamatinib previously for any indication.
10. Subject has a known allergy and/or sensitivity to the test article or its components.
11. Subject has had a splenectomy within the past 4 weeks.
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| E.5 End points |
| E.5.1 | Primary end point(s) | | The primary efficacy endpoint is achievement of durable hemoglobin response (Yes/No) defined as achieving a hemoglobin level ≥ 10 g/dL with an increase from Baseline in hemoglobin level of ≥2 g/dL on 3 consecutive available visits during the 24-week treatment period, in which hemoglobin measurements eligible for this definition occurred outside a Rescue Treatment Visit Exclusion Period. | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | |
| E.5.2 | Secondary end point(s) | Secondary Efficacy Endpoints:
The secondary efficacy endpoints within the 24 weeks of treatment are:
1.Hemoglobin response on at least one visit (Yes/No)
2.Achievement of a change from Baseline in hemoglobin level of 2 g/dL or greater (Yes/No)
3.Change in hemoglobin value from Baseline to End of Treatment (Week 14 to Week 24)
4.Use of permitted rescue medications after Week 4 (Yes/No)
5.Change from Baseline to Week 24 in FACIT-F
Additional efficacy will be evaluated and detailed in the SAP.
Safety Endpoints:
The following safety endpoints will be evaluated:
•Incidence and severity of treatment-emergent adverse events (TEAEs)
•Incidence and severity of TEAEs of interest
•Change from Baseline for select laboratory tests over time (e.g., hematology, chemistry)
•Change from Baseline in blood pressure over time
•Change from Baseline in absolute neutrophil count (ANC) over time
•Change from Baseline in liver function tests (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST]), total bilirubin, direct and indirect bilirubin) over time.
Pharmacokinetic Endpoints:
Plasma concentration of the active component of fostamatinib (R406) relative to the date and time of last dose of study drug, at Weeks 2, 4, 12 and 18 of the treatment period. | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | |
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | No |
| E.6.13 | Others | No |
| 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) | No |
| 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 | Yes |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 46 |
| 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 | | Australia | | Belarus | | Canada | | Georgia | | Russian Federation | | Serbia | | Ukraine | | United States | | Austria | | Belgium | | Czechia | | Denmark | | France | | Germany | | Hungary | | Italy | | Norway | | United Kingdom | | Bulgaria | | Netherlands | | Romania | | Spain | |
| 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 | | The end of the study will be when the last subject has completed either the Week 24 visit or their last follow-up study visit, whichever is later. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 24 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
