E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary Immune Thrombocytopenia |
|
E.1.1.1 | Medical condition in easily understood language |
Primary Immune Thrombocytopenia |
|
E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
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 | 10074678 |
E.1.2 | Term | Primary immune thrombocytopenic purpura |
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 safety and tolerability of ARGX-113 (short and long term)
To evaluate the safety of repeated use of ARGX-113 |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the patients with initial response i.e., platelet count ≥ 30 × 109/L and/or at least doubling of the Baseline count and absence of bleeding.
- To evaluate the clinical effect of ARGX-113 ARGX-113 (short term and long term) on:
- platelet counts;
- use of rescue treatment;
- bleeding events.
- To evaluate the efficacy of repeated use of ARGX-113.
- To assess the effect of ARGX-113 on quality of life.
- To assess the PK of ARGX-113.
- To assess the PD effects of ARGX-113.
- To evaluate the immunogenicity of ARGX-113.
Specifically for the extended FU period:
To assess the duration of the treatment effect for all patients who did
not relapse during the treatment period. This will be based on:
- local platelet counts;
- use of rescue treatment;
- bleeding events.To assess the PK of ARGX-113.
To assess the PD effects of ARGX-113.
To evaluate the immunogenicity of ARGX-113. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Main study
1. Ability to understand the requirements of the study, and comply
withthe study protocol procedures (including required study visits).
2. Male or female patients aged ≥ 18 to ≤ 85 years.
3. Eligible patients must receive standard-of-care treatment for ITP
following the ASH guidelines and International Working Group (IWG)
stable in dose and frequency for at least 4 weeks prior to Screening.
4. Confirmed diagnosis of ITP according to the American Society of
Hematology Criteria 2011 with (average) blood platelet counts < 30 ×
10E9/L and who have not experienced major bleeding in the last 4
weeks prior to Screening.
5. Women of childbearing potential must have a negative serum
pregnancy test at Screening and a negative urine pregnancy test at
Baseline prior to administration of IMP.
6. Female participants of childbearing potential must agree to use a
highly effective method of birth control (i.e., pregnancy rate of less than
1% per year) during the study and for 90 days after the discontinuation
of IMP.
7. Non-sterilized male patients who are sexually active with a female
partner of childbearing potential must use effective double contraception
Additional Inclusion Criteria for the Extended Follow-up Period
- Sign the amended ICF of the main study including its extended
followup
period
- Completed Visit 16 of the FU period of the protocol with a platelet
count ≥ 30 × 10E9/L and/or at least doubling of the Baseline platelet
count and absence of bleeding and remained on the same SoC
Eligibility criteria for the open-label treatment period (first treatment
cycle)
1. Please refer to inclusion criteria 5, 6 and 7 from the main study.
2. Provide written informed consent
3. Received at least 3 doses of the IMP and had at least 2 weeks of
follow-up in the main study.
4. Patient is at the same SoC as in the main study. Dose and/or
frequency increase is allowed, changing or stopping the SoC is not
allowed.
5. During up to 21 weeks of FU, the patient is relapsing i.e. platelet count
decreases to below 30 x 10E9/L or the patient's platelets never went up
to 30 x 10E9/L and are still below 30 x 10E9/L, and absence of bleeding.
Eligibility criteria for subsequent open-label retreatment cycles
The patient has the right to receive more than 1 retreatment cycle if:
1. Patient reached a platelet count of at least twice the platelet count
measured on the day of the first IMP administration during the previous
(re)treatment cycle, confirmed on at least 2 separate consecutive
occasions (at least 1 day apart but with maximum 7 days in between the
2 measurements), and measured during the treatment period up to
minimum 4 weeks of follow-up.
2. Patient received at least 3 doses of the IMP and had at least 4 weeks
follow-up in the previous treatment cycle.
3. Patient is at the same SoC as in the previous treatment cycle. Dose
and/or frequency increase is allowed, changing or stopping the SoC is
not allowed.
4. Patient is relapsing i.e. platelet count decreases to below 30 x 10E9/L
or the patient's platelets never went up to 30 x 10E9/L and are still
below 30 x 10E9/L, and absence of bleeding. |
|
E.4 | Principal exclusion criteria |
1. Use of anticoagulants, or any drug with antiplatelet effect (e.g., acetylsalicylic acid [aspirin] or other salicylate containing medications, cyclooxygenase inhibitors, adenosine diphosphate (ADP) receptor inhibitors, phosphodiesterase inhibitors, glycoprotein IIB/IIIA inhibitors, adenosine reuptake inhibitors, thromboxane inhibitors, antimalarials, and prostacyclins) during the study and within 3 weeks prior to Screening.
2. Patients who have received any blood support or transfusion within 4 weeks prior to Screening.
3. Use of IVIg or anti-D immunoglobulin treatment within 4 weeks prior to Screening.
4. Use of recombinant thrombopoietin at any time.
5. Use of rituximab within 6 months prior to Screening. Use of any anti-CD20 other than rituximab at any time is not permitted.
6. Use of corticosteroids which has not been stable for at least 4 weeks prior to Screening.
7. Use of immunosuppressants is not permitted within 4 weeks prior to Screening, with the exception of the following oral immunosuppressants: azathioprine [up to 2.5 mg/kg/day], danazol [up to 15 mg/kg/day], mycophenolate mofetil [up to 3 g/day], mycophenolate sodium [up to 2160 mg/day]) which must have been stable for at least 4 weeks prior to Screening.
8. Use of any other biological therapy or investigational drug than those previously indicated within 3 months or 5 half-lives of the drug (whichever is longer) prior to Screening.
9. Received vaccinations within 4 weeks prior to Screening or planned during the study.
10. At Screening, have clinically significant laboratory abnormalities given as below:
a. Aspartate aminotransferase (AST) or ALT > 3 × upper limit of normal (ULN).
b. Total serum bilirubin of > 1.5 x ULN (except for Grade 1 hyperbilirubinemia as defined by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], due solely to a documented medical diagnosis of Gilbert’s syndrome).
c. Serum creatinine of > 1.5 mg/dL or creatinine clearance < 50 mL/min (using Chronic Kidney Disease Epidemiology - Creatinine formula).
d. Hemoglobin ≤ 9 g/dL.
e. Thyroid stimulating hormone or thyroglobulin outside of the central laboratory normal range.
f. International normalized ratio (INR) > 1.5 or activated partial thromboplastin time > 1.5 × ULN.
g. Total immunoglobulin G (IgG) level < 6 g/L.
h. Presence of > 1+ proteinuria
Note: A patient with isolated laboratory values that meet the thresholds listed above may be considered eligible. The agreed upon medical rationale, discussed between the investigator and sponsor, must be documented in the patient's chart prior to patient enrolment in the study
11. History of myeloproliferative or lymphoproliferative disorders at any time; or have a history of malignancy at any time unless deemed cured by adequate treatment with no evidence of recurrence for ≥ 5 years prior to Screening. Patients with completely excised nonmelanoma skin cancers or cervical carcinoma in situ would be permitted at any time.
12. History of cerebrovascular accident or myocardial infarction within the last 12 months, before Screening, or current severe/unstable angina, arrhythmia, or at risk of ventricular arrhythmia, symptomatic congestive heart failure (New York Heart Association Class III or IV), or uncontrolled hypertension (Grade 3 to 4 CTCAE). Uncontrolled hypertension is defined as a repeated elevation in the blood pressure exceeding 140 mmHg and over 90 mmHg despite appropriate treatments.
13. History of any thrombotic or embolic event within 12 months prior to Screening.
14. History of coagulopathy or hereditary thrombocytopenia or a family history of thrombocytopenia.
15. Known history or symptoms of systemic lupus erythematosus, antiphospholipid antibody syndrome or any other clinically documented
auto-immune disease other than ITP.
16. Prior history or symptoms suggestive of untreated Helicobacter pylori infection (recurrent nausea, vomiting, stomach burn, excessive burping, feeling bloated, and unexplained weight loss).
17. History of a recent major surgery (that involve major organs e.g., brain, heart, lung liver, bladder, or gastrointestinal tract) within 4 weeks of Screening or that in the opinion of the investigator may compromise patient’s participation.
18. Active infection; a recent serious infection (i.e., requiring injectable antimicrobial therapy or hospitalization) within the 8 weeks prior to Screening;
Known history or known infection with viral infection with human immunodeficiency virus (HIV 1 and 2 antibodies). Known seropositive or active infection with hepatitis C virus (HCV) hepatitis. Known active or chronic viral infection with hepatitis B virus (HBV). Patients must have a negative TB Quantiferon test at Screening. Patients with an undetermined Quantiferon TB result will be allowed one retest, if not negative on retesting, the patient will be excluded.
Please refer to the protocol on page 41 for the listed points 19 to 23. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
-Incidence and severity of of treatment-emergent AEs (TEAEs) and serious AEs (SAEs).
- Changes from Baseline (mean, median, minimum and maximum values, shifts) in vital signs, electrocardiogram parameters (ECGs), physical examination abnormalities, and clinical laboratory assessments. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Various time points throughout the study |
|
E.5.2 | Secondary end point(s) |
-Frequency and proportion of patients with initial response i.e., platelet count ≥ 30 × 109/L and/or at least doubling of the Baseline count and absence of bleeding at any time during the study.
- Mean change in platelet counts compared to Baseline.
-Frequency and proportion of patients with following response at any time during the study 5,1:
o Complete response (CR): Platelet count ≥ 100×109/L, confirmed on at least 2 separate consecutive occasions ≥ 7 days apart, and the absence of bleeding;
o Response (R): Platelet count ≥ 30 and < 100×109/L, and a greater than 2-fold increase in platelet count from Baseline, confirmed on at least 2 separate consecutive occasions ≥ 7 days apart, and the absence of bleeding;
o No response (NR): Platelet count < 30 × 109/L or less than doubling of the Baseline count or bleeding;
-Time to initial response: time from starting treatment to time to reach CR or R;
-Duration of response: time from the achievement of CR or R to loss of CR or R;
-Frequency and proportion of patients with response to ≥ 50×10E9/L:
Platelet count increase to at least ≥ 50×10E9/L at any time during the
study.
- Frequency and proportion of patients requiring rescue therapy.
-General bleeding assessment by the World Health Organization (WHO)
bleeding scale and SMOG index of the ITP specific bleeding assessment
tool (ITP-BAT)*.
- Change from Baseline in the Short Form-36 item Health Status
Questionnaire (SF-36) and the Functional Assessment of Cancer Therapy
(FACT-Th6)*.
- PK parameters of ARGX-113 including maximum observed
concentration (Cmax), time of maximum concentration (tmax), plasma
concentration prior to dosing (Ctrough), apparent terminal half-life
(t1/2,λz), and accumulation ratio (Rac).*
- Evaluation of pharmacodynamic markers*: Total IgG, IgG isotypes**
IgG1, IgG2, IgG3, IgG4; and antiplatelet antibody levels. In addition,
IgA, IgD, IgE, and IgM will also be assessed**.
- Evaluate the incidence of antidrug antibodies (ADA) to ARGX-113*.
*not for the extended FU period (except WHO bleeding scale)
**IgG isotypes and IgA, IgA, IgE, IgM will not be assessed in the
openlabel
treatment period |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Various time points throughout the study |
|
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 | No |
E.6.10 | Pharmacogenetic | Yes |
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 |
|
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) | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
open label treatment after main study |
|
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 | 35 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 |