| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary immune thrombocytopenia (ITP) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Disorder that can lead to easy or excessive bruising and bleeding due to low levels of the cells that help blood clot |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10083843 |
| E.1.2 | Term | Primary immune thrombocytopenia |
| 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 efgartigimod PH20 SC compared to placebo PH20 SC in achieving a sustained platelet count response in patients with chronic primary ITP, with a sustained platelet count response defined as platelet counts of ≥50×10^9/L for at least 4 of the 6 visits between week 19 and week 24 of the trial
|
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of efgartigimod PH20 SC compared to placebo PH20 SC in overall platelet count response
• To evaluate the incidence and severity of bleeding events while receiving treatment with efgartigimod PH20 SC compared to placebo PH20 SC
•To evaluate the efficacy of efgartigimod PH20 SC compared to placebo PH20 SC in International Working Group response
•To evaluate the safety and tolerability of efgartigimod PH20 SC administered qw or every other week (q2w) compared to placebo PH20 SC
• To evaluate the use of rescue treatment and changes in concurrent ITP therapy while receiving treatment with efgartigimod PH20 SC compared to placebo PH20 SC
• To evaluate the effects of efgartigimod PH20 SC treatment on quality-of-life measures and patient-reported outcomes compared to placebo PH20 SC
• To assess the immunogenicity of efgartigimod and rHuPH20
• To assess the pharmacokinetics of efgartigimod PH20 SC
• To assess the pharmacodynamic effects of efgartigimod PH20 SC |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Ability to understand the requirements of the trial and provide written informed consent (including consent for the use and disclosure of research-related health information), willing and able to comply with the trial protocol procedures (including attending the required trial visits).
2a. Is at least the local legal age of consent for clinical studies when signing the ICF.
3. Confirmed diagnosis of primary ITP made at least 3 months before randomization and based on the American Society of Hematology Criteria, and no known etiology for thrombocytopenia.
4. Diagnosis supported by a response to a prior ITP therapy (other than TPO-RAs), in the opinion of the investigator.
5. Mean platelet count of <30×10^9/L from at least 3 documented, qualifying counts within the 3 preceding months where at least 2 of the qualifying counts must be taken during the screening period: 1 platelet count collected during the screening period and the predose platelet count on the day of randomization (visit 1). If the third count is not available from the 3 preceding months, this third platelet count can be obtained during the screening period.
6. A documented history of a platelet count of <30×10^9/L before screening.
7. At the start of the trial, the participant is either receiving concurrent ITP treatment(s) and has received at least 1 prior therapy for ITP in the past, or the participant does not take treatment for ITP (see note) but has received at least 2 prior treatments for ITP. Participants receiving permitted concurrent ITP treatment(s) at baseline must have been stable in dose and frequency for at least 4 weeks before randomization.
Permitted concurrent ITP medications include corticosteroids, danazol, vinca alkaloids, oral immunosuppressants, dapsone, fostamatinib, and/or oral TPO-RAs.
Note: Participants not receiving concurrent ITP therapy are also eligible for the trial if they have not received prior ITP therapy for at least 4 weeks before baseline, and 6 months in case of prior ITP therapy with an anti-CD20 therapy (eg, rituximab).
8b. Agree to use contraceptive measures consistent with local regulations and the following:
Female participants of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline before receiving IMP. |
|
| E.4 | Principal exclusion criteria |
1. Secondary ITP/thrombocytopenia associated with another condition, eg, lymphoma, chronic lymphocytic leukemia, viral infection, hepatitis, induced or alloimmune thrombocytopenia, thrombocytopenia associated with myeloid dysplasia, or hematopoietic stem cell transplant.
2. Use of anticoagulants (eg, vitamin K antagonists, direct oral anticoagulants) within 4 weeks prior to randomization.
3. Use of any transfusions within 4 weeks prior to randomization.
4. Use of Ig (IV, SC, or intramuscular route) or plasmapheresis (PLEX) within 4 weeks prior to randomization.
5. Use of romiplostim within 4 weeks prior to randomization.
6. Undergone splenectomy less than 4 weeks prior to randomization.
7. Use of an investigational product within 3 months or 5 half-lives (whichever is longer) before the first dose of the IMP.
8. Use of any monoclonal antibody or Fc fusion proteins, other than those previously indicated, within 6 months before the first dose of the IMP (eg, anti-CD20).
9. At the screening visit, clinically significant laboratory abnormalities as follows:
• Hemoglobin ≤9 g/dL
- OR –
• International normalized ratio >1.5 or activated partial thromboplastin time >1.5×upper limit of normal
- OR –
• total IgG level <6 g/L
10. History of malignancy unless deemed cured by adequate treatment with no evidence of recurrence for ≥3 years before the first administration of IMP. Participants with the following cancer can be included at any time:
a. Adequately treated basal cell or squamous cell skin cancer
b. Carcinoma in situ of the cervix
c. Carcinoma in situ of the breast or
d. Incidental histological finding of prostate cancer (TNM stage T1a or T1b)
11. Uncontrolled hypertension, defined as a repeated elevated blood pressure exceeding 160 mmHg (systolic) and/or 100 mmHg (diastolic) despite appropriate treatments.
12a. History of any major thrombotic or embolic event (eg, myocardial infarction, stroke, deep venous thrombosis, or pulmonary embolism) within 5 years before randomization.
13. History of coagulopathy or hereditary thrombocytopenia or a family history of thrombocytopenia.
14. Evidence of an active clinically significant bleeding of an organ or internal mucosal bleeding, other than expected in ITP, that warrants emergent treatment or therapeutic procedure based on the investigator’s judgment (eg, intracranial hemorrhage, pulmonary hemorrhage, bleeding with ongoing need for packed red blood cell transfusion).
15. Estimated high risk of a clinically significant bleeding of an organ or internal mucosal bleeding, other than expected in ITP, that warrants emergent treatment or therapeutic procedure according to the investigator’s judgment.
16. Clinical evidence of other significant serious diseases, have had a recent major surgery, or who have any other condition in the opinion of the investigator, that could confound the results of the trial or put the participant at undue risk.
17. Positive serum test at screening for an active viral infection with any of the following conditions:
a. Hepatitis B virus (HBV) that is indicative of an acute or chronic infection, unless associated with a negative HBV DNA test
(https://www.cdc.gov/hepatitis/HBV/PDFs/SerologicChartv8.pdf).
b. Hepatitis C virus (HCV) based on HCV-antibody assay (unless associated with a negative HCV RNA test).
c. Human immunodeficiency virus (HIV) based on test results that are associated with an acquired immunodeficiency syndrome (AIDS)-defining condition or a CD4 count ≤ 200 cells/mm^3.
18. Known hypersensitivity reaction to efgartigimod, rHuPH20, or 1 of its excipients.
19. Previously participated in a clinical trial with efgartigimod and have received at least 1 administration of the IMP.
20a. Pregnant or lactating or intends to become pregnant during the trial.
21. Clinically significant uncontrolled active or chronic bacterial, viral, or fungal infection at screening.
22. Any other known autoimmune disease that, in the opinion of the investigator, would interfere with an accurate assessment of clinical symptoms of ITP or put the participant at undue risk.
23. Clinical evidence of significant unstable or uncontrolled acute or chronic diseases other than ITP (eg, cardiovascular, pulmonary, hematologic, gastrointestinal, endocrine, hepatic, renal, neurological, malignancy, infectious diseases, uncontrolled diabetes) despite appropriate treatments which could put the participant at undue risk.
24. Current or history of (ie, within 12 months of screening) alcohol, drug, or medication abuse.
25. Received a live/live-attenuated vaccine less than 4 weeks before screening. The receipt of any inactivated, sub-unit, polysaccharide, or conjugate vaccine at any time before screening is not considered an exclusion criterion. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of patients with chronic ITP with a sustained platelet count response defined as achieving platelet counts of ≥50×10^9/L for at least 4 of the 6 visits between week 19 and week 24 of the trial |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Up to 5 weeks (between week 19 –24) |
|
| E.5.2 | Secondary end point(s) |
1. Extent of disease control defined as the number of cumulative weeks over the planned 24-week treatment period with platelet counts of ≥50×10^9/L in the chronic ITP population (Key Secondary Endpoint 1)
2. Proportion of patients in the overall population (chronic and persistent ITP) with a sustained platelet count response defined as achieving platelet counts of ≥50×10^9/L for at least 4 of the 6 visits between week 19 and week 24 (Key Secondary Endpoint 2)
3. Proportion of patients in the overall population achieving platelet counts of ≥50×10^9/L for at least 6 of the 8 visits between week 17 and 24 of the trial (Key Secondary Endpoint 3)
4. Proportion of patients in the overall population with overall platelet response defined as achieving a platelet count of ≥50×10^9/L on at least 4 occasions at any time during the 24-week treatment period
5. Extent of disease control defined as the number of cumulative weeks until week 12 with platelet counts of ≥50×10^9/L in the overall population
6. Proportion of patients in the overall population with overall platelet response defined as achieving a platelet count of ≥50×10^9/L on at least 4 occasions at any time until week 12
7. Mean change from baseline in platelet count at each visit in the overall population
8. Time to response defined as the time to achieve 2 consecutive platelet counts of ≥50×10^9/L in the overall population
9. The number of cumulative weeks over the planned 24-week treatment period with platelet counts of ≥30×10^9/L and ≥20×10^9/L above baseline in the overall population
10. In patients with baseline platelet count of <15×10^9/L, the number of cumulative weeks over the planned 24-week treatment period with platelet counts of ≥30×10^9/L and ≥20×10^9/L above baseline in the overall population
11. Incidence and severity of the World Health Organization (WHO)-classified bleeding events in the overall population (Key Secondary Endpoint 4)
12. Proportion of patients with an IWG response
13. Proportion of patients with an IWG complete response
14. Proportion of patients with an initial response
15. Incidence and severity of AEs, AEs of special interest (AESIs), and SAEs in the overall population
16. Vital signs, ECG, and laboratory assessments in the overall population
17. Rate of receipt of rescue therapy (rescue per patient per month) in the overall population
18. Proportion of patients for whom dose and/or frequency of concurrent ITP therapies have increased at week 12 or later in the overall population
19. Change from baseline in PRO (Functional Assessment of Chronic Illness Therapy Fatigue Scale [FACIT-Fatigue], Functional Assessment of Cancer Therapy questionnaire-Th6 [Fact-Th6]) and QoL (Short Form-36 [SF-36]) at planned visits in the overall population
20. Incidence and prevalence of antibodies to efgartigimod and/or rHuPH20 in the overall population
21. Titers of antibodies to efgartigimod and/or rHuPH20 in the overall population
22. Presence of neutralizing antibodies (NAb) against efgartigimod and/or rHuPH20, and titers of NAb against rHuPH20 in the overall population
23. Serum efgartigimod concentration observed predose (Ctrough) in the overall population
24. Pharmacodynamics markers: total IgG and antiplatelet antibody levels in the overall population |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to 24 weeks
2. Up to 5 weeks (between week 19-24)
3. Up to 7 weeks (between week 17-24)
4. Up to 24 weeks
5. Up to 12 weeks
6. Up to 12 weeks
7. Up to 35 weeks
8. Up to 35 weeks
9. Up to 24 weeks
10. Up to 24 weeks
11. Up to 35 weeks
12. Up to 35 weeks
13. Up to 35 weeks
14. Up to 35 weeks
15. Up to 35 weeks
16. Up to 35 weeks
17. Up to 35 weeks
18. Up to 23 weeks (between week 12-35)
19. Up to 24 weeks
20. Up to 35 weeks
21. Up to 35 weeks
22. Up to 35 weeks
23. Up to 35 weeks
24. Up to 35 weeks |
|
| 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 | No |
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| 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) | 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 67 |
| 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 |
| Argentina |
| Chile |
| Colombia |
| New Zealand |
| Peru |
| Tunisia |
| Ireland |
| Taiwan |
| Australia |
| Bulgaria |
| China |
| Denmark |
| France |
| Georgia |
| Germany |
| Greece |
| Israel |
| Italy |
| Japan |
| Jordan |
| Korea, Republic of |
| Mexico |
| Norway |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Serbia |
| South Africa |
| Spain |
| Thailand |
| Turkey |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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