| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Inflammatory Demyelinating Polyneuropathy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Inflammation of peripheral nervous system |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| 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 | 10077384 |
| E.1.2 | Term | Chronic inflammatory demyelinating polyneuropathy |
| E.1.2 | System Organ Class | 100000004852 |
|
| 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 |
Stage A: To assess the activity of efgartigimod PH20 SC (efgartigimod co-formulated with recombinant human hyaluronidase PH20 [rHuPH20]) based on the percentage of patients classified as treatment responders.
Stage B: To determine the efficacy of efgartigimod PH20 SC compared to placebo based on the time needed for the occurrence of the first evidence of clinical deterioration. |
|
| E.2.2 | Secondary objectives of the trial |
Stage A
- To assess the time to clinical improvement.
-To determine the treatment effect of efgartigimod PH20 SC based on clinical functional assessments of motor function and muscle strength.
-To assess the short-term safety and tolerability of efgartigimod PH20 SC.
-To assess the pharmacokinetics (PK) of efgartigimod PH20 SC.
-To assess the pharmacodynamic (PD) effect of efgartigimod PH20 SC.
-To assess the immunogenicity of efgartigimod and rHuPH20.
- To assess the EuroQol 5 dimensions and 5 levels of health-related quality-of life questionnaire (EQ-5D-5L).
Stage B
-To determine the efficacy of efgartigimod PH20 SC compared to placebo based on clinical functional assessments of disease disability and motor function and muscle strength.
-To assess the safety and tolerability of efgartigimod PH20 SC
-To assess the PK of efgartigimod PH20 SC
-To assess the PD effect of efgartigimod PH20 SC
-To assess the immunogenicity of efgartigimod and rHuPH20
-To assess the EQ-5D-5L |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients are eligible to be included in the trial only if all of the following criteria apply:
1. Ability to understand the requirements of the trial, provide written informed consent (include consent for the use and disclosure of research-related health information), willingness and ability to comply with the trial protocol procedures (including required trial visits)
2. Male or female patient aged 18 years or older, at the time of signing the informed consent.
3. Diagnosed with probable or definite CIDP according to criteria of the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS 2010), progressing or relapsing forms.
4. CIDP Disease Activity Status (CDAS) score ≥2 at screening
5. An INCAT score ≥2, at the first run-in visit (RI-V1; for patients entering run-in) or Stage A baseline (A-V1; for treatment-naïve patients with documented evidence for worsening on the total adjusted INCAT disability score within 3 months prior to screening). Patients with an INCAT score of 2 at trial entry must have this score exclusively from the leg disability score; for patients with an INCAT score of ≥3 at trial entry, there are no specific requirements for arm or leg scores.
6. Fulfilling any of the following treatment conditions:
-Currently (ie, within the last 6 months) treated with pulsed corticosteroids, oral corticosteroids equivalent to prednisolone/prednisone ≤10mg/day, and/or IVIg or SCIg, and the patient is willing to discontinue this treatment at the first run-in visit (RI-VI); or
-Without previous treatment (treatment-naive); or
-Treatment with corticosteroids and/or IVIg or SCIg discontinued at least 6 months prior to screening
Note: Patients not treated with monthly or daily corticosteroids, IVIg or SCIg for at least 6 months prior to screening are considered as equal to treatment-naïve patients.
7. Women of childbearing potential who have a negative pregnancy test at screening and a negative urine pregnancy test up to Stage A baseline (D1A).
8.a. Women of childbearing potential must use an acceptable method of contraception from signing the ICF until the date of the last dose of IMP.
9. Inclusion criterion removed in protocol amendment 4. |
|
| E.4 | Principal exclusion criteria |
Patients are excluded from the trial if any of the following criteria apply:
1. Pure sensory atypical CIDP (EFNS/PNS definition(11)).
2. Polyneuropathy of other causes, including the following:
-Multifocal motor neuropathy;
-Monoclonal gammopathy of uncertain significance with anti-myelin-associated glycoprotein immunoglobulin M (IgM) antibodies;
-Hereditary demyelinating neuropathy;
-Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin change syndromes;
-Lumbosacral radiculoplexus neuropathy;
-Polyneuropathy most likely due to diabetes mellitus;
-Polyneuropathy most likely due to systemic illnesses;
-Drug- or toxin-induced polyneuropathy.
3. Any other disease that could better explain the patient’s signs and symptoms.
4. Any history of myelopathy or evidence of central demyelination.
5. Current or past history (within 12 months of screening) of alcohol, drug or medication abuse.
6. Severe psychiatric disorder (such as severe depression, psychosis, bipolar disorder), history of suicide attempt, or current suicidal ideation that in the opinion of the investigator could create undue risk to the patient or could affect adherence with the trial protocol.
7. Patients with clinically significant active or chronic uncontrolled bacterial, viral, or fungal infection at screening, including patients who test positive for an active viral infection at screening with:
− Active Hepatitis B Virus (HBV): serologic panel test results indicative of an active (acute or chronic) infection;
− Active Hepatitis C Virus (HCV): serology positive for HCV-Ab;
− Human Immunodeficiency Virus (HIV) positive serology associated with an Acquired Immune Deficiency Syndrome (AIDS)-defining condition or with a cluster of differentiation 4 (CD4) count ≤200 cells/mm3.
8. Total IgG level <6 g/L at screening.
9.a. Treatment with the following:
-Within 3 months (or 5 half-lives of the drug, whichever is longer) before screening: plasma exchange or immunoadsorption, any concomitant Fc-containing therapeutic agents or other biological, or any other investigational product;
-Within 6 months before screening: rituximab, alemtuzumab, any other monoclonal antibody, cyclophosphamide, interferon, tumor necrosis factor–alpha inhibitors, fingolimod, methotrexate, azathioprine, mycophenolate, any other immunomodulating or immunosuppressive medications, and oral daily corticosteroids >10 mg/day.
Note: Patients using IVIg, SCIg, pulsed corticosteroids, and oral daily corticosteroids ≤10 mg/day can be included.
- Patients who (intend to) use prohibited medications and therapies during the trial.
10.a. Pregnant and lactating women and those intending to become pregnant during the trial.
11. Patients with any other known autoimmune disease that, in the opinion of the investigator, would interfere with an accurate assessment of clinical symptoms of CIDP.
12. Patients who received a live-attenuated vaccine fewer than 28 days before screening. Receiving an inactivated, sub-unit, polysaccharide, or conjugate vaccine any time before screening is not exclusionary.
13. Patients who have a history of malignancy unless deemed cured by adequate treatment with no evidence of recurrence for ≥3 years before the first IMP administration. Patients with the following cancer can be included anytime:
-Adequately treated basal cell or squamous cell skin cancer,
-Carcinoma in situ of the cervix,
-Carcinoma in situ of the breast, or
-Incidental histological finding of Prostate cancer (TNM [tumor, nodes, and metastases classification] stage T1a or T1b).
14. Patients who previously participated in a trial with efgartigimod and have received at least one administration of IMP.
15. Patients with known medical history of hypersensitivity to any of the ingredients of IMP.
16. Patients with clinical evidence of other significant serious disease or patients who underwent a recent or have a planned major surgery, or any other reason which could confound the results of the trial or put the patient at undue risk. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Stage A
Percentage of patients with confirmed evidence of clinical improvement (ECI).
Stage B
Stage B: Time to first adjusted INCAT deterioration compared to Stage B baseline
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Stage A
Up to 12 weeks (with option 1 additional week for confirmation of ECI) during the open-label stage A
Stage B
Every Stage B visit |
|
| E.5.2 | Secondary end point(s) |
Stage A
- Time to initial confirmed ECI
- Change from Stage A baseline (D1A) over time in adjusted INCAT score
- Change from Stage A baseline (D1A) over time in Medical Research Council (MRC) Sum score
- Change from Stage A baseline (D1A) over time in 24-item Inflammatory Rasch-built Overall Disability Scale (I-RODS) disability scores
- Change from Stage A baseline (D1A) over time in Timed Up-and-go (TUG) score
- Change from Stage A baseline (D1A) over time in Mean grip strength
- Exposure adjusted occurrence of treatment-emergent adverse events and serious adverse events
- Incidence of clinically significant laboratory abnormalities
- Pre-dosing efgartigimod serum concentrations over time
- Changes of serum IgG levels (total and IgG subtypes) over time
- Percentage of patients with and titers of binding antibodies towards efgartigimod and/or rHuPH20 and the presence of neutralizing antibodies against efgartigimod and/or rHuPH20
- Presence of neutralizing antibodies (NAb) against efgartigimod and titers of NAb against rHuPH20
-Changes from D1A in EQ-5D-EL over time
Stage B
- Time to CIDP disease progression.
Note: Time to CIDP disease progression is defined by the time from first dose of double-blind IMP to the first I-RODS score decrease ≥4 points compared to Stage B baseline using the centile metric.
- Percentage of patients with improved functional level compared to Stage B baseline as measured by an increase in the 24-item I-RODS score up to Week 48
- Change from Stage B baseline over time in adjusted INCAT score
- Change from Stage B baseline over time in MRC Sum score
- Change from Stage B baseline over time in 24-item I-RODS disability score
- Change from Stage B baseline over time in TUG score
- Change from Stage B baseline over time in mean grip strength
- Time to 10% decrease in the 24-item I-RODS
- Exposure adjusted occurrence of treatment-emergent adverse events and serious adverse events
- Incidence of clinically significant laboratory abnormalities
- Pre-dosing efgartigimod serum concentrations over time
- Changes of serum IgG levels (total IgG) over time
- Percentage of patients with and titers of binding antibodies towards efgartigimod and/or rHuPH20 and the presence of neutralizing antibodies against efgartigimod and/or rHuPH20
- Presence of NAb against efgartigimod and titers of NAb against rHuPH20
-Changes from Stage B baseline in EQ-ED-5L over time |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Stage A
Up to 12 weeks (with option 1 additional week for confirmation of ECI) during the open-label stage A
Stage B
Up to 48 weeks during the randomized placebo-controlled stage B |
|
| 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) | 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 | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 61 |
| 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 |
| Canada |
| China |
| Israel |
| Japan |
| Taiwan |
| United States |
| Austria |
| France |
| Latvia |
| Poland |
| Bulgaria |
| Netherlands |
| Romania |
| Spain |
| Czechia |
| Germany |
| Italy |
| Belgium |
| Denmark |
| Georgia |
| Hungary |
| Russian Federation |
| Turkey |
| Ukraine |
| United Kingdom |
| Serbia |
|
| 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 trial is defined as the last patient last visit in the ARGX-113-1802 trial, ie, any of the following:
1) the last visit before roll-over to the Open-Label Extension (OLE) trial,
2) the follow-up visit 28 days after the last dose of IMP for patients not participating in the OLE trial or,
3) the follow-up visit 28 days after early discontinuation, if applicable. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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