Evaluating the Pharmacodynamic Noninferiority of Efgartigimod PH20 SC Administered Subcutaneously as Compared to Efgartigimod Administered Intravenously in Patients With Generalized Myasthenia Gravis

Phase 3

Completed

• Conditions: Generalized Myasthenia Gravis
• Interventions: Biological: efgartigimod PH20 SC; Biological: efgartigimod IV

• Registration Number: NCT04735432
• Lead Sponsor: argenx

Brief Summary

The purpose of this study is to investigate the Pharmacodynamics (PD), Pharmacokinetics (PK), safety, tolerability, immunogenicity, and clinical efficacy of efgartigimod coformulated with recombinant human hyaluronidase PH20 (rHuPH20) as compared to efgartigimod IV infused in patients with generalized myasthenia gravis (gMG). The study duration is approximately 12 weeks. After screening, patients will be randomized to receive either efgartigimod infusions or efgartigimod PH20 subcutaneously (SC)

Detailed Description

Main objective of the trial: To demonstrate that the pharmacodynamic (PD) effect of injections of 1000 mg efgartigimod PH20 SC (efgartigimod co-formulated with recombinant humanhyaluronidase PH20 for subcutaneous administration), administered once weekly for 4 administrations, is NI (noninferior) to IV infusions of efgartigimod (efgartigimod formulation for intravenous infusion) at a dose of 10 mg/kg administered once weekly for 4 administrations.

Secondary objectives: To compare the PD effect of efgartigimod PH20 SC and efgartigimod IV over time; To evaluate the pharmacokinetics (PK) of efgartigimod PH20 SC and efgartigimod IV; To evaluate the safety, tolerability, and immunogenicity of efgartigimod PH20 SC and efgartigimod IV; To evaluate the clinical efficacy of efgartigimod PH20 SC and efgartigimod IV.

Study Timeline

• Study First Submitted: 2021-01-26
• Study First Submitted QC: 2021-02-01
• Study First Posted: 2021-02-03
• Study Start: 2021-02-05
• Primary Completion: 2021-11-02
• Study Completion: 2021-12-13
• Results First Submitted: 2022-11-22
• Status Verified: 2023-01
• Results First Submitted QC: 2023-01-31
• Last Update Submitted: 2023-01-31
• Results First Posted: 2023-02-28
• Last Update Posted: 2023-02-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 110

Inclusion Criteria

Bullet list of each inclusion criterium:

1. Must be capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

2. At least 18 years of age at the time of signing the informed consent form.

3. Diagnosed with generalized Myasthenia Gravis (gMG) with confirmed documentation and supported by at least 1 of the following:

   1. History of abnormal neuromuscular transmission demonstrated by single fiber electromyography or repetitive nerve stimulation
   2. History of positive edrophonium chloride test
   3. Demonstrated improvement in Myasthenia Gravis (MG) signs upon treatment with oral acetylcholinesterase (AChE) inhibitors as assessed by the treating physician

4. Meeting the clinical criteria as defined by the Myasthenia Gravis Foundation of America (MGFA) class II, III, IVa, or IVb

Exclusion Criteria

Bullet list of each exclusion criterium:

1. Are pregnant or lactating, or intend to become pregnant during the study or within 90 days after the last dose of Investigational Medicinal Product.

2. Has any of the following medical conditions:

   1. Clinically significant uncontrolled active or chronic bacterial, viral, or fungal infection at screening

   2. Any other known autoimmune disease that, in the opinion of the investigator, would interfere with an accurate assessment of clinical symptoms of myasthenia gravis or put the participant at undue risk.

   3. History of malignancy unless deemed cured by adequate treatment with no evidence of reoccurrence for ≥3 years before the first administration of the IMP. Participants with the following cancers can be included at any time:

      • adequately treated basal cell or squamous cell skin cancer
      • carcinoma in situ of the cervix
      • carcinoma in situ of the breast
      • incidental histological findings of prostate cancer (TNM Classification of Malignant Tumors stage T1a or T1b).

   4. Clinical evidence of other significant serious diseases, or the participant has had a recent major surgery, or who have any other condition that, in the opinion of the investigator, could confound the results of the study or put the participant at undue risk.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
efgartigimod PH20 SC	efgartigimod PH20 SC	Patients receiving efgartigimod PH20 subcutaneous (SC) treatment
efgartigimod	efgartigimod IV	Patients receiving efgartigimod intravenous (IV) treatment

Primary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Total IgG Levels at Day 29 (mITT Analysis Set)	From week 0 to week 4	ANCOVA Analysis of Percent Change From Baseline in Total IgG Level at Day 29 (ie, 7 days after the fourth IV or SC administration).

Secondary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Total IgG Levels Over Time (mITT Analysis Set)	From baseline to week 10	Total IgG level percent change from baseline over time for the overall population.
Percent Change From Baseline in IgG Subtype Levels Over Time (mITT Analysis Set)	Baseline to week 10	Median (IQR) Percent Change From Baseline for the IgG Subtypes (IgG1, IgG2, IgG3, and IgG4) in the Overall Population.; The highest number of patients among all weeks for the analysis is chosen for each arm.; Descriptive statistics have been used for this secondary end point.
Efgartigimod IV Serum Pharmacokinetic Parameter Cmax	From Baseline to Week 3	Evaluation of maximum observed concentration (Cmax) (after all doses for the IV treatment arm). The analysis will present data from Baseline to Week 3.; Descriptive statistics have been used for this secondary end point.
Incidence of ADA Against Efgartigimod (Safety Analysis Set)	From baseline to week 10	Incidence of antidrug antibodies (ADA) against Efgartigimod in the overall population. ADA analysis is performed with a validated ELISA in a 3-tiered approach (ADA screening analysis, confirmatory analysis and a titration assay). Descriptive statistics have been used for this secondary end point.
Incidence of Antibodies Against rHuPH20 in the SC Treatment Arm (Safety Analysis Set)	From baseline to week 10	Incidence of antibodies against rHuPH20 in the Efgartigimod PH20 SC Arm. antibody analysis is performed with a validated ELISA in a 3-tiered approach (screening analysis, confirmatory analysis and a titration assay) Descriptive statistics have been used for this secondary end point.
QMG Responders (ITT Analysis Set)	From Baseline to Week 10	Evaluation of number and percentage of Quantitative Myasthenia Gravis (QMG) responders in the overall population (ITT Analysis Set).; Descriptive statistics have been used for this secondary end point. One subject in the EFG IV arm had no post-baseline QMG assessment and thus was excluded from the denominator.
Change From Baseline in QMG Score Over Time (ITT Analysis Set)	From baseline to week 10	Evaluation of QMG Total Score change from baseline over time for the overall population (ITT Analysis Set). The QMG (Quantitative Myasthenia Gravis) quantifies disease severity based on impairments of body function and structures as defined by the International Classification of Functioning, Disability and Health. The QMG consists of 13 items that assess ocular, bulbar, and limb function. Six of the 13 items are timed endurance tests measured in seconds. Each item has a possible score from 0 to 3. The total possible score is 39, where higher total scores indicate more severe impairments. It is based on qualitative testing of specific muscle groups to assess limb function.; Descriptive statistics have been used for this secondary end point. A participant was considered a QMG responder if he/she showed a reduction of at least 3 points from baseline on the QMG score for at least 4 consecutive weeks.
Percent Change From Baseline in AChR-Ab Levels Over Time in AChR- Ab Positive Patients (mITT Analysis Set)	From baseline to week 10	Percent reduction from baseline in AChR-Ab levels over time in AChR-Ab positive patients measured in mITT Analysis Set.; Descriptive statistics have been used for this secondary end point.
MG-ADL Responders (ITT Analysis Set)	From baseline to week 10	Evaluation of number and percentage of Myasthenia Gravis Activities of Daily Living (MG-ADL) responders in the overall population. The MG-ADL is an 8-item patient-reported scale that assesses MG symptoms and their effects on daily activities. It evaluates a participant's capacity to perform different activities in their daily life, including talking, chewing, swallowing, breathing, brushing their teeth, combing their hair, or getting up from a chair. The MG-ADL also assesses double vision and eyelid droop. It is a discrete quantitative variable in which the 8 items are rated by the participant on a scale of 0 to 3. The total score can range from 0 to 24, with higher total scores indicating more impairment. A participant was considered a MG-ADL responder if he/she showed a reduction of at least 2 points from baseline on the MG-ADL score for at least 4 consecutive weeks. Descriptive statistics have been used for this secondary end point.
AUEC of the Percent Change From Baseline in Total IgG Level (mITT Analysis Set)	From baseline to week 10	AUEC of the percent reduction from baseline total IgG per dosing interval (days 1-8, days 8-15, days 15-22, and days 22-29), days 1-29, days 1-57 and over the entire study (days 1-71).; The highest number of patients among all weeks for the analysis is chosen for each arm.; Descriptive statistics have been used for this secondary end point.
Еfgartigimod IV and PH20 SC Serum Pharmacokinetic Parameter Ctrough	From Week 1 to Week 4.	Evaluation of observed predose concentration (Ctrough) (after all doses for the IV and SC treatment arms). The analysis will present data from Week 1 to Week 4.; Descriptive statistics have been used for this secondary end point.
Incidence and Severity of AEs and SAEs (Safety Analysis Set)	From baseline to week 10	Evaluation of incidence and severity of treatment-emergent adverse events (TEAEs) and incidence of serious AEs (SAEs).; Descriptive statistics have been used for this secondary end point.
Change From Baseline in MG-ADL Total Score Over Time (ITT Analysis Set)	From baseline to week 10	Evaluation of MG-ADL Total Score Change from baseline over time for the overall population (ITT Analysis Set). Descriptive statistics have been used for this secondary end point.; The MG-ADL is an 8-item patient-reported scale that assesses MG symptoms and their effects on daily activities. It evaluates a participant's capacity to perform different activities in their daily life, including talking, chewing, swallowing, breathing, brushing their teeth, combing their hair, or getting up from a chair. The MG-ADL also assesses double vision and eyelid droop. It is a discrete quantitative variable in which the 8 items are rated by the participant on a scale of 0 to 3. The total score can range from 0 to 24, with higher total scores indicating more impairment. A participant was considered a MG-ADL responder if he/she showed a reduction of at least 2 points from baseline on the MG-ADL score for at least 4 consecutive weeks.

Trial Locations

Locations (47)

Investigator site 2 - US0010108; 🇺🇸 Boca Raton, Florida, United States

Investigator Site 43 - 0010019; 🇺🇸 Cleveland, Ohio, United States

Investigator Site 22 - PL0480005; 🇵🇱 Kraków, Poland

Investigator site 14 - GE9950003; 🇬🇪 Tbilisi, Georgia

Investigator Site 47 - US0010113; 🇺🇸 Augusta, Georgia, United States

Investigator Site 11 - US0010111; 🇺🇸 Amherst, New York, United States

Investigator site 1 - US0010110; 🇺🇸 Port Charlotte, Florida, United States

Investigator Site 41 - US0010004; 🇺🇸 Orange, California, United States

Investigator Site 30 - DE490006; 🇩🇪 Berlin, Germany

Investigator Site 34 - JP0810005; 🇯🇵 Sendai, Japan

Investigator Site 29 - DE490009; 🇩🇪 Münster, Germany

Investigator Site 10 - ES0340039; 🇪🇸 Valencia, Spain

Investigator Site 46 - US0010009; 🇺🇸 Texas City, Texas, United States

Investigator Site 18 - JP0810002; 🇯🇵 Chiba, Japan

Investigator Site 20 - JP0810009; 🇯🇵 Tokyo, Japan

Investigator Site 31 - JP0810055; 🇯🇵 Sapporo, Hokkaido, Japan

Investigator Site 21 - PL0480001; 🇵🇱 Gdańsk, Poland

Investigator Site 9 - PL0480024; 🇵🇱 Kraków, Poland

Investigator Site 33 - JP0810058; 🇯🇵 Hiroshima, Japan

Investigator Site 44 - GE9950004; 🇬🇪 Tbilisi, Georgia

Investigator site 15 - HU0360013; 🇭🇺 Budapest, Hungary

Investigator Site 39 - IT0390008; 🇮🇹 Roma, Italy

Investigator Site 37 - ES0340021; 🇪🇸 Barcelona, Spain

Investigator Site 45 - GE9950016; 🇬🇪 Tbilisi, Georgia

Investigator site 6 - JPN0810004; 🇯🇵 Hanamaki, Japan

Investigator Site 7 - NL0310001; 🇳🇱 Leiden, Netherlands

Investigator Site 17 - IT0390003; 🇮🇹 Milan, Italy

Investigator Site 35 - RU0070002; 🇷🇺 Novosibirsk, Russian Federation

Investigator Site 16 - HU0360020; 🇭🇺 Debrecen, Hungary

Investigator Site 25 - ES0340002; 🇪🇸 Madrid, Spain

Investigator Site 36 - RU0070014; 🇷🇺 Saint Petersburg, Russian Federation

Investigator Site 42 - US0010015; 🇺🇸 Kansas City, Kansas, United States

Investigator site 2 - US0010032; 🇺🇸 Carlsbad, California, United States

Investigator site 4 - US0010008; 🇺🇸 Cordova, Tennessee, United States

Investigator site 5 - BE0320007; 🇧🇪 Gent, East-Flanders, Belgium

Investigator site 13 - GE9950002; 🇬🇪 Tbilisi, Georgia

Investigator site 12 - GE9950001; 🇬🇪 Tbilisi, Georgia

Investigator Site 19 - JP0810007; 🇯🇵 Osaka, Japan

Investigator Site 8 - PL0480007; 🇵🇱 Katowice, Poland

Investigator Site 32 - JP0810059; 🇯🇵 Tokyo, Japan

Investigator Site 26 - ES0340038; 🇪🇸 Barcelona, Spain

Investigator Site 23 - PL0480018; 🇵🇱 Lublin, Poland

Investigator Site 24 - PL0480022; 🇵🇱 Warsaw, Poland

Investigator Site 27 - US0010006; 🇺🇸 Tampa, Florida, United States

Investigator Site 40 - US0010003; 🇺🇸 Chapel Hill, North Carolina, United States

Investigator Site 28 - US0010066; 🇺🇸 Austin, Texas, United States

Investigator Site 38 - US0010077; 🇺🇸 Durham, North Carolina, United States