A Study to Assess the Efficacy and Safety of a Subcutaneous Formulation of Efgartigimod PH20 SC in Adults With Pemphigus (Vulgaris or Foliaceus) (ADDRESS)

• ClinicalTrials.gov Identifier: NCT04598451
• Recruitment Status: Completed
• First Posted: October 22, 2020
• Last Update Posted: September 22, 2023
• Sponsor: argenx
• Information provided by (Responsible Party): argenx

Tracking Information

• First Submitted Date: October 8, 2020
• First Posted Date: October 22, 2020
• Last Update Posted Date: September 22, 2023
• Actual Study Start Date: December 1, 2020
• Actual Primary Completion Date: August 22, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 17, 2021)

Proportion of Pemphigus Vulgaris (PV) participants who achieve complete clinical remission (CR) on minimal Prednisone therapy [ Time Frame: 30 weeks treatment period ]

Proportion of Pemphigus Vulgaris participants who achieve Clinical Remission on minimal Prednisone therapy

Original Primary Outcome Measures (submitted: October 16, 2020)

Proportion of Pemphigus Vulgaris (PV) patients who achieve complete clinical remission (CR) on minimal Prednisone therapy [ Time Frame: 30 weeks treatment period ]

Proportion of Pemphigus Vulgaris patients who achieve Clinical Remission on minimal Prednisone therapy

Current Secondary Outcome Measures (submitted: July 28, 2022)

• Proportion of Pemphigus Vulgaris (PV) and Pemphigus Foliaceus (PF) participants who achieve complete clinical remission (CR) on minimal Prednisone therapy [ Time Frame: 30 weeks treatment period ]
  Proportion of Pemphigus Vulgaris and Pemphigus Foliaceus participants who achieve complete clinical remission on minimal Prednisone therapy
• Cumulative prednisone dose over the trial in Pemphigus Vulgaris participants [ Time Frame: Up to 30 weeks ]
  Cumulative prednisone dose over the trial in Pemphigus Vulgaris participants
• Time to complete clinical remission in Pemphigus Vulgaris participants [ Time Frame: Up to 30 weeks ]
  Time to complete clinical remission in Pemphigus Vulgaris participants
• Time to Disease Control (DC) in Pemphigus Vulgaris (PV) participants [ Time Frame: Up to 30 weeks ]
  Time to Disease Control in Pemphigus Vulgaris participants
• Proportion of Pemphigus Foliaceus (PF) participants who achieve complete clinical remission (CR) on minimal prednisone therapy [ Time Frame: 30 weeks treatment period ]
  Proportion of Pemphigus Foliaceus (PF) participants who achieve complete clinical remission (CR) on minimal prednisone therapy
• Cumulative prednisone dose over the trial in Pemphigus Vulgaris and Pemphigus Foliaceus participants [ Time Frame: Up to 30 weeks ]
  Cumulative prednisone dose over the trial in Pemphigus Vulgaris and Pemphigus Foliaceus participants
• Time to complete clinical remission in Pemphigus Vulgaris and Pemphigus Foliaceus participants [ Time Frame: Up to 30 weeks ]
  Time to complete clinical remission in Pemphigus Vulgaris and Pemphigus Foliaceus participants
• Time to disease control in Pemphigus Vulgaris and Pemphigus Foliaceus participants [ Time Frame: Up to 30 weeks ]
  Time to disease control in Pemphigus Vulgaris and Pemphigus Foliaceus participants
• Rate of treatment failure [ Time Frame: Up to 30 weeks ]
  Rate of treatment failure
• Rate of flare [ Time Frame: Up to 30 weeks ]
  Rate of flare
• Pemphigus Disease Area Index at each visit [ Time Frame: Up to 41 weeks ]
  Pemphigus Disease Area Index at each visit
• Incidence of Treatment-Emergent Adverse Events (TEAE), Adverse Events of Special Interest (AESI), and Serious Adverse Events (SAE) [ Time Frame: Up to 41 weeks ]
  Incidence of Treatment-Emergent Adverse Events, Adverse Events of Special Interest, and Serious Adverse Events
• Severity of Treatment-Emergent Adverse Events (TEAE), Adverse Events of Special Interest (AESI), and Serious Adverse Events (SAE) [ Time Frame: Up to 41 weeks ]
  Severity of Treatment-Emergent Adverse Events, Adverse Events of Special Interest, and Serious Adverse Events
• Composite Glucocorticoid Toxicity Index (C-GTI) comprising the Aggregate Improvement Score (AIS) and the Cumulative Worsening Score (CWS) [ Time Frame: Up to 30 weeks ]
  Composite Glucocorticoid Toxicity Index comprising the Aggregate Improvement Score and the Cumulative Worsening Score
• EuroQol Five-Dimension Five-Level Scale (EQ-5D-5L) score [ Time Frame: 30 weeks treatment period ]
  EuroQol Five-Dimension Five-Level Scale score
• Autoimmune Bullous Disease Quality of Life (ABQOL) score [ Time Frame: 30 weeks treatment period ]
  Autoimmune Bullous Disease Quality of Life score
• Efgartigimod serum concentrations [ Time Frame: Up to 38 weeks ]
  Efgartigimod serum concentrations
• Total immunoglobulin G and subtype (IgG1, IgG2, IgG3, IgG4) serum levels [ Time Frame: Up to 41 weeks ]
  Total immunoglobulin G and subtype (IgG1, IgG2, IgG3, IgG4) serum levels
• Anti desmoglein-1 and -3 autoantibodies serum levels [ Time Frame: Up to 41 weeks ]
  Anti desmoglein-1 and -3 autoantibodies serum levels
• Incidence of anti-drug antibodies (ADA) to efgartigimod PH20 SC [ Time Frame: Up to 38 weeks ]
  Incidence of anti-drug antibodies to efgartigimod PH20 SC
• Prevalence of anti-drug antibodies (ADA) to efgartigimod PH20 SC [ Time Frame: Up to 38 weeks ]
  Prevalence of anti-drug antibodies to efgartigimod PH20 SC
• Incidence of antibodies produced against recombinant human hyaluronidase (rHuPH20) (plasma levels) [ Time Frame: Up to 31 weeks ]
  Incidence of antibodies produced against recombinant human hyaluronidase (rHuPH20) (plasma levels)
• Prevalence of antibodies produced against recombinant human hyaluronidase (rHuPH20) [ Time Frame: Up to 31 weeks ]
  Prevalence of antibodies produced against recombinant human hyaluronidase (rHuPH20)
• Number of participants or caregivers completing the self-administration training [ Time Frame: Up to 41 weeks ]
  Number of participants or caregivers completing the self-administration training
• Percentage of participants or caregivers completing the self-administration training [ Time Frame: Up to 41 weeks ]
  Percentage of participants or caregivers completing the self-administration training
• Number of participants or caregivers determined by the site staff to be sufficiently competent to self-administer efgartigimod PH20 SC [ Time Frame: Up to 41 weeks ]
  Number of participants or caregivers determined by the site staff to be sufficiently competent to self-administer efgartigimod PH20 SC
• Percentage of participants or caregivers determined by the site staff to be sufficiently competent to self-administer efgartigimod PH20 SC [ Time Frame: Up to 41 weeks ]
  Percentage of participants or caregivers determined by the site staff to be sufficiently competent to self-administer efgartigimod PH20 SC
• Number of participants or caregivers that self-administer efgartigimod PH20 SC under site staff supervision [ Time Frame: Up to 41 weeks ]
  Number of participants or caregivers that self-administer efgartigimod PH20 SC under site staff supervision
• Percentage of participants or caregivers that self-administer efgartigimod PH20 SC under site staff supervision [ Time Frame: Up to 41 weeks ]
  Percentage of participants or caregivers that self-administer efgartigimod PH20 SC under site staff supervision

Original Secondary Outcome Measures (submitted: October 16, 2020)

• Proportion of Pemphigus Vulgaris (PV) and Pemphigus Foliaceus (PF) patients who achieve complete clinical remission (CR) on minimal Prednisone therapy [ Time Frame: 30 weeks treatment period ]
  Proportion of Pemphigus Vulgaris and Pemphigus Foliaceus patients who achieve complete clinical remission on minimal Prednisone therapy
• Cumulative prednisone dose over the trial in Pemphigus Vulgaris patients [ Time Frame: Up to 30 weeks ]
  Cumulative prednisone dose over the trial in Pemphigus Vulgaris patients
• Time to complete clinical remission in Pemphigus Vulgaris patients [ Time Frame: Up to 30 weeks ]
  Time to complete clinical remission in Pemphigus Vulgaris patients
• Time to Disease Control (DC) in Pemphigus Vulgaris (PV) patients [ Time Frame: Up to 30 weeks ]
  Time to Disease Control in Pemphigus Vulgaris patients
• Proportion of Pemphigus Foliaceus (PF) patients who achieve complete clinical remission (CR) on minimal prednisone therapy [ Time Frame: 30 weeks treatment period ]
  Proportion of Pemphigus Foliaceus (PF) patients who achieve complete clinical remission (CR) on minimal prednisone therapy
• Cumulative prednisone dose over the trial in Pemphigus Vulgaris and Pemphigus Foliaceus patients [ Time Frame: Up to 30 weeks ]
  Cumulative prednisone dose over the trial in Pemphigus Vulgaris and Pemphigus Foliaceus patients
• Time to complete clinical remission in Pemphigus Vulgaris and Pemphigus Foliaceus patients [ Time Frame: Up to 30 weeks ]
  Time to complete clinical remission in Pemphigus Vulgaris and Pemphigus Foliaceus patients
• Time to disease control in Pemphigus Vulgaris and Pemphigus Foliaceus patients [ Time Frame: Up to 30 weeks ]
  Time to disease control in Pemphigus Vulgaris and Pemphigus Foliaceus patients
• Rate of treatment failure [ Time Frame: Up to 30 weeks ]
  Rate of treatment failure
• Rate of flare [ Time Frame: Up to 30 weeks ]
  Rate of flare
• Pemphigus Disease Area Index at each visit [ Time Frame: Up to 41 weeks ]
  Pemphigus Disease Area Index at each visit
• Incidence of Treatment-Emergent Adverse Events (TEAE), Adverse Events of Special Interest (AESI), and Serious Adverse Events (SAE) [ Time Frame: Up to 41 weeks ]
• Severity of Treatment-Emergent Adverse Events (TEAE), Adverse Events of Special Interest (AESI), and Serious Adverse Events (SAE) [ Time Frame: Up to 41 weeks ]
• EuroQol Five-Dimension Five-Level Scale (EQ-5D-5L) score [ Time Frame: 30 weeks treatment period ]
• Autoimmune Blister Quality of Life (ABQOL) score [ Time Frame: 30 weeks treatment period ]
• Efgartigimod serum concentrations [ Time Frame: Up to 38 weeks ]
• Total immunoglobulin G and subtype (IgG1, IgG2, IgG3, IgG4) serum levels [ Time Frame: Up to 41 weeks ]
  Total immunoglobulin G and subtype (IgG1, IgG2, IgG3, IgG4) serum levels
• Anti desmoglein-1 and -3 autoantibodies serum levels [ Time Frame: Up to 41 weeks ]
  Anti desmoglein-1 and -3 autoantibodies serum levels
• Anti-drug antibodies (ADA) to efgartigimod (serum plasma) and recombinant human hyaluronidase PH20 (plasma levels) [ Time Frame: Up to 38 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Assess the Efficacy and Safety of a Subcutaneous Formulation of Efgartigimod PH20 SC in Adults With Pemphigus (Vulgaris or Foliaceus)
• Official Title: A Randomized, Double-Blinded, Placebo-Controlled Trial to Investigate the Efficacy, Safety, and Tolerability of Efgartigimod PH20 SC in Adult Patients With Pemphigus (Vulgaris or Foliaceus)
• Brief Summary: This is a prospective, multicenter, randomized, double-blinded, placebo-controlled trial to investigate the efficacy, safety, patient outcome measures, tolerability, immunogenicity, PK, and PD of efgartigimod PH20 SC in adult participants aged from 18 years with PV or PF. The trial comprises a screening period of up to 3 weeks, a treatment period of up to 30 weeks, and an 8-week follow-up period for participants who do not enroll into the open-label extension (OLE) trial ARGX-113-1905. The primary objective of the ARGX-113-1904 trial is to demonstrate the efficacy of subcutaneous administration of efgartigimod co-formulated with recombinant human hyaluronidase PH20 (Efgartigimod PH20 SC) compared to placebo in the treatment of participants with Pemphigus Vulgaris (PV). Secondary objectives are to also demonstrate the efficacy of efgartigimod PH20 SC in the treatment of participants with Pemphigus Foliaceus (PF), and to demonstrate early onset of action and a prednisone-sparing effect. After confirmation of eligibility, participants will be randomized in a 2: 1 ratio to receive efgartigimod PH20 SC or placebo
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Pemphigus Vulgaris
• Pemphigus Foliaceus

Intervention

• Biological: efgartigimod PH20 SC
  Subcutaneous injection of efgartigimod using rHuPH20 (PH20) as a permeation enhancer
• Other: Placebo
  Subcutaneous injection of placebo
• Drug: prednisone
  Oral prednisone tablets

Study Arms

• Experimental: efgartigimod PH20 SC
  patients receiving efgartigimod PH20 SC on top of prednisone
  Interventions:

  • Biological: efgartigimod PH20 SC
  • Drug: prednisone
• Experimental: placebo
  patients receiving placebo on top of prednisone
  Interventions:

  • Other: Placebo
  • Drug: prednisone

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 6, 2023): 222
• Original Estimated Enrollment (submitted: October 16, 2020): 150
• Actual Study Completion Date: August 22, 2023
• Actual Primary Completion Date: August 22, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Ability to understand the requirements of the trial, to provide written informed consent (including 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. The participant is male or female, and aged from 18 years at the time of signing the informed consent form (ICF).
3. The participant has a clinical diagnosis of PV (mucosal, cutaneous, mucocutaneous) or PF which has been confirmed by cutaneous histology, positive direct immunofluorescence (IF), and positive indirect IF and/or enzyme-linked immunosorbent assay (ELISA).

4. The participant meets one of the following profiles:

   1. Newly diagnosed disease with PDAI ≥15 at baseline and naïve to treatment
   2. Newly diagnosed disease with PDAI ≥15 while receiving a first course of oral prednisone (or equivalent). According to clinical judgment, the participant has shown no significant improvement of PV or PF signs for at least 2 weeks before baseline and is considered fit to start prednisone treatment at 0.5 mg/kg qd at baseline.
   3. Experiencing flare with PDAI ≥15, a maximum of 4 years since diagnosis, and off prednisone therapy ± a conventional immunosuppressant (e.g., azathioprine, cyclophosphamide, methotrexate, mycophenolate mofetil) or dapsone. Note: conventional immunosuppressants and dapsone must be discontinued before baseline.
   4. Experiencing flare with PDAI ≥15, a maximum of 4 years since diagnosis, and receiving a tapered dose of oral prednisone (or the equivalent), provided that prednisone has been given at stable dose ± a conventional immunosuppressant for at least 2 weeks and patients are fit to start prednisone treatment at 0.5 mg/kg qd at baseline.

5. Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating clinical trials and:

   1. Male participants: Male participants must agree to use acceptable method of contraception, and not donate sperm from signing the ICF until the end of the study.

   2. Female participants: Women of childbearing potential must:

      • have a negative serum pregnancy test at screening and negative urine pregnancy test at baseline before the IMP can be administered.
      • agree to use a highly effective or acceptable contraception method, which should be maintained at minimum until after the last dose of IMP
6. For Japanese participants enrolled in sites in Japan only: A Japanese participant is defined as a participant whose parents and 4 grandparents are Japanese, and who has Japanese nationality, was born in Japan, has not lived outside of Japan for a total of >10 years, and currently lives in Japan.

Exclusion Criteria:

1. Participant has a confirmed diagnosis of paraneoplastic pemphigus, drug-induced pemphigus, pemphigus vegetans, pemphigus erythematosus, or any other non-PV/non-PF autoimmune blistering disease.
2. Participants with mild disease severity as defined by PDAI <15 at baseline.
3. Participants who show a significant improvement of PV or PF in the period from screening to baseline according to clinical judgment (eg, the patient has achieved DC or a substantial reduction in PDAI activity score during screening period).
4. The participant has been administered therapy(ies) other than oral prednisone or conventional immunosuppressants (e.g., azathioprine, cyclophosphamide, methotrexate, mycophenolate mofetil) or dapsone within 2 months before the baseline visit and that can affect clinical disease activity. For example, excluded medications are intravenous methylprednisolone, dapsone, sulfasalazine, tetracyclines, nicotinamide at doses above the recommended daily allowance (RDA)/dietary reference intake (DRI), plasmapheresis/ plasma exchange, immunoadsorption, and IVIg.
5. Use of any monoclonal antibody (including rituximab or another anti-CD20 biologic) within 6 months before the baseline visit.
6. Known hypersensitivity to any of the components of the administered treatments.
7. The participant has a known contraindication to oral prednisone.
8. The participant has a history of refractory disease, as defined by a failure to respond to first-line and second-line therapies

9. Participants who have a history of malignancy unless deemed cured by adequate treatment with no evidence of recurrence for ≥3 years before first IMP administration. Participants with any of the following cancers can be included at any time, provided they are adequately treated prior to their participation in the study:

   • Basal cell or squamous cell skin cancer,
   • Carcinoma in situ of the cervix,
   • Carcinoma in situ of the breast,
   • Incidental histological finding of prostate cancer
10. Participants with clinical evidence of other significant serious disease or participants who recently underwent or have planned a major surgery during the period of the trial, or any other condition in the opinion of the investigator, that could confound the results of the trial or put the patient at undue risk.
11. Pregnant and lactating women and those intending to become pregnant during the trial.
12. Current or history (i.e. within 12 months of screening) of alcohol, drug, or medication abuse.
13. Any other known autoimmune disease that, in the opinion of the investigator, would interfere with an accurate assessment of clinical symptoms of PV or PF or put the participant at undue risk.
14. The participant has a Karnofsky Performance score <60%.
15. Vaccination with live viral vaccines within 28 days prior to randomization.
16. The participant has clinically significant uncontrolled active or chronic bacterial, viral, or fungal infection.
17. Positive serum test at screening for an active viral infection with any of the following conditions: Hepatitis B Virus, Hepatitis C Virus , HIV.
18. The participant has total immunoglobulin G (IgG) <6 g/L at screening.
19. The participant has previously participated in a trial with efgartigimod and has received at least one administration of IMP.
20. Use of an investigational drug within 3 months or 5 half-lives of the drug (whichever is longer) prior to first IMP administration

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Bulgaria, China, France, Georgia, Germany, Greece, Hungary, India, Israel, Italy, Japan, Poland, Romania, Russian Federation, Serbia, Spain, Turkey, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT04598451
• Other Study ID Numbers: ARGX-113-1904
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: argenx
• Original Responsible Party: Same as current
• Current Study Sponsor: argenx
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: argenx
• Verification Date: September 2023