Study to Evaluate The Safety And Effectiveness of XmAb®5871 In Patients With IgG4-Related Disease (INDIGO)

• Register: EUCTR
• Last refreshed on: 15 June 2020
• Main ID: EUCTR2017-002214-31-BE
• Date of registration: 22/10/2018
• Prospective Registration: Yes
• Primary sponsor: Xencor, Inc.
• Public title: Study to Evaluate The Safety And Effectiveness of XmAb®5871 In Patients With IgG4-Related Disease (INDIGO)
• Scientific title: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of XmAb®5871 in Patients with IgG4-Related Disease (INDIGO)
• Target sample size: 240
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-002214-31
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Canada, Czech Republic, France, Germany, Hungary, Israel, Italy, Netherlands, Poland, Spain, Sweden, United Kingdom, United States

Contacts

• Name: Debra Zack, MD, PhD
• Affiliation: Xencor Inc.

• Name: Debra Zack, MD, PhD
• Affiliation: Xencor Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male or female 12 years of age or older
2. Able to provide written informed consent. For subjects 12 to 18 years of age, the adolescent signs a patient assent form, and the parent or the legal guardian must sign the ICF.
3. Meet the ACR/EULAR classification criteria for IgG4-RD with a score of = 20
4. Must have active IgG4-RD signs/symptoms that require, as assessed by the Investigator, the initiation of corticosteroid therapy or the increase in background long-term corticosteroid therapy (if previously on a stable dose of = 10 mg/day prednisone equivalent).
5. An oral corticosteroid dose must be maintained at a stable dose for 14 to 28 days during the 28-day screening period prior to randomization.
6. Must be able and willing to receive corticosteroid therapy during the induction phase of the trial and be able to taper off any systemic corticosteroid therapy per protocol
7. Must be willing to stop other IgG4-RD directed medications during screening (eg. methotrexate, mycophenolate mofetil, 6-mercaptopurine or azathioprine).
8. Must have a negative serum pregnancy test within 14 days before
randomization.
9. Female subjects of childbearing potential must agree to use a highly effective method of birth control from screening until 8 weeks after the last dose of XmAb5871/placebo is given. Women are considered to be of childbearing potential unless it is documented that they are premenarche OR over the age of 60 OR postmenopausal by history with no menses for 1 year and confirmed by follicle stimulating hormone (FSH) OR have a history of hysterectomy and/or bilateral oophorectomy and/or bilateral salpingectomy. Highly effective methods of birth control include combined hormonal birth control (oral, intravaginal, transdermal) or progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, intrauterine), intrauterine devices (IUDs), intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner (provided partner is the sole sexual partner and there has been a medical assessment of surgical success), or sexual abstinence (when this is in line with the preferred and usual lifestyle of
the subject). Sexual counseling of adolescent study subjects should take place prior to entrance into the study.
10. No history of severe allergic reactions to monoclonal antibodies.
11. Are able and willing to complete the entire study according to the study schedule.
12. Are willing to forego other forms of experimental treatment during the study.

Are the trial subjects under 18? yes
Number of subjects for this age range: 2
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 143
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 95

Exclusion criteria:
1. Any Exclusion Criteria as listed in the ACR/EULAR IgG4-RD Classification Criteria (see Appendix 1 of Protocol)
2. Initiation of corticosteroid therapy (or increase in long-term corticosteroid therapy) for new or exacerbated signs/symptoms of IgG4-RD > 14 days before enrolment
3. Corticosteroid dose has exceeded 60 mg/day prednisone equivalent given orally within 14 days prior to screening or will exceed 60 mg/day during the screening .period.
4. Corticosteroids have been given by the IV or IM route within 14 days prior to screening or will be given by these routes of administration during the screening period.
5. IgG4-RD requiring long-standing corticosteroid therapy at a dose of > 10 mg/day prednisone equivalent
6. Subjects with disease in only 1 organ system whose primary manifestation is fibrosis (for example, neuro-meningeal involvement, retroperitoneal fibrosis, fibrosing or sclerosing mesenteritis) will be excluded.
7. History or evidence of a clinically unstable/uncontrolled disorder, condition or disease (including but not limited to cardiopulmonary, oncologic, renal, hepatic, metabolic, hematologic or psychiatric) other than IgG4-RD that, in the opinion of the Investigator would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
8. Malignancy within 5 years (except successfully treated in situ cervical cancer, resected squamous cell or basal cell carcinoma of the skin, breast cancer with no recurrence = 5 years following therapy, or prostate cancer with no recurrence =3 years following prostatectomy).
9. Presence of recurrent or chronic infections, defined as =3 infections requiring antimicrobials over the past 6 months prior to screening.
10. Active infection requiring hospitalization or treatment with parenteral antimicrobials within the 30 days prior to randomization or oral antimicrobials within the 14 days prior to randomization.
11. Prior use of rituximab (or other B cell depleting agents) within 5 months of randomization.
12. Use of any investigational agent within 5 half-lives of the agent (or 3 months if the half-life is unknown) prior to randomization.
13. White blood cell count < 2.5 x 103/µL.
14. Absolute neutrophil count (ANC) < 1.0 x 103/µL.
15. Elevated serum creatinine > 2.5 x upper limit of normal (ULN) OR estimated creatinine clearance < 40 mL/minutes calculated by the Cockroft-Gault formula at screening.
16. Hemoglobin < 10 g/dL.
17. Platelet count < 75 x 109/L.
18. Positive test result for human immunodeficiency virus (HIV) I and II antibody, hepatitis B surface antigen, (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C virus antibody (HCV Ab).
19. Has received live vaccines within 4 weeks before randomization.
20. Inability to communicate reliably with the Investigator.
21. Subject is pregnant or breast feeding or planning to become pregnant while enrolled in the study.
22. Positive pregnancy test at screening or at any time during the study.
23. Subjects who do not agree to use medically acceptable methods of contraception.
24. Known or suspected sensitivity to mammalian cell-derived products or any components of the study drug.
25. Unable or unwilling to partake in follow-up assessments or required protocol procedures.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

IgG4-Related Disease
MedDRA version: 20.0 Level: LLT Classification code 10071581 Term: IgG4 related sclerosing disease System Organ Class: 100000004859

Intervention(s)

Product Code: XmAb5871
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: XmAb5871
Current Sponsor code: XmAb5871
Other descriptive name: XMAB5871
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 125.0-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Primary end point(s): Time to IgG4-RD disease flare (TDF), defined as the reappearance of signs/symptoms of IgG4-RD or the appearance of new signs/symptoms of IgG4-RD, that requires IgG4-RD rescue therapy. Subjects will have met the following criteria for IgG4-RD disease flare if at any time point during the study, after randomization, up to and including Study Day 701 (Week 101):
1. There has been a worsening of IgG4-RD RI of at least 1, AND
2. There is evidence of worsening of disease by change in physical exam, change in imaging, or change in biochemical parameters, AND
3. The Investigator assesses that there is a need for the institution of rescue therapy (ie, any IgG4-RD directed therapy, including but not limited to, additional corticosteroid dose or duration other than protocol-specified amounts, methotrexate, azathioprine, mycophenylate mofetil, B-cell depleting therapy, or other investigational therapy)

Secondary Objective: • To evaluate the effect of every other week SC administration of XmAb5871 on the proportion of subjects that remain free of IgG4-RD disease flares from randomization to Study Day 701 (Week 101)
• To evaluate the effect of every other week SC administration of XmAb5871 on the type and cumulative amount of IgG4-RD rescue therapy administered from randomization to Study Day 701 (Week 101)
• To evaluate the effect of every other week SC administration of XmAb5871 on the number and frequency of IgG4-RD disease flares from randomization to Study Day 701 (Week 101)
• To evaluate differences between treatment arms in corticosteroid-associated toxicity as measured by the Glucocorticoid Toxicity Index (GTI)
• To evaluate the safety and tolerability of every other week SC administration of XmAb5871 in subjects with active IgG4-RD

Main Objective: To evaluate the effect of every other week subcutaneous (SC) administration of XmAb5871 on the time to IgG4-related disease (IgG4-RD) flare following an initial course of corticosteroid therapy in subjects with active IgG4-RD

Timepoint(s) of evaluation of this end point: any time point

Secondary Outcome(s)

Secondary end point(s): Secondary Efficacy:
• The proportion of subjects that remain free of IgG4-RD disease flares from randomization to Study Day 701 (Week 101)
• Type and cumulative amount of IgG4-RD rescue therapy usage from randomization to Study Day 701 (Week 101)
• Number and frequency of IgG4-RD disease flares from randomization to Study Day 701 (Week 101) or study withdrawal

Secondary Safety:
• Incidence of AEs
• Incidence of AEs related to corticosteroids or other rescue therapies
• Glucocorticoid Toxicity Index (GTI)Vital signs assessment
• Clinical laboratory assessments
• ECG assessments
Secondary Immunogenicity:
• Frequency and titer of serum anti-XmAb5871 antibodies (ADA); association with AEs and changes in effective exposure
Secondary Pharmacokinetic:
• Trough serum concentrations of XmAb5871
Secondary Pharmacodynamic:
• Change from baseline in ABC count
• Change from baseline in B cell CD19 RO
• Change from baseline in serum IgG4 concentration
• Change from baseline in B cell qPCR IgG4/IgG BCR RNA ratio (exploratory studies may be done on this sample to elucidate B- and T-cell receptor repertoires and major histocompatibility complex alleles; if done, these may be reported in a separate report)
• Change from baseline in circulating plasmablast count (may be performed at selected sites)
• Change from baseline in circulating CD4+ CTLs (may be performed at selected sites)
• Change from baseline pancreatic endocrine and exocrine function
Secondary Pharmacogenomics:
• Incidence of Fc?RIIa R131H polymorphism
• Incidence of Fc?RIIb I232T polymorphism

Timepoint(s) of evaluation of this end point: week 101, for other time points see protocol

Secondary ID(s)

2017-002214-31-GB

XmAb5871-06

Source(s) of Monetary Support

Xencor, Inc.