Safety, Tolerability and Activity of BIVV009 in Healthy Volunteers and Patients With Complement Mediated Disorders

NCT02502903 | Completed Phase 1 DMC

• 3 other identifiers: LTS16214BIVV009-012014-003881-26
• Study Type: interventional
• Target: 122
• Locations: 1 country
• Sites: 1

Brief Summary

Prospective, double-blind, randomized, placebo-controlled First-In-Human study with four sub-parts: Part A, a single ascending dose study (SAD) in normal human volunteers (NHVs), Part B, a multiple ascending dose study (MAD) in NHVs, Part C, a multiple dose (MD) study in patients with a complement-mediated disorder, and Part E, a multiple dose (MD) study in patients with cold agglutinin disease previously treated with BIVV009 within the scope of a BIVV009 clinical trial or named patient program use. Note: For parts A-C as well as at the start of part E, study drug was named TNT009. The study drug name is changed to BIVV009 with final version Final 15.0 of the clinical study protocol.

Conditions

Bullous Pemphigoid (BP); Cold Agglutinin Disease (CAD); Warm Autoimmune Hemolytic Anemia (WAIHA); End-stage Renal Disease (ESRD)

Outcome Measures

Primary Outcomes (1)

• Drug-related Adverse Event profile of BIVV009

  Serious and Non-Serious adverse events probably or possibly attributable to BIVV009

  6 weeks

Secondary Outcomes (5)

• Pharmacokinetic profile of BIVV009

  6 weeks

• Classical pathway complement system activity

  6 weeks

• Complement System-Related biomarkers

  6 weeks

• Coagulation System-Related biomarkers

  6 weeks

• Disease-Related Biomarkers

  6 weeks

Study Arms (4)

Part A

PLACEBO COMPARATOR

Single ascending dose (SAD) in NHVs, 7 cohorts, BIVV009 by IV infusion (0.3,1, 3, 10, 30, 60, or 100 mg/kg) or placebo.

Drug: BIV009; Other: Placebo

Part B

PLACEBO COMPARATOR

Multiple ascending dose (MAD) in NHVs, 2 cohorts, 4 weekly IV doses of BIVV009 (30 or 60mg/kg) or placebo.

Drug: BIV009; Other: Placebo

Part C

EXPERIMENTAL

Multiple dose (MD) in a single cohort of patients with various complement-mediated disorders. All patients in Part C will receive a single IV test dose of BIVV009 of 10 mg/kg followed by 4 weekly doses of 60 mg/kg.

Drug: BIV009

Part E

EXPERIMENTAL

Multiple dose (MD) in a single cohort of patients with cold agglutinin disease previously treated with BIVV009. All patients in Part E will receive a single IV test dose at week 0, week 1, and every 2 weeks thereafter until EOT. Patients who weigh less than 75 kg will receive fixed doses of 6.5 grams of BIVV009; patients who weigh 75 kg or more will receive fixed doses of 7.5 grams of BIVV009. Dose will be increased from 6.5g to 7.5g dose level if patients current weight is \>= 75 kg and there is evidence of hematologic breakthrough OR patients current weight is \>= 75 kg and there has been at least a 10 percent increase from the patients last recorded weight. Dose will be decreased from 7.5g to 6.5g for patients whose last weight was \>= 75 kg and current weight decreased to \< 75 kg. Dose decrease will require Sponsor approval.

Drug: BIV009

Interventions

BIV009 DRUG

Part A; Part B; Part C; Part E

Placebo OTHER

Also known as: saline solution 0.9 %

Part A; Part B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Part A/B:
• healthy male or female volunteers, age \>= 18 years old
• if female, must be post-menopausal, surgically sterilized, or willing/able to use dual, redundant methods of contraception (e.g., barrier plus oral contraceptives) throughout the study
• previously vaccinated against encapsulated bacterial pathogens (Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae) or willing to undergo vaccination
• able to comprehend and to give informed consent
• able to co-operate with the investigator, to comply with the requirements of the study, and to complete the full sequence of protocol-related procedures
• Part C:
• male or female, age \>=18 years old
• if female, must be post-menopausal, surgically sterilized, or willing/able to use dual, redundant methods of contraception (e.g., barrier plus oral contraceptives) throughout the study
• previously vaccinated against encapsulated bacterial pathogens (Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae) or willing to undergo vaccination
• able to comprehend and to give informed consent
• able to co-operate with the investigator, to comply with the requirements of the study, and to complete the full sequence of protocol-related procedures
• History of one of the following complement-mediated disorders:
• bullous pemphigoid (BP)
• cold agglutinin disease (CAD)

You may not qualify if:

• Part A/B:
• clinically significant medical history or ongoing chronic illness that would jeopardize the safety of the subject or compromise the quality of the data derived from his/her participation in this study
• clinically relevant infection of any kind within the preceding month
• clinically relevant abnormal findings on physical examination or clinically relevant laboratory abnormalities
• history of infusion hypersensitivity, allergic or anaphylactic reactions to other therapeutic proteins
• substance abuse, mental illness, or any reason that makes it unlikely in the judgment of the Investigator for the subject to be able to comply fully with study procedures
• use of medication during 2 weeks before the start of the study, which in the judgment of the investigator may adversely affect the subject's welfare or the integrity of the study's results (excluding hormonal contraception in female subjects)
• females who are pregnant (positive pregnancy test at screening or during study phase), lactating, or, if having reproductive potential, are considered potentially unreliable with respect to contraceptive practice
• concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days prior to treatment start
• body weight \> 98 kg for all subjects in all dose cohorts other than the 100 mg/kg dose cohort of Part A, for which the body weight upper limit is 58 kg
• Part C:
• active acute or chronic viral, bacterial, fungal, or mycobacterial infection, or history of same within preceding month
• known malignancy (other than locally limited, previously surgically removed basal cell carcinoma of the skin, lymphoproliferative disorders causally related to the complement-mediated diseases under study, etc.)
• clinically significant hepatobiliary disorder
• history of infusion hypersensitivity, allergic or anaphylactic reactions to other therapeutic proteins

Sponsors & Collaborators

• Bioverativ, a Sanofi company: lead
• Celerion Clinical Research GmbH: collaborator
• Assign Data Management and Biostatistics GmbH: collaborator
• ABF Pharmaceutical Services GmbH: collaborator
• Quest Diagnostics-Nichols Insitute: collaborator
• Covance: collaborator
• PPD Laboratories - Virginia: collaborator
• Softworld Inc. - Cambridge, MA: collaborator

Study Sites (1)

Medical University of Vienna

Vienna, 1090, Austria

Location

Related Publications (5)

• Vo A, Ammerman N, Jordan SC. New Therapies for Highly Sensitized Patients on the Waiting List. Kidney360. 2024 Aug 1;5(8):1207-1225. doi: 10.34067/KID.0000000000000509. Epub 2024 Jul 12.

  PMID: 38995690 DERIVED

• Jager U, D'Sa S, Schorgenhofer C, Bartko J, Derhaschnig U, Sillaber C, Jilma-Stohlawetz P, Fillitz M, Schenk T, Patou G, Panicker S, Parry GC, Gilbert JC, Jilma B. Inhibition of complement C1s improves severe hemolytic anemia in cold agglutinin disease: a first-in-human trial. Blood. 2019 Feb 28;133(9):893-901. doi: 10.1182/blood-2018-06-856930. Epub 2018 Dec 17.

  PMID: 30559259 DERIVED

• Eskandary F, Jilma B, Muhlbacher J, Wahrmann M, Regele H, Kozakowski N, Firbas C, Panicker S, Parry GC, Gilbert JC, Halloran PF, Bohmig GA. Anti-C1s monoclonal antibody BIVV009 in late antibody-mediated kidney allograft rejection-results from a first-in-patient phase 1 trial. Am J Transplant. 2018 Apr;18(4):916-926. doi: 10.1111/ajt.14528. Epub 2017 Oct 31.

  PMID: 28980446 DERIVED

• Muhlbacher J, Jilma B, Wahrmann M, Bartko J, Eskandary F, Schorgenhofer C, Schwameis M, Parry GC, Gilbert JC, Panicker S, Bohmig GA. Blockade of HLA Antibody-Triggered Classical Complement Activation in Sera From Subjects Dosed With the Anti-C1s Monoclonal Antibody TNT009-Results from a Randomized First-in-Human Phase 1 Trial. Transplantation. 2017 Oct;101(10):2410-2418. doi: 10.1097/TP.0000000000001804.

  PMID: 28926521 DERIVED

• Derhaschnig U, Gilbert J, Jager U, Bohmig G, Stingl G, Jilma B. Combined integrated protocol/basket trial design for a first-in-human trial. Orphanet J Rare Dis. 2016 Oct 4;11(1):134. doi: 10.1186/s13023-016-0494-z.

  PMID: 27716293 DERIVED

MeSH Terms

Conditions

Pemphigoid, Bullous; Anemia, Hemolytic, Autoimmune; Kidney Failure, Chronic

Interventions

Saline Solution

Condition Hierarchy (Ancestors)

Skin Diseases, Vesiculobullous; Skin Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Renal Insufficiency, Chronic; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 7, 2015
• First Posted: July 20, 2015
• Study Start: July 13, 2015
• Primary Completion: March 31, 2021
• Study Completion: March 31, 2021
• Last Updated: April 25, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will share

Locations

AU (1)