Eculizumab to Cemdisiran Switch in aHUS

NCT03999840 | Withdrawn Phase 2 DMC

• 2 other identifiers: Cemdisiran in aHUS2018-004382-13
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Atypical Hemolytic Uremic Syndrome (aHUS) is a rare, lifethreatening, chronic disease of complement-mediated thrombotic microangiopathy (TMA) characterized by acute onset of renal impairment, thrombocytopenia, and microangiopathic hemolytic anemia. The estimated incidence of aHUS is approximately 0.5 per million per year. aHUS affects both adults and children, but is observed primarily in children and young adults. Atypical HUS commonly develops due to dysregulation of the alternative complement pathway and can be sporadic (80%) or familial(20%). The clinical course of aHUS is often unpredictable and can be dependent upon the specific genetic abnormality present within the complement system, if any, and/or triggering events associated with complement activation or inflammation, including autoimmune disease, transplant, pregnancy, infection, metabolic conditions, and drug use. In patients with dysregulated complement activity, such as those with complement mutations commonly observed in aHUS, the kidney vasculature is often the site of thrombosis stemming from endothelial injury. Cemdisiran has been designed to reduce the level of C5 mRNA in the liver, thereby reducing levels of circulating C5 protein, inhibiting terminal complement pathway activity, and preventing formation and deposition of the MAC (C5-b9) on endothelial cells in the kidney. As a result, complement-mediated endothelial cell damage in patients with aHUS and subsequent progression to End Stage Renal Disease (ESRD) may be reduced.

Conditions

Atypical Hemolytic Uremic Syndrome

Keywords

aHUS; cemdisiran; synthetic RNA interference

Outcome Measures

Primary Outcomes (1)

• Ex vivo complement activation on the surface of cultured microvascular endothelial cells exposed to patient sera

  Persistent inhibition of serum-induced complement (C5b-9) deposition on ADP-activated cultured HMEC-1 (deposition \<150%: upper limit of normal range) up to week 32 (Core study) during cemdisiran therapy as compared to complement reactivation during placebo treatment.

  Changes from baseline and 16,32,44,60, 84 and 108 weeks after randomization.

Study Arms (2)

IMP

EXPERIMENTAL

Cemdisiran (600 mg) or placebo will be administered subcutaneously every four weeks up to week 32 (end of the Core Study).

Drug: cemdisiran

Placebo

PLACEBO COMPARATOR

Cemdisiran (600 mg) or placebo will be administered subcutaneously every four weeks up to week 32 (end of the Core Study).

Drug: Placebos

Interventions

cemdisiran DRUG

Cemdisiran has been designed to reduce the level of C5 mRNA in the liver, thereby reducing levels of circulating C5 protein, inhibiting terminal complement pathway activity, and preventing formation and deposition of the MAC (C5-b9) on endothelial cells in the kidney.

Also known as: ALN-CC5

IMP

Placebos DRUG

The control drug for this study will be a placebo (sodium chloride 0.9% w/v for SC administration). Placebo will be prepared and labelled identically to cemdisiran.

Placebo

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• years and older at the time of consent;
• Written informed consent (of parents or the guardian in case of underage participants) to enter the study;
• Consent to stop eculizumab therapy during the whole study period and to resume eculizumab therapy in case of disease recurrence
• \>40 kg body weight;
• On stable disease status with eculizumab continuous therapy for aHUS for ≥ 12 consecutive months (stability assessed on the basis of hematological/biochemical parameters by the Investigator)
• Estimated GFR (by the simplified MDRD equation) \> 30/ml/min 1.73 m2;
• Known high risk of aHUS recurrence due to at least one of the following criteria;
• History of aHUS recurrence after interruption of eculizumab therapy;
• Plasma dependent and/or recurrent disease before the introduction of eculizumab therapy;
• Documented mutations in complement factors that are associated with a high risk of disease recurrence such as mutations in Factor H, I or B;
• Females childbearing potential and non-sterile males must agree to use a method of contraception;
• Documented previous immunisation against Neisseria meningitidis (serotypes A, C, Y, W135 e B) by anti A, C, W and Y vaccine and anti B vaccine (Bexsero®) and antibiotic prophylaxis in accordance with the KDIGO guidelines and local standard of care of the PI at the trial Center, OR de-novo immunisation against Neisseria meningitidis and antibiotic prophylaxis in accordance with the KDIGO guidelines and local standard of care of the PI at the trial Center, if necessary. Documented previous immunization against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Study participants who do not have a sufficient history for some or all of these vaccines should be vaccinated.

You may not qualify if:

• Solid organ or bone marrow/stem cell transplantation;
• Alanine transaminase (ALT) \>3×ULN, INR \>2 (or \>3.5 if on anticoagulants), or total bilirubin \>3×ULN (unless bilirubin elevation is due to Gilbert's syndrome);
• Clinical or biochemical evidence of active thrombotic; microangiopathy or flare of aHUS at the time of enrolment
• Evidence of Shigatoxin associated HUS;
• Patients who did not relapse despite prolonged (\>3 months) interruption of eculizumab therapy (these would probably be low risk patients that are expected to be event-free throughout the whole study period independent of treatment allocation and could have a dilution effect for event analyses);
• Patients with a confirmed diagnosis of sepsis, defined as positive blood cultures within 7 days of the screening visit and not treated with antibiotics to which the organism is sensitive;
• Presence or suspicion of active and untreated systemic bacterial infection that, in the opinion of the Investigator confounds an accurate diagnosis of aHUS or impedes the ability to manage the aHUS disease;
• Evidence of human immunodeficiency virus (HIV) (positive serology for HIV antibody \[HIV Ab\]), hepatitis B infection (positive hepatitis B surface antigen \[HbsAg\]), or hepatitis C infection (positive anti-HCV antibody \[HCV Ab\]) at Screening or historically
• Unresolved meningococcal disease;
• Known Systemic Lupus Erythematosus (SLE) or antiphospholipid antibody positivity or syndrome;
• Exposure to any other investigational drug acting directly on the complement system (except for eculizumab) within 5 half-lives of screening is prohibited;
• Chemotherapeutic agents within 3 months of enrolment in the study are prohibited;
• History of malignancy within 5 years of screening;
• Participation in other clinical trials within 4 weeks of signing the consent form;
• Any severe systemic disorder that could interfere with the evaluation of the study treatment (e.g. hepatic disease) that in the opinion of the Investigator would affect the outcome of the study or interfere with interpretation of results;

Sponsors & Collaborators

• Mario Negri Institute for Pharmacological Research: lead
• Alnylam Pharmaceuticals: collaborator

Study Sites (1)

Centro di Ricerche Cliniche per le Malattie Rare " Aldo e Cele Daccò"

Ranica, BG, 24020, Italy

Location

MeSH Terms

Conditions

Atypical Hemolytic Uremic Syndrome

Condition Hierarchy (Ancestors)

Hemolytic-Uremic Syndrome; Uremia; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Thrombotic Microangiopathies; Thrombocytopenia; Blood Platelet Disorders; Cytopenia

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: In order to have a balanced distribution of risk factors for disease recurrence and considering the small number of patients and of expected events, before randomization patients will be stratified according to previous history of disease relapse (after eculizumab interruption and/or after a course of plasma therapy) YES or NO.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This will be a prospective, randomized, double blind, placebocontrolled trial organized in a Core Study, an Extension follow-up period and a Safety Period. The study duration for each patient is 108 weeks (core study 32 weeks, extension follow up 52 weeks and safety follow up 24 weeks).

Study Record Dates

• First Submitted: June 25, 2019
• First Posted: June 27, 2019
• Study Start: January 1, 2021
• Primary Completion: January 1, 2024
• Study Completion: March 1, 2024
• Last Updated: March 10, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)