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.
Condition or disease | Intervention/treatment | Phase |
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Atypical Hemolytic Uremic Syndrome | Drug: cemdisiran Drug: Placebos | Phase 2 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 0 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Intervention Model Description: | 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). |
Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
Masking Description: | 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. |
Primary Purpose: | Treatment |
Official Title: | A Phase II, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Safety and Efficacy of Cemdisiran (ALN-CC5) Following Withdrawal of Chronic Eculizumab Therapy in Patients With Atypical HUS at High Risk of Recurrence |
Estimated Study Start Date : | January 2021 |
Estimated Primary Completion Date : | January 2024 |
Estimated Study Completion Date : | March 2024 |
Arm | Intervention/treatment |
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Experimental: IMP
Cemdisiran (600 mg) or placebo will be administered subcutaneously every four weeks up to week 32 (end of the Core Study).
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Drug: cemdisiran
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.
Other Name: ALN-CC5
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Placebo Comparator: Placebo
Cemdisiran (600 mg) or placebo will be administered subcutaneously every four weeks up to week 32 (end of the Core Study).
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Drug: Placebos
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.
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Ages Eligible for Study: | 12 Years and older (Child, Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Known high risk of aHUS recurrence due to at least one of the following criteria;
Exclusion Criteria:
Italy | |
Centro di Ricerche Cliniche per le Malattie Rare " Aldo e Cele Daccò" | |
Ranica, BG, Italy, 24020 |
Tracking Information | |||||
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First Submitted Date ICMJE | June 25, 2019 | ||||
First Posted Date ICMJE | June 27, 2019 | ||||
Last Update Posted Date | March 10, 2021 | ||||
Estimated Study Start Date ICMJE | January 2021 | ||||
Estimated Primary Completion Date | January 2024 (Final data collection date for primary outcome measure) | ||||
Current Primary Outcome Measures ICMJE |
Ex vivo complement activation on the surface of cultured microvascular endothelial cells exposed to patient sera [ Time Frame: Changes from baseline and 16,32,44,60, 84 and 108 weeks after randomization. ] 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.
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Original Primary Outcome Measures ICMJE |
Serum-induced thrombus formation on HMEC-1 [ Time Frame: Changes from baseline and 16,32,44,60, 84 and 108 weeks after randomization. ] 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.
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Change History | |||||
Current Secondary Outcome Measures ICMJE | Not Provided | ||||
Original Secondary Outcome Measures ICMJE | Not Provided | ||||
Current Other Pre-specified Outcome Measures | Not Provided | ||||
Original Other Pre-specified Outcome Measures | Not Provided | ||||
Descriptive Information | |||||
Brief Title ICMJE | Eculizumab to Cemdisiran Switch in aHUS | ||||
Official Title ICMJE | A Phase II, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Safety and Efficacy of Cemdisiran (ALN-CC5) Following Withdrawal of Chronic Eculizumab Therapy in Patients With Atypical HUS at High Risk of Recurrence | ||||
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. |
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Detailed Description | Not Provided | ||||
Study Type ICMJE | Interventional | ||||
Study Phase ICMJE | Phase 2 | ||||
Study Design ICMJE | Allocation: Randomized Intervention Model: Parallel Assignment Intervention Model Description: 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). Masking Description: 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. Primary Purpose: Treatment
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Condition ICMJE | Atypical Hemolytic Uremic Syndrome | ||||
Intervention ICMJE |
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Study Arms ICMJE |
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Publications * | Not Provided | ||||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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Recruitment Information | |||||
Recruitment Status ICMJE | Withdrawn | ||||
Actual Enrollment ICMJE |
0 | ||||
Original Estimated Enrollment ICMJE |
12 | ||||
Estimated Study Completion Date ICMJE | March 2024 | ||||
Estimated Primary Completion Date | January 2024 (Final data collection date for primary outcome measure) | ||||
Eligibility Criteria ICMJE |
Inclusion Criteria:
Exclusion Criteria:
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Sex/Gender ICMJE |
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Ages ICMJE | 12 Years and older (Child, Adult, Older Adult) | ||||
Accepts Healthy Volunteers ICMJE | No | ||||
Contacts ICMJE | Contact information is only displayed when the study is recruiting subjects | ||||
Listed Location Countries ICMJE | Italy | ||||
Removed Location Countries | |||||
Administrative Information | |||||
NCT Number ICMJE | NCT03999840 | ||||
Other Study ID Numbers ICMJE | Cemdisiran in aHUS 2018-004382-13 ( EudraCT Number ) |
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Has Data Monitoring Committee | Yes | ||||
U.S. FDA-regulated Product |
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IPD Sharing Statement ICMJE |
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Responsible Party | Mario Negri Institute for Pharmacological Research | ||||
Study Sponsor ICMJE | Mario Negri Institute for Pharmacological Research | ||||
Collaborators ICMJE | Alnylam Pharmaceuticals | ||||
Investigators ICMJE | Not Provided | ||||
PRS Account | Mario Negri Institute for Pharmacological Research | ||||
Verification Date | March 2021 | ||||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |