Atypical Hemolytic Uremic SyndromePhase 2DANCENCT03999840
Eculizumab to Cemdisiran Switch in aHUS
A Phase 2 study testing cemdisiran in people with Atypical Hemolytic Uremic Syndrome, run by Mario Negri Institute for Pharmacological Research at 1 site in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 12 years and older
- Conditions the study is for
- Atypical Hemolytic Uremic Syndrome
- What is being tested?
- cemdisiran
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- 1 siteItaly
- Study dates
- Jan 2021to Mar 2024
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 12 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)
- Hematological remission at screening and inclusion;
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- 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.
Who cannot join
- 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 required intensified eculizumab therapy because of uncontrolled disease (these patients could be at very high risk of relapse after the shift, even in the cemdisiran treatment arm and their inclusion could be unsafe);
- 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);
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- 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;
- Active systemic autoimmune diseases other than the target condition. Dermatologic diseases such as atopic dermatitis or psoriasis will not be a reason for exclusion unless there are associated systemic symptoms such as arthritis;
- 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;
- Failure to satisfy the Investigator of fitness to participate for any other reason or any condition (e.g. severe depression or psychiatric disorder) that, in the opinion of the Investigator, could increase the subject's risk by participating in the study or confound the outcome of the study;
- If female, the subject is pregnant or lactating or intending to become pregnant before, during, or within 90 days after last dose; or intending to donate ova during such time period;
- If male, the subject intends to donate sperm while on the study or for 90 days after last study drug administration;
- The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within one year prior to screening. Alcohol abuse is defined as regular weekly intake of >14 units (unit: 1 glass of wine [125 mL] =1 measure of spirits=1/2 pint [0.25 mL] of beer). Alcohol is limited to no more than 2 units per day for the duration of the study;
- Patients with a poor prognosis that is expected to limit their life expectancy to less than 3 months, in the opinion of the Investigator;
- History of multiple drug allergies or history of allergic reaction to an oligonucleotide or GalNAc;
- History of intolerance to subcutaneous (SC) injection(s) or significant abdominal scarring that could potentially hinder cemdisiran administration or evaluation of local tolerability.
Trial locations and contacts
1 site in 1 country.
Italy1 site
Centro di Ricerche Cliniche per le Malattie Rare " Aldo e Cele Daccò"
Ranica, BG, 24020
About this study
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
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%).
Read more
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
- Being tested
- cemdisiran, Placebos
- Keywords
- aHUS, cemdisiran, synthetic RNA interference
- Medical subject headings
- Atypical Hemolytic Uremic Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
cemdisiranDrug
Also called ALN-CC5
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.
PlacebosDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| IMP | Experimental | Cemdisiran (600 mg) or placebo will be administered subcutaneously every four weeks up to week 32 (end of the Core Study). Receives: 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). Receives: Drug: Placebos |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Changes from baseline and 16,32,44,60, 84 and 108 weeks after randomization.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jun 2019
- Study startJan 2021 (estimated)
- Primary completionJan 2024 (estimated)
- Study completionMar 2024 (estimated)
Why it stopped: Due to the COVID global pandemic Sponsor has not received the economic support necessary for the study conduction.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Atypical Hemolytic Uremic SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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 blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Mario Negri Institute for Pharmacological Research
- Sponsor type
- University, hospital or other
- Collaborators
- Alnylam Pharmaceuticals
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03999840
- Sponsor's protocol ID
- Cemdisiran in aHUS
- Other IDs
- 2018-004382-13, 2018
- Acronym
- DANCE
- Status last verified
- Mar 2021
- First submitted
- 25 Jun 2019
- Last updated
- 10 Mar 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 10 Mar 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03999840
- Acronym / sponsor ID
- DANCE / Cemdisiran in aHUS
- Conditions
- Atypical Hemolytic Uremic Syndrome
- Keywords
- aHUS, cemdisiran, synthetic RNA interference
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Due to the COVID global pandemic Sponsor has not received the economic support necessary for the study conduction.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Mario Negri Institute for Pharmacological ResearchUniversity, hospital or other
- Collaborators
- Alnylam Pharmaceuticals
- Study start
- Jan 2021 (estimated)
- Primary completion
- Jan 2024 (estimated)
- Study completion
- Mar 2024 (estimated)
- First posted
- 27 Jun 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- 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).
| Arm | Type | Receives |
|---|---|---|
| IMP | Experimental | Drug: cemdisiranCemdisiran (600 mg) or placebo will be administered subcutaneously every four weeks up to week 32 (end of the Core Study). |
| Placebo | Placebo comparator | Drug: PlacebosCemdisiran (600 mg) or placebo will be administered subcutaneously every four weeks up to week 32 (end of the Core Study). |
Who may qualify
- Ages
- 12 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (13 listed)
- 12 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)
Key exclusion criteria (24 listed)
- 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 required intensified eculizumab therapy because of uncontrolled disease (these patients could be at very high risk of relapse after the shift, even in the cemdisiran treatment arm and their inclusion could be unsafe);
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| cemdisiranAlso: ALN-CC5Cemdisiran 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. | Drug | IMP |
| PlacebosThe 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. | Drug | Placebo |
Primary outcome
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.
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Mar 2021.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing cemdisiran in people with Atypical Hemolytic Uremic Syndrome, run by Mario Negri Institute for Pharmacological Research at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 10 Mar 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Mar 2021.