BridgeMD
A Phase 3, Open-Label, Single-arm, Multicenter Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Activity, and Safety of Ravulizumab Administered Subcutaneously in Pediatric Participants (2 to < 18 years of age) with Paroxysmal Nocturnal Hemoglobinuria (PNH) or Atypical Hemolytic Uremic Syndrome (aHUS)
EU CTIS ID: 2022-502335-19-00
What this study is testing
To characterize the PK and PD of treatment with ravulizumab SC in pediatric participants with PNH or aHUS
- Therapeutic confirmatory (Phase III)
A plain-language read of the study's public EU CTIS listing. The study team confirms the details.
Who can take part
You may be able to join if
- Must be 2 to < 18 years of age at the time of informed consent
- Inclusion Criteria Specific for PNH Cohort: 10. Documented diagnosis of PNH confirmed by high-sensitivity flow cytometry evaluation (Borowitz, 2010) of red blood cells (RBCs) and white blood cells (WBCs), with granulocyte or monocyte clone size of ≥ 5%
- Complement inhibitor treatment-naïve participants must have the presence of 1 or more of the following PNH-related signs or symptoms within 3 months of Screening: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia, history of a MAVE (including thrombosis), dysphagia, or erectile dysfunction; or history of packed red blood cell transfusion due to PNH.
- LDH values at Screening as follows: a. Complement inhibitor treatment-naïve participants must have LDH ≥ 1.5 × ULN analyzed by the central laboratory b. Eculizumab- or ravulizumab-experienced participants must have LDH ≤ 1.5 × ULN (sample must be obtained within 1 day prior to the scheduled eculizumab/ ravulizumab dosing day [ie, at trough eculizumab/ravulizumab level] and analyzed by the central laboratory)
- Inclusion Criteria Specific for aHUS Cohort: Complement inhibitor treatment-naïve participants must have evidence of TMA, including thrombocytopenia, evidence of hemolysis, and kidney injury, based on the following laboratory findings: a. Platelet count < 150000/μL during the Screening Period or within 28 days prior to the start of the Screening Period, and b. LDH ≥ 1.5 × ULN for age and sex during the Screening Period or within 28 days prior to the start of the Screening Period, and c. Hemoglobin ≤ lower limit of normal (LLN) for age and sex during the Screening Period or within 28 days prior to the start of the Screening Period, and d. Serum creatinine level ≥ 97.5th percentile for age at Screening (participants who require dialysis for acute kidney injury are also eligible regardless of serum creatinine level)
- Eculizumab- or ravulizumab-experienced participants must have confirmed diagnosis of aHUS including all of the following laboratory findings documented by local laboratories at the time of the TMA event: a. Increase in LDH > ULN, and b. Increase in serum creatinine > ULN, and c. Decrease in platelets < LLN
You likely can't join if
- History of bone marrow transplantation
- Unstable medical conditions (eg, myocardial ischemia, active gastrointestinal bleed, severe congestive heart failure, anticipated need for major surgery within 6 months of Day 1, coexisting chronic anemia unrelated to PNH) that would make participants unlikely to tolerate the requirements of the protocol
- Known medical or psychological condition(s) or risk factor that, in the opinion of the Investigator, might interfere with the participant’s full participation in the study, pose any additional risk for the participant, or confound the assessment of the participant or outcome of the study
- Known or suspected history of drug or alcohol abuse or dependence within 1 year prior to the start of the Screening Period
- History of hypersensitivity reactions to: a. Commonly used antibacterial agents, including beta-lactams, penicillin, aminopenicillins, fluoroquinolones (specifically including ciprofloxacin), cephalosporins, and carbapenems, which in the opinion of the Investigator would make it ifficult to properly provide either empiric antibiotic therapy or treat an active infection b. Any ingredient contained in the study intervention, including hypersensitivity to murine proteins
- Concomitant use of anticoagulants is prohibited if not on a stable regimen for at least 2 weeks prior to study entry
See the full eligibility criteria
Who can join
- Must be 2 to < 18 years of age at the time of informed consent
- Inclusion Criteria Specific for PNH Cohort: 10. Documented diagnosis of PNH confirmed by high-sensitivity flow cytometry evaluation (Borowitz, 2010) of red blood cells (RBCs) and white blood cells (WBCs), with granulocyte or monocyte clone size of ≥ 5%
- Complement inhibitor treatment-naïve participants must have the presence of 1 or more of the following PNH-related signs or symptoms within 3 months of Screening: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia, history of a MAVE (including thrombosis), dysphagia, or erectile dysfunction; or history of packed red blood cell transfusion due to PNH.
- LDH values at Screening as follows: a. Complement inhibitor treatment-naïve participants must have LDH ≥ 1.5 × ULN analyzed by the central laboratory b. Eculizumab- or ravulizumab-experienced participants must have LDH ≤ 1.5 × ULN (sample must be obtained within 1 day prior to the scheduled eculizumab/ ravulizumab dosing day [ie, at trough eculizumab/ravulizumab level] and analyzed by the central laboratory)
- Inclusion Criteria Specific for aHUS Cohort: Complement inhibitor treatment-naïve participants must have evidence of TMA, including thrombocytopenia, evidence of hemolysis, and kidney injury, based on the following laboratory findings: a. Platelet count < 150000/μL during the Screening Period or within 28 days prior to the start of the Screening Period, and b. LDH ≥ 1.5 × ULN for age and sex during the Screening Period or within 28 days prior to the start of the Screening Period, and c. Hemoglobin ≤ lower limit of normal (LLN) for age and sex during the Screening Period or within 28 days prior to the start of the Screening Period, and d. Serum creatinine level ≥ 97.5th percentile for age at Screening (participants who require dialysis for acute kidney injury are also eligible regardless of serum creatinine level)
- Eculizumab- or ravulizumab-experienced participants must have confirmed diagnosis of aHUS including all of the following laboratory findings documented by local laboratories at the time of the TMA event: a. Increase in LDH > ULN, and b. Increase in serum creatinine > ULN, and c. Decrease in platelets < LLN
- Eculizumab- or ravulizumab-experienced participants must have clinical evidence of response to eculizumab or ravulizumab indicated by stable TMA parameters (via central laboratory results) at Screening, including: a. LDH < 1.5 × ULN, and b. Platelet count ≥ 150000/μL, and c. Estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73m2 using the Schwartz formula
- Among participants with a kidney transplant: a. Known history of aHUS prior to current kidney transplant, or b. No known history of aHUS, and persistent evidence of TMA at least 4 days after modifying the immunosuppressive regimen (eg, suspending or reducing the dose) of calcineurin inhibitor ([CNI]; eg, cyclosporine, tacrolimus) or mammalian target of rapamycin inhibitor ([mTORi]; eg, sirolimus, everolimus)
- Among participants with onset of TMA postpartum, persistent evidence of TMA for > 3 days after the day of childbirth.
- Male or female
- Female participants of childbearing potential and male participants must be willing to follow protocol-specified contraception guidance
- Body weight ≥ 10 kg at Screening
- To reduce the risk of meningococcal infection (N meningitidis), all participants must be vaccinated against meningococcal infection from serogroups A, C, Y, W135, and B within 3 years prior to, or at least 2 weeks prior to Day 1, according to national/local guidelines. Participants who do not meet this requirement must be vaccinated against meningococcal infection according to national/local guidelines and receive prophylactic antibiotics for at least 2 weeks after meningococcal vaccination if Day 1 occurs < 2 weeks after initial vaccination.
- Must have received vaccination for Streptococcus pneumoniae according to national and local vaccination schedule guidelines
- Must have received vaccination for Haemophilus influenzae type b according to national and local vaccination schedule guidelines
- Complement inhibitor-experienced participants must have been treated with eculizumab or ravulizumab according to the labeled dosing recommendation for at least 90 days prior to Screening with no missed doses within 2 months prior to study entry and no more than 2 doses outside of the visit window.
- Participant’s legal guardian/legally authorized representative must be capable of giving written informed consent and the participant must be capable of giving written informed assent (if applicable as determined by the central or local institutional review board [IRB]/independent ethics committee [IEC]) which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol (Section 10.1.3).
What rules you out
- History of bone marrow transplantation
- Unstable medical conditions (eg, myocardial ischemia, active gastrointestinal bleed, severe congestive heart failure, anticipated need for major surgery within 6 months of Day 1, coexisting chronic anemia unrelated to PNH) that would make participants unlikely to tolerate the requirements of the protocol
- Known medical or psychological condition(s) or risk factor that, in the opinion of the Investigator, might interfere with the participant’s full participation in the study, pose any additional risk for the participant, or confound the assessment of the participant or outcome of the study
- Known or suspected history of drug or alcohol abuse or dependence within 1 year prior to the start of the Screening Period
- History of hypersensitivity reactions to: a. Commonly used antibacterial agents, including beta-lactams, penicillin, aminopenicillins, fluoroquinolones (specifically including ciprofloxacin), cephalosporins, and carbapenems, which in the opinion of the Investigator would make it ifficult to properly provide either empiric antibiotic therapy or treat an active infection b. Any ingredient contained in the study intervention, including hypersensitivity to murine proteins
- Concomitant use of anticoagulants is prohibited if not on a stable regimen for at least 2 weeks prior to study entry
- Participation in another experimental therapy or investigational device study within 4 weeks before initiation of study intervention on Day 1 in this study or within 5 half-lives of that investigational product, whichever is greater (except for participation in observational studies [eg, PNH Registry])
- Received any other experimental C5 antagonist at any time
- Pregnant, breastfeeding, or intending to conceive during the course of the study
- Inability for participant/caregiver to complete the requirements for SC self-administration
- Inability to travel to the clinic for specified visits during the Primary Evaluation Period or fulfil the logistic requirements of study intervention administration
- History of N meningitidis infection
- Exclusion Criteria Specific for PNH Cohort: More than 1 LDH value > 2 × ULN within the 3 months prior to study entry (eculizumab-experienced participants or ravulizumab-experienced participants only)
- MAVE in the 6 months prior to study entry (eculizumab-experienced participants or ravulizumab-experienced participants only)
- Platelet count < 30,000/mm3 (30 × 109/L) at Screening
- Absolute neutrophil count < 500/μL (0.5 × 109/L) at Screening
- Exclusion Criteria Specific for aHUS Cohort: Hemolytic uremic syndrome related to known genetic defects of cobalamin C metabolism
- Identified drug exposure-related HUS
- Any known abnormal TMA parameters within 90 days prior to screening (ie, LDH ≥ 1.5 × ULN, or platelet count < 150,000/μL, or eGFR ≤ 30 mL/min/1.73m2 using the Schwartz formula) (eculizumab-experienced participants or ravulizumab-experienced participants only)
- Known familial or acquired ADAMTS13 (“a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13”) deficiency (activity < 5%)
- Known Shiga toxin-related hemolytic uremic syndrome (ST-HUS) as demonstrated by a positive test for Shiga toxin or culture of Shiga toxin producing bacteria
- Positive direct Coombs test which in the judgment of the Investigator is indicative of a clinically significant immune-mediated hemolysis not due to TMA
- History of unexplained infections
- Participants with a confirmed diagnosis of ongoing sepsis defined as positive blood cultures within 7 days prior to the start of screening and untreated with antibiotics
- Presence or suspicion of active and untreated systemic bacterial infection that, in the opinion of the Investigator, confounded an accurate diagnosis of aHUS or impeded the ability to manage the aHUS disease
- Heart, lung, small bowel, pancreas, or liver transplant
- Among participants with a kidney transplant, acute kidney dysfunction within 4 weeks of transplant consistent with the diagnosis of acute cell-mediated or antibody-mediated rejection according to Banff 2013 criteria
- Among participants without a kidney transplant, history of kidney disease other than aHUS, such as: a. Known kidney biopsy finding suggestive of underlying disease other than aHUS b. Known kidney ultrasound finding consistent with an alternative diagnosis to aHUS (eg, small kidneys for age) c. Known family history and/or genetic diagnosis of noncomplement-mediated genetic renal disease (eg, focal segmental glomerulosclerosis)
- Known systemic sclerosis (scleroderma), systemic lupus erythematosus or antiphospholipid antibody positivity or syndrome
- Chronic dialysis (defined as dialysis on a regular basis as renal replacement therapy for end-stage kidney disease)
- Received chronic IV immunoglobulin within 8 weeks prior to the start of Screening, unless for unrelated medical condition (eg, hypogammaglobinemia); or chronic rituximab therapy within 12 weeks prior to the start of Screening
- Received other immunosuppressive therapies such as steroids, mTORi (eg, sirolimus, everolimus), CNI (eg, cyclosporine or tacrolimus) unless: a. Part of an established post-transplant antirejection regimen, or b. Participant had confirmed anti-complement factor antibodies requiring immunosuppressive therapy, or c. Steroids were being used for a condition other than aHUS (eg, asthma)
- Use of tranexamic acid within 7 days prior to Screening
- Active systemic bacterial, viral, or fungal infection within 14 days prior to study intervention administration on Day 1
- For complement inhibitor treatment-naïve participants, received plasma exchange/plasma infusion, for 28 days or longer, prior to the start of the Screening Period for the current TMA
- Presence of fever ≥ 38°C (100.4°F) within 7 days prior to study intervention administration on Day 1
- Known history or positive serology of hepatitis B or C viral infection
- Known human immunodeficiency virus (HIV) infection (known history or evidenced by HIV type 1 or type 2 [HIV-1, HIV-2] antibody
- History of malignancy within 5 years of Screening with the exception of nonmelanoma skin cancer or carcinoma in situ of the cervix that has been treated with no evidence of recurrence
- History of or ongoing major cardiac, pulmonary, renal, endocrine, or hepatic disease (eg, active hepatitis) that, in the opinion of the Investigator or Alexion, precludes the participant’s participation in an investigational clinical study
The study team makes the final eligibility decision.
Where it's taking place
- United Kingdom
Questions & answers
Do participants get paid in this trial?
This listing doesn't specify compensation. Many trials still reimburse travel or offer a stipend, so it's worth asking the study team when you connect.
Is it free to join, and do I need insurance?
Searching and applying through BridgeMD is free. In clinical trials the study-related treatment and visits are generally provided at no cost to you. You usually don't need insurance to take part - confirm specifics with the study team.
How long does this study last?
The listing doesn't state an exact length. The study team walks you through the schedule and number of visits before you decide to enroll.
Who can join this trial?
This study is enrolling all sexes, 0-17 years, 18-64 years. The study team makes the final eligibility decision.
Where is this trial taking place?
Study sites include United Kingdom. Enter your location above to see the nearest site and check your eligibility.
Explore other conditions
BridgeMD is an information and trial-matching tool - not medical advice, and not the study sponsor. Details come from EU CTIS; the study team decides eligibility.