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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Alexion Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

completed 8 Nov 2023

Decision date (initial)

2023-08-07

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Alexion Pharmaceuticals, Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacodynamic, Safety, Pharmacokinetic

To characterize the PK and PD of treatment with ravulizumab SC in pediatric participants with PNH or aHUS

Secondary objectives 7

1. PK and PD (Both Cohorts) To characterize the PK and PD of treatment with ravulizumab SC in pediatric participants with PNH or aHUS
2. Efficacy (PNH Cohort Only) To assess the efficacy of treatment with ravulizumab SC in pediatric participants with PNH
3. Efficacy (aHUS Cohort Only) To assess the efficacy of treatment with ravulizumab SC in pediatric participants with aHUS
4. Health-related QoL (Both Cohorts) To assess the effect of treatment with ravulizumab SC on fatigue and QoL based on patient-reported and caregiver-reported outcomes in pediatric participants with PNH or aHUS
5. Safety (Both Cohorts) To evaluate safety of ravulizumab SC in pediatric participants with PNH or aHUS
6. Device Performance (Both Cohorts) To assess performance of ravulizumab OBDS in pediatric participants with PNH or aHUS
7. Immunogenicity (Both Cohorts) To assess immunogenicity of ravulizumab SC in pediatric participants with PNH or aHUS

Conditions and MedDRA coding

Treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH) or Atypical Hemolytic Uremic Syndrome (aHUS)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002077-PIP01-16, EMEA-001943-PIP01-16

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. Must be 2 to < 18 years of age at the time of informed consent
2. Male or female
3. Female participants of childbearing potential and male participants must be willing to follow protocol-specified contraception guidance
4. Body weight ≥ 10 kg at Screening
5. 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.
6. Must have received vaccination for Streptococcus pneumoniae according to national and local vaccination schedule guidelines
7. Must have received vaccination for Haemophilus influenzae type b according to national and local vaccination schedule guidelines
8. 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.
9. 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).
10. 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%
11. 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.
12. 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)
13. 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)
14. 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
15. 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
16. 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)
17. Among participants with onset of TMA postpartum, persistent evidence of TMA for > 3 days after the day of childbirth.

Exclusion criteria 40

1. History of bone marrow transplantation
2. History of N meningitidis infection
3. History of unexplained infections
4. Active systemic bacterial, viral, or fungal infection within 14 days prior to study intervention administration on Day 1
5. Presence of fever ≥ 38°C (100.4°F) within 7 days prior to study intervention administration on Day 1
6. Known history or positive serology of hepatitis B or C viral infection
7. Known human immunodeficiency virus (HIV) infection (known history or evidenced by HIV type 1 or type 2 [HIV-1, HIV-2] antibody
8. 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
9. 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
10. 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
11. 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
12. Known or suspected history of drug or alcohol abuse or dependence within 1 year prior to the start of the Screening Period
13. 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
14. Concomitant use of anticoagulants is prohibited if not on a stable regimen for at least 2 weeks prior to study entry
15. 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])
16. Received any other experimental C5 antagonist at any time
17. Pregnant, breastfeeding, or intending to conceive during the course of the study
18. Inability for participant/caregiver to complete the requirements for SC self-administration
19. Inability to travel to the clinic for specified visits during the Primary Evaluation Period or fulfil the logistic requirements of study intervention administration
20. 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)
21. MAVE in the 6 months prior to study entry (eculizumab-experienced participants or ravulizumab-experienced participants only)
22. Platelet count < 30,000/mm3 (30 × 109/L) at Screening
23. Absolute neutrophil count < 500/μL (0.5 × 109/L) at Screening
24. Exclusion Criteria Specific for aHUS Cohort: Hemolytic uremic syndrome related to known genetic defects of cobalamin C metabolism
25. Identified drug exposure-related HUS
26. 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)
27. Known familial or acquired ADAMTS13 (“a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13”) deficiency (activity < 5%)
28. 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
29. Positive direct Coombs test which in the judgment of the Investigator is indicative of a clinically significant immune-mediated hemolysis not due to TMA
30. 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
31. 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
32. Heart, lung, small bowel, pancreas, or liver transplant
33. 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
34. 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)
35. Known systemic sclerosis (scleroderma), systemic lupus erythematosus or antiphospholipid antibody positivity or syndrome
36. Chronic dialysis (defined as dialysis on a regular basis as renal replacement therapy for end-stage kidney disease)
37. 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
38. 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)
39. Use of tranexamic acid within 7 days prior to Screening
40. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Summary statistics of ravulizumab concentrations at Day 1 postdose, Day 15 predose, Day 15 postdose, and Day 71 predose Summary statistics of serum free C5 concentrations at Day 1 postdose, Day 15 predose, Day 15 postdose, and Day 71 predose

Secondary endpoints 7

1. PK and PD (Both Cohorts) Serum ravulizumab concentrations over time through Week 52 Absolute values, change from baseline, and percentage change from baseline for free serum C5 concentrations over time through Week 52
2. Efficacy (PNH Cohort Only) Percentage change from baseline in LDH to Week 10 and Week 52 Incidence of BTH through Week 10 and Week 52 Achievement of transfusion avoidance through Week 10 and Week 52 Achievement of stabilized hemoglobin through Week 10 and Week 52 Change from baseline in PNH RBC clone size at Week 52
3. Efficacy (aHUS Cohort Only) Dialysis requirement status through Week 10 and Week 52 Observed value and change from baseline in eGFR through Week 10 and Week 52 Observed value and change from baseline in serum creatinine through Week 10 and Week 52 Observed value and change from baseline in hematologic parameters through Week 10 and Week 52: • Platelets • LDH • Hemoglobin
4. Health-related QoL (Both Cohorts) Change from baseline in patient-reported fatigue, as measured by Pediatric FACIT-Fatigue (participants ≥ 8 years of age) to Week 10 and Week 52 Change from baseline in PedsQL 4.0 Generic Core Scale to Week 10 and Week 52
5. Safety (Both Cohorts) Incidence of AEs and SAEs Incidence of ADEs and serious ADEs in participants treated with ravulizumab SC via OBI
6. Device Performance (Both Cohorts) Reported outcome of attempted full-dose administration via OBI Reported device deficiencies/complaints and associated device investigations
7. Immunogenicity (Both Cohorts) ADA incidence, response categories and titer in study participants treated with ravulizumab SC for the duration of the study

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Alexion Pharmaceuticals Inc.

Sponsor organisation

Alexion Pharmaceuticals Inc.

Address

121 Seaport Boulevard

City

Boston

Postcode

02210-2050

Country

United States

Scientific contact point

Organisation

Alexion Pharmaceuticals Inc.

Contact name

Masayo Ogawa

Public contact point

Organisation

Alexion Pharmaceuticals Inc.

Contact name

European Clinical Trial Information

Third parties 1

Locations

2 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Application history

1 submissions — initial application plus substantial / non-substantial modifications