Primary:• To evaluate PK noninferiority of ravulizumab SC versus ravulizumab IV in adult patients with PNH Secondary• To characterize PK of ravulizumab SC• To characterize PD of ravulizumab SC• To characterize immunogenicity of ravulizumab SC• To…
ID
Source
Brief title
Condition
- Red blood cell disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary PK endpoint: Day 71 serum ravulizumab C-trough
Secondary outcome
PK Endpoint: C-trough over time
PD Endpoint: Free serum C5 concentrations over time
Immunogenicity Endpoint: Incidence of treatment-emergent ADAs over time
HRQoL and Treatment Satisfaction Endpoints:
• Change in FACIT-Fatigue Scale, Version 4, from Baseline to Day 183
• Change in EORTC QLQ-C30 Version 3.0, from Baseline to Day 183
• Reported treatment satisfaction and patient preference as measured by the
TASQ score at Baseline and Day 183
Safety Endpoints:
• Change in physical examinations, vital signs, electrocardiograms, and
laboratory assessments over time
• Incidence of adverse events and serious adverse events
• Incidence of adverse device effects and serious adverse device effects
Efficacy Endpoints:
• Change over time in LDH
• Incidence of breakthrough hemolysis
• Achievement of transfusion avoidance
• Achievement of stabilized hemoglobin
Performance Endpoint:
• Reported outcome of attempted full-dose administration (including device
failure/malfunction)
Background summary
Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra rare and life threatening
acquired hemolytic disorder caused by uncontrolled activation of the terminal
complement pathway. Chronic, uncontrolled complement component 5 (C5) cleavage
and release of C5a and C5b 9 lead to red blood cell (RBC) hemolysis. Hemolysis
results in the release of intracellular free hemoglobin and lactate
dehydrogenase (LDH) into circulation; irreversible binding to and inactivation
of nitric oxide (NO) by hemoglobin and inhibition of NO synthesis;
vasoconstriction and tissue bed ischemia due to absence of vasodilatory NO as
well as possible microthrombi manifesting as abdominal pain, dysphagia, and
erectile dysfunction; platelet activation; and a proinflammatory and
prothrombotic state. A substantial proportion of patients with PNH experience
renal dysfunction and pulmonary hypertension. Patients also experience venous
or arterial thrombosis in diverse sites, including the abdomen or central
nervous system. Secondary effects in addition to the risk of major end organ
damage from thrombosis include abdominal pain, extreme or unrelenting fatigue,
difficulties in concentrating or thinking, and reduced activities of daily
living (ADL).
The main objective of effective PNH treatment with targeted therapy is to
provide immediate, complete, and sustained inhibition of terminal complement
activity to block intravascular hemolysis and thereby prevent thrombosis.
Currently, the only approved treatment for PNH that blocks terminal complement
activity is eculizumab (Soliris®), a humanized monoclonal antibody (mAb)
derived from the murine anti-human C5 antibody m5G1.1 and specifically binds to
the complement protein C5 with high affinity. Eculizumab is administered by
intravenous (IV) infusion every other week.
Ravulizumab (ALXN1210) is a humanized mAb that binds to C5 and blocks its
activation by complement pathway convertases, thereby preventing the release of
the proinflammatory anaphylatoxin C5a and the formation of the terminal
complement complex via C5b. Ravulizumab was designed through minimal targeted
engineering to substitute 4 amino acids in the eculizumab heavy chain
(Sheridan, 2018). These changes extend the half life of ravulizumab relative to
eculizumab, while preserving the high degree of specificity and selectivity for
binding to C5 of eculizumab.
The purpose of this study is to compare the Pharmacokinetic (PK), specifically
predose serum concentration (Ctrough), of ravulizumab SC administered via an
OBDS versus ravulizumab IV administration in patients who are clinically stable
and have been treated with eculizumab for at least 6 months prior to study
entry.
The efficacy of ravulizumab IV was shown to be noninferior to eculizumab in
Phase 3 clinical studies in complement inhibitor-naïve patients and in patients
who had previously received treatment with eculizumab. Ravulizumab SC may
provide additional benefit by reducing the treatment burden associated with
chronic IV dosing. The safety of ravulizumab SC via an OBDS in patients with
PNH at the doses specified in this protocol is supported by data from clinical
studies of ravulizumab IV and SC in healthy volunteers and clinical studies of
ravulizumab IV in patients with PNH, in addition to postmarketing data on the
West Smart Dose Platform used with other approved therapies. The benefit/risk
of ravulizumab SC administration to patients with PNH is anticipated to be
favorable.
Study objective
Primary:
• To evaluate PK noninferiority of ravulizumab SC versus ravulizumab IV in
adult patients with PNH
Secondary
• To characterize PK of ravulizumab SC
• To characterize PD of ravulizumab SC
• To characterize immunogenicity of ravulizumab SC
• To evaluate HRQoL and treatment satisfaction on ravulizumab SC
• To evaluate safety of ravulizumab SC and ravulizumab OBDS
• To evaluate efficacy of ravulizumab SC
• To assess performance of ravulizumab OBDS
Study design
This is a Phase 3, randomized, open-label, parallel-group, multicenter study to
evaluate PK noninferiority of ravulizumab SC administered via an OBDS compared
with intravenously administered ravulizumab IV in adult patients with PNH who
are clinically stable and have been previously treated with eculizumab for at
least 3 months prior to study entry.
The study will consist of an up to 30-day Screening Period, a 10-week
Randomized Treatment Period, and an Extension Period of up to 3.5 years (182
weeks) or until the product is registered or approved (in accordance with
country-specific regulations), whichever occurs first. Patients will be
stratified by weight group (>= 40 kg to < 60 kg and >= 60 kg to < 100 kg) and
then randomized in a 2:1 ratio to receive either ravulizumab SC or ravulizumab
IV.
Intervention
Ravulizumab subcutaneously (SC):
- Loading Dose on Day 1: Ravulizumab IV 2400 mg (Weight group >= 40 to < 60 kg)
or Ravulizumab IV 2700 mg (Weight group >= 60 to < 100 kg)
- SC Doses on Days 15, 22, 29, 36, 43, 50, 57, and 64:Ravulizumab SC 490 mg (2
ravulizumab OBDS kits per weekly dose; On Day 15, patients who randomized to
the ravulizumab SC group will self-administer ravulizumab SC in the clinic with
oversight by trained study site personnel as part of the required training
program for self-administration at home. On Days 29, 43, 57, and 64,
ravulizumab SC will be self-administered by the patient in the clinic with
oversight by trained study site personnel. On Days 22, 36, and 50, ravulizumab
SC can be self-administered by the patient at home. With approval from the
Sponsor, the patient can self-administer ravulizumab SC at the clinic on dosing
days that are not scheduled in-clinic visits.)
- Maintenance Doses on Day 71 and qw through Day 1275: Ravulizumab SC 490 mg (2
ravulizumab OBDS kits per weekly dose; Self-administered by the patient)
Ravulizumab intravenously (IV):
- Loading Dose on Day 1: Ravulizumab IV 2400 mg (Weight group >= 40 to < 60 kg)
or Ravulizumab IV 2700 mg 9 Weight group >= 60 to < 100 kg)
- Maintenance Dose on Day 15: Ravulizumab IV 3000 mg (Weight group >= 40 to <
60 kg) or Ravulizumab IV 3300 mg ((Weight group >= 60 to < 100 kg)
- Maintenance Doses on Day 71 and qw through Day 1275: Ravulizumab SC 490 mg (2
ravulizumab OBDS kits per weekly dose; Self-administered by the patient at home
or self-administered in the clinic with oversight by trained study site
personnel on scheduled visit days. With approval from the Sponsor, the patient
can self-administer ravulizumab SC at the clinic on dosing days that are not
scheduled in-clinic visits. On Day 71, patients who had been randomized to the
ravulizumab IV group will self-administer ravulizumab SC in the clinic with
oversight by trained study site personnel as part of the required training
program for at-home self-administration.)
Study burden and risks
Patients are asked to undergo procedures described on pages 18-28 of the study
protocol. The study will consist of an up to 4-week Screening Period, a 10-week
Randomized Treatment Period, and a 182-week Extension Period. The study
procedures include physical examination, blood and urine sample collection,
vital signs, ECG, meningococcal vaccination (if not done before), completion of
questionnaires and eDiary, answer questions of investigator and study team and
administration of study drug including using an OBDS device for subcutaneous
administration.
Additionally, fertile subjects are asked to use contraceptives, and female
subjects of childbearing potential will have pregnancy tests and blood will be
taken for HIV testing.
The study medication as well performing the study-related procedures may cause
discomforts and risks. Ravulizumab may also have discomforts and risks that are
still unknown. These may be mild or serious, and in some cases may be very
serious, long-lasting, or may never go away. There is also a risk of death.
Following side effects have been reported based on the clinical experience in
patients with PNH using Ravulizumab.
Meningococcal Infection: Patients receiving ravulizumab, even after a single
dose, are at increased risk for development of serious infections caused by
Neisseria meningitidis. This is a bacterial infection that can the brain
(meningococcal meningitis) or be present in blood (meningococcal sepsis).
Meningococcal infections can rapidly become life-threatening or fatal
especially if not recognized and treated early. Subjects will receive a
vaccination against meningococcal infections. Vaccination alone may not be
sufficient to prevent infection with Neisseria meningitidis.
Very common side effects (seen in more than 10 % of PNH patients): upper
respiratory tract infection, nasopharyngitis, headache
Common side effects (seen in 1% to 10% of PNH patients): nausea, abdominal
pain, vomiting, diarrhea, indigestion, flu-like illness, fever, tiredness,
muscle pain and spasms, back pain, joint pain, dizziness, rash and itchiness
Uncommon side effects (seen in less than 1% of PNH patients): meningococcal
infection and meningococcal sepsis (blood infection), chills
Study Procedures:
Blood draws - Subjects may experience pain, bruising, or bleeding at the site
of puncture. There is also the possibility of infection. Although the total
amount of blood drawn over time is predicted to be well tolerated, anemia may
occur.
Intravenous (IV) infusions - There may be discomfort during IV placement, on
rare occasions this may cause pain, bleeding, bruising, swelling, clotting of
the vein, leakage of medication or solution into the surrounding tissues, and
possibly infection at the insertion site of the IV line.
Subcutaneous (SC) infusions - Study drug is administered with an injection
under the skin using 2 OBDS devices per dose. Subjects may experience localized
pain, redness, itchiness, bruising, rash, or infection at the site where the SC
injection is given.
On-body delivery system (OBDS) device - This is a wearable, single use patch
injector. It is intended to be worn on the body (upper arm, abdomen, or thigh)
for about 10 minutes. It is attached to the body with an adhesive (like a
band-aid) and removed when the SC infusion is completed. As with any adhesive,
there may be a small risk of skin irritation. Some symptoms of skin irritation
at the site may include: rash, itchiness, and redness.
The meningococcal vaccination can cause temporary local swelling at the
injection site.
The efficacy of ravulizumab IV was shown to be noninferior to eculizumab in
Phase 3 clinical studies in complement inhibitor-naïve patients and in patients
who had previously received treatment with eculizumab. Ravulizumab SC may
provide additional benefit by reducing the treatment burden associated with
chronic IV dosing. The safety of ravulizumab SC via an OBDS in patients with
PNH at the doses specified in this protocol is supported by data from clinical
studies of ravulizumab IV and SC in healthy volunteers and clinical studies of
ravulizumab IV in patients with PNH, in addition to postmarketing data on the
West Smart Dose Platform used with other approved therapies. The benefit/risk
of ravulizumab SC administration to patients with PNH is anticipated to be
favorable.
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Age
Inclusion criteria
1. Patients must be at least 18 years of age at the time of signing the
informed consent.
2. Treated with eculizumab according to the labeled dosing recommendation for
PNH (900 mg every 14 days ± 2 days) for at least 3 months prior to study entry
with no missed doses within 2 months prior to study entry and no more than 2
doses outside of the visit window.
3. Lactate dehydrogenase levels <= 1.5 × ULN (upper limit of normal), according
to central laboratory, at Screening. Sample must be obtained within 24 hours of
or immediately prior to a scheduled eculizumab dose administration (ie, at
trough eculizumab level).
4. Documented diagnosis of PNH confirmed by high-sensitivity flow cytometry
evaluation (Borowitz, 2010).
5. Vaccinated against meningococcal infections within 3 years prior to, or at
the time of, initiating study drug to reduce the risk of meningococcal
infection (N meningitidis).
6. Body weight > 40 to < 100 kg, and in the opinion of the Investigator, are
likely to remain within this body weight range for the duration of the study.
7. Female patients of childbearing potential and male patients with female
partners of childbearing potential must follow protocol-specified contraception
guidance while on treatment and for at least 8 months after last dose of study
drug.
8. Patients (or their legally authorized representative) must be willing and
able to give written informed consent and to comply with all study visits and
procedures, including self administration of ravulizumab SC doses, and the use
of any data collection device(s) to directly record patient data.
Exclusion criteria
1. More than 1 LDH value > 2 × ULN within the 3 months prior to study entry.
2. Major adverse vascular event (MAVE) in the 6 months prior to study entry.
3. Platelet count < 30,000/mm3 (30 × 10*9/L) at Screening.
4. Absolute neutrophil count < 500/µL (0.5 × 10*9/L) at Screening.
5. History of bone marrow transplantation.
6. History of N meningitidis infection.
7. History of unexplained infections.
8. Active systemic bacterial, viral, or fungal infection within 14 days prior
to study drug administration on Day 1.
9. Presence of fever >= 38°C (100.4°F) within 7 days prior to study drug
administration on Day 1.
10. Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2
antibody titer).
11. 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.
12. History of or ongoing major cardiac, pulmonary, renal, endocrine, or
hepatic disease (eg, active hepatitis) that, in the opinion of the Investigator
or Sponsor, precludes the patient*s participation in an investigational
clinical study.
13. 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 patients unlikely to tolerate the requirements of the
protocol).
14. History of hypersensitivity to any ingredient contained in the study drug
including hypersensitivity to murine proteins.
15. Female patients who plan to become pregnant or are currently pregnant or
breastfeeding.
16. Female patients who have a positive pregnancy test result at screening or
on Day 1.
17. Known medical or psychological condition(s) or risk factor that, in the
opinion of the Investigator, might interfere with the patient*s full
participation in the study, pose an additional risk for the patient, or
confound the outcome of the study.
18. Known or suspected history of drug or alcohol abuse or dependence within 1
year prior to Screening.
19. Inability to complete the requirements for SC self-administration.
20. Inability to travel to the clinic for specified visits during the
Randomized Treatment Period or fulfil the logistic requirements of study drug.
21. Concomitant use of anticoagulants is prohibited if not on a stable regimen
for at least 2 weeks prior to study entry.
22. Participation in another study or use of any experimental therapy within 30
days before initiation of study drug 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]).
23. Received any other experimental C5 antagonist at any time.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | 128367 |
| EudraCT | EUCTR2017-002370-39-NL |
| CCMO | NL67982.068.18 |