The primary objective of this study is to assess the noninferiority of ALXN1210 compared to eculizumab in adult patients with PNH who have never been treated with a complement inhibitor. Noninferiority will be claimed if after 26 weeks of treatment…
ID
Source
Brief title
Condition
- Red blood cell disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The coprimary efficacy endpoints of the study are:
* Transfusion avoidance, defined as the proportion of patients who remain
transfusion-free and do not require a transfusion per protocol-specified
guidelines through Day 183 (Week 26)
* Hemolysis as directly measured by LDH-N levels from Day 29 (first scheduled
evaluation status post initiation of maintenance dosing) through Day 183 (Week
26)
Secondary outcome
1. Percentage change in LDH from Baseline to Day 183 (Week 26)
2. Change in quality of life (QoL) assessed via the Functional Assessment of
Chronic Illness Therapy (FACIT)-Fatigue Scale, Version 4, from Baseline to Day
183 (Week 26)
3. Proportion of patients with breakthrough hemolysis, defined as at least one
new or worsening symptom or sign of intravascular hemolysis (fatigue,
hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia
[hemoglobin < 10 g/dL], major adverse vascular event [MAVE, including
thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated
LDH * 2 × upper limit of normal [ULN], after prior LDH reduction to < 1.5 × ULN
on therapy
4. Proportion of patients with stabilized hemoglobin, defined as avoidance of a
* 2 g/dL decrease in hemoglobin level from baseline in the absence of
transfusion through Day 183 (Week 26)
Pharmacokinetic and Pharmacodynamic Endpoints
* Change in serum ALXN1210 and eculizumab concentration over time
* Change in chicken red blood cell (cRBC) hemolytic activity over time
(exploratory)
* Change in free complement component 5 (C5) concentrations over time
More details for end points can be found in protocol section 6.2.
Background summary
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic disorder
that occurs most frequently in adults. The pathology and clinical presentations
in patients with PNH are driven by uncontrolled terminal complement activation
on red blood cells (RBCs).
The only approved treatment for PNH is eculizumab (Soliris®). Eculizumab is a
humanized monoclonal antibody that specifically binds to the complement protein
C5 with high affinity. ALXN1210 was engineered from eculizumab to preserve
immediate and complete C5 inhibition while providing sustained complement
inhibition throughout a prolonged dosing interval (1 month or longer). ALXN1210
and eculizumab share > 99% amino-acid sequence homology.
The main objective of effective PNH treatment with targeted therapy is to
provide immediate, complete, and sustained inhibition of terminal complement
activity to block hemolysis and prevent thrombosis. More specifically,
incomplete C5 blockade may increase risk of potentially life-threatening
breakthrough hemolysis (Hill 2012a, Lee 2013). Any loss of efficacy at the end
of a dosing interval or missed doses due to inconvenience of dosing intervals
may put patients at substantial medical risk. Patients treated with eculizumab
are required to receive maintenance infusions every 2 weeks. Given that PNH is
a chronic disease, this regimen may have a significant impact on patients in
terms of individual patient concerns associated with missed work and more
importantly may impact treatment compliance.
ALXN1210 has been designed to have the same rapid onset of action and effective
blockade of complement, with an increased serum half-life to yield an increased
duration of pharmacologic activity relative to eculizumab. The substantially
longer half-life of ALXN1210 is expected to produce sustained terminal
complement inhibition during a longer dosing interval and thus reduce the
potential risk of breakthrough complement-mediated hemolysis during the
treatment period, thus improving the overall health of patients.
Study objective
The primary objective of this study is to assess the noninferiority of ALXN1210
compared to eculizumab in adult patients with PNH who have never been treated
with a complement inhibitor.
Noninferiority will be claimed if after 26 weeks of treatment: 1) the lower
bound of the 95% confidence interval (CI) for the difference
(ALXN1210-eculizumab) in transfusion avoidance (TA) rate is greater than -20%,
and 2) the lower bound of the 95% CI for the odds ratio of ALXN1210 compared to
eculizumab for lactate dehydrogenase normalization (LDH-N) is greater than 0.39.
Secondary Objectives
The secondary objectives of the study are to assess the following:
* To characterize the safety and tolerability of ALXN1210 in this patient
population
* To evaluate the efficacy of ALXN1210 by additional efficacy measures
* To characterize the pharmacokinetics/pharmacodynamics (PK/PD) and
immunogenicity of ALXN1210
* To evaluate the long-term safety and efficacy of ALXN1210
* To evaluate the safety and efficacy in patients who switch from eculizumab to
ALXN1210 in the Extension Period
Study design
Study ALXN1210-PNH-301 is a Phase 3, open-label, randomized, active-controlled,
multicenter study to evaluate the safety and efficacy of ALXN1210 versus
eculizumab administered by intravenous (IV) infusion to adult patients with PNH
who are naïve to complement inhibitor treatment. The study will enroll
approximately 214 patients (107 patients per treatment group).
The study consists of a 4-week screening period, a 26 week randomized treatment
period, and an extension period of up to 2 years. Patients will be stratified
into 1 of 6 groups based on their transfusion history (0, 1 to 14, or > 14
units of pRBCs in the 1 year prior to first dose of study drug) and screening
LDH levels (1.5 to < 3 × ULN or * 3 × ULN). The patients within each of the 6
groups will then be randomly assigned in a 1:1 ratio to receive ALXN1210 or
eculizumab. Enrollment of patients without a history of transfusion in the past
year will be capped at 20%.
Prior to randomization and within 5 days prior to study drug administration on
Day 1, each patient*s hemoglobin must be evaluated by either local or central
laboratory. If at that time the patient*s hemoglobin value meets
protocol-specified transfusion guidelines, the patient must be transfused with
pRBCs to a hemoglobin level above the protocol-specified transfusion threshold
in order to be eligible for randomization. The patient*s post-transfusion
hemoglobin value should be confirmed by local or central laboratory to be above
the protocol-specified transfusion threshold.
Patients randomly assigned to the ALXN1210 group will receive a loading dose of
ALXN1210 (2400 mg for patients weighing * 40 to < 60 kg, 2700 mg for patients
weighing * 60 to < 100 kg, 3000 mg for patients weighing * 100 kg) on Day 1,
followed by maintenance doses of ALXN1210 (3000 mg for patients weighing * 40
to < 60 kg, 3300 mg for patients weighing * 60 to < 100 kg, 3600 mg for
patients weighing * 100 kg) on Day 15 and every 8 weeks (q8w) thereafter for a
total of 26 weeks of treatment. Patients randomly assigned to the eculizumab
group will receive induction treatment with 600 mg of eculizumab IV on Days 1,
8, 15, and 22, followed by maintenance treatment with eculizumab 900 mg on Day
29 and every 2 weeks (q2w) thereafter for a total of 26 weeks of treatment.
After completion of all assessments on Day 183, patients will enter an
extension period and receive ALXN1210 until the product is registered or
approved (in accordance with country-specific regulations) or for up to 2
years, whichever occurs first. Beginning on Day 183, patients who had been
randomized to the ALXN1210 treatment group will receive a maintenance dose (as
described above) of ALXN1210 q8w, and patients who had been randomized to the
eculizumab group will receive a loading dose (as described above) of ALXN1210
followed 2 weeks later and q8w thereafter by a weight-based maintenance dose of
ALXN1210.
Intervention
Administration of study studydrug ALXN1210 and eculizumab (active control) via
IV infusion. Dosage is based on patients weight.
Study burden and risks
Potential risks associated with ALXN1210 include infections (N. meningitidis
and other encapsulated organisms), immunogenicity, and hypersensitivity.
Please refer to the IB, section 2.2 for a detailed description of Potential
Risks Associated with ALXN1210, Summary of Data, and Monitoring Guidance for
the Investigator
College Street 100
New Haven CT 06510
US
College Street 100
New Haven CT 06510
US
Listed location countries
Age
Inclusion criteria
1. Male or female * 18 years of age
2. PNH diagnosis confirmed documented by high-sensitivity flow cytometry
3. 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 (hemoglobin <10 g/dL), history of a major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction; or history of pRBC transfusion due to PNH.
4. LDH level * 1.5 × ULN at screening.
5. Documented meningococcal vaccination not more than 3 years prior to, or at the time of, initiating study treatment.
6. Female patients of childbearing potential must use highly effective contraception starting at screening and continuing until at least 8 months after the last dose of ALXN1210
7. Willing and able to give written informed consent and comply with study visit schedule
Exclusion criteria
1. Treatment with a complement inhibitor at any time.
2. History of bone marrow transplantation.
3. Body weight < 40 kilograms.
4. Females who are pregnant, breastfeeding or who have a positive pregnancy test at screening or Day 1
5. Participation in another interventional clinical 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.
6. History of or ongoing major cardiac, pulmonary, renal, endocrine, or hepatic disease that, in the opinion of the investigator or sponsor, would preclude participation
7. Unstable medische conditions (bv, myocardial ischemia, actieve gastrointestinal bloedingen, zware congestive hartfalen, anticipated need for major surgery within 6 months of randomization, coexisting chronic anemia unrelated to PNH).
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 |
|---|---|
| EudraCT | EUCTR201600202511-NL |
| ClinicalTrials.gov | NCT02946463 |
| CCMO | NL58963.091.16 |