The primary objective of this study is to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety, andefficacy of ALXN1210 in pediatric patients with paroxysmal nocturnal hemoglobinuria (PNH).
ID
Source
Brief title
Condition
- Haemolyses and related conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint:
* PK/PD parameters (trough and peak) at Baseline and Weeks 2, 10, 18, and 26
o PK: maximum serum concentration (Cmax), trough serum concentration (measured
at end of dosing
interval at steady state; Ctrough), accumulation ratio
o PD: change in free C5 concentrations and in chicken red blood cell (cRBC)
hemolytic activity over time
Secondary outcome
Secondary endpoint:
* Percentage change in LDH from baseline to Day 183 (Week 26)
* Transfusion avoidance (TA), defined as the proportion of patients who remain
transfusion-free and do not
require a transfusion through Day 183 (Week 26)
* Change in quality of life (QoL), as measured by Pediatric Functional
Assessment of Chronic Therapy (FACIT)
Fatigue questionnaire (patients * 5 years of age), from baseline to Day 183
(Week 26)
* 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)
* Percentage change in free hemoglobin from baseline to Day 183 (Week 26)
* 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,
major adverse vascular event [MAVE, including thrombosis], dysphagia, or
erectile dysfunction) in the
presence of elevated LDH as follows:
o For patients who enter the study naïve to complement inhibitor treatment,
elevated LDH * 2 × ULN after
prior LDH reduction to < 1.5 × ULN on therapy
o For patients who enter the study stabilized on eculizumab treatment, elevated
LDH * 2 × ULN
Safety
The safety and tolerability of ALXN1210 will be evaluated from baseline to Week
26 and throughout the extension
period by physical examinations, vital signs, physical growth,
electrocardiograms (ECGs), laboratory assessments,
and incidence of adverse events (AEs) and serious adverse events (SAEs). The
proportion of patients who develop
antidrug antibodies (ADAs) will also be assessed.
Background summary
PNH is an ultra-rare, debilitating, and life-threatening disease, driven by
chronic uncontrolled complement activation.The resulting inflammation and
cellular damage lead to systemic complications, principally through
intravascular hemolysis and thrombophilia (Brodsky, 2014; Socie, 1996).
PNH has an estimated worldwide incidence of 1.3 per million population (Hill,
2006). The onset of PNH is typically in adulthood, with pediatric cases
accounting for < 5% of reported cases (Ware, 1991). Given the extremely small
target population, studies of children with PNH have
been limited to case reports, case series, and a small clinical trial (Reiss,
2005).
Patients with PNH are at risk of substantial morbidity and mortality and
altered quality of life. The current standard of care for the treatment of PNH
is eculizumab (Soliris®).The efficacy and safety of eculizumab for the
treatment of PNH are well established. The approved dosage regimen for
eculizumab for PNH involves 4 weekly induction doses, followed by maintenance
doses administered every 2 weeks starting at Week 5.
Given that PNH is a chronic disease, the current eculizumab regimen may
significantly affect patients, many of whom have to miss days of work or school
to accommodate treatment. In some cases, patients may refuse treatment or be
may be unable to comply with the treatment frequency
of eculizumab. Practice survey research supports the assumption that the less
frequent infusions associated with ALXN1210 will have a positive impact on
daily life for patients and their caregivers.
In this Phase 3, open-label study, the PK, pharmacodynamics (PD), efficacy, and
safety of ALXN1210 will be assessed in pediatric patients with PNH.
Study objective
The primary objective of this study is to assess the pharmacokinetics (PK),
pharmacodynamics (PD), safety, and
efficacy of ALXN1210 in pediatric patients with paroxysmal nocturnal
hemoglobinuria (PNH).
Study design
This is a Phase 3, open-label, single-arm multicenter study to evaluate the
PK/PD, safety, and efficacy of ALXN1210 administered by intravenous (IV)
infusion to pediatric patients (< 18 years of age) with PNH. The study consists
of a 4-week Screening Period, a 26-week Primary Evaluation
Period, and an Extension Period. Consenting patients will be screened for study
eligibility up to 4 weeks prior to Day 1. Patients who satisfy all of
the inclusion criteria and all of the exclusion criteria will be enrolled into
the Primary Evaluation Period and receive a weight-based loading dose of
ALXN1210 on Day 1, followed by weight-based maintenance treatment with ALXN1210
on Day 15 and once every 8 weeks (q8w) thereafter for patients weighing * 20
kg, or once every 4 weeks (q4w) for patients weighing < 20 kg, for a total of
26 weeks of treatment. For patients entering the study on eculizumab therapy,
Day 1 of study treatment will occur 2 weeks from the patient*s last dose of
eculizumab.
An interim analysis of data, including ALXN1210 PK and free complement
component 5 (C5) levels, will be conducted after 4 patients weighing * 5 kg to
< 40 kg have completed dosing through Day 71. Enrollment of patients will
proceed without interruption while the analysis is ongoing. The accrued safety
and PK/PD data will be assessed to ensure that ALXN1210 treatment is well
tolerated and is providing adequate complement inhibition. Based on this
review, the dose regimen may be adjusted.
In addition, an independent Data Monitoring Committee (DMC) will review safety
data from the study on a regular basis.
After completion of all assessments on Day 183, all patients will enter an
Extension Period and continue to receive ALXN1210 according to the appropriate
weight-based regimen. The Extension Period will continue until the product is
registered or approved (in accordance with country-specific regulations) or for
up to 2 years, whichever occurs first. The end of trial is defined as the last
patient*s last visit or follow-up ( whether on site or via phone call) in the
Extension Period.
Intervention
ALXN1210 loading doses on Day 1 and maintenance doses on Day 15 and q8w
thereafter for patients weighing
* 20 kg, or q4w for patients weighing < 20 kg will be administered by IV
infusion. Dosages are based on the
patient*s body weight recorded on dosing day or the most recently recorded
weight, as shown in table 5 in the protocol ( page 32)
Study burden and risks
This study includes a screening period, a treatment period, and an extension
period. Participation in this study is anticipated to be approximately 2,5
years. The screening period will take up to 28 days, the
treatment phase will take 26 weeks and the extension period will last up to 2
years
In total, the patient will visit the hospital approximately between 22 and 35
times ( depending if the weight is > 20 kg or below 20 kg).
The following tests and procedures will take place during the different visits:
9x completion of questionnaires about the general quality of life
15 x physical examination and assessment of PNH symptoms and vital signs
12x Pregnancy test (only for children who menstruate)
12x Urine sample collection
15x Blood samples collection
study medication dosing:
patients>-20 kg: max 21x
patients<20 kg: max 33x
If patients receive a supplemental dose of study drug, additional PK/PD samples
will be collected and one additional physicial examination including vital
signs will be done.
vaccinations:
- meningococcal vaccination if the patient has not been vaccinated before for
PNH and the study doctor feels the patient is old enough
- vaccinations for influenzae type b (Hib) and Streptococcus pneumoniae if this
is considered needed by the study doctor.
Please refer to the IB and patient information regarding side effects that are
expected and for other risks and discomforts.
The current standard of care for the treatment of PNH is eculizumab (Soliris®).
The efficacy and safety of eculizumab for the treatment of PNH are well
established. The approved dosage regimen for eculizumab for PNH involves 4
weekly induction doses, followed by maintenance doses administered every 2
weeks starting at Week 5.
Given that PNH is a chronic disease, the current eculizumab regimen may
significantly affect patients, many of whom have to miss days of work or school
to accommodate treatment. In some cases, patients may refuse treatment or be
may be unable to comply with the treatment frequency
of eculizumab. Practice survey research supports the assumption that the less
frequent infusions associated with ravulizumab will have a positive impact on
daily life for patients and their caregivers.
Serious side effects of the study drug ravulizumab:
Patients receiving ravulizumab, even after one dose, are at increased risk of
developing a serious meningococcal infection (meningitis) caused by the
bacteria Neisseria meningitidis. The infection can affect the tissues around
the brain and spinal cord (meningococcal meningitis) of can occur in blood
(meningococcal sepsis). Meningococcal infections can rapidly become
life-threatening or fatal, especially if not recognized and treated early.
Patients may therefore be vaccinated against meningococcal infections. This
vaccination alone may not be sufficient to prevent meningococcal infection.
There is also a risk of getting other serious infections such as a gonococcal
infection spread by the body through Neisseria gonorrhoeae.
Other side effects of study drug ravulizumab:
Very common side effects (seen in more than 10 % of the patients)
* Diarrhea
* Nausea
* Fever
* Tiredness
* Nasopharyngitis (swelling of the nasal passages and throat)
* Upper respiratory tract infection (common cold)
* Headache
Common side effects (seen in 1% to 10% of the patients)
* Abdominal pain
* Vomiting
* Indigestion
* Flu-like illness
* Weakness
* Muscle pain
* Muscle spasms
* Back pain
* Joint pain
* Dizziness
* Rash
* Itchiness
*
Uncommon side effects (seen in less than 1% of the patients):
* Chills
During the standard of care, patients visit the hospital every 1-3 months to
check PNH and blood is drawn during these visits, physical examinations are
done and any problems are discussed with the physician. If the child receives
treatment for PNH, blood is drawn during each visit in the hospital and there
is contact with the physician every 4-6 weeks. Where relevant, the study visits
will be combined as much as possible with the regular visits. Additional
procedures ( like ECG, completion of questionnaires and additional blood draws)
have been highlighted in the ICF in the schedule of events.
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Age
Inclusion criteria
1. Male and female patients < 18 years of age and weighing * 5 kg at the time
of consent.
2. Documented diagnosis of PNH, confirmed by high-sensitivity flow cytometry
evaluation of red blood cells (RBCs) and white blood cells (WBCs), with
granulocyte or monocyte clone size of * 5%.
3. For patients not currently treated with complement inhibitor, presence of 1
or more of the following PNHrelated signs or symptoms within 3 months of
Screening: fatigue, hemoglobinuria, abdominal pain, shortness of breath
(dyspnea), anemia, history of a major adverse vascular event (including
thrombosis), dysphagia, or erectile dysfunction; or history of packed RBC
transfusion due to PNH.
4. Lactate dehydrogenase (LDH) values at Screening as follows:
a. For patients not currently treated with eculizumab, LDH level * 1.5 × upper
limit of normal (ULN).
b. For patients who are currently taking eculizumab, LDH * 1.5× ULN (sample
must be obtained on a
scheduled eculizumab-dosing day prior to dose administration [ie, at trough
eculizumab level] and
analyzed by the central laboratory).
5. To reduce the risk of meningococcal infection (Neisseria meningitidis), all
patients must be vaccinated against meningococcal infections within 3 years
prior to, or at the time of, initiating study drug. Patients who initiate study
drug treatment less than 2 weeks after receiving a meningococcal vaccine must
receive treatment with appropriate prophylactic antibiotics until 2 weeks after
vaccination. Patients who cannot be vaccinated must receive antibiotic
prophylaxis for the entire treatment period and for 8 months following last
dose.
6. Patients must have been vaccinated against Haemophilus influenzae type b
(Hib) and Streptococcus pneumoniae according to national and local vaccination
schedule guidelines, as appropriate.
7. Female patients of childbearing potential (ie, have achieved menarche) and
male patients with female partners of childbearing potential must follow
protocol-specified guidance for avoiding pregnancy while on treatment and for 8
months after last dose of study drug.
8. Patient's legal guardian must be willing and able to give written informed
consent and the patient must be willing to give written informed assent (if
applicable as determined by the central or local Institutional Review Board
[IRB]/Institutional (or Independent) Ethics Committee [IEC]) and comply with
the study visit schedule.
Exclusion criteria
1. Platelet count < 30,000/mm3 (30 × 109/L) at Screening.
2. Absolute neutrophil count < 500/*L (0.5 × 109/L) at Screening.
3. History of bone marrow transplantation.
4. History of N. meningitidis infection.
5. History of unexplained, recurrent infection.
6. Active systemic bacterial, viral, or fungal infection within 14 days prior
to study drug administration on Day 1.
7. History of malignancy within 5 years of Screening with the exception of
adequately treated nonmelanoma skin cancer or carcinoma in situ of the cervix.
8. 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 trial.
9. Unstable medical conditions (eg, myocardial ischemia, active
gastrointestinal bleed, severe congestive heart failure, anticipated need for
major surgery within 6 months of Screening, coexisting chronic anemia unrelated
to PNH) that would make them unlikely to tolerate the requirements of the
protocol.
10. Concomitant use of anticoagulants is prohibited if not on a stable regimen
for at least 2 weeks prior to Day 1.
11. History of hypersensitivity to any ingredient contained in the study drug,
including hypersensitivity to murine proteins.
12. Females who plan to become pregnant or are currently pregnant or
breastfeeding.
13. Females of childbearing potential who have a positive pregnancy test result
at Screening or on Day 1.
14. Participation in another interventional treatment 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.
15. Known or suspected history of drug or alcohol abuse or dependence within 1
year prior to the start of Screening.
16. Known medical or psychological condition(s) or risk factor that, in the
opinion of the Investigator or Sponsor, might interfere with the patient*s full
participation in the study, pose any additional risk for the patient, or
confound the assessment of the patient or outcome of the study.
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 | EUCTR2017-002820-26-NL |
| CCMO | NL63627.041.17 |