The primary objectives of this study are to establish the efficacy and safety of APL-2 compared to eculizumab in patients with PNH who continue to have Hb levels
ID
Source
Brief title
Condition
- Red blood cell disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objectives of this study are to establish the efficacy and safety
of APL-2 compared to eculizumab in patients with PNH who continue to have Hb
levels <10.5 g/dL despite treatment with eculizumab.
Primary Efficacy Endpoint
* Week 16 change from baseline in hemoglobin level
Secondary outcome
Secondary Efficacy Endpoints
* Week 16 change from baseline in reticulocyte count
* Week 16 change from baseline in lactate dehydrogenase (LDH) level
* Week 16 change from baseline in FACIT-fatigue scale score
* Number of PRBC units transfused from Week 4 to Week 16 (Day 28 to Day 112)
* Hemoglobin response in the absence of transfusions (Yes/No). Hemoglobin
response is defined as a 1g/dL increase in hemoglobin from Baseline at Week 16
* Reticulocyte normalization in the absence of transfusions at Week 16
(Yes/No). Reticulocyte normalization is defined as the reticulocyte count being
below the upper limit of the normal range
Background summary
Phase 1 clinical experience has demonstrated that APL-2 provides sustained
inhibition of hemolytic activity in PNH patients who have never received
eculizumab (Protocol APL2-CP-PNH-204, New Zealand) and in patients receiving
eculizumab (Protocol APL-CP0514, US) who continue to be anemic (Hb <10.5 g/dL).
To date, no safety signals have emerged from on-going studies in PNH patients
that preclude further development. Thus, this proposed Phase 3 study*s aim is
to confirm treatment efficacy and safety of APL-2 monotherapy for the treatment
of PNH.
Study objective
The primary objectives of this study are to establish the efficacy and safety
of APL-2 compared to eculizumab in patients with PNH who continue to have Hb
levels <10.5 g/dL despite treatment with eculizumab.
Study design
This is a prospective, randomized, multi-center, open-label, active-comparator
controlled study. A total of approximately 70 PNH patients who are receiving
eculizumab and meet all the inclusion criteria and none of the exclusion
criteria will be randomized to receive either APL-2 or eculizumab. The
treatment period of the study will consist of three parts: a 4-week run-in
period, a 16-week randomized controlled period and a 32-week open-label APL-2
only period.
During the 4-week run-in period (Week -4 to Day -1) all subjects will receive
self-administered twice-weekly subcutaneous doses of APL-2 1,080 mg in addition
to the subjects* current dose of eculizumab treatment. On Day 1, subjects will
receive their dose of APL-2 and may receive eculizumab depending on their
dosing schedule. To account for variance in subject dosing schedules for
eculizumab, subjects may receive their eculizumab dose on Day 1 or up to 4 days
prior to Day 1. Subjects will then be randomized to either Group 1 (monotherapy
APL-2) or Group 2
(monotherapy eculizumab). Subjects in Group 1 will receive APL-2, and subjects
in Group 2 will receive eculizumab for the remainder of the 16-week randomized
controlled period. During the randomized controlled period, subjects will
return to the clinical site at Weeks 1, 2, 4, 6, 8, 12 and 16 for efficacy and
safety assessments.
The randomization will be stratified by the following values:
* Number of units of PRBC transfused within the 12 months prior to Day -28 (<3
; *3)
* Platelet count at screening (<100,000 ; *100,000)
Week 4 to Week 16 is defined as the active-comparator controlled period, over
which endpoints are assessed. The wash-out period will take place over the
first 4 weeks, i.e. withdrawal of eculizumab (Group 1) or APL-2 (Group 2) on
Day 1 for 4 weeks.
After completion of the active-comparator controlled period (the end of Week
16), all subjects will continue into a 32-week open-label period during which
all subjects will receive twice-weekly doses of APL-2 1,080 mg. During this
period, subjects will return to the clinical site on Weeks 17, 18, 20, 22 and
24 and every 4 weeks thereafter until Week 48 for efficacy and safety
assessments. Those subjects who received eculizumab in the randomized
controlled period will receive APL-2 in addition to eculizumab for 4 weeks
(Weeks 17-20). The wash-out period will then occur over the next 4 weeks (Weeks
21-24).
After completion of the 52-week treatment period (Week 48), subjects will be
offered entry into an open label extension study. Should the subject not enter
the open label extension study they will exit the study and return to the site
for 2 additional safety visits 6 weeks apart.
Subjects who withdraw from treatment prior to the Week 48 visit will be
encouraged to continue their participation in the study and return to the study
site for their scheduled study procedures, with the exception of APL-2
administration. Subjects who withdraw from the study prior to Week 48 and are
currently being treated solely with APL-2 are recommended to receive at least
one dose of eculizumab before discontinuing APL-2.
An external, independent Data and Safety Monitoring Board (DSMB) will assess
the progress and cumulative safety/tolerability data of the study.
Subjects who fail the screening procedures should not be re-screened for the
study unless this is agreed in advance and documented in writing with the
sponsor.
Intervention
Group 1 :APL2
* 1,080 mg twice weekly
o Dose adjustment to 1,080mg every 3 days if required
* Subcutaneous infusion
* Group 2: Eculizumab :
The dose of eculizumab will remain the same as dose patients received prior to
entering this trial. Intravenous.
Study burden and risks
Possible risks, side effects, and discomforts include:
* Infections - pt may be at increased risk for infections caused by certain
types of organisms such as Streptococcus pneumonia, Neisseria Meningitidis, or
Haemophilus influenza.
Symptoms include:
o Fever
o Headache
o Stiff neck
o Nausea
o Vomiting
o Eye sensitivity to light
o Confusion
* Allergic reactions - all medications have a potential risk of an allergic
reaction, which if not treated promptly, could become life-threatening.
o Rash
o Fast pulse
o Sweating
o Feeling of dread
o Swelling around the eyes and mouth
o Swelling of the throat
o Wheezing
o Having a hard time breathing
o Sudden drop in blood pressure (making you feel dizzy or lightheaded)
o Inability to breathe without assistance
* Blood samples - pt may have discomfort or pain when your blood is collected.
pt may feel faint or pass out. There is also a slight possibility of infection,
bruising, or bleeding at the puncture site.
* ECG - skin irritation is rare but could occur during an ECG from the
electrodes or gel that is used.
* Antibiotic therapy - In the event that the study doctor decides that pt has
to take antibiotics throughout the study, there is a possibility that pt will
experience some side effects from the antibiotic treatment.
* Infusion site reactions - there is a possibility that pt could experience
redness, swelling, and pain or tenderness at the site of infusion. There is
also a slight possibility of infection.
* Vaccination - Like any medication, vaccines can cause side effects. The side
effects associated with getting vaccines are almost always mild (such as
redness and swelling where the shot was given) and usually go away within a few
days.
* Since the study drug (APL-2) is investigational, when taken alone or in
combination with other medications, there may be other risks that are unknown.
6400 Wewtwind Way Suite A
Crestwood KY 40014
US
6400 Wewtwind Way Suite A
Crestwood KY 40014
US
Listed location countries
Age
Inclusion criteria
2. Primary diagnosis of PNH confirmed by high-sensitivity flow cytometry
3. On treatment with eculizumab. Dose of eculizumab must have been stable for at least 3 months prior to the Screening Visit
4. Hb <10.5 g/dL at the Screening Visit
5. Absolute reticulocyte count > 1.5x ULN at the Screening Visit
6. Platelet count of >50,000/mm3 at the Screening Visit
7. Absolute neutrophil count >500/mm3 at the Screening Visit
Exclusion criteria
1. Active bacterial infection within 4 weeks prior to Day -28 (Run-in Period)
2. Receiving iron, folic acid, vitamin B12 and EPO, unless the dose is stable, in the 4 weeks prior to Screening
3. Hereditary complement deficiency
4. History of bone marrow transplantation
5. History or presence of hypersensitivity or idiosyncratic reaction to compounds related to the investigational product or SC administration
6. Participation in any other investigational drug trial or exposure to other investigational agent within 30 days or 5 half-lives (whichever is longer)
10. Myocardial infarction, CABG, coronary or cerebral artery stenting and /or angioplasty, stroke, cardiac surgery, or hospitalization for congestive heart failure within 3 months or greater than Class 2 Angina Pectoris or NYHA Heart Failure Class >2
11. QTcF > 470 ms, PR > 280 ms
12. Mobitz II 2nd degree AV Block, 2:1 AV Block, High Grade AV Block, or Complete Heart Block unless the patient has an implanted pacemaker or implantable cardiac defibrillator (ICD) with backup pacing capabilities
13. Receiving Class 1 or Class 3 antiarrhythmic agents, or arsenic, methadone, ondansetron or pentamidine at screening
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 | EUCTR2017-004268-36-NL |
| ClinicalTrials.gov | NCT03500549 |
| CCMO | NL66816.091.18 |