The primary objective of this study is to assess the efficacy of twice per week subcutaneous (SC) doses of pegcetacoplan 1080 mg compared toplacebo in subjects with sporadic ALS as measured by the Combined Assessment of Function and Survival (CAFS)…
ID
Source
Brief title
Condition
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy Endpoint:
• CAFS rank score (joint-rank score) at week 52
Primary Safety Endpoints:
• Incidence and severity of TEAEs
• Change from baseline in vital signs and clinical laboratory tests
• Positive responses (Yes) to the Columbia Suicide Severity Rating Scale
Secondary outcome
Secondary Efficacy Endpoints:
• Change from baseline in ALSFRS-R at week 52
• Change from baseline in %SVC (at clinic visits) at week 52
• Change from baseline in HHD megascore at week 52
• Time to death, permanent tracheostomy, or permanent assisted ventilation up to
week 52
• Time to death up to week 52
• Change from baseline in ALSAQ-40 at week 52
• Change from baseline of the randomized treatment period (visit 2) and of the
open-label treatment period (visit 15) to week 104 for ALSFRS-R, %SVC, HHD, and
ALSAQ-40
• Time to death, permanent tracheostomy, or permanent assisted ventilation up to
week 104
• Time to death up to week 104
Exploratory Endpoints:
• Change from baseline in European Quality of Life-5 Dimensions-5 Level at
week 52, week 104, and week 156
• Change from baseline in Zarit Burden Interview score at week 52, week 104,
and week 156
• Change from baseline of %SVC (home spirometry) at week 52 and week 104
• Time to percutaneous endoscopic gastrostomy tube placement up to week 52,
week 104, and week 156
• Change from baseline in serum neurofilament light chain at week 52, week 104,
and week 156
• Change from baseline in serum phosphorylated neurofilament heavy chain at
week 52,
week 104, and week 156
• Change from baseline in electrical impedance myography at week 52, week 104,
and week 156 (only at select investigational sites chosen to complete this)
• Pegcetacoplan pharmacokinetic concentrations at week 52, week 104, and week
156
• Changes from baseline at week 52, week 104, and week 156 in complement
biomarkers:
* Classical hemolytic complement pathway activity
* Alternative hemolytic complement pathway activity
* C3 levels
• Immunogenicity: presence of antibodies to polyethylene glycol moiety and
peptide
moiety of pegcetacoplan during the randomized and open-label treatment periods
• Change from baseline of the randomized treatment period (week 1) and of the
open-label treatment period (week 52) to week 156 for ALSFRS-R, %SVC
(in-clinic),
HHD, and ALSAQ-40
• Time to death, permanent tracheostomy, or permanent assisted ventilation up to
week 156
• Time to death up to week 156
Background summary
The proposed trial is a Phase 2, randomized, double-blind, placebo-controlled,
multicenter study to evaluate the efficacy and safety of pegcetacoplan (also
known as APL-2) in subjects with Amyotrophic Lateral Sclerosis (ALS). ALS is a
fatal neurodegenerative disorder for which there is no cure and limited
treatment options. Therefore, there is a need to investigate therapies that
could potentially improve function and increase survival in this patient
population.
Pegcetacoplan is a PEGylated peptide wherein pharmacologically active
pentadecapeptide is chemically bound to each end of a linear polyethylene
glycol (PEG) with average molecular weight of 40 kDa (PEG40). The peptide
moieties bind to primate complement C3 and exert a broad inhibition of the
complement cascade. The PEG40 portion of the drug molecule imparts improved
solubility and longer residence time in the body after administration of the
drug. Subcutaneously administered pegcetacoplan is being studied in multiple
other complement-mediated indications (paroxysmal nocturnal hemoglobinuria
[PNH], cold agglutinin disease [CAD], and complement-dependent nephropathies).
To date, no safety signals have emerged from ongoing studies that preclude
further development of pegcetacoplan. Clinical data from completed studies in
other indications suggest that targeting C3 may be an effective therapeutic
approach. Based on its mechanism of action, pegcetacoplan has the potential to
slow the progression of ALS by targeting the complement system at the level of
C3 thus preventing the degeneration of motor neurons.
In this study, pegcetacoplan will be administered as a SC infusion at a dose of
1080 mg twice per week using a commercially approved pump. A dose of 1080 mg
twice per week was associated with substantial and sustained inhibition of the
complement system and was well-tolerated in both healthy volunteers and
patients with other complement-mediated diseases. Therefore, a dose of 1080 mg
twice per week is planned as the most appropriate regimen for this clinical
trial, maximizing potential pharmacology and benefit to the patients.
Drug/device compatibility testing has been conducted and demonstrated that
pegcetacoplan is compatible with the delivery devices that will be used within
the study. Additional details are provided in the IMPD.
Study APL2-ALS-206 has been designed in accordance with the EMA Guideline on
clinical investigations of medicinal products for the treatment of amyotrophic
lateral sclerosis, November 2015. As such, the use of placebo in this trial is
appropriate in order to assess the effects of pegcetacoplan on ALS. Patients
enrolled in the study will be allowed to use riluzole or edaravone (in
countries where it is approved) during the study if the dose remains stable
throughout the duration of study participation.
Approximately 228 subjects will participate in this study at up to 70 research
sites globally, for a duration of 116 weeks. After a 6 week screening period,
subjects will be randomized in a 2:1 ratio to either the pegcetacoplan
treatment arm or the placebo arm. Safety and efficacy will be assessed and
will include once per week at-home measurements, monthly calls, and clinic
visits. All subjects completing 52 weeks of randomized treatment will be
treated with open label pegcetacoplan 1080 mg twice per week up to Week 104
followed by an exit visit 6 weeks later unless they enter the Sponsor-planned
long-term extension protocol. Subjects who do not continue to open label
treatment will continue to an exit visit 6 weeks after the last dose.
Study objective
The primary objective of this study is to assess the efficacy of twice per week
subcutaneous (SC) doses of pegcetacoplan 1080 mg compared to
placebo in subjects with sporadic ALS as measured by the Combined Assessment of
Function and Survival (CAFS) rank score (joint-rank
score).
Secondary objectives:
•To assess the effect of pegcetacoplan compared to placebo as measured by the
Revised ALSFRS-R score
•To assess the effect of pegcetacoplan compared to placebo on disease
progression as measured by respiratory function through percentage of
slow vital capacity (%SVC)
•To determine the effect of pegcetacoplan compared to placebo on muscle
strength as measured by handheld dynamometry (HHD)
•To determine the effect of pegcetacoplan compared to placebo on survival or
specified state of disease progression
•To assess the effect of pegcetacoplan compared to placebo on healthrelated
quality of life as measured by ALSAQ-40
•To assess the safety of pegcetacoplan during the randomized and openlabel
treatment periods through incidence and severity of TEAEs, clinical
laboratory tests (hematology, chemistry), vital signs, and physical
examinations
•To assess the long-term efficacy of pegcetacoplan using ALSFRS-R, %SVC,HHD,
and ALSAQ-40 during the open-label treatment period
Study design
This is a phase 2, randomized, double-blind, placebo-controlled, multicenter,
efficacy and safety study
of SC pegcetacoplan 1080 mg twice per week conducted in approximately 228
subjects with ALS.
The planned length of participation in the study for each subject is a maximum
of approximately
168 weeks. This study will consist of 5 parts:
• Part 1: Up to 6-week screening period
• Part 2: 52-week randomized treatment period
• Part 3: 52-week open-label (pegcetacoplan) treatment period
• Part 4: 52-week open-label long-term extension treatment period
• Part 5: 6-week off-treatment follow-up period
Part 1
Screening (Up to 6 Weeks)
• Informed consent will be obtained at screening prior to any study-related
procedures being
conducted
• Subjects (and/or caregiver) will be trained on the use of at-home assessments.
Part 2
Randomized Treatment Period (52 Weeks)
• Approximately 228 subjects who meet all of the inclusion criteria and none of
the
exclusion criteria will be randomized 2:1 to either the pegcetacoplan treatment
group or to
the placebo treatment group. Safety and efficacy will be assessed and will
include once per
week at-home measurements, monthly calls, and clinic visits.
• Pegcetacoplan treatment group
* Subjects randomized to pegcetacoplan will receive SC pegcetacoplan 1080 mg
twice
per week for 52 weeks.
• Placebo treatment group
* Subjects randomized to placebo will receive SC placebo twice per week for 52
weeks.
Subjects who discontinue treatment early and do not complete Part 2 will
continue to Part 5.
Part 3
Open-Label (Pegcetacoplan) Treatment Period (52 weeks)
At the end of Part 2, all subjects from both treatment groups will continue to
Part 3. All subjects
participating in Part 3 will be treated with pegcetacoplan 1080 mg twice per
week up to week 104.
Subjects who complete Part 3 will enter Part 4. Subjects who do not continue to
Part 3, or who have
started Part 3 but discontinue treatment early, will continue to Part 5.
Part 4
Open-Label (Pegcetacoplan) Long-Term Extension Treatment Period (52 weeks)
At the end of Part 3, any subject who, in the opinion of the investigator, is
experiencing clinical benefit
from pegcetacoplan administration will be invited to continue to Part 4, the
open-label long-term
extension treatment period. All subjects participating in Part 4 will be
treated with pegcetacoplan
1080 mg twice per week up to week 156. Subjects who complete Part 4 will enter
Part 5. Subjects who
do not continue to Part 4, or who have started Part 4 but discontinue treatment
early, will continue to
Part 5.
Part 5
Off-Treatment Follow-up Period (6 weeks)
During Part 5, all subjects who have discontinued the investigational product
(blinded
pegcetacoplan/placebo or open-label pegcetacoplan) will complete a follow-up
visit 6 weeks later.
Intervention
In this study, pegcetacoplan will be administered as a SC infusion at a dose of
1080 mg twice per week using a commercially approved pump. A dose of 1080 mg
twice per week was associated with substantial and sustained inhibition of the
complement system and was well-tolerated in both healthy volunteers and
patients with other complement-mediated diseases. Therefore, a dose of 1080 mg
twice per week is planned as the most appropriate regimen for this clinical
trial, maximizing potential pharmacology and benefit to the patients.
Drug/device compatibility testing has been conducted and demonstrated that
pegcetacoplan is compatible with the delivery devices that will be used within
the study. Additional details are provided in the IMPD.
Approximately 228 subjects will participate in this study at up to 70 research
sites globally, for a duration of 116 weeks. After a 6 week screening period,
subjects will be randomized in a 2:1 ratio to either the pegcetacoplan
treatment arm or the placebo arm. Safety and efficacy will be assessed and
will include once per week at-home measurements, monthly calls, and clinic
visits. All subjects completing 52 weeks of randomized treatment will be
treated with open label pegcetacoplan 1080 mg twice per week up to Week 104
followed by an exit visit 6 weeks later unless they enter the Sponsor-planned
long-term extension protocol. Subjects who do not continue to open label
treatment will continue to an exit visit 6 weeks after the last dose.
Study burden and risks
Risks with pegcetacoplan:
• Injection site reaction: redness, itching, pain, swelling, hardening
• Tiredness
• Dizziness
• Headache
• Restlessness
• Fever
• Severe infection
• Rash
• Urticaria
• Allergic reaction
• Diarrhea
• Flatulence
• Nausea
• Calcium increased
• Liver enzymes increased
• Decrease of red blood cells
• Decrease of blood platelets
Risks with placebo: mild injection/infusion site reactions.
Blood Draws: tenderness, pain, bruising, bleeding and/or infection.
ECG:minor skin irritation from the electrodes.
Pregnancy risks: There is limited data about the possible risk of pegcetacoplan
to pregnant women and the unborn baby. Therefore, pegcetacoplan should not be
given to pregnant women and women who are breastfeeding.
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Listed location countries
Age
Inclusion criteria
Sporadic ALS diagnosed as definite, probable, or laboratory-supported probable
as defined
by the revised El Escorial criteria (Brooks et al. 2000)
2. At least 18 years of age
3. Slow vital capacity >=60% of the predicted value at screening
4. Onset of ALS symptoms within 72 weeks prior to screening
5. Total ALSFRS-R score of >=30 at screening
6. Women of childbearing potential defined as any woman who has experienced
menarche
and who is NOT permanently sterile or postmenopausal
a. must have a negative pregnancy test at screening and
b. must agree to use protocol defined methods of contraception for the duration
of the
study and 90 days after their last dose of investigational product.
i. Postmenopausal is defined as 12 consecutive months with no menses
without an alternative medical cause.
7. Males must agree to
a. use protocol defined methods of contraception and
b. refrain from donating sperm for the duration of the study and 90 days after
their
last dose of investigational product.
8. Have vaccination against Streptococcus pneumoniae, Neisseria meningitidis
(types A, C,
W, Y, and B), and Haemophilus influenzae (type B) either within 5 years prior
to baseline
visit 2b, or agree to receive vaccination at least 7 days prior to baseline
visit 2b.
Vaccination is mandatory, unless documented evidence exists that subjects are
nonresponders to vaccination (as evidenced by titers or display titer levels
within
acceptable local limits).
9. Willing and able to give informed consent and comply with study procedure
and
assessments (including at-home assessments
Exclusion criteria
Confirmed or suspected other causes of neuromuscular weakness
2. Diagnosis of another neurodegenerative disease(s)
3. Subject with significant cognitive impairment, clinical dementia, or
psychiatric illness that
in the opinion of the investigator may increase subject*s risk by participating
in the study
or confound the outcome of the study
4. Subjects with a significant pulmonary disorder not attributed to ALS or who
require
treatments that might complicate the evaluation of the effect of ALS on
respiratory
function (eg, chronic obstructive pulmonary disease, pulmonary fibrosis, cystic
fibrosis,
pulmonary arterial hypertension)
5. Current use or anticipated need, in the opinion of the investigator, of a
diaphragm pacing
system during the randomized treatment period
6. Riluzole initiation or change in dose within 30 days prior to the start of
the screening
period or planned initiation during study participation. If using riluzole, the
subject should
remain on the drug throughout Part 2 of study participation, but the dosage may
be altered
or the drug discontinued at any time by the investigator for any safety
concern.
Riluzole-naïve subjects are allowed in the study.
7. Edaravone initiation or change in dose within 60 days prior to the start of
the screening
period or planned initiation during study participation. If using edaravone,
the subject
should remain on the drug throughout Part 2 of study participation, but the
dosage may be
altered or the drug discontinued at any time by the investigator for any safety
concern.
Edaravone-naïve subjects are allowed in the study.
8. Positive response to Item 4 or 5 of the Columbia Suicide Severity Rating
Scale
9. Subjects with detectable hepatitis C by polymerase chain reaction at
screening
10. Subjects with chronic inactive hepatitis B with viral loads >1000 IU/mL
(>5000
copies/mL) at screening. Eligible subjects who are chronic active carriers
(<=1000 IU/mL)
must receive prophylactic antiviral treatment according to local country
guidelines
(eg, entecavir, tenofovir, lamivudine)
11. History of an aggressive lymphoma or presence of a lymphoma requiring
therapy by itself
12. Active or overt malignant disease other than basal cell carcinoma or
cutaneous squamous
cell carcinoma
13. Received organ transplant
14. Presence or suspicion of liver dysfunction as indicated by elevated alanine
aminotransferase,
aspartate aminotransferase, or bilirubin levels >2 × the upper limit of normal
15. Presence or suspicion of severe recurrent or chronic infections that, in
the opinion of the
investigator, increase the subject*s risk by participating in the study.
16. Participation in any other investigational drug trial or exposure to other
investigational
agent, device, or procedure within 30 days or within 5-half lives of the
treatment
(whichever is longer) prior to the start of the screening period or during
study participation
17. Use of any other complement inhibitor within 30 days or within 5-half lives
of the treatment
(whichever is longer) prior to the start of the screening period or during
study participation
18. If breastfeeding, unwilling to discontinue for the duration of the study
and for at least
6 months after final dose of drug
19. Inability to cooperate or any condition that, in the opinion of the
investigator, could increase
the subject*s risk by participating in the study or confound the outcome of the
study
20. Subjects with known allergy or hypersensitivity to pegcetacoplan or to any
of the components
21. Known or suspected hereditary fructose intolerance
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 | EUCTR2019-003797-10-NL |
| ClinicalTrials.gov | NCT04579666 |
| CCMO | NL74696.041.20 |