Primary objective:• To evaluate the safety and tolerability of WVE-210201Secondary objectives:• To evaluate the effect of WVE-210201 on dystrophin production• To evaluate the concentration of WVE-210201 in plasma following treatment with WVE-210201…
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Source
Brief title
Condition
- Musculoskeletal and connective tissue disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety:
To assess the safety and tolerability of WVE-210201, the following will be
monitored and collected:
1. Adverse events (AEs)
2. Physical examination findings, including vital signs
3. Safety laboratory tests (hematology, chemistry, coagulation, urinalysis,
complement etc.)
4. Electrocardiograms
5. Echocardiograms
WVE-210201 concentration in plasma and urine:
1. Blood samples will be collected for determining plasma concentration of
WVE-210201.
2. Urine samples will be collected for determining concentration of WVE-210201
Immunogenicity:
1. Blood samples will be collected for assessing anti-drug and anti-dystrophin
antibodies in plasma
Pharmacodynamic Assessments:
1. Dystrophin protein levels and exon skipping will be assessed using muscle
biopsy samples
Measurements of Motor Function
1. Performance of the Upper Limb (PUL, Version 2.0)
2. Respiratory function tests (peak flow rate [PFR], cough peak flow [CPF], and
forced vital capacity [FVC])
3. Upper limb proximal strength assessed by handheld myometer
4. North Star ambulatory assessments
5. Lower limb motor function by timed function tests (including 10-meter
walk/run time, sit to stand from
chair, 4-stair climb time, and time to rise from the floor)
Secondary outcome
-
Background summary
Duchenne Muscle Dystrophy (DMD) is a disease caused by a mutation in the
dystrophin gene. The dystrophin protein is important for protecting the muscles
from stress and damage.
In DMD patients, one or more of the exons in the dystrophin gene are missing.
As a result, the gene cannot give proper instructions for making dystrophin.
Because of this mutation DMD patients are not able to make enough working
dystrophin which is needed to help protect their muscles from damage.
WVE-210201 is designed to skip a specific part of the dystrophin gene (the
instructions for making dystrophin protein) called exon 51. In people with DMD
who are missing certain exons of the dystrophin gene, skipping exon 51 may
allow the body to produce a shortened but still working form of the dystrophin
protein. This may result in improved muscle function in people with DMD.
Study objective
Primary objective:
• To evaluate the safety and tolerability of WVE-210201
Secondary objectives:
• To evaluate the effect of WVE-210201 on dystrophin production
• To evaluate the concentration of WVE-210201 in plasma following treatment
with WVE-210201
• To evaluate the concentration of WVE-210201 in urine following treatment with
WVE-210201
Exploratory Objectives:
• To assess the effect of WVE-210201 on motor function and strength
Study design
This is an open-label extension study (OLE) to evaluate the safety,
tolerability, pharmacodynamics,
pharmacokinetics and exploratory functional effects of multiple doses of
WVE-210201 in male pediatric patients
with DMD amenable to exon 51 skipping intervention. Up to 40 male patients, who
have successfully completed
the WVE-DMDX51-001 study will be enrolled in the open label extension (OLE)
study in North America and the
European Union (EU).
Both ambulatory and non-ambulatory patients will be enrolled in this study. The
study will include a Screening
Visit (up to 4 weeks), Treatment Visits for 13 weeks, and Follow-up for 12
weeks.
Written informed consent (and minor assent when applicable) will be obtained
from a patient*s parent or legal
guardian (and the patient as applicable) prior to participation in this study.
Each patient will receive
WVE-210201 once every week for 13 weeks. Patients will be assessed for safety
and tolerability,
pharmacodynamics, and muscle function and strength. Blood and urine samples
will be collected for measuring
concentrations of WVE-210201.
Screening Period
The Screening period is intended to allow determination of patient eligibility
for the study. It will begin when the
study informed consent is signed by the patient and/or parent or legal guardian
(as appropriate). In addition, the
patient may be required to provide assent (as applicable). Patients who have
successfully completed the
Phase 1 trial (WVE-DMDX51-001), will be eligible to participate. However, they
will need to be re-evaluated for
certain eligibility criteria.The Screening period may last up to 4 weeks (28
days). Patients may start screening for the OLE study after a
minimum of 2 weeks from the last follow-up visit in the Phase 1 study (Day 85).
If the Day 85 visit for the Phase
1 trial, WVE-DMDX51-001, was completed within 4 weeks prior to Day 1 of this
study, the applicable Phase 1
Day 85 values may be used for the Screening visit values in this study. The
required screening evaluations are
outlined in the Schedule of Assessments (Table 2). Screening assessments can
occur on multiple days, provided
they are within the Screening period. The Investigator will determine whether
patients meet eligibility criteria
and will collect the demographic and medical data permitting full
characterization of the patient.
Treatment
In the OLE study, all patients will receive weekly intravenous (IV) doses of
WVE-210201 for 13-weeks at one of
the four following dose levels: 1, 2, 5 and 10 mg/kg. Patients receiving 0.5
mg/kg in the Phase 1 study will be
enrolled in the 1 mg/kg cohort of the open label extension (OLE) study. All
other dose cohorts will receive
WVE-210201 according to their cohort assignment in Phase 1.
After the first treatment, patients will remain in the clinic for 24 hours
postdose for additional safety assessments.
Patients will return to the clinic weekly for WVE-210201 administration through
the planned end of treatment
(EOT) period (until Day 92 [±3 days]). On each dosing day, patients will
undergo predose and postdose safety
assessments. Additional safety assessments, pharmacodynamic assessments, and
muscle strength and functional
assessments will be done throughout the study. Blood and urine samples will be
collected for measuring WVE-
210201 concentrations.
The effect of WVE-210201 treatment on dystrophin protein level, dystrophin
localization and exon-skipping will
be analyzed using muscle biopsy samples. Blood samples will also be collected
for immunogenicity analysis.
Biopsy
Open muscle biopsies will be collected from the deltoid muscle at baseline and
at the end of treatment (Day 92).
Needle biopsies will be collected from the tibialis anterior (TA) muscle at
baseline and at the end of treatment.
The baseline biopsies must be collected at least 2 weeks prior to Day 1, if the
patient is otherwise eligible to
participate in the study.
Follow-up Phase
Assessments of patient safety will be conducted during a 12-week follow up
phase in which no treatment with
WVE-210201 will be administered. Visits will occur every 4 weeks during this
period (up to Day 176 ±3 days)
after the last dose of WVE-210201.
Early Termination
Early termination assessments will be done according to the study design (Table
2). If the patient terminates
before Day 30, urine and blood samples (planned for Day 30) will also be
collected. If a patient terminates prior
to the Day 92 visit (±3 days), all assessments planned for the Day 92 visit
including collection of muscle biopsies
will be performed at the early termination (ET) visit. In addition, hematology
and clinical chemistry samples
(planned for Day 85) will be collected. If a patient terminates after Day 120,
ECHO will not need to be repeated.
Intervention
WVE-210201 will be provided as a solution for dilution for infusion. In this
OLE study, all patients will receive
weekly IV doses of WVE-210201 for 13 weeks at one of the following four dose
levels: 1, 2, 5 and 10
mg/kg. The route of administration will be IV. The infusion should be
administered over approximately a 60
minute period, however at the discretion of the Investigator, and based upon
the patient*s cardiopulmonary status,
the infusion time may be extended to a maximum of 3 hours if necessary to avoid
volume overload.
Study burden and risks
WVE-210201 is just starting to be studied studied in humans. Therefore there is
not much information about the safety of WVE-210201 in humans and the risks are
not known. In studies in animals (mice and monkeys) given WVE-210201, it was
well tolerated at doses up to those planned for this study.
WVE-210201 is a type of drug called an antisense oligonucleotide. Based on
what we know about other similar drugs, there may be a risk of potential damage
to the liver or kidneys, changes in the blood (a decrease in platelets which
are involved in clotting and an increase in the time it takes for the blood to
clot) and changes in the immune reactions that can cause inflammation. At
doses much higher than those that will be used in this study, some mice had
damage to their liver after treatment with WVE-210201. These risks will be
monitored closely throughout the study and the study treatment will be stopped
if the study doctor feels that the subjects' safety may be compromised.
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Age
Inclusion criteria
1. Patient and/or parent or legal guardian must have the ability and be
willing to provide written informed consent/minor assent prior to any
study-related procedures.
2. Patient successfully completed the Phase 1 study with WVE-210201,
WVE-DMDX51-001.
3. Willing and able to comply with scheduled visits, drug administration
plan, laboratory tests, study restrictions, and all study procedures.
4. Stable pulmonary and cardiac function, as measured by:
a. Reproducible percent predicted forced vital capacity (FVC) >=50%
b. Left ventricular ejection fraction (LVEF) >55% in patients <10 years
of age and >45% in patients >=10 years of age, as measured (and
documented) by echocardiogram.
5. Sexually mature males must be willing to use contraception for the
duration of the study, if the patient is sexually active.
6. Patient and caregivers must agree not to post any study-related
information on social media
Exclusion criteria
1. Clinically significant medical finding on the physical examination other
than DMD that, in the judgment of the Investigator will make the patient
unsuitable for participation in, and/or unable to complete the study
procedures.
2. Other prior or ongoing medical conditions including:
a. Acute illness within Screening period;
b. Abnormal physical findings, other than those associated with
musculoskeletal findings attributable to DMD.
3. Laboratory abnormality, that, in the Investigator's opinion, could
adversely affect the safety of the patient, make it unlikely that the
course of treatment or follow up would be completed, or impair the
assessment of study results. These include, but are not limited to:
a. Renal insufficiency;
b. Impaired hepatic function as measured by glutamate dehydrogenase
(GLDH) >= 2.5x upper limit of normal (ULN) and Bilirubin >= 2x ULN (or
INR >= 1.5x ULN;
c. Activated partial thromboplastin time [aPTT] values above the ULN;
d. Platelet count less than lower limit of normal (LLN).
e. Any evidence of clinically significant structural or functional heart
abnormality would prohibit participation in this study.
f. Troponin I value above 2x ULN
4. Parent or legal guardian is directly or indirectly involved in the
conduct and administration of this study as an Investigator, subinvestigator,
study coordinator, or other study staff member, or the
patient is a first-degree family member, significant other, or relative
residing with one of the above persons involved directly or indirectly in
the study.
Design
Recruitment
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 | EUCTR2018-000975-34-NL |
| CCMO | NL66674.000.18 |