Primary objectiveTo assess the safety and tolerability after single and multiple intravenous administrations of PPSGG in patients suffering from anti-MAG neuropathy.Secondary objectives- To evaluate the PK of PPSGG after single and multiple…
ID
Source
Brief title
Condition
- Demyelinating disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety endpoints:
- Frequency, duration, severity and outcome of AEs, treatment emergent AEs
(TEAEs), and Serious AEs (SAEs) from time of informed consent signature to the
EOS visit including follow-up as required.
- Any concomitant medications and relevant non-drug therapies.
- Signs and symptoms of infusion-related reactions on infusion days
continuously during the infusion of the study drug until 1 hour after the end
of infusion, and at 8 and 24 hours (Day 2) after the start of administration.
- Physical examination from screening, baseline, on infusion day (before dosing
with the IMP), and 8 during SAD and EOS visit and during MAD during each visit
until the EOS visit.
- Vital signs with the 12-lead ECG at screening, on infusion days predose,
during the infusion of the IMP at 60 min (120 min for optional 3200 mg dose)
and then at 2 hours and 8 hours after start of infusion during SAD and EOS
visit. During the MAD, vital signs with the 12-lead ECG at each day of visit
until the EOS.
- 1-lead ECG on infusion days continuously during the infusion of the IMP until
2 hours after start of infusion for both the SAD and MAD.
- Safety hematology, clinical chemistry and urinalysis at screening, baseline,
on Day 8, and EOS during the SAD and on Day 8, 28, 42, 98 and EOS during the
MAD.
- Blood sampling for anti-drug-antibodies (ADA) (immunogenicity) at screening
and predosing, then Day 28 (EOS) in the SAD and Days 42 and EOS in the MAD.
Pharmacokinetic endpoints:
PPSGG*s PK will be determined in serum in the SAD phase on infusion Day 1 (30
min, 60 min, 2h, 6h, and 8h after start of administration), and on Day 2, 4, 8,
14 and 28 of the SAD phase. The sampling for the potential 3200 mg dose would
be at 30 min, 60 min, 2h, 3h, 6h, 8h and 10h after start of infusion.
In the MAD phase on each of Days 1, 3, 5, and 42 at predose, at 30 min, 60 min,
at 2h, 6h, and 8h after start of infusion. An additional PK sample will be
taken on Day 150 (EOS). The time points for PK sampling for the MAD phase will
be confirmed based on the PK data collected during SAD phase.
Pharmacodynamic endpoints:
PPSGG*s PD biomarkers will be determined in serum in the SAD phase during
screening, baseline, on infusion day (30 min, 60 min, 2h, 8h after start on
infusion) and on Day 2, 4, 8, 14 and EOS (Day 28). During the MAD phase on each
of Days 1, 3, 5 and 42 at predose, at 30 min, 60 min, at 2h, and 8h after start
of infusion. Then PD samples taken on Days 2, 4, 6, 7, 8, 9, 10 and Day 11 at
predose and 2h after start of infusion.
Efficacy endpoints:
Clinical efficacy assessments will be performed at screening, and Day 14, and
EOS during SAD and during MAD then every 8 weeks.
Clinical efficacy outcome for the SAD and MAD phases
- ONLS score.
- Time to walk 10 meters.
- RODS.
- Ataxia score.
End points for the MAD phase only:
All the above and then additionally every 8 weeks from Day 14 the following
ones:
- INCAT sensory sum score.
- Grip Strength.
Secondary outcome
Endpoints for the MAD phase only
- Neurofilament light chain (NfL) to measure the degree of axonal damage.
- B-cell activating factor (BAFF).
- Indirect immunofluorescence on sciatic nerves.
- Motor Unit Number Index (MUNIX) in selected sites.
Background summary
Anti-myelin-associated glycoprotein (MAG) neuropathy is a demyelinating
polyneuropathy associated with a monoclonal immunoglobulin M (IgM) gammopathy
with anti-MAG activity. Patients with anti-MAG neuropathy suffer from
sensorimotor deficits, sensory ataxia, paresthesias, muscle weakness,
neuropathic pain, and tremor.
Currently there is no treatment for anti-MAG neuropathy approved by the
European Medicines Agency or the US Food and Drug Administration.
Study objective
Primary objective
To assess the safety and tolerability after single and multiple intravenous
administrations of PPSGG in patients suffering from anti-MAG neuropathy.
Secondary objectives
- To evaluate the PK of PPSGG after single and multiple intravenous
administrations.
- To investigate PD of PPSGG in reducing anti-MAG IgM levels.
- To obtain preliminary efficacy data from neurological evaluations and
clinical outcomes using different clinical scores.
Study design
Phase I: First in Human, open label, SAD escalation study in anti-MAG
neuropathy patients to assess the safety, tolerability, PK and PD parameters of
PPSGG.
After completion and evaluation of the SAD phase a MAD phase will follow.
Phase IIa: randomized, dose escalation, double blind (patient and investigator
blinded), placebo-controlled MAD in anti-MAG neuropathy patients to assess the
safety, immunogenicity, tolerability, PK, PD and preliminary efficacy
parameters of PPSGG.
- Phase I: Single Ascending Dose (SAD)
The single rising dose escalation phase will enroll 6 patients in each of the 4
or 5 ascending dose cohorts. The first administration of PPSGG of any cohort
will be provided to a single patient (sentinel patient). The decision to
continue dosing the remaining patients in a given cohort will be based on all
available safety data collected during the first 72 hours after treatment of
the sentinel patient. The decision to escalate to the following dose (once a
cohort is completed) will be based on all available safety data, collected
during a minimum of 72 hours after the start of the infusion for all patients,
where no stopping rules are met and analyzed by an Independent Data Monitoring
Committee (IDMC). The study drug will be administered as a 60 min (120 min for
optional 3200 mg dose) IV infusion.
In the SAD phase each patient will have, within 2 months, the following 8
visits: Screening, Baseline, Treatment (4 visits), end of study (EOS) and
Follow-up.
- Phase IIa: Multiple Ascending Dose (MAD) - adaptive trial
The multiple rising dose phase will enroll 2 dose cohorts of at least 12
patients each (10 on active and 2 on placebo). Dose levels will be determined
based on the safety, tolerability, PK and PK/PD outcome (anti-MAG IgM titers)
from the SAD phase. The dosing of both cohorts in the MAD phase will not exceed
the exposures achieved in the SAD phase (Cmax and AUC0-tau), and will commence
at a dose at least one dose level lower than safely completed in the SAD. The
dosing frequency will be defined based on the PK/PD relationship established
during the SAD phase (PPSGG half-life, anti-MAG IgM kinetic) and simulation of
it. The study drug will be administered for up to 11 times (as a 60 min (120
min for optional 3200 mg dose) IV infusion) for six weeks to explore the effect
on anti-MAG antibody levels. For safety purposes the first 2 patients in each
cohort of the MAD phase will be randomized to receive active or placebo
treatment in a double-blind fashion. The decision to continue dosing in a given
cohort will be based on safety data of the first 2 patients collected during 2
weeks (minimum) after the start of the infusion. The decision to escalate to
the following dose will be based on safety data collected during the first 2
weeks after the start of infusion and analyzed by an IDMC.
In the MAD phase each patient will have, within 6 months, up to 17 visits:
Screening, Baseline, Treatment (up to 14 visits), EOS and Follow-up.
The MAD phase dosing regimen will be adapted for accordance with PK/PD
modeling, safety and tolerability data collected during the SAD phase. The
dosing of both cohorts in the MAD phase will not exceed the exposures achieved
in the SAD phase (Cmax and AUC0-tau), and will commence at a dose at least one
dose level lower than safely completed in the SAD. Dosing regimen includes the
dose level administered, the frequency of dosing and the duration of dosing,
i.e. the number of doses administered. Based on the safety toxicology studies
performed in animals the maximum doses is 11 infusions in 6 weeks. The goal is
to define a potential dose and regime to reliably, safely and sustainably
reduce anti-MAG IgM antibody levels by at least 50%.
The following assessments will be performed in each of the two phases (SAD and
MAD):
- Safety and tolerability (adverse events (AEs), vital signs, laboratory data,
electrocardiograms (ECGs), and local tolerability assessment).
- Blood sampling for anti-drug antibodies (ADA) development (immunogenicity).
- Blood sampling for PPSGG pharmacokinetics.
- Blood sampling for pharmacodynamics: (anti-MAG titers (Bühlmann Titer Units),
paraprotein levels, anti-human natural killer- 1 antibodies (anti-HNK-1 Titers)
and total IgM.
- Clinical assessments based on overall neuropathy limitations scale (ONLS)
score, time to walk 10 meters, and Rasch-built overall disability scale (RODS)
and Ataxia scores.
The following assessments will be performed in the MAD phase only :
o INCAT sensory sum score (ISS)
o Motor Unit Number Index (MUNIX) in selected sites only.
o Grip strength
o Neurofilament light chain (NfL) to measure the degree of axonal damage.
o B-cell activating factor (BAFF).
o Indirect immunofluorescence on sciatic nerves.
Each phase (SAD and MAD) will be split in two parts: (1) an active
administration phase with single (SAD) or multiple (MAD) infusions and (2) an
observation phase of 1 and 3 months respectively for the SAD and MAD.
After this, patients whose antibody levels have not returned to baseline will
enter in the follow-up phase, the duration of which will depend on the
evolution of the anti-MAG IgM antibody levels.
Intervention
Subjects in the first phase, SAD, who comply with all the inclusion criteria
and do not meet any of the exclusion criteria will be assigned to a single dose
escalation study.
SAD phase: Single IV infusion of 200, 400, 800 mg and 1600 mg per patient in 4
cohorts. A higher dose (3200 mg) may be administered if safe to do and
satisfactory antibody reduction has not been demonstrated in previous cohorts.
The study will enroll 6 patients per cohort (4 or 5 cohorts).
The study drug will be administered as a single 60 min IV infusion on Day 1 in
the morning (between 7 AM and 10 AM).
The potential dose of 3200 mg will require a 120 minutes infusion.
The MAD phase that consists of two sequential and ascending cohorts.
The MAD phase dosing regimen will be adapted for in accordance with PK/PD
modelling, safety and tolerability data collected during the SAD phase. The
dosing of both cohorts in the MAD phase will not exceed the exposures achieved
in the SAD phase (Cmax and AUC0-tau), and will commence at a dose at least one
dose level lower than safely completed in the SAD. Based on the safety
toxicology studies performed in animals the maximum number of doses is 11
infusions in 6 weeks.
Study burden and risks
In the SAD phase each patient will have the following 8 visits over about 2
months: Screening, Baseline, Treatment (4 visits), Follow-up and end of study
(EOS).
In the MAD phase each patient will have up to 17 visits over about 6 months:
Screening, Baseline, Treatment (for 6 weeks, max 11 infusions), Follow-up and
EOS.
A visit will take approximately 2 hours, except for the dosing days, where over
a period of 8 hours PK samples are taken.
During these visits the following actions occur:
physical examination, collection of demographic data, discussion of medical
history, checking eligibility criteria, making a 12-lead ECG & continues heart
monitor, blood collection, urinalysis, pregnancy test (if applicable),
discussing adverse events, discussing concomitant medication. During these
visits the
subject will complete various test and questionnaires.
All female subjects of childbearing potential must use adequately acceptable
methods of birth control to prevent pregnancy. Male subjects have to use
adequate contraception to prevent pregnancy of their partners.
Blood sampling related risks:
During the hospital visits blood samples will be taken. The insertion of the
needle can be painful or there may be blue spots developing at the injection
site. In addition, the subject may suffer from dizziness, light headedness or
fainting.
Medication-related risks:
This study is the first administration of PPSGG in humans; therefore, no prior
human safety and tolerability data are available. As with any drug, it is
possible that adverse reactions are caused by PPSGG. There may be unknown or
unforeseeable risks. However, the risk to patients in this study will be
minimized by adherence to the inclusion/exclusion criteria, close clinical
monitoring in an hospital setting, strict adherence to standard practice
including training of staff and provision of manuals for study procedures,
infusion procedure, stopping rules for an individual patient, as well as a
safety review after the first part of the study and monitoring by an IDMC. Key
safety data will be reviewed by Polyneuron in an open manner on an ongoing
basis. The IDMC will regularly review safety data to assess whether the
benefit/risk of each treatment arm remains acceptable.
Evaluation of the safety of PPSGG in dogs and rats demonstrated a favorable
toxicity profile (see IB). In a 6-week repeat-dose study in rats and dogs of
doses from 20 mg/kg up to 200 mg/kg IV of 11 infusions over 6 weeks followed
by a 2-week recovery, there were no clinical signs, no effects on organ weight
or macroscopic observations, and no safety pharmacology findings; clinical
chemistry and hematology results were remarkable. Neither microscopic findings
were reported.
Based on the experimental animal studies that were carried out, investigation
of the safety and tolerability of PPSGG showed no special dangers for humans.
Therefore, based on the safety profile of PPSGG the risks in participating in
the trial are considered acceptable. However, they include the usual risks of
participating in clinical trials, which are related to possible allergic
reactions, infusion related adverse event, blood drawing via venepuncture.
Patients* safety will be observed during all study phases. Before the drug
administration, participants will be informed about the potential and/or
observed adverse effects, if any, that occurred in the previous cohort.
Medical progress is based on research which ultimately must rest in part on
experimentation involving humans. Eligible patients may consider participation
in this clinical trial because they want to contribute to the advancement of
medical knowledge. Still, considerations related to the well-being of the
individual patients enrolled into this clinical study must take precedence over
the interests of science and society. Based on the available information and
the design of the study, Polyneuron and the Principal investigator consider the
trial to be ethically acceptable. The duration of hospitalization and the
medical surveillance are considered adequate to ensure safety of the patients
There are preclinical findings of undetermined clinical relevance that will be
mitigated by careful clinical monitoring. Thus, vital signs and ECG will be
monitored before and after the first dose during the SAD phase and before and
after the doses during the MAD phase and at other visits throughout the study.
Patients will return to the study site on a regular basis. During these visits,
safety, tolerability, efficacy, and PK/PD data will be collected. Standard
safety assessments will include vital signs, ECGs, clinical laboratory
evaluations (hematology, blood chemistry and urinalysis), and AEs as outlined
in the Schedule of Assessments. In addition to the standard clinical laboratory
assessments, patients will be regularly monitored for signs and symptoms,
inflammation, and hematologic and hepatic function. Patients will be informed
to report any symptoms to the clinical staff to assure proper assessment and so
that care can be administered in a timely manner.
In addition, the clinical opinion of the Investigator will be used to protect
individual patient safety during the trial.
Hochbergerstrasse 60C
Basel 4057
CH
Hochbergerstrasse 60C
Basel 4057
CH
Listed location countries
Age
Inclusion criteria
- Written informed consent.
- Age between 18 and 80 years, male and female.
- Patient with a confirmed diagnosis of monoclonal IgM associated with
monoclonal gammopathy of undetermined significance (MGUS) with anti-MAG
activity (titer of > 10*000 Bühlmann Titer units [BTU]) and demyelinating
neuropathy defined by electrophysiological criteria according to European
Federation of Neurological Societies/Peripheral Nervous System paraproteinemic
demyelinating neuropathy (EFNS/PNS PDN) guideline, 2010.
- Clear clinical signs of disability: with at least ONLS * 2 in lower
extremities.
- Inflammatory Neuropathy Cause and Treatment sensory sum score (ISS) * 2.
- Patients must have adequate hepatic function as evidenced by total bilirubin
< 26 µmol/l (1.5 mg/dL), and alkaline phosphatase and aspartate
transaminase/alanine aminotransferase < 2X the upper limit of normal (ULN).
- Absence of cause of neuropathy independent from anti- MAG activity: e.g.
diabetes, hypothyroidism, past or current dependence on alcohol, past or
current treatment with neurotoxic drugs.
- Patients must have adequate renal function as evidenced by serum creatinine
<2 mg/dL or calculated creatinine clearance of *60 mL/min within 28 days before
the first investigational medicinal product (IMP) administration using the
Modification of Diet in Renal Disease (MDRD) formula.
- Capability to meet the requirements of the study.
Exclusion criteria
- Patients with total serum IgM levels >30 g.
- Hematological malignancy (e.g. known multiple myeloma or confirmed
Waldenström's macroglobulinemia based on bone marrow analysis).
- Patients with any history of malignancy of any organ system (other than
localized basal cell carcinoma of the skin), treated or untreated, within the
past 5 years, regardless of whether there is evidence of local recurrence or
metastases.
- Previous immunosuppressive treatment with intravenous immunoglobulin (IVIG)
or apheresis/plasmapheresis in the preceeding 3 months, and/or cyclophosphamide
and biologicals (e.g. rituximab): in the preceeding 6 months prior to enrolment.
- Other neurological, neuromuscular, rheumatologic or orthopedic conditions
with significant impact on the capability of walking preventing evaluation of
neurological scores.
- Anti-MAG neuropathy patients with persistent clinically significant
laboratory abnormalities not related to the anti-MAG neuropathy, such as
significant renal dysfunction, hepatic dysfunction, cardiac disease or other
significant neurological disorder.
- Anti-MAG neuropathy patients with a modified Rankin Scale (mRS) score > 4.
- Participation in another interventional clinical trial.
- Any other significant finding that would increase, according to the
Investigator, the risk of having an adverse outcome from participating in the
study.
- Any other medical condition, including mental illness or substance abuse
deemed by the investigator(s) to likely interfere with the patient's ability to
sign informed consent, cooperate and participate in the study, or interfere
with the interpretation of the results.
- Patients who have undergone major surgery * 2 weeks prior to starting study
drug or who have not recovered from the side-effects of surgery.
- A history of clinically significant ECG abnormalities, or any of the
following ECG abnormalities at screening:
PR > 200 msec.; QRS complex > 120 msec.; QTcF > 450 msec (males); QTcF > 460
msec (females); History of familial long QT syndrome or known family history of
Torsades de Pointes; Use of agents known to prolong the QT interval unless they
can be permanently discontinued for the duration of the study.
- Sexually active males must use a condom during intercourse after the start of
the IMP administration and for at least one week after stopping study
medication and should not father a child in this period after completion of the
study medication (SAD and MAD phases). A condom is required to be used also by
vasectomized men in order to prevent delivery of the drug via seminal fluid. In
addition, male participants should not donate sperm for the time period
specified above.
- Use of other investigational drugs at the time of enrolment, or within 5
half-lives of enrolment, or within 30 days, whichever is longer; or longer if
required by local regulations.
- Women of child-bearing potential, defined as all women physiologically
capable of becoming pregnant, unless they are using highly effective methods of
contraception during dosing and for 1 week after discontinuation of the
investigational drug.
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 | EUCTR2020-000067-23-NL |
| CCMO | NL72912.041.20 |