* To assess safety and tolerability of single oral doses of NMD670 in healthy male and female subjects * To assess safety and tolerability of repeated oral doses of NMD670 in healthy male subjects * To assess safety and tolerability of single oral…
ID
Source
Brief title
Condition
- Autoimmune disorders
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Tolerability / safety endpoints
The following endpoints will be determined at time points indicated in the
Schedule of Assessments.
* Serious adverse events (SAEs) and adverse events (AEs) will be collected
throughout the study at every study visit.
* Concomitant medication
* Clinical laboratory tests
o Haematology
o Chemistry
o Urinalysis
o Coagulation
* Vital signs
o Pulse Rate (bpm)
o Systolic blood pressure (mmHg)
o Diastolic blood pressure (mmHg)
o Respiratory rate
* ECG
o Heart Rate (HR) (bpm), PR, QRS, QT, QTcF
* 24-hour Holter recording
* Handgrip dynamometry
o Grip release profile; timeprofile from 100% maximum voluntary contraction
(MVC) to 5% of the 100%MVC
o 100%MVC (Part C only)
Secondary outcome
Pharmacokinetic endpoints
Blood and urine samples for assay of NMD670 and its acyl glucuronide metabolite
will be taken at timepoints indicated in the Visit and Assessment Schedule.
PK endpoints for single dose cohorts:
* NMD670: Cmax, tmax, AUClast, AUCinf, AUC extrapolated, t*, Lambda_z, CL/F,
and Vz/F, Cmax/D, AUCinf/D.
* Metabolite Evaluation plasma [Acyl glucuronide of NMD670 (NMD1190), NMD670
R-isomer (NMD1239)]: Cmax, tmax, AUClast, AUCinf, AUC extrapolated, t*
* Urine PK endpoints for NMD670: Aelast, Aelast%, CLR.
* Urine PK endpoints for Acyl glucuronide of NMD670 (NMD1190) and NMD670
R-isomer (NMD1239): Aelast, Aelast%.
PK endpoints for multiple dose cohorts:
* NMD670: AUC0-24h, Cmax (per dose), tmax (per dose), t* (following second dose
of the day), Lambda_z (following second dose of the day), CL/F (day 9 only),
Vz/F (day 9 only), MRT0-24h (day 9 only); Ctrough on intervening days (see
Visit and Assessment schedule) and the last day of dosing; Rac(Cmax per dose)
and Rac(AUC0-24h), Cmax/D and AUC0-24h/D.
* Metabolite Evaluation plasma [Acyl glucuronide of NMD670 (NMD1190), NMD670
R-isomer (NMD1239)]: AUC0-24h, Cmax (per dose), Cmin (per dose), tmax (per
dose), t* (following second dose of the day), Lambda_z (following second dose
of the day), Ctrough on intervening days (see Visit and Assessment schedule)
and the last day of dosing; Rac(Cmax per dose) and Rac(AUC0-24h).
Exploratory endpoint: plasma protein binding (PPB), fraction unbound
Background summary
Myasthenia gravis is an auto-immune disease, caused by antibodies against the
acetylcholine receptor (AChR) or other molecular structures on the
post-synaptic side of the neuromuscular junction in skeletal muscle fibres.
Loss of AChR results in reduced strength of neuromuscular transmission that can
lead to failing muscle fibre activation and eventually muscle weakness and
excessive fatigability. There is a need for safe and efficacious therapies to
improve muscle function in these patients, because of the side effects caused
by existing therapies, consisting of peripheral acetylcholinesterase inhibitors
and immunosuppressive drugs. At the neuromuscular junction, the transmission of
the nerve action potential to the muscle membrane involves flow of both
excitatory and inhibitory currents. Excitation of muscle requires that the
excitatory current outweighs inhibitory current flow. In myasthenia gravis the
excitatory current flow is reduced due to the loss of AChR. Skeletal muscle
specific ClC-1 chloride ion channels carry the inhibitory currents that
counteract neuromuscular transmission. Inhibition of ClC-1 reduces the
inhibitory current and thereby increases muscle membrane excitability and
strengthens neuromuscular transmission. This was shown to lead to recovery of
muscle function in nonclinical models of several neuromuscular diseases
(Pedersen, Riisager, de Paoli, Chen, & Nielsen, 2016a).
NMD670 is a selective negative modulator of the ClC-1 channel, that is being
developed as an oral treatment to improve motor function and improve quality of
life in patients with myasthenia gravis, and possibly other diseases that lead
to dysfunction of neuromuscular transmission.
Study objective
* To assess safety and tolerability of single oral doses of NMD670 in healthy
male and female subjects
* To assess safety and tolerability of repeated oral doses of NMD670 in healthy
male subjects
* To assess safety and tolerability of single oral doses of NMD670 in patients
with myasthenia gravis
Study design
This is a first in human, double-blind, randomised, placebo-controlled, single
and multiple escalating dose trial in healthy male and female subjects and
patients with myasthenia gravis, to investigate the safety, tolerability and
pharmacokinetics of NMD670. This study will be in three parts, Part A (SAD),
Part B (MAD) and Part C (patients).
Part A1 (cohorts 1 and 3) will test single doses of NMD670 in a double-blind,
randomised, placebo-controlled, partial crossover and dose-escalating design in
healthy male subjects. A total of up to nine dose levels will be investigated
in three cohorts of subjects. Each cohort will consist of nine subjects, each
subject will have three study sessions. Each subject will receive escalating
doses of NMD670 on two occasions and placebo on one occasion, the order will be
randomized in a cross-over fashion. Each dose level will be randomized in a 6:3
ratio (active vs. placebo).
Part A1 cohort 2 is to determine the effect of food on the exposure of single
oral doses of NMD670, one of the tested doses will be administered in both the
fasted and fed condition. Subjects of Cohort 2 will receive dose level 4, 5 and
6. Subjects will then return for a fourth visit in which they will receive dose
level 4, 5 or 6 (or matching placebo) in the fed condition, in the same
randomization as the chosen dose level in the fasted condition. The
administration in fed condition will only be performed after the chosen dose
level has been confirmed to be safe in the fasted condition
Part A2 of the study will investigate the safety, tolerability and
pharmacokinetics of NMD670 in 8 healthy female subjects of non-childbearing
potential, in randomized, double-blind, placebo-controlled single dose
administration of NMD670. Subjects will receive dose level 6, if that dose
level has been confirmed safe in Part A1.
Part B of the study will test repeated doses of NMD670 in a double-blind,
randomised, placebo-controlled, parallel, dose-escalating study design in
healthy male subjects. This study part will be conducted in up to 32 healthy
male volunteers, divided in up to four cohorts of eight subjects. Dosing will
occur for 10 consecutive days QD, or in a bi-daily (BID) dosing schedule, based
on the half-life observed in Part A.
Part C is a double-blind, placebo-controlled, three-way cross-over comparison
of two single oral doses of NMD670 in men and women with stable symptomatic
myasthenia gravis. Enrolment of upUp to 12 patients is are planned to complete
the study. For each subject, the study will consist of three study periods
during which subjects will receive either a single dose of NMD670 or placebo.
Intervention
Part A1 (cohort 1 and cohort 3); single doses of NMD670 (2 active 1 placebo)
Part A1 Food effect cohort (cohort 2); single doses of NMD670 (3 active and 1
placebo, or 2 active and 2 placebo (2 repeated dose levels in a fasted and fed
state)
Part A2;single dose of 800mg NMD670
Part B; Multiple ascending dose part, dosing of dose levels chosen after PK
evaluation of part A for 10 consequtive days QD, BID or TID
Part C; two single oral doses of NMD670 and 1 dose of placebo
Study burden and risks
In short, the risks to individuals enrolled to this trial have been minimised
by the choice of starting dose; by careful dose escalation under medical
surveillance; and by the specific monitoring of the target organ for this
investigational drug * namely skeletal muscle. The potential benefits apply to
future patients with myasthenia gravis who may have the opportunity to receive
a novel drug which can relieve symptoms acutely and which is likely to be free
from the cholinergic side effects associated with acetylcholinesterase
inhibitors, the only alternative currently available for acute symptom relief
in myasthenia gravis
Palle Juul-Jensens Boulevard 82
Århus N DK-8200
DK
Palle Juul-Jensens Boulevard 82
Århus N DK-8200
DK
Listed location countries
Age
Inclusion criteria
Main inclusion criteria healthy volunteers (Part A and B)
1. Signed informed consent prior to any study-mandated procedure
2. Part A1: Healthy male subjects, 18 to 45 years of age, inclusive at
screening.
3. Part A2: Healthy female subjects of non-childbearing potential, 18-65 years
of age, inclusive at screening.
4. Part B: Healthy male subjects 18-65 years of age, inclusive at screening.
5. Body mass index (BMI) between 18 and 30 kg/m2, inclusive at screening, and
with a minimum weight of 50 kg.
6. All males must practice effective contraception during the study and be
willing and able to continue contraception for at least 90 days after their
last dose of study treatment.
7. Has the ability to communicate well with the Investigator in the Dutch
language and willing to comply with the study restrictions.
Main inclusion criteria myasthenia gravis patients (Part C)
1. Signed informed consent prior to any study-mandated procedure
2. Male and female subjects 18 and above years of age, inclusive at screening.
3. Diagnosis of myasthenia gravis, MGFA class I, II, III or IVa, based on
characteristic muscle weakness and a positive AChR or muscle-specific tyrosine
kinase (MuSK) antibody test. Subjects with MGFA 0 using pyridostigmine
(mestinon) may be included, if muscle weakness is present when refraining from
pyridostigmine (as assessed by a medical doctor based on an interview of the
patient at screening).
4. Patients using steroids should be using a stable dose of steroids for at
least 1 month before dosing, and the dose of steroids should be expected to
remain stable for the duration of the study.
5. Body mass index (BMI) between 18 and 34 kg/m2, inclusive at screening, and
with a minimum weight of 50 kg.
6. All women of child bearing potential and all males must practice effective
contraception during the study and be willing and able to continue
contraception for at least 90 days after their last dose of study treatment.
7. Has the ability to communicate well with the Investigator in the Dutch
language and willing to comply with the study restrictions.
8. Must be able to cease the use of pyridostigmine as per study requirements,
if applicable.
Exclusion criteria
Main exclusion criteMain exclusion criteria healthy volunteers (Part A and B)
1. Evidence of any active or chronic disease or condition that could interfere
with, or for which the treatment of might interfere with, the conduct of the
study, or that would pose an unacceptable risk to the subject in the opinion of
the investigator (following a detailed medical history, physical examination,
vital signs (systolic and diastolic blood pressure, pulse rate, body
temperature) and 12-lead electrocardiogram (ECG)). Minor deviations from the
normal range may be accepted, if judged by the Investigator to have no clinical
relevance.
2. Clinically significant abnormalities, as judged by the investigator, in
laboratory test results (including hepatic and renal panels, complete blood
count, chemistry panel and urinalysis). In the case of uncertain or
questionable results, tests performed during screening may be repeated before
randomization to confirm eligibility or judged to be clinically irrelevant for
healthy subjects.
3. Use of any medications (prescription or over-the-counter [OTC]), within 14
days of study drug administration, or less than 5 half-lives (whichever is
longer). Exceptions are paracetamol (up to 4 g/day) and ibuprofen (up to
1g/day). Other exceptions will only be made if the rationale is clearly
documented by the investigator.
4. Positive test for drugs of abuse at screening or pre-dose. Retesting is
allowed at the discretion of the Investigator.
5. Alcohol will not be allowed from at least 24 hours before screening or
pre-dose.
6. Smoker of more than 10 cigarettes per day prior to screening or who use
tobacco products equivalent to more than 10 cigarettes per day and unable to
abstain from smoking whilst in the unit.
7. Any confirmed significant allergic reactions (urticaria or anaphylaxis)
against any drug, or multiple drug allergies (non-active hay fever is
acceptable).
8. Any known factor, condition, or disease that might interfere with treatment
compliance, study conduct or interpretation of the results such as drug or
alcohol dependence or psychiatric disease.
9. History of trauma to the lower extremities or other conditions (most
importantly neurological or muscle diseases) that, in the opinion of the
investigator, could affect the electrophysiological measurements.
10. Excessive exercise within 7 days before study drug administration.
11. Clinically significant abnormalities in coagulation.
Main exclusion criteria myasthenia gravis patients (Part C)
1. Evidence of any active or chronic disease or condition apart from myasthenia
gravis, that could interfere with, or for which the treatment of might
interfere with, the conduct of the study, or that would pose an unacceptable
risk to the subject in the opinion of the investigator (following a detailed
medical history, physical examination, vital signs (systolic and diastolic
blood pressure, pulse rate, body temperature) and 12-lead electrocardiogram
(ECG)). Deviations from the normal range may be accepted, if judged by the
Investigator to have no clinical relevance.
2. Clinically significant abnormalities, as judged by the investigator, in
laboratory test results (including hepatic and renal panels, complete blood
count, chemistry panel and urinalysis).
5. Use of any medications that could influence the safety and conductance of
the study (see prohibited concomitant medication) within 14 days of study drug
administration, or less than 5 half-lives (whichever is longer).
9 Positive test for drugs of abuse at screening or pre-dose (unless the test is
positive for prescribed drugs). Retesting is allowed at the discretion of the
Investigator.
10. Alcohol will not be allowed from at least 24 hours pre-dose.
11. Any confirmed severe allergic reactions against any drug, or multiple drug
allergies (non-active hay fever is acceptable).
12. Loss or donation of blood over 500 mL within three months (males) or four
months (females) prior to screening or intention to donate blood or blood
products during the study.
13. Any known factor, condition, or disease that might interfere with treatment
compliance, study conduct or interpretation of the results such as drug or
alcohol dependence or relevant psychiatric disease (as judged by the
investigator).
14. History of trauma to the lower extremities or other conditions (most
importantly neurological or muscle diseases) that, in the opinion of the
investigator, could affect the electrophysiological measurements.
15. Clinically significant abnormalities in coagulation.
16. If a woman, pregnant, or breast-feeding, or planning to become pregnant
during the study.
17. Gout or clinically relevant elevations in uric acid.
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
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-000750-10-NL |
| CCMO | NL73152.056.20 |
| OMON | NL-OMON25316 |