Safety, pharmacokinetics and pharmacodynamic effects of NMD670

• Register: Netherlands Trial Register
• Last refreshed on: 3 April 2023
• Main ID: NL8692
• Date of registration: 2020-06-04
• Prospective Registration: Yes
• Primary sponsor: NMD Pharma A/S
• Public title: Safety, pharmacokinetics and pharmacodynamic effects of NMD670
• Scientific title: A randomised, double-blind, placebo controlled, single and multiple dose escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of NMD670 in male and female healthy subjects and patients with myasthenia gravis.
• Date of first enrolment: 2020-07-01
• Target sample size: 79
• Recruitment status: Recruiting
• URL: https://www.onderzoekmetmensen.nl/en/trial/25316
• Study type: Interventional
• Study design: Randomized controlled trial, Double blinded (masking used), Placebo, Crossover

Contacts

• Name: Geert Jan Groeneveld
• Affiliation: Centre for Human Drug Research

• Name: Geert Jan Groeneveld
• Affiliation: Centre for Human Drug Research

Key inclusion & exclusion criteria

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 generalized myasthenia gravis, MGFA class II, III or IVa, based on characteristic muscle weakness and a positive AChR antibody test.
4. Patients using steroids should be using a stable dose of steroids for at least 1 month before screening, and the dose of steroids should be expected to remain stable for two months following screening.
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 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. Positive Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening.
4. Systolic blood pressure (SBP) greater than 140 or less than 90 mm Hg, and diastolic blood pressure (DBP) greater than 90 or less than 50 mm Hg at screening.
5. Abnormal findings in the resting ECG at screening defined as:
a. QTcF> 450 or < 300 msec for men and QTcF> 470 or < 300 msec for women
b. Notable resting bradycardia (HR < 45 bpm) or tachycardia (HR > 100 bpm)
c. Personal or family history of congenital long QT syndrome or sudden death;
d. ECG with QRS and/or T wave judged to be unfavourable for a consistently accurate QT measurement (e.g., neuromuscular artefact that cannot be readily eliminated, arrhythmias, indistinct QRS onset, low amplitude T wave, merged T- and U-waves, prominent U waves);
e. Evidence of atrial fibrillation, atrial flutter, complete branch block, Wolf-Parkinson-White Syndrome, or cardiac pacemaker
6. 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.
7. Use of any vitamin, mineral, herbal, and dietary supplements within 7 days of study drug administration, or less than 5 half-lives (whichever is longer). Exceptions will only be made if the rationale is clearly documented by the investigator.
8. Participation in an investigational drug or device study (last dosing of previous study was within 90 days prior to first dosing of this study).
9. History of abuse of addictive substances (alcohol, illegal substances) or current use of more than 21 units alcohol per week, drug abuse, or regular user of sedatives, hypnotics, tranquillisers, or any other addictive agent.
10. Positive test for drugs of abuse at screening or pre-dose. Retesting is allowed at the discretion of the Investigator.
11. Alcohol will not be allowed from at least 24 hours before screening or pre-dose.
12. 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.
13. Subjects will not be allowed to have excessive caffeine consumption, defined as >800 mg per day.
14. Any confirmed significant allergic reactions (urtica

Age minimum:
Age maximum:
Gender:

Health Condition(s) or Problem(s) studied

Myasthenia Gravis

Intervention(s)

NMD670

Primary Outcome(s)

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(s)

Pharmacokinetic endpoints
Blood and urine samples for assay of NMD670 and its metabolite will be taken at timepoints indicated in the Visit and
Assessment Schedule.
• PK endpoints for single dose cohorts: Cmax, tmax, AUClast, AUCinf, AUC extrapolated, t½, Lambda_z, CL/F, and Vz/Fof NMD670.
Cmax/D, AUCinf/D.
• PK endpoints for multiple dose cohorts: AUCtau, AUCinf (after first dose), Cmax, Cmin, tmax t½, Lambda_z, CL/F, Vz/F, MRTT and MRT8 (after the first dose); Ctrough on intervening days (see Visit and Assessment schedule) and the last day of dosing; Rac(Cmax)
and Rac(AUC) of NMD670. Cmax/D and AUCtau/D after the first and the last dose.
• Metabolite Evaluation plasma: Tmax, AUC
• Metabolite evaluation urine: Aelast, Aelast%, CLR.

Secondary ID(s)

NL73152.056.20

NL8692

Source(s) of Monetary Support

NMD Pharma A/S

Ethics review

Status: Approved
Approval date: 04/06/2020
Contact:

Results

• Date Completed: 02/05/2022