The Sponsor is developing the test medicine NPJ5008 to treat a rare and life-threatening condition called fulminant hypermetabolic crisis (FHC) triggered by anaesthetic gases, antipsychotic medications or extreme exertion/exercise. When triggered by anaesthetic gases the condition is better known as malignant hyperthermia (MH). Injury, Occupational Diseases, Poisoning
Conditions
Interventions
This is a single-centre, two-part, part-randomised, open-label, IV, single-dose study in healthy male and female (women of non-childbearing potential only) subjects. Subjects who took part in Part 1 a
urine samples for urinalysis will also be collected. Adverse event (AE) monitoring, vital signs including continuous peripheral oxygen saturation monitoring, 12-lead electrocardiograms (ECGs), hand gr
Sponsors
Norgine, Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Healthy males or females of non-childbearing potential 2. Aged 18 to 55 years, inclusive, at the time of signing informed consent 3. Body mass index (BMI) of 19.0 to 30.0 kg/m2 as measured at screening; subjects enrolled into the higher dose group in Part 2 (240 mg NPJ5008) may have a BMI of 19.0 to 32.0 kg/m2 as measured at screening 4. Weigh at least 55 kg 5. Must be willing and able to communicate and participate in the whole study 6. Must provide written informed consent 7. Must agree to adhere to the contraception requirements
Exclusion criteria
Exclusion criteria: 1. Subjects who have received any IMP in a clinical research study within the 90 days prior to first dose 2. Subjects who are, or are immediate family members of, a study site or sponsor employee 3. Subjects who have previously been administered IMP in this study 4. Subjects who have taken part in Part 1 are not permitted to take part in Part 2 5. Evidence of current SARS-CoV-2 infection 6. Upper respiratory tract infection in the 14 days before first IMP administration, pneumonia in the 6 months prior to IMP administration 7. History of any drug or alcohol abuse in the past 2 years 8. Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 Units = 125 mL glass of wine, depending on type) 9. A confirmed positive alcohol breath test at screening or admission 10. Current smokers and those who have smoked within the last 12 months. A confirmed breath carbon monoxide reading of greater than 10 ppm at screening or admission. 11. Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months 12. Females of childbearing potential including those who are pregnant or lactating (all female subjects must have a negative highly sensitive urine pregnancy test at screening). A woman is considered of childbearing potential unless she is permanently sterile (hysterectomy, bilateral salpingectomy, and bilateral oophorectomy) or is postmenopausal (had no menses for 12 months without an alternative medical cause and a serum follicle stimulating hormone [FSH] concentration =40 IU/L) 13. Subjects who do not have suitable veins for multiple venepunctures/cannulation and IV infusions as assessed by the investigator or delegate at screening 14. Clinically significant abnormal clinical chemistry, haematology or urinalysis as judged by the investigator. Subjects with Gilbert’s Syndrome are not allowed. 15.Subjects with AST, ALT or total bilirubin greater than the upper limit of norma 16. Confirmed positive drugs of abuse test result 17. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) antibody results 18. History of clinically significant cardiovascular, renal, hepatic, dermatological, chronic respiratory or GI disease, neurological or psychiatric disorder, as judged by the investigator 19. Serious adverse reaction or serious hypersensitivity to any drug 20. Known allergy or adverse reaction to dantrolene or any of the formulation excipients (macrogol, hydroxypropylbetadex, mannitol) 21. Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active. 22. Donation of blood or plasma within the previous 3 months or loss of greater than 400 mL of blood 23. Subjects who are taking, or have taken, any prescribed or over-the-counter drug or herbal remedies (other than up to 4 g of paracetamol per day and HRT) in the 14 days before IMP administration. Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as determined by the investigator. 24. Evidence of significant airway restriction or obstruction as assessed by spirometry at screening e.g. forced expiratory volume in 1 second (FEV1) <80% predicted or forced vital capacity (FVC) <80% predicted, FEV1/FVC <0.7 (70%) at screening. 25. Subjects with sympto
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part 1: Statistical analysis of dantrolene AUC(0-last) and AUC(0-inf) values assessed from blood samples taken from pre-dose to up to 72 hours after dosing. This analysis includes adjusted geometric means for test and reference formulation, ratio of adjusted geometric means and corresponding 90% confidence intervals (CIs). If each of the 90% CIs lies within the acceptance interval of 80.00% to 125.00% then the formulations will be considered bioequivalent. Part 2: Safety and tolerability tests for both products by assessing: adverse events, vital signs including ECGs, hand grip tests, physical examinations and laboratory safety tests. Blood samples will be taken at selected time points from pre-dose until 72 hours post-dose for PK and safety laboratory assessments. Measurement of vital signs, electrocardiograms, laboratory safety tests and physical examinations will be done at screening and at intervals from admission until discharge. | — |
Secondary
| Measure | Time frame |
|---|---|
| Part 1 and Part 2: Assessment of PK parameters (Tlag, Tmax, Cmax, AUC(0-6), AUC(0-72), AUC(0-last), AUC(0-inf), lambda-z, T1/2, CL, Vz, Cmax/D, AUC(0-last)/D and AUC(0-inf)/D ) where analysis of the concentration-time data will be performed using appropriate non-compartmental techniques from plasma samples taken from pre-dose to 72 hours post final dose. Part 1: Safety and tolerability tests for the test product by assessing: adverse events, vital signs including ECGs, hand grip tests, physical examinations, spirometry and laboratory safety tests. Blood samples will be taken at selected time points from pre-dose until 72 hours post-dose for PK and safety laboratory assessments. Blood samples will be taken at selected time points throughout Periods 1 and 2 for PK and safety laboratory assessments; urine samples for urinalysis will also be collected. Measurement of vital signs including continuous peripheral oxygen saturation monitoring, spirometry, 12-lead ECGs, hand grip tests and physical examinations will be done at screening and at intervals from admission until discharge. | — |
Countries
England, United Kingdom
Contacts
Public ContactRichard Ng
Outcome results
None listed