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Trial registered on ANZCTR


Registration number
ACTRN12613000971730
Ethics application status
Approved
Date submitted
28/08/2013
Date registered
2/09/2013
Date last updated
1/07/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
A study in healthy males to assess the safety and tolerability of two different formulations of the study drug, (MSP-2017), administered intranasally.
Scientific title
A Phase 1, Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamic Effects of Two Different Intranasal Formulations of MSP-2017 in Healthy Adult Male Subjects.
Secondary ID [1] 283099 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
This study is for healthy volunteers. The intended use of the investigational product is to self-terminate acute episodes of paroxysmal supraventricular tachycardia (PSVT), a non-life threatening cardiac arrhythmia. 289938 0
Condition category
Condition code
Cardiovascular 290312 290312 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Study Treatments/Medications:
There will be two active formulations. All formulations will be administered by the intranasal route.
Active Test Formulations:
The active investigational product (API) is (-)-MSP-2017 (code-named MSP-2017).
The two Active Test Formulations (MSP-2017A and MSP-2017B) are the API formulated in two different, but closely related, aqueous solutions:
MSP-2017A: water, MSP-2017, acetic acid, n-dodecyl-D-maltoside, disodium EDTA, sulfuric acid.
MSP-2017B: water, MSP-2017, acetic acid, disodium EDTA, sulfuric acid.

Single doses of both MSP-2017A and MSP-2017B will be evaluated at ascending concentrations with subsequent cohorts, but doses will not alter within a cohort. The starting doses for both MSP-2017A and MSP-2017B will be 3.5 mg (nominal 0.05 mg/kg based on 70 kg subject).
Each subject in each dose level cohort will receive two single doses of either both active drugs or both placebos. Within each cohort, the eight subjects will be randomly assigned to one of four groups. For those assigned active drug:
N=3: Active MSP-2017A and Active MSP-2017B
N=3: Active MSP-2017B and Active MSP-2017A
Doses will be escalated sequentially through the cohorts. The starting dose and incremental dose increase through the cohorts will be determined based on the results of the preclinical studies. Before the subsequent cohort of eight subjects can be enrolled and dosed at the next highest dose level, feasibility of escalation will be evaluated based on safety observations from the previous, lower dose level. Evaluation will be a full safety review by the Safety Evaluation Committee (SEC), which will include at least one certified cardiologist, the Principal Investigator and the Sponsor’s Medical Monitor after each dosing cohort is complete.
It is intended that at no time will a dose be increased by more than twice that of the previous dose. However, a greater increase may be permitted if there are no detectable plasma concentrations of MSP-2017 or there is no effect on the pharmacodynamic parameters, provided the greater increase is deemed to be safe by the SEC. Dose escalation is planned to be identical for both MSP-2017 formulations, however, the data will be reviewed independently for each MSP-2017 formulation and the SEC may allow deviation from the planned dose escalation schedule for either MSP-2017 formulations independently in response to the results from each cohort. If = 2 subjects administered a dose of one of the MSP-2017 formulations experience a clearly determined DLT at that dose level, dosing must cease with that formulation and the MTD for that MSP-2017 formulation will be determined. However, the SEC may deem it safe to continue dose escalation with the second MSP-2017 formulation for subsequent cohort(s) of eight subjects with six subjects receiving that MSP-2017 formulation and two receiving a single dose of the matched Placebo.
Dose escalation will proceed until two or more of six active (drug) subjects experience a DLT or until dose level #6 is achieved. However, if the maximum tolerated dose (MTD) is not achieved for each or one of the MSP-2017 formulations after six dose levels, an additional two cohorts (i.e., 16 subjects) will be enrolled, resulting in a total of 64 subjects enrolled in the study. The MTD for that active drug will be considered the dose level immediately below the dose at which two of six subjects who received the MSP-2017 formulation experienced a DLT. If no DLT occurs, the MTD for the active drug(s) will be declared as the highest dose evaluated.
Subjects will be randomly assigned to one of four groups within each cohort which will involve administration of a single intranasal dose on Day 1 (right nostril) and Day 3 (left nostril), when possible depending on dose level, of either MSP-2017A then MSP-2017B, or MSP-2017B then MSP-2017A, or Placebo A then Placebo B or Placebo B then Placebo A.
Intervention code [1] 287816 0
Treatment: Drugs
Comparator / control treatment
Placebo Reference Formulations:
Placebo A: water, n-dodecyl-beta-D-maltoside, disodium EDTA.
Placebo B: water, disodium EDTA.
Each subject in each dose level cohort will receive two single doses of either both active drugs or both placebos. Within each cohort, the eight subjects will be randomly assigned to one of four groups. For those assigned placebo:
N=1: Placebo A and Placebo B
N=1: Placebo B and Placebo A
Subjects will be randomly assigned to one of four groups within each cohort which will involve administration of a single intranasal dose on Day 1 (right nostril) and Day 3 (left nostril), when possible depending on dose level, of either MSP-2017A then MSP-2017B, or MSP-2017B then MSP-2017A, or Placebo A then Placebo B or Placebo B then Placebo A.
Control group
Placebo

Outcomes
Primary outcome [1] 290348 0
In general, safety analyses will be performed and the results summarized by cohort and treatment group.
Treatment-emergent AEs will be summarized using the latest version of MedDRA by System Organ Class (SOC) and Preferred Term (PT), classified from verbatim terms.
Laboratory results will be classified according to PI clinical judgment of clinical significance and summarized by treatment group.
Vital sign measurements will be summarized at each scheduled time-point using descriptive statistics.
Nasal irritation assessments will be summarized at each scheduled time-point using descriptive statistics.
Physical examination findings will be presented in subject listings.
Based upon the results from the above, the Maximum Tolerated Dose (MTD) will be determined.
The safety of the MSP-2017 formulations will be evaluated by collection of the following minimum safety criteria assessed at baseline (when the subject signs the informed consent form) and at subsequent specified time-points:
*Monitoring of adverse events and serious AEs.
*Physical examinations.
*Vital signs (resting heart rate, semi-supine systolic/diastolic blood pressure, respiratory rate, and temperature).
*ECG measurements.
*Clinical laboratory tests (hematology, biochemistry, coagulation, urinalysis)
*Reasons for treatment discontinuation due to toxicity.
Safety will be evaluated in terms of adverse events (AEs), clinical laboratory results (hematology and serum chemistry), vital sign measurements (blood pressure, heart rate, respiratory rate, and oral body temperature), safety issues identified on 12 lead ECG results, and physical examination findings.
Timepoint [1] 290348 0
Adverse events will be recorded from time of signed consent through to end of study date.
Physical examinations will be conducted at screening, check-in (day -2) (if more than 2 weeks after screening), Day 4, end of study follow up (day 10) and early termination.
BP & Heart Rate criteria must be met at Check-in on Day -2 and Day -1 as well as at Screening.
BP & Heart Rate on Days 1 & 3: Pre-dose at -20, -10 min & Post-dose at 1.5, 3, 5, 7, 10, 15, 25, 50, 90, 360, 720 min and on Days 2 & 4 at 1440 min.
Vital Signs (BP, Temp, HR) also collected on Day 4, end of study follow up (day 10) and early termination.
ECGs at Screening to be evaluated by a cardiologist.
Safety digital ECGs on Days 1 & 3: Pre-dose at -30 min & Post-dose at 3, 5, 10, 15, 25, 90, 360 min and on Days 2 & 4 at 1440 min.
ECGs also conducted at check in and Day -1, Day 10 end of study follow up and early termination.
Clinical labs to be collected at screening, Day -2, Day 4, Day 10 and early termination.
Reasons for treatment discontinuation due to toxicity will be assessed at early termination.
Secondary outcome [1] 304338 0
To determine the pharmacokinetics of MSP-2017 and its metabolite (MSP-2030) in each of two different intranasal MSP-2017 formulations (MSP-2017A and MSP-2017B);
Timepoint [1] 304338 0
Blood samples will be collected from subjects through an indwelling cannula or through a fresh vein puncture. The 0 hour (pre-dose) blood samples will be taken within 60 minutes prior to dosing.
A total of 28 blood samples will be collected from each subject for pharmacokinetic analysis. One each dosing occasion, one blood sample (2 mL) will be collected at each of the following time-points: pre-dose (0 hours), and at 0.5, 1.5, 3, 5, 7, 10, 15, 25, 50, 90, 360, 720, 1440 minutes post-dose.
Secondary outcome [2] 304339 0
To determine the effect of MSP-2017 on PR, QTc, and other ECG intervals, heart rate, and blood pressure in the two different intranasal MSP-2017 formulations (MSP-2017A and MSP-2017B);
Timepoint [2] 304339 0
24 hour Holter recordings will be performed at Screening, Day -1 and on each dosing day. Continuous 12 lead Holter monitoring with ECG extraction (in triplicate at a minimum) will be recorded and analyzed by a core laboratory.
Secondary outcome [3] 304340 0
To determine the effect of MSP-2017 on the PK/PD modeling of the changes in the PR and QTc intervals of the different intranasal MSP-2017 formulations (MSP-2017A and MSP-2017B);
Timepoint [3] 304340 0
24 hour Holter recordings will be performed at Screening, Day -1 and on each dosing day. Continuous 12 lead Holter monitoring with ECG extraction (in triplicate at a minimum) will be recorded and analyzed by a core laboratory.
Secondary outcome [4] 304341 0
To determine the differences in pharmacokinetics between two different intranasal formulations of MSP-2017 (MSP-2017A and MSP-2017B);
Timepoint [4] 304341 0
Blood samples will be collected from subjects through an indwelling cannula or through a fresh vein puncture. The 0 hour (pre-dose) blood samples will be taken within 60 minutes prior to dosing. Pharmacokinetic sampling: A total of 28 pharmacokinetic blood samples will be collected from each subject during the study. On each dosing occasion, 14 (2 mL) blood samples will be collected at the following times: pre-dose (0 hours) and at 0.5, 1.5, 3, 5, 7, 10, 15, 25, 50, 90, 360, 720 and 1440 minutes post-dose.
Secondary outcome [5] 304342 0
To determine the differences between two different intranasal formulations of MSP-2017 (MSP-2017A and MSP-2017B) on the effect on PR, QTc interval and blood pressure, with a particular focus on systolic blood pressure and the time course of effect
Timepoint [5] 304342 0
Blood pressure and heart rate measurements will be made at -20, -10 minutes (in triplicate) before each dose and then following each dose, in duplicate, at 1.5, 3, 5, 7, 10, 15, 25, 50, 90, 360, 720 and 1440 minutes (noting that if only one measurement is obtained then the single measurement will be used). Measurements will be made using an automated, validated and calibrated BP device. Baseline will be defined as the mean of the 3 measurements made at -20, -10 minutes.

Eligibility
Key inclusion criteria
This study will be conducted in normal, healthy, adult, male subjects aged between 19-60 years and with a BMI < 27.5. Eligible subjects will have no history of clinically significant disease, or abnormality of the nasal passage that could interfere with administration or absorption of the study drug.
Minimum age
19 Years
Maximum age
60 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Clinically significant medical condition, which, in the opinion of the Principal Investigator, would jeopardize the safety of the subject or impact the validity of the study results.
- A history of atrioventricular block, myocardial infarction (MI) or angina, non-sustained or sustained ventricular tachycardia (VT), family history of sudden death or prolonged QT interval, vaso-vagal syncope , sick sinus syndrome, supraventricular tachycardia, atrial flutter, Atrial fibrillation (AFib), stroke, transient ischemic attack (TIA), syncope, congestive heart failure (CHF), or Torsade de Pointes.
- Any acute or chronic condition of the nasal cavity
- Systolic blood pressure <110 or >150 mmHg, diastolic blood pressure <50 or >90 mmHg and heart rate (HR) <55or >95 bpm or an orthostatic fall in systolic BP at two minutes standing (from the 30 degree supine position) of >/= 15 mmHg.
Corrected QT (interval) using Fridericia’s correction (QTcF) >440 msec, flat or biphasic T waves, QRS >100ms, evidence of a prior MI, pathologic U waves or U waves that interfere with the QT measurement, or PR interval >200 ms or AV block or left anterior hemiblock (LAHB) or left posterior hemiblock (LPHB) or RBBB or LBBB; evidence of pre-excitation or PR interval <10 ms.
- Results from screening holter monitor showing:
a. Sustained first degree AV block with a PR >240ms for > 30min, or second or third degree AV block (blocked PAC’s are permitted);
b. Atrial fibrillation, atrial flutter, atrial tachycardias lasting > 8 beats, ventricular tachycardia (>3 beats in duration at a rate > 120 BPM);
c. Wolff–Parkinson–White syndrome with pre-excitation;
d. Sinus pauses >3 seconds unless due to blocked PAC’s; or
e. Significant sick sinus syndrome.
- Used nicotine-containing products within 6 weeks before screening and unable to abstain from using these products
- Unable to abstain from consuming caffeine and/or xanthine products for defined periods
- Known sensitivity to verapamil or adenosine.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
21/10/2013
Actual
21/10/2013
Date of last participant enrolment
Anticipated
Actual
1/07/2014
Date of last data collection
Anticipated
Actual
Sample size
Target
48
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 287854 0
Commercial sector/Industry
Name [1] 287854 0
Milestone Pharmaceuticals Inc.
Country [1] 287854 0
Canada
Primary sponsor type
Commercial sector/Industry
Name
CPR Pharma Services
Address
Suite C, 32 West Thebarton Road
Thebarton SA 5031
Country
Australia
Secondary sponsor category [1] 286583 0
None
Name [1] 286583 0
Address [1] 286583 0
Country [1] 286583 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289799 0
Alfred Health Human Ethics Committee
Ethics committee address [1] 289799 0
The Alfred Hospital
55 Commercial Road,
Melbourne
Victoria
3004
Ethics committee country [1] 289799 0
Australia
Date submitted for ethics approval [1] 289799 0
26/08/2013
Approval date [1] 289799 0
04/10/2013
Ethics approval number [1] 289799 0

Summary
Brief summary
The primary purpose of this study on healthy volunteers is to determine the safety and tolerability of two different formulations of study drug when administered via the intranasal route. There will be four study treatments: two active formulations and two placebos, or dummy treatments. Neither the study staff or the participants will know which treatment they are on. All formulations will be administered by the intranasal route using a single use nasal spray syringe. Each participant in each dose level group will receive two single doses of either both active drugs or both placebos, with the doses administered 48 hours apart via the nasal spray, in alternating nostrils.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 42482 0
Dr Jason Lickliter, MBBS PhD FRACP
Address 42482 0
Nucleus Network Limited
Level 5 Burnet Institute
AMREP Precinct
89 Commercial Road
Melbourne
Victoria 3004
Country 42482 0
Australia
Phone 42482 0
+61 3 9076 8960
Fax 42482 0
Email 42482 0
[email protected]
Contact person for public queries
Name 42483 0
Jason Lickliter, MBBS PhD FRACP
Address 42483 0
Nucleus Network Limited
Level 5 Burnet Institute
AMREP Precinct
89 Commercial Road
Melbourne
Victoria 3004
Country 42483 0
Australia
Phone 42483 0
+61 3 9076 8960
Fax 42483 0
Email 42483 0
nucleusnetwork.com.au
Contact person for scientific queries
Name 42484 0
Douglas Wight, M.Sc.
Address 42484 0
Milestone Pharmaceuticals
6100 Royalmount Ave.
Montreal, QC H4P 2R2
Country 42484 0
Canada
Phone 42484 0
+1 514 496-4276
Fax 42484 0
Email 42484 0
[email protected]

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No Supporting Document Provided



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